ISSN 2364-2351 | A 60711 |
Life Sciences and Industry Magazine Autumn Edition 2017 | Volume 16 | 20 €
Interview José Pfizer, IP Head of 4SC AG, explains how innovative SMEs perceive the EU’s unitary patent
Big Data War
The Bytes of Cancer Neurodegeneration
Archaea
Bioeconomy
Biomanufacturing
Drug developers are hunting for a cure to Huntington’s disease
Are these extremophiles the solution to the energy crisis?
Insect protein – the Next Big Thing in food and feed?
Latest R&D and packaging trends for CROs, CMOs & CPOs
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INTRO
European Biotechnology | Autumn Edition | Vol. 16 | 2017
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Streamlining Digital Engagement with HCPs Today, there are greater expectations among healthcare providers for engagement with life sciences companies to be digital. For life sciences companies, there is significant potential to leverage digital technologies to reach more HCPs. Yet, despite the rise of digital channels in life sciences, providing the right information to HCPs quickly and effectively remains a challenge. HCPs want information from life sciences companies available digitally at their fingertips, but they do not have the time or inclination to wade through multiple websites and portals. Adding to the complexity, most life sciences companies maintain rigorous registration processes for access to branded sites and portals. This means a physician may need a dozen different registration identifiers with a single pharmaceutical company. Multiply this across numerous pharmaceutical companies, and the JAN VAN DEN BURG is vice problem grows from a minor inconvenience to a significant president of commercial strategy at burden for HCPs. Veeva Systems in Europe. In this role, Jan is helping to shape advances in cloud-based software to enable modern multichannel communications between life sciences companies and healthcare providers. He has more than 20 years of experience in software and services, mostly dedicated to pharmaceuticals. Prior to joining Veeva, Jan led the life sciences sales and marketing group in IBM Global Business Services, and he set up and ran the European business for Proscape Technologies.
To address this growing challenge, the world’s largest pharmaceutical companies have come together to form an industrystandards group called Align Biopharma. Founding members include Allergan, AstraZeneca, Biogen, GlaxoSmithKline, Novartis, and Pfizer. The group’s goal is to make it faster and easier for HCPs to connect with life sciences companies by implementing universal technology standards that will simplify access to information. Align Biopharma will define standards that are open and global to streamline digital interactions with HCPs. Initially, the group will focus on two new standards to facilitate seamless digital engagement and simplify the HCP experience: identity management, as well as consent and communication preferences.
Picture: Veeva Systems
To start, Align Biopharma recently finalized and introduced an identification and authentication standard to enable single sign-on for HCPs to access online content through many different channels across companies. This standard will allow biopharma and technology companies to align around a common way to provide HCPs with easy access, and validate that the relevant licensed provider is getting what he or she needs quickly. It will replace dozens of passwords with only one.
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As digital transformation charges forward in life sciences, companies will find new and innovative ways to continue to collaborate and improve engagement with HCPs. Face-to-face interaction will remain important, but the transition to digital is happening fast – and common standards will be key to enabling a transformation for all life sciences companies.
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Contents
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Cover Story
Insight Europe
regional news
6 Germany postpones ratification process for European Unitary Patent and Unitary Patent Court until after Brexit
46 Northern Europe: Sweden, Denmark, Finland
10 Interview: “SME Perspective on the Unitary Patent” Dr. Jose Pfizer, Head of Intellectual Property, 4SC AG, Martinsried 12 Biofuels: New study shows EU policymaker’s “tank or table” paradigm isn’t based on facts 14 EU Inmare project/Bioeconomy: Diving for industrial enzymes 15 European Biotech Week showcases biotech and bio-based solutions to MEPs
18
AI and cancer – the modern data wars Big Data is changing the way doctors make decisions, and redefining privacy. Should companies be allowed to lock up patient information in proprietary databases? Or should it be open access? Does medical data like a tumour’s DNA sequence belong to the patient, or should it be pseudonymised for use in studies aimed at curing the disease? And not least – how quickly will cognitive systems really make a difference in outcomes? A lot of money is at stake in the field, as well as people’s lives.
16 Expert comment: Germany’s freeze of the Unified Patent Court, Dr. Ute Kilger, Boehmert & Boehmert
Economy 28 Novartis AG’s CAR-T success to be discussed at BIO-Europe
48 Western Europe: France, Belgium, The Netherlands and the UK 50 Central Europe: Germany, Switzerland and Austria 54 Southern Europe: Italy, Spain and Portugal 56 Eastern Europe: Poland, Czech Republic, Slovak Republic and Estonia
Science & Technology 90 Bioeconomy: Insect protein producers target food and feed markets in Europe 92 Untangling neurodegeneration; Cancer drug from mahagony tree; Refurbished Parkinson’s drug; Halting tumour escape
29 Update on clinical trials
92 Swiss researchers find long-sought source of neurotoxicity in Alzheimer’s disease
32 What’s on at BIO-Europe in Berlin
Service
35 Analyst commentary: Samir Devani, Managing Director, Rx Securities
81 News from partner associations: SBA, BIO Deutschland, DIA, EuropaBio, EBN
36 Euro Biotech Stocks
105 Company index 104 Events 106 Encore
89 EMA News
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Picture: publicdomainpictures.net CC1.0
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CONTENTS
European Biotechnology | Autumn Edition | Vol. 16 | 2017
NEURODEGENERATION
BIOECONOMY
EDITORIAL
Digital reshape
Curing Huntington’s It slowly but relentlessly destroys your body and your mind, and there’s nothing doctors can do to stop it. At least, until now. 25 years after an American scientist discovered the genetic mutation that causes Huntington’s disease, medical research is finally beginning to catch up. An ongoing trial is attempting to stop the disease in its tracks. And one day a gene therapy solution might effectively cure it.
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Green methane
40
They live in some of the most extreme environments on Earth, including hydrothermal vents and geysers. Archaea are fascinating microorganisms that seem to have changed little since the dawn of life. Now they could help us solve one of our most pressing modern problems – how to store excess power from renewable sources.
Pictures: Wikimedia Commons/James St. John (top), visualspace /istockphoto.com (middle), Adents (bottom)
SPECIAL
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CROs, CPOs & CMOs 59 Prepared for next-gen biologics 64 Polpharma Biologics: expanding scale and reach 66 Insight into Biomarkers 68 Advanced formulations for biologics 74 Interview: Aldo Poli, CEO, Opis 76 Need a contemporary manufacturing strategy? 79 Rapid implementation of off-line serialisation 83 Serialisation using labels 84 Injection pens in clinical trials 86 New products
Digitalisation is set to become the buzzword of 2017. Whether you’re talking about patient selection for clinical trials, cancer therapy decision support, customer relations, direct-to-consumer advertising or even supply chain management – everyone is convinced digitalisation is the key to efficiency. For some, however, the word is an empty one. Recently one German biotech CEO stressed that “it’s just a tool, not the solution”. In other words, don’t expect it to cure cancer. On p.18, our cover story shows what kind of value creation digital data from cancer mutations and treatment outcomes could contribute in the long run to more personalised therapies. Although there’s hype and PR in overselling computational correlation analyses, researchers from companies and hospitals agree that it will one day improve prognosis and decision support. A big issue, though, is access to results. Looking forward to the CPHI and BIO-Europe, we’ve addressed the topics that are most relevant to the sector, among them the EU unitary patent (see p. 6–8), the latest outsourcing trends in biomanufacturing, pharma packaging, and contract research, along with the latest news from the growing bioeconomy sector. A new EU strategy is being drafted (p.15) while EU companies are working to replace GM soy protein with insect-based feed (p. 90). Enjoy!
Thomas Gabrielczyk Editor-in-Chief
29.09.2017 11:18:52 Uhr
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Insight Europe
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Distinguished IP experts met in July at the European Patent Office to get a firsthand update on the Unitary Patent, organised by Premier Cercle
UPC: Germany set to delay ratification until after Brexit Unitary patent EU member states have fought for years to create an alternative to the
costly European bundle patent. Right before ratification of the laws for the unitary patent, and unitary patent court (UPC) for litigation, Germany has halted hiring judges for the UPC, due to a constitutional complaint brought by life sciences IP expert Ingve Stjerna, and unclear prognoses for Brexit’s potential legal impact on the UK’s participation in the new system.
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by all EU member states – except Spain, Poland and Croatia – to come into force, at least 13 EU member states must transfer the UPC agreement (UPCA) into national law, including mandatory ratification by Germany, France and the UK, the countries with the most patents.
A highly welcome complaint … On 1st August, the 14th EU member state (Estonia) agreed. However, in June, members of the UPC Preparatory Committee announced they would not be able to meet the December 2017 deadline for the UPC’s entry into operation: A constitutional complaint filed by Düsseldorfbased life science patent attorney Ingve Stjerna (see p. 8) blocked the signature of
Federal President Franz-Peter Steinmeier to the German Parliament’s “Yes” to the UPC in April. Stjerna claims (see p.16):
›› The law, which was approved at 1.30 a.m. on 10th March by only 35 members of the German Bundestag, required a two-thirds majority, and thus breaches Art. 23 (1), sentence 3, in conjunction with Art. 79 (2) Basic Law. ›› He notes that the judges of the UPC are not independent nor do they have democratic legitimacy (citing breach of the principle of openness towards European law owing to alleged irreconcilability of the UPC with Union law). ›› Additionally, Stjerna argues that the structure and powers of the UPC administrative committee is quite similar
Picture: Premier Cercle
Since 1973, the European Patent Office (EPO) has granted European patents to the 38 signatories of the European Patent Convention (EPC). Such patents, however, become divided into a bundle of national patents, which require fees for translation, national validation, and renewal in each country and any litigation cases must be handled nationally – in part with contradicting results. To bring patenting costs in Europe closer to those in the US (€13,000 over 20 years) and in order to ease filing and litigation, at least for the EU members of the EPC, the European Commission (EC) drafted legislation for implementing a unitary patent across its member states and a single unitary patent court (UPC). Though the intergovernmental treaty on the establishment of the UPC was signed in 2013
27.09.2017 13:38:04 Uhr
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Insight Europe
European Biotechnology | Autumnr Edition | Vol. 16 | 2017
would contradict EU legislation. The resulting legal uncertaintly might have driven Germany’s decision to wait and see.
Ingve Stjerna, the Life Science IP expert who filed the constitutional complaint
to the structure and powers of the administrative committee of the EPO. ›› His final point appears most relevant. He argues that a UPC, altered to include non-EU- but EPC member states, would not apply to EU legislation under which it was drafted.
… allows Germany a time out. As the Federal Constitutional Court was still in negotiations with stakeholders, such as the German Bar Association and European Patent Lawyers Association, over their views on the admissibility of the complaint after Germany’s parliamentary elections at the end of September, the ready-to-sign laws must go through another legislative process (3–4 months) starting next year at the earliest, says Heiner Flocke, Head of Germany’s Patentverein. de e.V. Furthermore, sources close to the German Justice Ministery told European Biotechnology that Germany and the UK have agreed to postpone UPC ratification until after Brexit. Accordingly, German stopped all hiring of German UPC judges until it is clear whether Brexit won’t legally block participation of the UK. When this issue went to print, the secretary of the preparatory committee had not yet answered an inquiry from European Biotechnology if it was true that the 36 German judges pre-selected for the UPC didn’t plug into the option for an interview.
Whistling in the dark? At a July meeting of distinguished IP experts, organised by Premier Cercle at the EPO in Munich, statements of numerous experts suggested that the delay wouldn’t mean that the implementation of the UPC system is at risk. Pointing to the fact that
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the EPO has already established a department and the financial rules for granting unitary patents, Benoît Battistelli, the outgoing president of the EPO said, “I am extremely optimistic that the UPC’s success will be quick and efficient.” Margot Fröhlinger, former Director at the EC in charge of IP and since 2012 principal director of patent law and multilateral affairs at the EPO, said that she would expect the UK to complete the ratification of the UPC agreement before the end of the year, according to information given to her on the legislative process in the UK. “There is not too much reason to worry about the situation in Germany either,” she added. Fröhlinger suggested that though large parts of the EU user community would welcome the UK’s UPC participation it was “a political decision, which will have to be addressed by the UK, the remaining member states and the European Union.” In contrast to a legal opinion given by the European Court of Justice in 2009, which excluded the participation of non-EU countries from the UPC, some legal experts have concluded “that the participation of the UK would indeed be possible, even after the exit from the EU,” Fröhlinger added.
Legal limbo In fact, supporters of the unitary patent, such as Prof. Winfried Tilmann, most recently suggested that non-EU EPC members such as a “Brexited” UK could participate in the unitary patent system through an extension agreement to Art. 142 EPC, while upholding operation of Directives 1257/12 and 1260/12. However, in its opinion, CJEI1/09, the European Court of Justice, made clear that a court which interprets EU legislation but is outside of EU’s institutional and judical framework,
Cost of filing and litigation under the new system was also on the agenda of Premier Cercle’s expert meeting in Munich: “It will be possible for users to file a patent application without paying any fee,” said Jérôme Debrulle from the Belgian Ministry of Economy. “If you consider all costs, it is less expensive to validate a unitary patent covering 26 EU member states than validating national patents in four EU member states,” he added. Low filing cost is confirmed by a 2015 analysis of the Charted Institute of Patent Attorneys. Both Big Pharma and SMEs would benefit from low filing costs. “Since for the pharmaceutical industry, maximum territorial scope is essential, at least for the important patents providing market exclusivity, the UP/UPC can be a convenient and efficient way of obtaining, maintaining, utilising, and enforcing patents, most effective with the maximum number of participating member states,” Dr. Jürgen Dressel, Head Global Patent Litigation Strategy, Novartis Pharma AG, told European Biotechnology. Critics, such as Stjerna, however, claim the costs for filing will be much higher – at about €33,000 – and argue that the system will be a particular threat for SMEs. IP experts from SMEs contradict this claim, but point to prohibitively high cost for litigation under the new system and greater vulnerability for key patents (p. 10). Stjerna cites IP expert Dr. Jochen Pagenberg, cofounder of IP firm Bardehle Pagenberg, suggesting he expects litigation cost to triple under the UPC compared to the current process cost in Germany. According to him, it won't achieve the claimed cost reduction for SMEs, due to overestimation of parallel litigation cost unter the existing system. Currently, Big Pharma (see European Biotechnology, Summer 2017) and SMEs aim at opting out of key patents as long as possible under the so-called Sunshine Clause until – if ever – the UP rules apply. L t.gabrielczyk@biocom.eu
Picture: Ingve Stjenra
Cost reduction for users – a question of perspective
28.09.2017 11:27:02 Uhr
EUROPEAN BIOTECH INDUSTRY STATE OF THE UNION EuropaBio mid-term alert to the EU Commission, Parliament and Council
Mid-way through President Juncker’s European Commission mandate, EuropaBio takes stock of the landscape for the EU’s Key Enabling Technologies and asks what now needs to be done to provide a smarter, stronger Union for future generations. Read it on www.europabio.org/SOTEU2017
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INSIGHT EUROPE
European Biotechnology | Autumn Edition | Vol. 16 | 2017
“We have mixed feelings …” Ingve Stjerna, plaintiff before the Federal Constitutional Court, argues that the UPC system does not deliver on its promise to make European patents cheaper and more affordable to Small and Medium-sized Enterprises (SMEs). European Biotechnology asked José Pfizer, Head of Intellectual Property at 4SC AG, to address the issue from the perspective of a German SME. UNITARY PATENT
and whether the judges in each individual case will have the necessary experience. The same applies in principle to infringement proceedings, except that the legal uncertainty is even greater here, since lawsuits can be brought before local or regional chambers that have previously handled only few patent disputes. SMEs may also become a particularly attractive target for suits by patent trolls before local or regional chambers, since, as mentioned above, they are more likely to settle than bigger players.
cannot be answered in a general way, and it will be necessary to weigh the possible costs for each individual case against the risk of an attack on the patent. The more important and valuable a specific patent is to the company, the more the “old” European patent, i.e. the bundle patent, is the preferable option. The potentially higher costs upon grant and validation could be justified, since it can be assumed that a unitary patent will be a more attractive target for attacks via nullity suits than a bundle patent. For existing patents, we will certainly opt out and thus decide against the applicability of the provisions of the Unified Patent Court. The official fees and translations have already been paid upon validation in the EPC contracting states. This means that – in cases where the patent is in force in many contracting states – annual renewal fees are the only remaining higher cost in comparison to the unitary patent. In our opinion, however, such additional costs are certainly acceptable in exchange for avoiding the aforementioned potential weaknesses of the unitary patent. EuroBiotech_ Do you agree with the claim that the unitary patent and UPC would be disadvantagous to SMEs? Pfizer_In general, unitary patents can be
expected to be more vulnerable, as the threshold for nullity suits is reduced in view of the comparably low office fees and the centralised procedure. The costs of a nullity procedure are, of course,
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DR JOSÉ PFIZER Since 2011, the German and European Patent Attorney has been Head of Intellectual Property at the Martinsried-based drug developer 4SC AG.
generally easier to bear for large companies than for SMEs, especially since the reimbursement of lawyers’ costs (for the party winning the case) is capped. Large companies clearly have longer staying power and are able to accommodate additional costs for lawyers’ fees in their budgets. For SMEs, this also increases the pressure to seek an early settlement in order to minimise the risk of incurring further costs. This is, of course, exacerbated by the legal uncertainty associated with the Unified Patent Court, as it is currently impossible to foresee which school of law future decisions will follow,
EuroBiotech_Do you think costs for filing and/or litigation of a patent will be cheaper or more expensive under the unitary patent system than under the existing system? Pfizer_Costs associated with patent grant
and validation are clearly dependent on the strategy the respective company usually applies. For companies that usually choose only a few countries, the uniform patent is potentially somewhat more expensive. On the other hand, biotech companies that usually validate in many or all EU countries will save substantially on grant and validation costs, in particular because translations become unnecessary. However, for the above-mentioned reasons, we anticipate that the expected increase in litigation proceedings will likely lead to significantly higher overall costs. The initial savings upon grant would then quickly be eaten up and the overall financial risk increases significantly. We are therefore currently looking at the upcoming advent of the unitary patent with mixed feelings. t.gabrielczyk@biocom.eu
Pictures: 4SC AG
EuroBiotech_If your company had the choice, would you seek a unified patent or a bundle patent? Pfizer_From our perspective at 4SC this
27.09.2017 13:38:50 Uhr
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Insight Europe
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Biofuels: study challenges EU’s “tank or table” paradigm EU A comprehensive sustainability assessment carried out by Cologne-based nova-Institute
“It is unique for a mainstream thesis, which has prevailed for over ten years, to be scrutinised in such a comprehensive and scientific way,” Dr. Christian Patermann, former Director for Biotechnology, Agriculture & Food at DG Research, told European Biotechnology. “I am curious how the study will impact the future of biofuels in Europe and how those MEPs who strongly resisted first generation biofuels will react,” he said. According to the study’s authors, results suggest that critiques against firstgeneration biofuels outlined in the current Commission REDII proposal – the new renewable energy directive for the period from 2020 to 2030 – are not founded on scientific evidence. “It would be counterproductive to further lower the share of first-generation fuels in the EU’s energy mix,” nova-Institute said in a press release. Twelve main criteria, Criteria
Sugar Sugar beet
Sugar cane
Starch Wheat
based on current standards and certification systems for bio-based fuels, were selected to evaluate the sustainability of first and second-generation bioethanol. The study’s authors were especially interested in testing the political claim that biofuels cause harm to food security.
Biofuels are CO2 killers The analysis shows that all feedstocks lead to substantial reductions in greenhouse gas emissions (GHG). While second-generation fuels perform better in this regard, this effect is strongly relativised when offset against the abatement costs. Reducing GHG emissions through second-generation biofuels is a rather expensive way to mitigate climate change. When it comes to political criticism regarding the possible negative impact on Virgin Wood
Maize
Forest
SRC
Waste Wood Forest residues
Agricultural Residues
Post-consumer wood
GHG footprint Level of subsidies needed/ GHG abatement costs Land use/land efficiency Food security, negative impact on Protein-rich co-products Employment, rural dev., livelihood of farmers & foresters LUC/iLUC Logistics/Infrastructure/ Availability Traceability Social impacts (land rights, human rights, education …) Biodiversity and marginal land, potential impacts Impact on water, air and soil quality
Overview of study results: Green – high performance/low risk; yellow – medium performance/medium risk; red – low performance/high risk.
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Organic Waste
food security of first generation biofuels, the evidence points into a different direction. The competition for arable land is counterbalanced by the excellent land efficiency of first-generation crops (particularly sugar beet) and protein-rich coproducts (wheat and corn). In this regard, utilising short rotation coppice (SRC) for biofuels poses much stronger competition for arable land, since they use up much larger acreages of arable land and provide no protein-rich co-products. The study’s authors conclude their results clearly show that the discrimination against first-generation biofuels of the current Commission proposal is in no way founded on scientific evidence. As biofuels made from any kind of feedstock reduce GHG emissions, they recommend maintaining food crop-based fuels at the current level of 7% and against lowering the share of first-generation fuels in the REDII. According to projections from the Commission, renewable energy sources will comprise 11% of the transport sector (RES-T) by 2020. Developing biofuels is the primary factor driving short-term growth, but their significance will diminish in the long-term. Biofuel penetration is mainly driven by the legally binding target of 10% renewable energy in the transport sector, but also by the EU Member State mandatory blending obligations and tax incentives; the Indirect Land Use Change (ILUC) amendment of the Renewables and Fuel Quality Directives; and corresponding changes in RES-T target accounting rules. L t.gabrielczyk@biocom.eu
Picture: @ nova-Institute, Cologne
shows that first and second-generation bioethanol is feasible for the EU’s climate strategy. The study challenges the “tank or table” credo of many EU policymakers, which claims biofuels are unsustainable because they use arable land and thus compete with food production.
28.09.2017 11:28:05 Uhr
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06.09.17 13:03 28.09.2017 11:29:51 Uhr
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Insight EuropE
European Biotechnology | Autumn Edition | Vol. 16 | 2017
News CRISPR deadlock
Black marks for EU EuropaBio, the EU’s biotech industry interest group, has tabled an evaluation of biotech-relevant EU policies and called on European policy makers to refocus on innovation and biotech in the second half of their mandate. The report (p. 102) provides information on what the sector needs to remain globally competitive. Specifically, EuropaBio calls for the overdue update of the EU’s Bioeconomy Strategy to create new markets and ensure cross-policy coherence. Furthermore, EuropaBio asks for a holistic and balanced approach to biotech innovation under the current incentives review, and efficient implementation of the existing GMO authorisation system.
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Diving for industrial enzymes INMARE project Global sales of indus-
trial enzymes for use in food processing, detergents, textiles, pulp, and paper have doubled since 2002 to US-$4 bn annually. Recognising the market potential, the European Union has awarded a grant of €6m to fund INMARE, a four-year, industry-driven project designed to identify and develop new microbial enzymes and metabolites from the oceans. Extremophile – marine microorganisms – are the study’s focus, as they could provide a source of enzymes that can tolerate the harsh physical and chemical conditions typical of industrial processes. Industrial partners of INMARE include producers of pharmaceuticals, cosmetics, and fine chemicals, such as Bayer AG, Novozymes A/S, Pharma Mar S.A., evocatal GmbH, INOFEA Ltd., and the Cluster Industrial Biot echnology CLIB2021.
Searching for all-rounders INMARE’s efforts are focused at the early stages of the biodiscovery pipeline towards finding better natural enzyme variants – so-called “enzyme all-rounders” – namely, enzymes with multiple activities, broad substrate spectra displaying stability in a broad range of physico-chemical conditions. These features allow such enzymes to perform a range of desirable functions under a set of realistic industrial conditions and overcome the laborious, costly enzyme optimisation process required to make enzymes
more stable and perform better in industrial processes. INMARE sampling locations range from shallow coastal inlets to deep sea floors. Materials from unique, microbial biodiversity hotspots – including deep sea and coastal water hydrothermal vents, Antarctic subglacial lakes, hypersaline anoxic lakes on the seabed, and highly alkaline areas along coastal chalk cliffs – have already been sampled and processed.
Searching for gold in lots of hits Within just 24 months, the screening of metagenomic libraries and strain collections has delivered more than 1,000 positive hits. Extensive substrate profiling in colorimetric, fluorimetric, and metabolomics platforms has allowed a panoramic view of substrate promiscuity for the selection, sequencing, and identification of genes of interest. Currently, several hundred enzymes demonstrating compelling bioactivity are already available in suitable expression systems. With 24 months still to go, INMARE researchers have already identified several enzyme targets with outstanding properties of interest for biotech applications. Industry partners will directly benefit from this research, to ensure that the newly established screening strategies are adopted and that the newly identified biocatalysts and bioactives are implemented in industrial processes, thus accelerating the appearance of a novel product on the market. L
Picture: Inmare
A fresh initiative from the Netherlands could end the political paralysis concerning the regulation of novel breeding methods such as CRISPR-based genome editing under existing EU law. Since the European Commission first announced it will decide how to regulate such methods, it has postponed setting the course thrice. GMO opponents filed a lawsuit aimed at legally defining all such crops as genetically modified and regulating them under Directive 2001/18/EC. A decision from the European Court is pending. At an informal meeting in Brussels, the Dutch delegation under Jan-Karel Kwisthout (Dutch Ministry of Infrastructure and the Environment) proposed to define criteria – i.e. genetically induced point mutations – under which such crops could be exempted and add such criteria to the annex of the Directive.
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Insight Europe
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Picture: BIOCOM
Valuating biotech’s benefits Europe an Biotech Wee k Highlighting the benefits biotechnology has brought to pharma development, agriculture and – last but not least – the bio economy, industry association Europa Bio celebrated the European Biotech Week with an exhibition, “Discovering European Biotech Innovation,” in the European Parliament in Brussels. “Biotechnology is possibly the most exciting and innovative European industry and research community: from helping our economy make smart, carbon neutral use of waste to developing crops that help farmers withstand all sorts of climatic challenges to creating treatments that respond to unmet medical needs, biotechnology improves our lives in many ways,” said John Brennan, EuropaBio’s new Secretary General. With 140 events across 19 countries,
EuropaBio wants to raise awareness for the needs of the sector. “Building a supportive legal framework that supports the bioeconomy is crucial to reach the EU’s climate goals,” said Boris Mannhardt, CEO of BIOCOM, which contributed to the bioeconomy exhibition.
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Though the European Commission explained it will update the EU’s bioeconomy strategy and link it to its circular economy policy, it’s not yet clear, how to make EU companies competitive with Asian and Pan-American industries. Stakeholders and MEPs met at the BBIJU’s cocktail reception at the end of the three-day programme in Brussels to exchange views on the topic. L
John Brennan, Boris Mannhardt and MEP Franc Bogovicˇ in Brussels
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INSIGHT EUROPE
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Germany’s freeze of the Unified Patent Court After decades of negotiations, the creation of the Unified Patent Court (UPC) reached the finishing straight. It promised a single European patent court to a single European market. To bring it to life, ratification by Germany and the UK is needed. The constitutional complaint against the UPC ratification in Germany led to a freeze of the UPC. EUROPEAN UNITARY PATENT
› Dr. Ute Kilger, Partner at Boehmert & Boehmert
Reasons to implement the UPC Up-to-date European patents may be granted at the European Patent Office (EPO) in a single procedure. After a European patent is granted, however, the patent is ultimately divided into individual national patents. These national patents have to be challenged and enforced before the respective national courts in Europe. It seems logical to create a unified court that would rule on a European patent that shall no longer be divided
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DR. UTE KILGER (German Patent Attorney and European Patent and Trademark Attorney, Partner at Boehmert & Boehmert) specialises in all kinds of patent-related issues concerning the obtaining and enforcement of property rights, due diligence, mergers and acquisitions, contract negotiations, and licensing agreements.
into national parts. It also seems logical that a European single market needs a single European patent court. A single European court would rule on the entire European patent and secure a unified case law in patent matters throughout the European market. Advocates for the Unified Patent Court hope to create more predictable court decisions throughout the European market. As the United Kingdom, Germany, and France are all strong members of both the European Union and the new Unified Patent Court (UPC), it is hoped
that the new unified European Patent Law will become a melange of the best of common law (UK) and civil law (DE, FR, NL). Judges can be selected out of a larger pool consisting of the “best brains” throughout Europe. It is thus hoped that the UPC will allow a better use of resources. Harmonisation of jurisprudence throughout Europe can be more easily achieved when efforts are taken in this direction as demonstrated at large European judges conferences, such as the conference recently held in Venice. Furthermore, it is hoped that the European jurisdiction will be more of a “heavy weight” player in comparison to the US and Chinese jurisdiction, as the European market is more important than just the German market alone. Supporters have always argued that the UPC may reduce costs to obtain a patent that is effective throughout the European Union. A main theme of European patent reform has been to allow patents to be obtained and enforced at lower costs compared to the traditional system.
Criticism towards the UPC Opponents of the UPC have strongly disputed the alleged cost reduction. Furthermore, they raised concerns about the inability to predict how new case law will evolve within the new body of the UPC. Concerns were also raised about the qualifications of the new EPC judges. Experienced judges can be found in countries that have a considerable amount of
Picture: Boehmert&Boehmert
The European Single Market is intended to guarantee the free movement of goods, capital, services, and labour within the European Union. Single market rules require the free movement from one EU member country to another of these so-called “four freedoms.” Those market rules take two forms: First, they remove barriers to trade. Second, they harmonise and unify national rules at EU level. For innovative industries, patents are important business tools to regulate access to the market. Patents provide a market monopoly to their holders giving them the right to hinder other market participants’ entrance to the market with the patented good or service. Thus, in a European single market it would seem to make sense to have a single unified court that rules on both the enforcement of European patents and proceedings that challenge and invalidate European patents.
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Insight Europe
European Biotechnology | Autumn Edition | Vol. 16 | 2017
patent litigation, particularly Germany, Great Britain, France, and The Netherlands. The new UPC, however, will consist of judges from all European countries, including those with no or limited cases of litigation. How can the quality of decisions be ensured if the UPC consists of less experienced judges?
Icons: GreenOptix/fotolia.com
The consitutional complaint vs UPC ratification in Germany Despite those concerns, it seemed that the UPC had reached the finishing straight. Now, the constitutional complaint filed in Germany has frozen the implementation of the UPC system. What is behind this complaint and on which allegations is this complaint based? The plaintiff asserts a breach of the limits to surrender sovereignty derived from the right to democracy (Art. 38 (1), clause 1, Basic Law). The following four violations are cited: ›› The first point basically claims that the Parliament did not have the necessary two-thirds majority to decide upon the ratification of the UPC. The plaintiff explains in one of his publications: “The Parliamentary proceedings on the ratification of the Agreement on a Unified Patent Court (UPCA) in Germany have revealed a state of political affairs which should cause concern to each citizen. It shows the practice of so-called ‘second-class adoptions’ in which legislative decisions are made by a materially inquorate Parliament, because nobody raises the objection necessary for the annulment of the session. It was in this manner that the legislative acts on the UPCA (UPC agreement) were unanimously adopted by 35 cheerful Members of Parliament (MPs) in the second and third reading in the early morning hours on 10/03/2017. ... A report on German law-making in the year 2017, in which the institutions involved could not care less about the German Constitution.“ The plaintiff argues that such a law had to be decided by at least two-thirds of the Members of the Bundestag. If plaintiff is success-
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ful on this point, the German Bundestag must repeat the legislation process and that would cost several more months. ›› The second point of the complaint is based on alleged democratic deficits and deficits in rule of law with regard to the regulatory power of the organs of the UPC, which are allegedly too far-reaching. ›› The third point of the compliant is related to the lack of an independent judiciary under the UPC. ›› Last but not least, the fourth point is based on the allegation the UPC violates the EU Law – breach of the principle of openness towards European law. The latter question could be referred to the CJEU and that would at least cost additional time before the UPC may come into force.
What is behind this legalistic hair-splitting? Is it a realistic possibility that the UPC may be blocked completely? Is it more realistic that the complaint will simply lead to a prolonged period of legal uncertainty before the UPC will become reality? What is the motivation behind the complaint? In one of his publications the
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plaintiff alleges that the new system “entails advantages only for a selected few, while it may even be detrimental to the majority of those affected, so that, had these consequences been disclosed from the outset, such project would not have stood any realistic chance to ever become law.“ He is of the opinion that “the political operators had always declared it to be a main theme of the European patent reform that it would allow for obtaining and enforcing patent protection at lower costs compared to the traditional system.“ The plaintiff claims, however, “that neither the subsequently determined renewal fees for unitary patent protection nor the level of reimbursable representation costs at the Unified Patent Court fulfill these promises.“ Thus, the new system would come at the expense of the SMEs that are more cost adverse than big pharma. The motive s of the plaintif f are unknown. Regardless of his motives, the next months will mean legal uncertainty for users. In all cases, it is recommended to be well-prepared for the new UPC system. SMEs, in particular, should prepare well in advance, so they do find themselves hampered by unexpected costs. L
Court of Appeal (Luxembourg)
Court of First Instance Local or Regional Divisions (Paris)
Central Division (Paris, London, Munich)
legally qualified judge technically qualified judge optional
Source: BIOCOM AG
Court structure of the planned European Unified Patent Court (UPC)
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Rubrik
Finding driver mutation patterns in tumour genomes could turn the fields of AI/bioinformatics into a stethoscope for the 21st Century
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European Biotechnology | Spring Edition | Vol. 16 | 2017
Pictures: xxx
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Cover Story
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Cancer data: A dive into the depths Correlation Sciences As Big Data analytics begin to inspire medical decisionmaking,
companies and scientists have gone to war over access to data derived from patient biopsies. Cancer profiling is a seminal situation. While some companies are seeking to profit from approaches to advanced mutation analysis, researchers are vociferous in demanding open access to proprietary databases behind company firewalls.
A
Pictures: Roche (right hand side), publicdomainpictures.net CC1.0 (left)
ccording to William – “call me Bill” – Kassler, human decisions are anything but perfect. “But machines can debug that,” stresses the Deputy Chief Health Officer & Lead Population Health Officer at IBM Watson Health in Boston. Speaking last summer at the Forum Science & Health conference in Munich, the ex-CDC policy advisor and former Medicare expert for value-based drug pricing predicted that cognitive computers would be the Next Big Thing in personalised medicine. Intelligent machines such as IBM Watson, he insisted, could learn rapidly. “Within just four years, Watson scaled down its error rate from over 40% to 5% in recognising language. And that’s just the beginning,” says Kassler. What if that power was turned to unravelling hidden patterns in tumour genomes?
based pricing by limiting reimbursement of costly targeted cancer therapies or immuno-oncological treatments to patient groups that have a proven benefit. It’s no secret that current Companion Diagnostics (CDx) are not designed for cancer mutation pattern detection. But because cancer-promoting effects are dependent on surrounding genes and an individual genomic context, AIdirected genome mining is currently en
›› collecting and interpreting the flood of medical discoveries from papers, slides, clinical trials, and other data ›› finding unrecognised patterns in real world data, including relevant mutations in cancer genomes, prognostic patterns in EMRs, images, lifestyle data from fitbits, etc.
Why data analytics could transform biopharma
Josh Lauer Lifecycle Leader, Foundation Medicine (FMI) at Roche
The first applications for these kinds of learning machines and algorithms are currently surfacing in personalised medicine, particularly in the highly lucrative field of cancer. Kassler knows that identifying drug responders to a growing number of cancer combination therapies and immunotherapies is still quite limited. He also knows that cash-strapped health systems want to switch to value
? !
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vogue in the sector. In 2013, IBM began promoting Watson as a ‘best treatment’ detector. The claim was based on mining cancer genomes and corresponding treatment data stored in Electronic Medical Records (EMRs). According to Kassler, Watson’s learning algorithms – which he brands “artificial intelligence” – could assist physicians on two fronts:
How can Roche help to expand FMI’s capabilities?
We have to build on FMI international traction by leveraging on presence in many countries. We have already launched the service in 12 countries. We look forward to bringing it to every market.
Exper ts like Roger Schank say that Watson simply “correlates data”, and that this ability is subsequently sold as ‘AI’ for marketing purposes. He stresses that an ability to sift through a large amount of data doesn’t define intelligence. The data-mining approach, however, has attracted Big Data analytics majors like IBM, Google, its spin-out Verily, Microsoft and a growing number of hightech SMEs. That’s because it can generate exactly the data needed by payors to prove the value of precision medicines. In a knock-on effect, major pharma developers have begun preparing for the dawn of Big Data-aided decision support
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Cover Story
European Biotechnology | Autumn Edition | Vol. 16 | 2017
analysis of a patient’s DNA to be used to identify and match individual tumour mutation patterns to suitable treatments.
Digitalising the tumour
Providers hit European market Ever since Germany‘s statutory health insurance decided last year to begin paying for diagnostic NGS analyses, Europe has become a target market for clinico genomic data miners. Other EU countries – including Italy, Finland, France and Lithuania – are soon to follow suit. In September, Thermo Fisher Scientific, Merck KGaA and cancer biobank expert Indivumed launched partnerships aimed at mining the cancer genome and establishing advanced companion diagnostics (see table) or better drugs. And personalised healthcare major Roche will soon sound the bell for cancer muta-
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tion profiling-based decision support in Europe. One strategic goal of the Swiss firm’s partnership with US-based NGS analytics specialist Foundation Medicine Inc. (FMI) is to monitor the evolution of tumour mutation profiles and relapse through liquid biopsy tests. Another is to develop cancer gene panels for therapy decision support and patient selection. Later this year, the Boston-based analytics specialist will open a laboratory facility at Roche’s Penzberg site near Munich. Roche has held a majority stake in the firm since 2015. FMI offers a unique tumour sequencing service that is already well established in the US. It has developed sophisticated algorithms that allow
Recent deals between digitalisation specialists and life science companies
Life Sciences
Partner
Subject
Agreed
Product
› Roche
Foundation Medicine Inc.
NGS of tumour biopsies + subsequent analysis
9/2015
Data report for oncologist/ pathologist
› Merck KgaA
Palantir Technologies
digitalisation of all kinds of data
1/2017
Data tools to speed up cancer drug development
› Freenome
Verily/Google
Analyze NGS data with AI
7/2017
Liquid biopsy cancer tests
› AstraZeneca, Janssen Biotech, Sanofi
Illumina
NGS of tumour biopsies + subsequent analysis
9/2017
Cancer gene panel tests
Pictures: Fotolia.com/crevis
by signing partnerships with the next-gen sequencing (NGS) analytics or software engineering companies that digitalise patient data. Big Pharma now expects them to have the tools to navigate through the cancer genome jungle – and link genomic patterns to outcomes stored in EMRs. The pharma and data analytics nuptials have been highlighted by a series of M&As and partnerships – most of them with Google-financed US companies like Verily, 23&me, Flatiron Health and Foundation Medicine Inc. Not to be left behind, Novartis also recruited its very first Chief Digital Officer in September.
“The principle is to obtain a tumour profile from Next Generation Sequencing of RNA and DNA in biopsy material from a cancer patient,” says Hagen Pfundner, Managing Director of Roche Pharma AG. “That profile will then be compared with 140,000 anonymised tumour profiles in FMI’s database, which the company has compiled in the US.” According to Pfundner, the process could prove a huge help to oncologists, pathologists and patients: “For example, if you have a patient with a tumour of unknown origin, FMI would generate a report that includes all known tumour DNA mutations, and also provide an overview of all potential therapies and ongoing clinical studies for which the patient may be eligible.” “The use of databases, which provide all diagnostically relevant data, is a great opportunity for personalised medicine,” says Ursula Redeker, Spokesperson for the Board of Roche Diagnostics. “Our long-term objective is to build up databases that also provide imaging and clinical data,” she adds. “I think the future of tumour profiling is moving towards molecular tumour boards – a sort of a digital expert system that combines data from various medical disciplines.” In the US, FMI works with Flatiron Health, an IT company specialised in
27.09.2017 15:36:12 Uhr
Microbiology
Cell Biology
Biotechnology
Process Control
European Biotechnology | Autumn Edition | Vol. 16 | 2017
electronic medical record solutions. This collaboration may close the information gap by linking FMI’s tumour profiles with real-life data from a patient’s diagnostic and therapeutic history, as well as with its outcomes. “This could prove beneficial in tumour diagnosis and prognosis, but also in drug research and development – particularly when it comes to finding new targets and suitable molecule formats,” says Redeker. “The analysis and integration of real-life data that complements clinical data offers huge benefits, and is the next logical step in personalised medicine,” says Pfundner. “It allows us to identify and recruit patients faster for clinical trials. Furthermore, it can help to identify and find the most suitable combination therapy for a patient. On the regulatory side, it has the potential to accelerate patient access to novel personalised combination therapies that have proved beneficial under real-world conditions. Compared to randomised clinical trials, that would speed up the approval of medicines.”
“It’s not a good idea to lock away NGS results of tumour biopsies in proprietary databases.” In mid-September, cancer tissue biobanking specialist Indivumed announced similar intentions. A collaboration with the CRO Helomics Corp. is aimed at linking analyses of human cancer biospecimens with annotated clinical data from consenting patients around the world. According to Indivumed CEO Hartmut Juhl, the company wants to establish a unique global cancer database using molecular information from tissue collected under stringent protocols: “Helomics is bringing in its research analytics expertise, CLIA service capabilities, and proprietary research platforms to develop the next stage of cancer biomarkers.” Swiss start-up Sophia Genetics S.A. (St. Sulpice, Switzerland), which raised US$30m in September to foster the global expansion of its cancer diagnostics annotation platform SOPHiA AI, is a direct competitor for FMI. Its machine-learning technology is currently being used in 334 hospitals across Europe, and has so far interpreted genome data from over 125,000 patients. According to the company’s CEO Jurgi Camblong, the technology enables “the hundreds of institutions in the network to safely and anonymously share their findings and knowledge while ensuring patient data privacy.” Camblong’s next goal is to ramp up commercial activity from Europe to Latin America, the Asia Pacific region, Canada and the US. In Germany, the largest genomic testing and medicines market in Europe, pathologists and oncologists have voiced concerns about R&D limitations through the proprietary database model, which has seemingly become an imminent part of the cancer genome dataminer business model. “It’s good to have different providers for high quality panel sequencing. It’s even good if providers apply their learning algorithms to genomic data,” says Christoph von Kalle, Director of the National Centre
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27.09.2017 15:36:20 Uhr
COVER STORY
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of Tumor Diseases in Heidelberg. “However, if the assays or the sequencing were reimbursed by payors, the results must not be locked up in proprietary databases. Follow-up analyses of available genomic data by researchers could bring huge benefit to the patient. Vice versa, treatment outcomes recorded at hospitals could be highly relevant to drug developers. At the end of the day, we must find a way to share data that is beneficial for the patient.” Albrecht Stenzinger, Head of the Center of Molecular Pathology in Heidelberg, which is now partnering with Thermo Fisher Scientific, agrees: “It’s not a good
European Biotechnology | Autumn Edition | Vol. 16 | 2017
idea to lock away NGS results of tumour biopsies in proprietary databases, as Myriad Genetics does for BRCA diagnosis. Companies that do so often sell their technology as overly complex. They put it in a black envelope so neither oncologists nor pathologists can see what has been done technically and bioinformatically – and then they say: buy it or don’t buy it – but it’s a must-have....But neither black boxes, nor inadequate simplistic assays will help us to better understand and treat tumours. Relapses to targeted or immuno-oncologic therapies after just one year or a couple of months remind us that we are only beginning to understand tumour biology.
For long-term success, it will be crucial to share other biological and clinical data and know-how in a fully transparent way and to collaborate on an equal footing to have better products and to gain knowledge,” says Stenzinger. Even the anonymisation of patient data before mutational profiling appears to be not such a great idea. Researchers looking to find novel cancer targets prefer pseudonymisation for several reasons: “If the tumour progresses and a patient’s data were anonymised, every new disease episode would be stored as a new identity, turning one dataset into two distinct datasets, without attributing it to the person it af-
“This can’t be done alone” European Biotechnology talked with Zhen Su, Vice President & Head of Global Medical Affairs – Oncology, Merck. He explained how Merck is collaborating with Project Data Sphere to lead the Global Oncology Big Data Alliance.
CANCER GENOMICS
Pictures: EMD Serono/Merck
ing in initiatives that push the boundaries of cancer research. Our fundamental belief that we are smarter together is why we are committed to investing in initiatives that identify and support patientcentric innovation via collaboration. We act with a strong sense of urgency. A proactive approach to break down the silos and accelerating this discovery of innovative approaches to patients is critical in the current cancer environment, where there is an enormous and significant unmet need. And we don’t believe this can be done alone. EuroBiotech_Why did you think you need collaboration? Su_We believe a critical path to address-
ing this unmet need is through Big Data.
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And this is about collaboration. Unleashing Big Data gives the best minds in the oncology community – from private, academic and government research organizations who share our commitment – access to information that allows them to pursue integrated innovations that are focused on finding solutions for cancer patients. EuroBiotech_Why do you think it’s good to collaborate with an open access platform? Su_The spirit of an open-access platform
breaks down the barriers and empowers a diverse, global community of scientists. A success story from this approach is the Project Data Sphere (PDS) Prostate Cancer DREAM challenge, where the winning team, who had never worked in prostate cancer in the past, used information from the PDS openaccess platform to help them considerably outperform the best existing model for predicting disease outcome among men with advanced prostate cancer.
ZHEN SU Since 2015, Dr. Zhen Su has been VP & Head of Global Medical Affairs - Oncology, Merck. With a 15-year career in academic and pharmaceutical medicine, the clinical expert – who came in from Sanofi – has close ties to the oncology, immuno-oncology and urology academic communities.
EuroBiotech_Any mutual benefits? Su_By investing in the Global Oncology
Big Data Alliance, which expands the existing PDS data platform, Merck aims to facilitate more of these successes from the sharing of Big Data and developing advanced analytics, to provide the global oncology community with the necessary tools to accelerate discovery, and development of innovative treatment approaches and ultimately deliver them to everyone who needs it.
Pictures: xxx
EuroBiotech_In mid-September, Merck and Project Data Sphere announced they will join forces to help accelerate innovative discovery, development and delivery of new approaches in cancer care. What was Merck’s motivation? Su_ Merck is deeply committed to invest-
28.09.2017 11:32:29 Uhr
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Cover Story
European Biotechnology | Autmn Edition | Vol. 16 | 2017
fects,” explains von Kalle. “Furthermore, if researchers subsequently find a biomarker that can help prevent cancer, the patients whose data were anonymised wouldn’t be able to benefit from this progress because it would be impossible to identify them.” He thinks pseudonymisation makes sense when controlled by an untouchable, independent organisation.
An alternative – data-sharing with mutual benefits Stenzinger’s latest collaboration is part of NGS major Thermo Fisher Scientific’s European roll-out of partnerships with leading institutes – so called Centers of Excellence – to establish clinical use assays and CDx that allow patient selection for targeted and cancer immune therapies. Announced at the ESMO conference in Madrid (8-12 September), the partnership offers mutual benefits without the need to build proprietary databases. In brief, Stenzinger’s center will translate its sophisticated gene panels to Thermo’s FDA-approved CDx platform. “The time of home-brew assays is over,” says Stenzinger, whose center switched almost completely to NGS in 2012 and now analyses 4,000 cases per year via DNAseq and RNAseq. “Today, you need industry partners to develop molecular assays that have clinical utility, and you must have a scalable infrastructure in place. Our industry partner benefits when we establish new gene panels. They may even be added to its commercial assay portfolio. In the future, there will be more clinically exploitable biological themes across tumour entities. One current example is defects in DNA repair genes as a predictive marker for PARP inhibition and selected chemotherapy regimen. Another is tumour mutational burden/load as a predictor of responsiveness to cancer immuno therapy. These two may even converge in the near future, and we’ll see the routine use of broad gene panels of 1 Mb and beyond in molecular pathology soon.” In fact, the FDA has already approved microsatellite instability as the first bio marker to predict responsiveness to MSD’s checkpoint inhibitor pembrolizumab
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Gaurav Singal Head Data Strategy and Quality Management at Foundation Medicine Inc.
? !
Who can benefit from NGSbased cancer profiling?
For both oncologists and drug developers, it’s important to have a universal platform that identifies multiple cancer driver genes in single tests.
across cancer modalities. TRK-A is another, and at the ESMO conference, Roche presented its first promising data from a liquid biopsy test that measures tumour mutational burden to predict reponsiveness to cancer immunotherapy. According to Madhushree Ghosh, Senior Director of Strategic Accounts at Thermo Scientific Fisher, “the expert/partner network enables us to not only reach researchers working in the field, but also pathologists and oncologists who will directly refer to our tests in their patient care. This enables us to develop CDx products that will enable drug submission correlation to our test, with a focus on biomarker-targeted therapies enabling better patient care.”
The spirit of an open-access platform breaks down barriers. Last year, the largest public database of cancer geneomes – the Cancer Genome Atlas (TCGA) – was moved into Amazon Web Services cloud. Is this a model for future clinico-genomic data-sharing? The database stores genomic data from 11,000 patients in 33 cancer modalities.
Even outside the cancer diagnostics space, data-sharing appears to work (see interview p. 22). At the ESMO conference, Merck KGaA announced it was joining forces with the non-profit initiative Project Data Sphere to jointly lead the Global Oncology Big Data Alliance (GOBDA). “The ultimate goal of our alliance is to unleash the power of Big Data to bring value to cancer patients,” said Merck board member Belén Garijo. Project Data Sphere’s Big Data analytics platform will be used to accelerate discovery, development and delivery of new approaches in cancer care. The GOBDA initiative has been formed to expand open-access to de-identified patient data sets, further enhancing analytical capabilities by building on Project Data Sphere’s digital platform. The current platform contains historical clinical trial data from almost 100,000 patients. It was provided by multiple organisations, and access to the information has already led to new and potentially practice-changing findings. GOBDA says it is planning to expand this platform to include rare tumour trials, experimental approaches and real-world patient data. Leveraging these data with Big Data analytics will help optimise clinical trials, build up a data register and advance understanding of what cancer treatments are available.
Overselling technology hopes IBM has promoted its cognitive system Watson as the coming AI standard in cancer analytics, while Google and Microsoft make similar claims for their AI solutions. But black-box cancer analytics tools still aren’t living up to developer promises. Hopes of Watson’s playing a future role in oncology were dealt a heavy blow when the M.D. Anderson Cancer Center shelved a US$62m project it started in 2013 in order to establish clinical decision support technology based on the cognitive system. The reason? An ongoing lack of documented results. According to Stenzinger, “in tumour biology, we’re still just scratching the surface.” L t.gabrielczyk@biocom.eu
Pictures: Roche/FMI
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European Biotechnology | Autumn Edition | Vol. 16 | 2017
Advertorial
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Where “bio” meets “technology” ACHEMA Does biotechnology mean more to you than enzymes, yeast, and bacteria? If you are looking for
the “tech” part in biotechnology, then ACHEMA 2018 is the place to be. And if it’s industrial biotechnology you are looking for, the world forum for the process industries will feel like home.
Pictures: DECHEMA
Have you recently been looking for pictures illustrating “biotechnology”? A Google search turns up very nice pictures of serious-looking people in labs handling pipettes and fragile glass vessels or micro tubes, and there is also a lot of DNA, and leaves sprouting from test tubes. If you want to see what industrial biotechnology looks like, however, instead of visiting Google, you should go a step further and visit ACHEMA 2018 in Frankfurt. Yeasts and bacteria need a homestead, and if they are industrial workers, theirs is not a tiny home, but an industrial loft. And their realtors exhibit at ACHEMA – these are the companies that enable biotechnological processes on an industrial scale. As chemical and biotechnological methods converge and become integrated into synthetic routes, so the steel vessels and pumps are joined by single-use fermenters, sophisticated automation and control measurement, and modular plants allowing for flex-
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ible and fast adaptation of products and processes.
“Biotech for chemistry” Like a common thread, the focal topic “biotech for chemistry” runs through all eleven exhibition groups:
›› Research and Innovation hosts companies and institutions presenting brandnew findings about how to harness even more microbes for chemistry. Are bacteria the way to go or do yeasts offer more effective pathways? ›› In the Laboratory and Analytical Techniques exhibition group you will find not only the furniture for your lab but also the equipment to look into the last atom of your product. ›› The Engineering exhibition group is especially interesting for all those who take the step from pilot-scale to fullsize. If you are planning an industrial plant, this group offers anything from 3D simulation software to service providers where you can commission a turn-key factory. ›› Fancy a separator for biomass or a distillation unit to purify your product? The Thermal and Mechanical Processes group is where to look. And of course you won‘t be left alone in your search for techniques and equipment to process your chemical into the product of your choice. Besides being the leading trade show for the process industries, ACHEMA is also
11 – 15 June 2018 Frankfurt am Main www.achema.de a major congress. Choose between more than 600 presentations ranging from bio- refineries, reaction technology, energy supply, and analytics to process design. At the PRAXISforums, exhibitors, suppliers, and users meet and discuss the “how to” of practical life.
Be part of it Save the date for your visit: 11–15 June 2018. Book your stand at www.achema.de Contact Dr. Kathrin Rübberdt DECHEMA phone: +49 69-7564-277 ruebberdt@dechema.de
29.09.2017 11:21:54 Uhr
We offer high quality
Lipid analysis services for a wide range of customers and applications:
Biotech and pharma industry, clinical research Drug discovery (mode-of-action studies, target validation, effect of delivery system on lipid metabolism), biomarker identification (pharmacodynamic, pharmacokinetic, CDx), clinical screening and diagnostics Food industry Intervention studies for development of functional food/nutraceuticals Cosmetics and Dermatology Cosmetic claim support, topical drug development, development of personalized cosmetics Academic research Lipid analysis of various model organisms
For enquiries, please contact: Lipotype GmbH | Oliver Uecke, Business Development Tatzberg 47 | 01307 Dresden | Germany T: +49 (0) 351 79653-45 | sales@lipotype.com
www.lipotype.com
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28.09.2017 11:34:21 Uhr
+ CUSTOMER REFERENCE Biotech and pharma industry, clinical research: drug discovery, biomarker, diagnostics, clinical screening
Lipid analysis for early stages of drug discovery
Lipotype performed lipid analysis for Flagship VentureLabs with the aim to better understand molecular compositions of chondrisomes, pharmaceutically active derivatives of mitochondria. The research of Flagship VentureLabs is on novel ways of preparation of chondrisomes that have beneficial structural characteristics, yield, concentration, stability, viability, integrity, or function. The lipidomic results facilitated the characterization of isolated chondrisomes in order to evaluate their quality and subsequently were used to file a recently published patent application. Fueled by curiosity and a quest for new sources of future value, Flagship conceives, creates, resources and grows firstin-category life sciences companies. The unique, systematic, hypothesis-driven innovation process empowers Flagship simultaneously to explore the worldâ&#x20AC;&#x2122;s biggest problems and to conceive disruptive scientific solutions. Flagship ventures deliver breakthrough medicines, maximize the potential of new agricultural practices, and power the world with innovative resources. At Flagship Pioneering, we deploy boundless curiosity and creativity within our institutional innovation foundry, VentureLabs. Flagship VentureLabs has originated more than 200 patents and 40 companies. These ventures establish entire new fields and uncover previously undiscovered areas of science. Some of our notable venture creation successes include Moderna Therapeutics, Seres Therapeutics, Axcella Health, Indigo Agriculture and Adnexus.
PUBLICATION: Methods and Compositions of Chondrisomes â&#x20AC;&#x201C; United States Patent Application 20170151287, 2017 G A Von Maltzahn, J M Milwid, M Mee, J R Rubens, D Chess, K Trudeau, K Mahdaviani, J Feala
About Lipotype LIPOTYPE is a spin-off company from the Kai Simons and Andrej Shevchenko labs of the world-renowned Max-Planck-Institute of Molecular Cell Biology and Genetics in Dresden, Germany. Drawing on many years of cutting edge research experience, Lipotype delivers comprehensive, absolutely quantitative lipid analysis services for clinical and biological samples on a high-throughput scale. Lipotype offers high quality lipid analysis services for a wide range of customers and applications including biomarker identification for clinical researchers, pharma and biotech companies, functional food development for the food industry, claim support for the cosmetics industry, as well as for the small-scale profiling needs of academic researchers.
Picture: AKIRA/amanaimagesRF (thinkstock)
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28.09.2017 11:34:31 Uhr
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economy
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Oncology drives growth of partnering event BIO-Europe BIO-Europe After a record-breaking 2016 event, BIO-Europe 2017 in Berlin will once again
In the run-up to the event, EBD Group published a report analysing the 20,000 meetings recorded at the 2016 event in Cologne. Oncology was the most frequently disclosed therapeutic area. This large cohort of companies was consistently active at BIO-Europe, and over 70% of meetings last year included at least one oncology company. Interestingly, this is not reflected in the volume and value of partnership deals made during the second half of 2016 and first half of 2017. Medtrack data reveals that oncology represented 26% of total deal volume (up from 22% in the prior analysis), coming in a close second after the field of gastroenterology (28%). In terms of total deal value, oncology fared even worse: After accounting for 36% in the prior analysis, this therapeutic area only accounted for 19% of the total partnership money of the past year. Did we enter a phase of somewhat smaller and
more selective investments following the boom of 2015–2016? Possibly, stakeholders wait for clinical outcomes of certain combination therapies and certain new immunotherapy approaches, only to jump on the same (or opposite) bandwagon afterwards.
Merus & Pieris lead by example Two of the most valued oncology partnerships of the past twelve months include biotech companies with firm ties to Europe. Dutch Merus NV signed a global strategic collaboration focused on the discovery and development of bispecific antibodies using its Biclonics technology platform last December. Including all potential realised and unrealised development and commercial milestones, US-based Incyte Corp. could pay up to US$3bn to Merus. Some weeks later, US biotech Pieris Pharmaceuticals, Inc. (with
Surfaces of T-cells with different receptors, among them chimeric antigen receptors (CAR) with long “stalks.”
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roots and operations in Germany) and French pharma company Les Laboratoires Servier agreed to jointly pursue several bispecific therapeutic programmes. Pieris is eligible for more than US$1.8bn. With the recent US approval of Swiss Novartis’ CAR-T therapy, platform technologies in this field are in high demand. Stock market prices for several European companies have risen sharply. Among them are Celyad and Medigene, which both had some news to spread this summer. Celyad (France) announced a license agreement with Novartis for patents for the production of allogeneic CAR-T cells in May. Medigene (Germany) presented its automated high-throughput screening platform for identifying T-cell receptors (TCR) suitable for TCR immunotherapies – which Medigene claims could even work better than CAR-T therapies. But the cell therapy field also experienced a setback when, in September, US state authority FDA forced Cellectis (France) to put two clinical trials of its off-the-shelf version of a CAR-T therapy on hold after their first patient was killed by adverse effects. Finally, there’s the contingent fate of CARTreg therapy developer Txcell. According to a mid-September statement, if he does not find the financial resources in the coming months to keep up the work, the French company’s CEO Stéphane Boissel said he might consider selling the biotech. Although not active in oncology (but in autoimmune diseases instead), Boissel will surely receive a lot of attention when he travels to Berlin to make a decisive deal. L m.laqua@biocom.eu
Picture: Cellectis
try to set the bar a little bit higher. The organiser, EBD Group, expects a high single-digit percentage growth in participants that would result in over 3,900 executives from an estimated 60+ countries willing to engage in dealmaking talks.
29.09.2017 11:22:22 Uhr
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Update of ongoing clinical trials fibrosis
In mid-August, Belgian Galapagos NV(Mechelen) reported clinical success of its unpartnered autotaxin (ectonucleotide pyrophosphatase/phosphodiesterase family member 2) inhibitor GLPG1690 in 23 patients with idiopathic pulmonary fibrosis. In IPF, lung function progressively worsens due to irreversible fibrotic remodelling of lung tissue leading to reduced mean forced vital capacity (FVC), a surrogate marker for lung function. In a small Phase II study that randomised 23 IPF patients 3:1 to receive GLPG1690 or placebo, the small molecule compound stopped FCV reduction for 12 weeks. While the treatment group’s FCV increased on average by 8 ml compared to baseline, it decreased by a median value of 87 ml in the five patients in the control group. Galapagos announced that the treatment was generally well tolerated. Also in August, Galapagos NV’s US competitor FibroGen Inc. (San Francisco) reported that its IPF antibody therapy pamrevlumab (FG-3019) met the FCV endpoint in a Phase II trial that randomised 103 IPF patients 1:1 to receive pamrevlumab or placebo for 48 weeks. While patients dosed once every three weeks with the connective tissue growth factor (CTGF) inhibitor the company develops as a cancer and IPF treatment had an average decrease in FVC of 129 ml at week 48, patients of the control group showed a median decrease of 308 ml (2.85% vs. 7.17%). In contrast to combination therapies of GLPG1690 with approved IPF treatments nintedanib (Boehringer Ingelheim) or pirfenidone (Roche), combos with pamrevlu mab were well tolerated. Mesothelioma
Two companies reported results of Phase II compounds to treat mesothelioma, a rapidly progressing form of lung cancer that is triggered by exposure to asbestos. Bayer AG’s (Leverkusen) antibody
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drug conjugate (ADC) anetumab ravtansine missed the endpoint of improvement in progression-free survival vs the tubulin blocker vinorelbine in a pivotal Phase II trail that enroled 248 patients with advanced malignant disease. While Bayer contributed the coupling chemistry and maytansinoid tubulin blocker DM4 of the ADC, the mesothelin-targeting antibody was developed at Munich-based MorphoSys AG. US developer Bristol-Myers Squibb Co. tried to use its PD1 checkpoint inhibitors nivolumab and CTLA4 blocker ipilimumab to slow down the progression of the cancer in chemotherapeutically pretreated patients. In the single arm pilot study that enroled 125 patients in metastatic stage, the combo met the endpoint of 12-week disease control rate in 50% of patients and showed an objective response rate of approximately 26%. Psoriasis
UCB S.A’s (Brussels, Belgium) drug candidate bimekizumab has met clinical endpoints in a proof-of-concept study of clearing the skin of patients with psoriatic arthritis. According to headline results, up to 79% of patients receiving three subcutanous doses of the inhibitor of the pro-inflammatory immune response mediators IL-17A/IL-17F over 12 weeks showed at least clearance of 90% of their skin lesions (Psoriasis Area and Severity Index 90, PASI 90), while up to 60% of patients showed complete clearance (PASI100). The company randomised 250 patients with moderate to severe disease to five treatment groups in the Phase IIb trail to receive the antibody or placebo. Detailed data, including data on the placebo group, will be published in H1/2018. The company is currently in its planning for Phase III trails. Septic shock
German antib o dy drug develop er Adrenomed AG (Berlin) announced it
27.09.2017 13:42:41 Uhr
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Regulatory Affairs
European Biotechnology | Autumn Edition | Vol. 16 | 2017
News
ADM
Mortal combat Medivir AB (Stockholm) has started dosing in a dose-finding Phase I/II study in patients with treatment-resistant solid tumours. The study aims to evaluate safety and first signs of efficacy for a combination therapy of Medivir’s SMAC mimetic Birinapant plus MSD’s approved checkpoint inhibitor pembrolizumab. Birinapant binds to and degrades Inhibitors of Apoptosis Proteins (IAPs), which both enables apoptosis (programmed cell death) in tumour cells, and activates the immune system.
Vascular integrity
ADM
Quadruple testing
First-in-class therapy Danish Genmab A/S’ antiCD38 antibody daratumumab has met the endpoint of progression-free survival in newly diagnosed patients with multiple myeloma (MM) not eligible for for autologous stem cell transplantation. An interim analysis of an ongoing pivotal Phase III study (NCT02195479) showed significant benefit of daratumumab plus a bortezomib/melphalan/prednisone (VMP) combo over VMP monotherapy. Genmab said it wants to file for FDA approval of daratumumab as first-line treatment in MM.
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Postulated MoA for adrecizumab, Adrenomed’s first-in-class antibody to treat septic shock and acute congestive heart failure. The antibody, which can’t pass the endothelium, leads to redistribution of adrenomedullin (ADM) from the interstitium – where it is produced – to the blood vessel lumen without affecting ADM activity. Relocation of adrenomedullin to the lumen prevents its vasodilatory effects in tissue but promotes its endothelium-stabilising effect.
is going to start enrolment for a clinical proof-of-concept Phase II trial (ADR-02) with its adrenomedullin-specific antibody adrecizumab in September, after having received regulatory and ethics board approval in Germany. The ADR02 trial will enrol 300 patients with early septic shock in Germany, Belgium, France, and the Netherlands to prove the safety and efficacy of adrecizumab. To date, there is no causative treatment for sepsis and septic shock that ends in multi-organ failure. Adrecizumab targets the vasodilatory hormone adrenomedullin, a key regulator of blood pressure and vascular tone, which plays a pivotal role in the development of septic shock. In preclinical studies, adrecizumab reduced vascular leakage, stabilised the circulation by restoring blood pressure, normalised fluid balance, reduced vasopressor demand, improved renal function, and reduced mortality from septic shock by 50%. Two Phase I studies
demonstrated excellent tolerability and safety of adrecizumab without any severe adverse effects (NCT02991508, NCT03083171). Safety data were presented at the end of September. In the ADR-02 study, the company will examine the effect of adrecizumab on patient-relevant outcomes such as mortality, overall survival, renal function etc.. The company will enrol the first patient in October. As to date, there is no drug on the market able to reduce septic shock mortality, a first-in-class drug would target a potential market of 1.5 million patients in the EU and the US. Melanoma
Genentech par tner BioNTech AG (Mainz, Germany) has published the results of its Phase I study on 13 melanoma patients vaccinated with its individualised Mutanome RNA cancer vaccine (Nature, doi:10.1038/nature23003). Two patients with metastases showed partial
Picture: Adrenomed AG
PharmaMar SA (Madrid) announced the start of a multicenter dose-finding combination study with plitidepsina for the treatment of multiple myeloma. In the study, plitidepsina will be combined with pomalidomide, bortezomib, and dexamethasone to evaluate the recommended dose, the efficacy of the combination, and the safety profile.
28.09.2017 11:35:17 Uhr
European Biotechnology | Autumn Edition | Vol. 16 | 2017
responses, one relapsed and one, who got add-on therapy with a PD1 checkpoint inhibitor, had a complete response. However, all patients showed immune responses to the dozen mRNA-encoded individual neo-antigens that the company identified by sequencing the genomes of tumour cells and subsequent computational prediction of binding to antigen-presenting HLA proteins. Eight patients remained progression-free for 23 months. HIV
Janssen Vaccines & Prevention BV (Leiden, The Netherlands) reported interim results from a Phase I/IIa study in 393 healthy HIV-uninfected adults in the US, Rwanda, Uganda, South Africa, and Thailand at the end of August. In animal tests, the companies prime-boost “mosaic” vaccines, which cover a wide variety of antigens from different HIV subtypes, showed a 66% protection after six vaccinations. Janssen, who announced that various mosaic-based vaccines “appeared to be well tolerated” in humans, observed antibody responses in 100% of study participants after the third vaccination, which further increased after the fourth vaccination. The vaccine regimens contain two prime doses of the mosaic viral vector Ad26.Mos.HIV and two boosts of either Ad26.Mos.HIV, MVA-Mosaic and/or different doses of the soluble protein Clade C gp140 adjuvanted with aluminum phosphate. Based on the study results, Janssen is going to start a Phase IIb study next year with Ad.26.Mos.HIV boosted with the clade C gp140 soluble protein.
ploratory study (first in NSCLC), share value dropped dramatically. The company, however, has followed a dual development strategy and is also assessing the TLR9 agonist in combination with cancer immunotherapeutics. HCC
French cancer med developer Transg è n e S A ( Illk ir ch - G r a f f e n s t a d e n, France) has started a Phase I/IIa study (NCT03071094) enrolling 30 treatmentnaive patients with hepatocellular carcinoma (HCC) to assess safety and doselimiting toxicities of a combination two cancer immunotherapies that have already been proven to be efficient: Trangenes’ intratumourally injected oncolytic virus therapy pexastimogene devacirepvec (3 doses), and Bristol-Myers Squibb’s intravenously (bi-weekly) administered checkpoint inhibitor nivolumab. In the Phase IIa part of the study, the company will assess the overall response rate (ORR), disease control rate (DCR) at four months and overall survival at 12 months. ALLERGIC RHINITIS
ASIT biotech (Brussels) has been granted approval to start a follow-up study with the 36 patients enrolled during the Phase I/IIa clinical trial of hdm-ASIT, its drug candidate for house dust mite rhinitis. The objective of the study is to determine whether longer natural exposure to house dust mites may have an impact on immunological and reactivity parameters, and assess a potential long-term effect of hdm-ASIT+™. SHORT BOWEL SYNDROME
Mologen AG’s (Berlin) TLR 9 agonist lefitolimod (MGN1703) has missed the primary endpoint of increasing NK cellbased antiviral responses in an exploratory Phase Ib/IIa trail with 12/15 patients with chronic HIV. According to the company, monotherapy with the activator of the innate immune system did not show a detectable effect on the blood-borne viral reservoir but increased T-cell and B-cell activation. As it was the second time that lefitolimod has failed in an ex-
29-31_EB_Autumn_2017_Trial_tg.indd 31
Z e a l a n d P h a r m a A / S’ (Glo s t r u p) Glepaglutide met the endpoint of reducing fecal wet weight output at three weeks vs placebo in an exploratory Phase II trial enrolling 16 patients with short bowel syndrome. The company said its long-acting GLP-2 analog was well tolerated in the dose-finding study. Secondary endpoints included safety and pharmacokinetics. The company announced it expects to start Phase III testing next year.
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27.09.2017 13:42:51 Uhr
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Advertorial
European Biotechnology | Autumn Edition | Vol. 16 | 2017
NOVEMBER 6–8, 2017 BERLIN, GERMANY
6–8 November, 2017 Berlin, Germany, CityCube Berlin
Bio-Europe The 23rd edition of the BIO-Europe international partner-
ing conference takes place in Berlin, Germany, November 6–8, 2017, bringing together top decision makers from global life science companies in search of in-licensing and investment opportunities for deals that propel drug development. Berlin, Germany will host what the international life science industry considers its most productive annual partnering event, BIO-Europe, taking place November 6–8, 2017 at the City- Cube Berlin. The main draw for executive-level decision makers from pharma, biotech, and finance is the ease of high-level “partnering,” oneto-one, private business development and discovery meetings that are the
› Quick facts 2016 EVENT RECORDS 3,692 attendees, 20,833 scheduled one-to-one meetings with 4,734 licensing opportunities posted from among 1,982 companies that attended from 63 countries. ONLINE REGISTRATION Please visit: ebdgroup.knect365. com/bioeurope/registration-information
32_EBM_2017_Event Profile_Bio Europe_Berlin.indd 32
backbone of the event, and have led to some of the biggest M&A and collaborative deals over the past two decades. Now in its 23rd edition, BIO-Europe is also highly regarded for the variety and high caliber of presenting companies, ranging from academic innovators and start-up biotech companies to mid-size pharma and biotech, which bring their innovative technologies, therapies, and solutions to the event with the goal of securing development and commercialization partners. If the partnering can be considered the engine, the presenting companies are the fuel that drives the event. BIO-Europe also features a diverse list of industry leaders speaking at workshops and on panels. Leading pharmaceutical companies, including all of the big names in pharma, sponsor the event, and send teams of scouts to engage around new and innovative products. Informal networking events in stunning local venues provide further dealmaking opportunities. L
Stoke the engine GREETING There is tangible excitement around the arrival of BIO-Europe every year. This event is a key strategy for global biotech, pharma, and investors who attend in search of new collaboration partners and deal opportunities. To add to the anticipation, this year BIOEurope is a partner of the new international scientific gathering known as Berlin Science Week. Berlin-Brandenburg is one of the leading life sciences and healthcare industr y centers in the world, with a unique research and clinical landscape supported by a close network of key players from industry, start-ups, finance, and medical research. BIO-Europe is expected to draw a high caliber of companies to this vibrant hub, not only from Germany but from across the globe, to fuel the insatiable drug development industry. With almost 3,700 attendees last year, this event, which pioneered partnering 23 years ago, continues to stoke the engine that drives the industry’s growing demand for transformational breakthroughs. See you in Berlin this November!
Anna Chrisman Group Managing Director EBD Group
Pictures: EBD Group
Reunion in Berlin
29.09.2017 11:23:29 Uhr
SEE YOU IN BERLIN! 23RD ANNUAL INTERNATIONAL PARTNERING CONFERENCE
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27.09.2017 13:43:28 Uhr
34
Advertorial
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Efficient cell line for the production of EPO biosimilars Asset Sale A GMP-compliant, continuous production process for recombinant α- or β-erythropoietin
(EPO) results in an exceptionally high steady state yield of 40–80 mg/l for 10 to 14 days. For strategic reasons, the EPO assets were transferred to ORPEGEN Peptide Chemicals GmbH. These assets, including the unpatented/unpublished CHO production cell line, are up for sale.
To date, in the multi-billion euro market for erythropoietin to treat kidney insufficiency or chemo-therapeutically induced anaemia, there is only one biosimilar for α-EPO, none for b-EPO, and another for ζ-EPO. Originally developed by ORPEGEN Pharma, an unpatented and unpublished CHO cell line produces – depending on the proprietary downstream purification process – either highly pure recombinant α-EPO (currently two originators and one biosimilar have received EU approval) or β-EPO (two originators: NeoRecormon, Mircera-Roche).
Cell line with unique selling points The original CHO cell line, developed on the basis of expired patents (2004) owned by Amgen, has been improved and optimised in many respects. › Y ield: In serum-free, GMP-compliant perfusion culture the proprietary cell line achieves an unusually high productivity of 40 to 80 mg per liter [mg/l] at steady state for 10 to 14 days. › S afety: During subcloning of the CHO cell line, only clones in which 1,3-α-galactose could not be detected were selected for further development. It has been clinically documented that faulty glycosylation of EPO with the 1,3-α-galactose antigen, which is toxic in humans, may
34_EB_Autumn_2017_Advertorial-Orpechem_ml.indd 34
Background
EMA-approved Epoietins Currently seven different erythropoietins have received market approval for anaemia treatments of patients in chemotherapy and patients with renal insufficiency. Certain blood transfusions are another field of application. Among them are α-EPOs, such as the originators Aranesp (Darbepoetin alfa, Amgen) and Erypro (Epoetin alfa, marketed by Janssen-Cilag and distributors). An EU approved α-EPO biosimilar, produced by Lek/Rentschler, is sold under the brand names Abseamed (Medice), Epoetin alfa Hexal (Hexal), and Binocrit (Sandoz). In addition, there is a ζ-EPO biosimilar, produced by Norbitec, which is sold under the brand name Retacrit (Hospira/Pfizer) and Silapo (Stada), with Erypro serving as a reference product. Amongst the b-EPO originators, Roche has to date a de facto monopoly in Europe, with NeoRecormaon and Mircera, a methoxy PEGylated product variant. The original θ-EPO, manufactured by Merckle Biotec, is sold under the brand names Biopoin (Teva) and Eporatio (Ratiopharm).
lead to anaphylaxis and, in the worst case, to patient death. › Cost-efficiency: Our in-house deve loped product purification allows, depending on the procedures employed for the downstream-processing, the production of two pharmaceutical products using the same cell line. They are bioequivalent to the original products like Eprex (Amgen; α-EPO) or NeoRecormon (Mircera-Roche; β-EPO). › Commercialisation: Because all information on the recombinant vector is confidential and was never published, the vector is patentable. The cell line can be acquired or licensed. After signing a Non-Disclo-
sure-Agreement (NDA), detailed QC data and further information will be provided.
For manufacturers We are seeking manufacturers of bio pharmaceuticals interested in acquiring or licensing the cell line and the relevant process know-how. Further information can be obtained from the owner of the cell line. Contact Prof. Dr. Christian Birr CEO OPC ORPEGEN Peptide Chemicals c.birr@orpechem.com
28.09.2017 11:36:21 Uhr
European Biotechnology | Autumn Edition | Vol. 16 | 2017
STOCK MARKETS
35
Finding winners in a tough market Managing Director, Rx Securities – The takeover of Actelion by J&J leaves European biotech searching for its next bellwether, and investors flush with cash to re-invest. M&A could have made a stronger showing year-to-date, but big deals are still occurring. SAMIR DEVANI
Envisaged at the beginning of this year, primarily due to the Trump administration’s plan to re-patriate capital, the M&A upsurge that was predicted for the global bio tech sector in 2017 has yet to materialise. This year also has seen the European biotech sector lose its bellwether stock, Actelion, to Johnson & Johnson. Although the buyout provided great returns for investors, it resulted in Europe searching for a new bellwether. However, the deal has left some key biotech funds flush with cash to re-invest, and invariably this will be positive news for some companies. Overall, European biotech stocks have underperformed the NASDAQ Biotech index year-to-date, but the heterogeneity of the sector means there are al-
ways some big winners and losers! Notable winners include Evotec, with its shares up over 150%, driven by its acquisition of Aptuit and the extension of its collaboration with Bayer. Summit Therapeutics’ shares are up approximately 40%, aided by a deal with BARDA for funding Phase III development of ridinilazole for Clostridium difficile infections. Faron Pharmaceuticals’ shares are up approximately 200% year-todate due to progress in its Phase III trial for traumakine in Acute Respiratory Distress Syndrome. Finally, Hansa Medical has seen its shares rise more than 80% based on positive data from its lead drug, IdeS, being tested as a desensitisation treatment before kidney transplantations.
Clinical data is a key driver of share prices for biotech stocks and even in riskadverse periods it can generate significant alpha for investors. The other main driver for biotech stock prices are licensing deals – proving you have a valuable asset. So far this year, there have been big deals for Basilea (licensed Cresemba in Europe to Pfizer), Ablynx (eight Nanobody-deal with Sanofi), and Bavarian Nordic (licensed HIV-1 and hepatitis B vaccines to Janssen). From a technology perspective, CAR-T has been hot for a while. Now, Novartis’ and Oxford Biomedica’s FDA approval for CTL019 brings the first CAR-T therapy to market. Response rates using this platform have been outstanding, but durability and safety questions remain. However, this has not stopped Gilead from offering US$11.9bn for fellow CAR-T therapy developer Kite Pharma!
News from the floor SOBI AB Citing threats from competitors, Nordea Bank downgraded shares of rare-disease drug maker Swedish Orphan Biovitrum (SOBI) from “hold” to “sell” in August. Nordea’s new target price is 100 SEK. After a small bump following that decision, SOBI’s shares recovered at around 120 SEK.
multiple sclerosis did not indicate any statistical difference between active and placebo treatment. Analyst Eric Le Berrigaud from Bryan, Garnier & Co. regards the title as highly speculative, “at least until Q1/2018 when the 12-month results from this trial will be known.” He estimates the fair value at €9 per share. In mid-September Geneuro’s shares were traded at €4.
Picture: Rx Securities
GENEURO SA Six-month results from
the CHANGE-MS Phase IIb study of Geneuro’s candidate GNbAC1 for the treatment of patients with relapsing remitting
35_EB_Autumn_2017_Analyst_ML.indd 35
TIZIANA LIFE SCIENCES PLC Beaufort Se-
curities reissued their speculative “buy” rating on shares of Tiziana Life Sciences in a
research note published in September. Now trading below GBX150, Beaufort seeks a price target of GBX400. This summer, the company discontinued funding of its preclinical B-cell Lymphoma 3 inhibitor programme and welcomed Kunwar Shailubhai as its new CEO. EVOTEC AG Approaching €19 after a
bullish ride for months, Deutsche Bank changed its rating of Evotec’s shares from “buy” to “hold.” The price target set by analyst Falko Friedrichs is €16.
27.09.2017 13:43:51 Uhr
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Euro Biotech Stocks
COMPANY
QUOTE
M-Cap
European Biotechnology | Autumn Edition | Vol. 16 | 2017
52 weeks indicator low high
COMPANY
QUOTE
M-Cap
4D Pharma plc
4.08
267,000k
Bone Therapeutics SA
10.1
72,600k
4SC AG
5.55
170,000k
Brain AG
18.39
340,000k
C4X Discovery Holdings plc
0.86
40,100k
Cantargia AB
0.72
22,600k
A1M Pharma AS
0.97
7,900k
AB Science SA
8.03
340,000k
AB-Biotics SA
1.68
21,100k
Abcam Ltd
11.6
2,400,000k
Carbios SAS
7.75
33,300k
Cassiopea SpA
28.01
280,000k
23.33
830,000k
Abivax SA
12.11
120,000k
Cellectis SA
Ablynx NV
13.09
790,000k
Cellink AB
Abzena Ltd
0.38
81,100k
Celon Pharma SA
Acarix AB
2.07
48,100k
Stock price push Regenerative Medicine Kiadis NV brings its lead therapy to
market with seven-league boots on. ATIR101 for blood cancers is designed to make allogeneic hematopoietic stem cell transplantations safer and more effective. The European marketing authorisation for ATIR101 is already pending, and the Dutch company has just received the Regenerative Medicine Advanced Therapy (RMAT) designation from the US drug authority, the FDA. Investors obviously appreciate the news, as the stock price escalated by 100%. L
9.5
71,300k
8.56
380,000k
Celyad SA
47.5
440,000k
Cerenis Therapeutics SA
1.88
34,100k
Circassia Pharmaceuticals plc
0.96
330,000k
Co.don AG
3.08
130,000k
Cosmo Pharmaceuticals NV
123.4
1,860,000k
Curetis AG
4.96
75,500k
Cytotools AG
10.51
22,700k
Cyxone AB
0.85
13,200k
73.67
1,820,000k
Deinove SA
1.94
20,300k
Destiny Pharma plc
1.88
76,900k
Diamyd Medical AB
0.33
18,000k
Diasorin SpA
74.15
4,190,000k
Diaxonhit Therapeutics SA
5.76
55,200k
5.2
33,900k 32,300k
DBV Technologies SA
Elanix Technologies AG e-Therapeutics plc
0.12
Active Biotech AB
0.57
55,900k
Ellen AB
0.02
3,500k
Addex Therapeutics Ltd
1.79
27,900k
Enzymatica AB
0.37
28,000k
Epigenomics AG
4.69
110,000k
Erytech Pharma SA
23.7
280,000k
Adocia SAS
15.01
100,000k
ALK-Abelló A/S
131.4
1,350,000k
Allergy Therapeutics plc
0.37
230,000k
Esperite NV
0.43
6,500k
Alligator Bioscience AB
2.87
200,000k
Eurofins Cerep SA
5010
25,300k
536.6
9,190,000k
Annexin Pharmaceuticals AB
1.1
7,300k
Eurofins Scientific SE
Aqua Bio Technology ASA
0.99
6,800k
Evgen Pharma plc
0.18
12,800k
Argenx SE
17.85
480,000k
Evolva SA
0.35
150,000k
Arocell AB
0.55
15,500k
Evotec AG
18.5
2,770,000k
Asit Biotech SA
4.06
51,700k
Expres2ion Biotech Holding AB
0.55
5,300k
Avacta Group plc
0.82
55,800k
Faron Pharmaceuticals Oy
9.32
260,000k 36,000k
9.9
260,000k
Fermentalg SA
3.02
Basilea Pharmaceutica AG
69.17
820,000k
Fit Biotech Oy
0.04
2,800k
Bavarian Nordic A/S
35.62
1,150,000k
Formycon AG
33
300,000k 4,280,000k
Avantium Holding NV
Bergenbio ASA
2.08
100,000k
Galapagos NV
83.05
Bio-On SpA
29.6
590,000k
Genedrive plc
0.4
7,600k
Biocartis NV
10.5
470,000k
Geneuro SA
4
58,800k
3.61
140,000k
Genfit SA
27.02
840,000k
Biogaia AB
31.91
550,000k
Genmab A/S
191.95
11,800,000k
Bioinvent International AB
0.26
80,300k
Genomed SA
4.48
6,200k
Biomed-Lublin SA
0.27
11,700k
2.6
11,300k
Genovis AB
0.39
25,100k
Genoway SA
1.95
11,700k
5
120,000k
Biofrontera AG
Biomérieux SA
Genomic Vision SA
69.68
8,300,000k
Bionaturis SA
1.69
8,600k
Biophytis
4.05
40,000k
Gensight Biologics SA
Bioporto Diagnostics A/S
0.44
62,100k
Genkyotex SA
1.57
120,000k
Biosearch Life SA
0.49
28,900k
Genus plc
23.02
1,400,000k
Biotec Pharmacon ASA
0.76
32,900k
Global Bioenergies SA
Bioventix plc
27.9
150,000k
Biovica International AB
1.55
12,500k
36-37_EB_Autumn_2017_StockMarket_mr.indd 36
16.49
70,600k
Hansa Medical AB
22.1
770,000k
Herantis Pharma Oyj
6.51
26,800k
52 weeks indicator low high
29.09.2017 11:24:12 Uhr
Euro Biotech Stocks
European Biotechnology | Autumn Edition | Vol. 16 | 2017
COMPANY
QUOTE
M-Cap
Hofseth Biocare ASA
0.14
32,800k
Horizon Discovery Group plc
2.65
410,000k
52 weeks indicator low high
COMPANY Oxford Biomedica plc
M-Cap
0.1
310,000k
Paion AG
2.67
160,000k
2.63
66,000k
3.5
780,000k
Hvivo plc
0.87
67,700k
PCI Biotech Holding ASA
Hybrigenics SA
0.59
28,100k
Pharma Mar SA
Immunicum AB
QUOTE
1.5
38,400k
Pharming Group NV
0.65
350,000k
3.77
110,000k
Pharnext SA
8.85
95,500k
10.73
180,000k
Photocure ASA
2.54
55,500k
Immupharma plc
0.57
76,200k
Physiomics plc
0.01
800k
Index Pharm. Holding AB
0.54
34,800k
Plant Advanced Technologies SA
23.2
20,900k
Poxel SA
5.54
120,000k
Premaitha Health plc
0.09
29,100k
Probi AB
37.58
430,000k
Immunodiagnostic Systems plc Immunovia AB
Infant Bacterial Therapeutics AB
13.12
68,900k
Innate Pharma SA
10.41
600,000k
Integragen SA
2.45
16,000k
Intervacc AB
0.87
14,000k
Inventiva SA
6.9
110,000k
Isofol Medical AB
2.26
72,300k
ISR Holding AB
0.55
9,800k
Kancera AB
0.22
32,600k
Karo Pharma AB
4.25
350,000k
Kiadis Pharma BV
9.15
160,000k
13
110,000k
Promore Pharma AB
Probiodrug AG
1.73
32,900k
Proteome Sciences plc
0.04
12,000k
26.86
6,200,000k
Quantum Genomics SAS
3.14
34,500k
Relief Therapeutics Holding AG
0.01
17,000k
Reneuron Group plc
0.02
61,000k
Qiagen NV
Kuros Biosciences AG
11.2
88,400k
Salvarx Group plc
0.34
12,400k
Lysogene SA
5.27
63,800k
Santhera Pharmaceuticals AG
31.65
200,000k
Mabion Ltd
24.23
280,000k
Sareum Holdings plc
0.01
27,700k
4.76
240,000k
Scancell Holdings plc
0.14
43,300k
12.54
170,000k
MDxHealth SA Medical Prognosis Institute A/S
1.4
33,800k
12.84
290,000k
Sensorion SA
4.37
31,300k
Medivir AB
6.48
130,000k
Shield Therapeutics plc
1.78
210,000k
Medigene AG
Selvita SA
Mereo Biopharma Group plc
3.48
250,000k
Silence Therapeutics plc
2.1
150,000k
Metabolic Explorer SA
2.27
53,000k
Simris Alg AB
1.5
14,300k
Midatech Pharma plc
0.84
39,700k
Skinbiotherapeutics plc
0.13
15,100k
Molecular Partners AG
22.87
470,000k
Stallergenes Greer plc
39.6
790,000k
Molecular Medicine SpA
0.42
180,000k
Summit Therapeutics plc
Mologen AG
3.13
110,000k
Swedish Orphan Biovitrum AB
Morphosys AG
70.51
2,100,000k
Motif Bio plc
0.38
110,000k
Nanobiotix SA
18.22
NEL ASA Neol Biosolutions SA Neovacs SA
0.62
38,800k
Neuron Biopharma SA
0.27
4,400k
Neurosearch A/S
0.46
Neurovive Pharmaceutical AB
0.43
Newron Pharmaceuticals SpA
2.21
160,000k
12.67
3,500,000k
Sygnis AG
1.65
74,500k
Synairgen Research Ltd
0.12
11,100k
320,000k
Targovax ASA
1.96
100,000k
0.31
280,000k
Theradiag SA
2.52
22,100k
0.25
2,300k
3.6
130,000k
Tigenix NV
1.01
260,000k
Tissue Regenix Group plc
0.14
160,000k
11,500k
Tiziana Life Sciences plc
1.68
210,000k
21,000k
Transgene SA
3.33
190,000k 28,000k
Thrombogenics NV
13.88
220,000k
Txcell SA
1.4
Nicox SA
9.69
290,000k
Valirx plc
0.01
2,400k
Nordic Nanovector ASA
8.91
430,000k
Valneva SE
2.9
230,000k
Novozymes Biopharma DK A/S
43.69
13,300,000k
Vectura Group plc
1.13
800,000k
Noxxon Pharma NV
10.25
22,300k
Veloxis Pharmaceuticals A/S
0.13
220,000k
Nuevolution A/S
1.76
80,100k
Vernalis plc
0.18
90,200k
Oncimmune Holdings plc
1.41
72,000k
Verona Pharma plc
1.59
170,000k
Oncodesign Biotechnology SA
11.54
78,000k
Vita 34 AG
11.6
51,600k
Oncopeptides AB
6.48
260,000k
Wilex AG
3.05
45,000k
Onxeo SA
1.79
89,200k
Wilson Therapeutics AB
9.11
230,000k
Optibiotix Health plc
0.74
58,500k
Xbrane Biopharma AB
0.34
9,300k
Oryzon Genomics SA
2.05
70,500k
Xintela AB
12.23
380,000k
OSE Pharma SA
3.49
49,600k
Zealand Pharmaceuticals A/S
15.66
480,000k
Oxford Biodynamics plc
1.84
160,000k
36-37_EB_Autumn_2017_StockMarket_mr.indd 37
37
52 weeks indicator low high
All quotes are listed in euro. All data is provided without guarantee. The effective date is 25 September 2017. These dedicated biotech companies are listed on European stock markets.
28.09.2017 11:37:07 Uhr
38
ADVERTORIAL
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Exciting. Innovative. Berlin. A fast-growing ecosystem Berlin is no longer well-known only for its amazing cultural landscape and clubbing locations. Today, the German capital is one of the top three European tech start-up cities. This is a major attraction for investors, big pharma companies, and high-class researchers from all over the world who come to settle in the HealthCapital region Berlin-Brandenburg. During BIO-Europe in November, it offers the opportunity to dive into a fast-growing life sciences ecosystem. COSMOPOLITAN HOTSPOT
tend event for biotech and pharma executives,” Clement says, pointing out the vast opportunities the region offers for potential future collaborations.
Did you know that Berlin is one of the world’s most attractive cities when it comes to foundations and spin-outs? It is currently home to more than 500 high-tech start-ups, on a level with other European megacities such as Paris or London. “Many companies – whether small or larger, new or established – appreciate the strengths and potentials of the German capital region and have settled here in recent years,” says Carolin Clement, Head of Unit Biotech and Pharma at Berlin Partner for Business and Technology, which helps companies to locate in the region. It is not only for this reason that this year’s BIOEurope takes place in Berlin. “We are happy to be the host for this must-at-
Every 20 hours a new digital start-up is founded in Berlin. But what makes Berlin so special? Quite definitely, its very own expertise in different high-tech sectors. On the one hand, there is a fast-growing IT community, which has seen a 64% growth in revenue since 2010. One in eight employees in the city is already involved in a digital business. On the other hand,
Berlin and its greater area has around 240 biotechnology companies with approximately 5,000 employees. With their strong focus on exciting biomedical topics, such as cardiovascular and metabolic diseases, immunotherapy and oncology, stem cell research, 3D printing and tissue engineering, they profit from the region‘s excellent infrastructure. Whether it’s the internationally renowned Charité clinic, the newly established Berlin Institute of Health, or the high-class institutes of the Max Planck Society and Helmholtz Association, to name but a few, Berlin is a top address for attracting the best talents in genome and proteome research, regener-
HealthCapital Berlin-Brandenburg in Numbers
360,000
in revenues in the health sector
employees in the health sector
about 3,000 clinical studies per year
Hennigsdorf Technology Center
›130 clinics with more than 35,000 beds
Companies in the Life Sciences sector 300
570
240
biotech pharma medtech
40+ university and non-
university research institutes in the life sciences section
30 Source: HealthCapital Berlin Brandenburg
38-39_EB_Autumn_2017_Advertorial_BerlinPartner_sw.indd 38
Campus Berlin-Buch
Berlin Biotech Park Innovation Park Wuhlheide Berlin Go:in Golm Innovation Center Adlershof Biotech Campus Potsdam Biotech Park Luckenwalde
8 Technology Parks in Berlin-Brandenburg
Pictures: Bart_Lo/fotolia.com (map)
€23bn
28.09.2017 11:37:43 Uhr
European Biotechnology | Autumn Edition | Vol. 16 | 2017
ative medicine, RNA technologies, gene therapy, glyco-engineering technology and digital health. In the past, this expertise has laid the groundwork for companies such as immunotherapy pioneer MOLOGEN AG. CEO Mariola Söhngen says, “The company has resided in Berlin since it was founded as a spin-off from the Free University. We value the excellent clinical and research landscape, and benefit from the network of research institutions and industry experts.” More recently established startups, such as Captain T-Cell or OMEICOS Therapeutics, which were both spun out by scientists of the Max Delbrück Center in Berlin-Buch, also welcome the innovative spirit found in the German capital. According to Karen Uhlmann, co-founder and Director Legal Corporate & Operations of OMEICOS, “The cardiovascular expertise is extremely strong in the region. This is substantially supportive to further develop our drug candidates, but also to find the right manpower for future growth.”
others, the SPARK initiative at BIH. This accelerator programme offers BIH-related scientists professional mentoring to start spin-off activities. In addi-
“Our Berlin Healthcare Lab has become the model for our globally connected Healthcare Hubs.” Peter Albiez, Chairmen of the Board, Pfizer Germany
tion, the BIH is also strongly focused on building the next generation of digital health experts with the BIH Digital Health Center.
Mariola Söhngen, CEO MOLOGEN AG
In addition to being a hot spot for startups and SMEs, Berlin has a venerable tradition of pharma drug development dating back to the 19th century. Today, its proximity to the health care system decision-makers in the German government and other European countries makes it a valuable location for several global players, such as Bayer, Pfizer, Sanofi, Takeda, Berlin-Chemie (as part of the Menarini group), and more than 20 medium-sized companies, offering jobs for a total of 10,000 employees.
Founded in 2013, the company is focusing on first-in-class small molecules based on omega-3 fatty acid analogs for the treatment of atrial fibrillation. First clinical trials with healthy volunteers started in February 2017. This year, OMEICOS also closed a Series B financing of more than €8m led by Vesalius Biocapital, along with SMS Company Group, KFW Group, VC Fund Technology Berlin and the High-Tech Founder’s Fund. “Due to the dense network of private and public seed investors as well as VC financiers, the Berlin area is a well-positioned environment for life science companies,” says Uhlmann, emphasizing in particular the supportive role of the local bank Investitionsbank Berlin (IBB) in the early phase of its foundation. Seed investors in Berlin are accompanied by, among
For big pharma in particular, Berlin has developed as a place to scout for ground-breaking new technologies. One example is the Berlin Research Lab (BRL) of US company Pfizer, supporting biotech innovation and diversity by bringing together companies and researchers from different areas of expertise. Another Pfizer initiative, the Berlin Healthcare Lab, was started to develop digital healthcare solutions. “We are delighted that this lab has become the model for our globally connected Healthcare Hubs,” says Peter Albiez, chairman of the board at Pfizer Germany, stressing that their main focus is on cooperating with local startups. Others, such as French pharma Sanofi, are convinced that their sales and marketing offices, with more than 1,000 employees within walking distance of the famous Berlin Philharmon-
“We value the excellent clinical and research landscape.”
38-39_EB_Autumn_2017_Advertorial_BerlinPartner_sw.indd 39
Advertorial
39
BIO-Europe When? November 6-7, 2017 Where? CityCube, Berlin, Germany What to expect? 3,600+ attendees; 4,700+ licensing opportunities; 150+ company presentations www.ebdgroup.com
ic, are in an excellent strategic position to boost distribution and market presence for Sanofi. “The business enterprise sector taking root here is simply overwhelming,” says Clement Kaiser, CEO of the German subsidary of Sanofi. Japanese pharma company Takeda aims at positioning its production site in Brandenburg as the centre of a global network for the distribution of Takeda’s medicinal products. Since 2014, it has invested around EUR100m in a new production module, scheduled to open at the end of 2017. The Berlin-Brandenburg area also offers plenty of opportunities for companies to complement their own expertise. Over 40 companies and scientific institutions are locally organized in the Network for Pharma Solutions (Net PhaSol), bringing together a portfolio of services in the field of drug development.“NetPhaSol is the perfect platform for us to meet new cooperation partners and to establish new products and ser vices,” says Melanie Herse-Näther from InnoRa GmbH, who acts as drug development service provider. Further information Carolin Clement, Berlin Partner for Business and Technology carolin.clement@berlin-partner.de www.healthcapital.de
28.09.2017 11:37:50 Uhr
40
Neurodegener ation
European Biotechnology | Autumn Edition | Vol. 16 | 2017
The hunt for a cure to Huntington’s control over body, mind and personality. It inevitably kills the patient, but usually only after at least a decade of suffering. The underlying cause of Huntington’s disease – a dominant mutation on Chromosome IV – was discovered almost 25 years ago. Now the first trials to target the condition at its source have begun. Chances of finding a cure have never been more realistic.
40-45_EB_Autumn_2017_Huntington_sk.indd 40
Picture: visualspace /istockphoto.com
Genetic Diseases It’s a disease that often strikes people in the prime of life, slowly destroying
29.09.2017 11:25:29 Uhr
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Picture: K. Lindenberg, University clinic Ulm (left); University clinic Ulm (right)
W
hen Hans Meier knocks over a shelf for the second time in a row in just a few minutes, a colleague jests that he must have had too much to drink the night before. The 46-year-old German engineer tries to smile back, but decides not to reply. He doesn’t reveal what he has known for years – to be precise, since the morning of September 24, 2001. Meier had long suspected something was seriously wrong, but that was the day it was confirmed by the results of a genetic test. From that moment on, Meier knew with certainty that one day, things would begin to fall apart in earnest. That a leg would collapse beneath him, that an arm would begin to tick uncontrollably, that once familiar names would begin to escape him as his brain declined into dementia. He knew that years of long decay would follow. Years where he would slowly, but with cruel certainty, lose control over all of his physical and mental capacities. He knew that within 15 to 20 years of unstoppable and squalid decay, his disease would kill him. That fate is one all patients with the inherited neurodegenerative disorder Huntington’s disease (HD) continue to face – even though the underlying genetic mutation that causes it was uncovered back in 1993. Over a quarter of a century later, trials involving HD patients in the US and Europe are finally raising hopes the disease could be stopped, and that a cure might indeed be possible one day in the not all-too-distant future. Early descriptions of the disease date back to the Middle Ages. The characteristic, uncontrollable movements sufferers often display lead to the name ‘chorea’, derived from the Greek word for ‘dance’. The discovery of what causes HD was one of the earliest successes in the then young research field of molecular genetics. And it was the personal success story of Nancy Wexler. HD had affected several members of Wexler’s immediate family, and desperate to find the cause, the neuropsychologist from Columbia University eventually pinpointed its source: a defective gene located on
40-45_EB_Autumn_2017_Huntington_sk.indd 41
chromosome IV. The so-called huntingtin gene (HTT) has an unusual section made up of repeats of three of the four building blocks of DNA, abbreviated A, C, T, and G. In the gene, the number of repeating CAG sequences is slightly different in every individual. But in HD patients, this number hits a critical threshold of 35 repeats or higher. If a person has 36 or more CAGs in a row, the protein that is transcribed and translated from the gene turns toxic. It accumulates in the brain’s nerve cells over decades, and eventually kills the carrier.
A cure around the corner? Wexler’s discovery made international headlines at the time. Suspected sufferers were soon able to check their genetic status, and find out whether they had inherited the mutation or not. But although the discoverer herself watched her mother die from the disease, she wasn’t keen to know about her own fate – one she couldn’t change. Without a therapeutic option, the scientist and many others have decided not to have
Bernhard Landwehrmeyer University Clinic Ulm
?
After the antisense drug is administered, how long does it take to see any effects?
!
We know from animal experiments that the antisense molecules need about four to six weeks to have an impact on disease symptoms, and that it lasts for about four months.
Neurodegeneration
41
the genetic test. “After finding the gene, I was totally disappointed that it took so long to actually do anything about it,” Wexler says today. She has since developed symptoms typical of HD. For those who are only beginning to experience the onset of the disease, there is now a ray of hope. For the first time ever, a drug is being tested in HD that doesn’t treat only symptoms, but targets the underlying cause of the disease by attempting to disrupt the production of the toxic huntingtin protein. In mice and monkeys it proved able to capture the transcript copy (mRNA) of the gene and block its translation. Since August 2015, 46 patients in Canada, Britain and Germany have been treated with an ‘antisense oligonucleotide’ (ASO) developed by Californian biotech company Ionis Pharmaceuticals (formerly Isis). Hans Meier is happy to be one of the guinea pigs. In August 2015, he received a call from his physician Patrick Weydt in the southern German city of Ulm – the centre of Europe’s Huntington’s network. About a third of the continent’s approximately 30,000 HD patients are registered and treated here. The neurologist, who now works at Bonn University Hospital, suggested that Meier take part in a Phase I trial with the Ionis test compound, and the engineer didn’t hesitate. Although he was still able to drive and communicate freely, and was in good physical condition, the signs of dawning HD were unmistakeable. He was still easily climbing the stairs to his apartment, although a bit stiff. But his arms stubbornly refused to remain at rest for more than a few seconds. And the urge to change his position when seated had grown very frequent.
Huntington’s – a family matter Although Meier’s mother also had the disease, it remained undiagnosed until shortly before her death. “She joined a sect, and we didn’t know whether the strangeness we observed in her behaviour was caused by that relationship or the symptoms of a disease.” She regularly forgot that her son was married, for example, or confused the past with
29.09.2017 11:25:36 Uhr
Neurodegener ation
the present. In 1998 she was finally diagnosed with Huntington’s. In 1999, she choked to death in a nursing home – a common complication for sufferers of HD as the swallowing reflex fades away. After that, it took her son two years to screw up enough courage to take the test. “Everyone forgets something occasionally, or gets a little confused. But after my mother’s diagnosis, I was always asking myself whether it was the first sign of HD,” Meier says. When the doctor at the Ulm clinic told him that he had indeed inherited the genetic predisposition for the condition, “it felt like someone had hit me in the face with a hammer.” At that point, physicians couldn’t provide even a glimmer of hope to patients like Meier, even though theoretical approaches for blocking HD transcripts have been knocking around ever since the gene was discovered. And there’s a good reason why they’ve remained theoretical: the exact function of HTT in humans remains a mystery. Research has shown that it’s crucial for early development, because mouse embryos deprived of the gene die quickly. However, more recent work indicates it might not play an absolutely critical role in metabolism in adult animals. Another reason it’s taken decades to reach this point is that longterm studies in mice and monkeys had to be as thorough as possible before
European Biotechnology | Autumn Edition | Vol. 16 | 2017
AAV-Vektor
anyone was willing to take responsibility for a first test of Ionis’ AOS compound (HTT-Rx) in humans.
Safety before efficacy A big hurdle for scientists has been a lack of technology able to differentiate between the two copies of HTT – the normal copy from one parent and the mutant copy from the other. “Both healthy and mutant RNA have CAG repeats,” says Weydt. It took scientists a long time to prove that targeting both wouldn’t harm a patient. What was important was to ensure that enough normal huntingtin protein remained in the cells. “The drug isn’t able to reduce
Prevalence of Huntington’s disease (HD) around the world
Population
Prevalence of HD (cases per 100,000 people)
› South Africa (black population)
0.06
› Japan
0.10–0.40
› Hong Kong
0.37
› Finland
0.60
› Europe and countries of European descent
4.00–10.00
› Northern Ireland
6.40
› South Wales (UK)
7.61
› Scotland (Grampian region)
9.94
› United States
10.00
› Tasmania
17.40
› Mauritius
46.00
› Venezuela (Lake Maracaibo region)
700.00
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amounts of huntingtin transcripts – either normal or mutant – below 50%,” says Weydt. Animal testing appears to show that it’s important to leave enough normal huntingtin protein, while at the same time inhibiting enough toxic huntingtin protein to show a therapeutic effect. So far, so good. But every therapy comes with a downside. The Ulm trial‘s principal investigator Bernhard Land wehrmeyer explains that the downside in this case is that an antisense approach is based on RNA molecules that need to be tinkered with chemically to survive the attack of enzymes whose job it is to break down nucleic acids. “This means that for the body, the drug is a foreign entity,” he says. “And we can’t rule out that the immune system will jump on and reject such molecules, even though we didn’t observe such a reaction in animals.” That concern is certainly a valid one, as the potential drug would have to be administered every few weeks – probably lifelong. The primary goal of the Ionis Phase I trial, Landwehrmeyer stresses, is therefore not to prove efficacy, but to determine the safety of the compound. Regular MRI checks are mandatory in order to detect any signs of inflammatory response to antisense molecules.
More patients enrolled than originally planned “Could you please stop wriggling,” a physician shouts at Meier through a micro phone. It’s the patient’s second hour in a row in an MRI. “If I could stop wriggling, I wouldn’t be here,” Meier shouts back. This morning he received a first injection via a spinal infusion. Now the engineer needs to lie on his side and arch his back before being given a local anaesthesic and a spinal tap. After that, he’ll have to remain still for another hour as cerebrospinal fluid slowly trickles out. “And I’m not allowed to move the entire time,” Meier grumbles. The injection tops up the volume of lost cerebro spinal fluid. Afterwards, Meier has to walk around the clinic. The movement
Picture: Voyager Therapeutics
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28.09.2017 11:39:10 Uhr
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06.09.17 13:43 27.09.2017 13:45:19 Uhr
Neurodegener ation
Lisa Stanek Senior Principal Scientist at Sanofi-Genzyme in Framingham, Massachusetts, USA
?
HD patients have a normal and a mutant Huntington gene variant. Is your RNAi-approach able to target just the mutant allele?
!
None of the strategies are allelespecific so far. The complication with allele-specificity is that the wild-type gene and mutant gene only differ by a couple of CAG repeats. They look very similar. So targeting the mutant versus the wild type is very, very challenging. Science might be able to do that eventually. But we have shown – and some other groups too – that partial suppression of the wild-type allele is safe. You can reduce wild-type Huntington’s by 50% for months and years, and there are no adverse events in mice or monkeys.
? !
Once approved, what would an HD cure like this cost?
I spend my days as a scientist trying to find cures. I have no say in the pricing of this therapeutic, obviously, although I find the whole ethical question of the pricing of gene therapies very interesting. If patients are cured after one treatment, then this will probably be an expensive therapeutic. But I hope that it will be available for every HD patient, because I see HD patients every day. And if you have ever seen the disease…it’s devastating.
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and diffusion should spread the injected fluid to his brain. A smoker, he’s allowed the occasional cigarette. During breaks from walking, Meier is required to perform many different types of tests: walking on tiptoe, walking on his heels, touching his nose, or answering endless questions on a number of forms. During other hourly breaks, the doctors take blood samples. “It’s excruciatingly boring,” Meier comments. But he’s willing to endure it, even though he knows he might be in the control group, and receiving only a placebo. Or that even if he is being given the drug, it might not help. “I’m doing this for my kids,” the father of two says. He’s less worried about his own fate than theirs. It took him years to tell them what he discovered that day in 2001. Back then his children were 9 and 10. First he told himself that they were too young to understand. Then he decided to wait until they were 18. Then he wanted to let them finish studying first. Then he wanted them to enjoy just one more year of not knowing. Finally, his daughter called him while he was on a business trip in China to tell him she was pregnant. Instead of joy or pride, Meier felt a wave of panic, desperation and guilty grief. Why hadn’t he told her sooner about the family burden – the inherited mutation for HD that she might carry? The chances were 50%. Although terrified of their reaction, he finally broke the news that he had Huntington’s, and that the first symptoms had arrived. Now his children also have to live with the uncertainty, and the question of whether they should take a genetic test that could confirm a terrible future. A cure – or even just a promising drug – could help ease the decision, simply by providing hope. The public won’t find out whether Ionis’ compound might be that drug before the end of 2017, and probably later. One sign of a possibly promising outcome is that the study has in the meantime enrolled more than the 36 patients originally planned. After the third of five infusions, Meier reports that his symptoms are fading. “And oth-
er than a light headache, I’ve suffered no side effects.”
Barriers to treatment “The outcome regarding a recovery from or even reversion of HD symptoms depends on the areas of the brain the drug reaches – whether the brainstem, the cortex or the spinal cord,” Landwehrmeyer says. It’s still unclear whether there’s been sufficient penetration to the basal ganglia in the striatum, the brain component most affected by HD. Chances of improvement appear better when symptoms are less acute. And having enough nerve cells seems to be a prerequisite for the brain to recover and regenerate. “At least in HD mice treated with the antisense molecules, the symptoms cease on a behavioural, as well as a pathological level.” But the drug doesn’t work like aspirin. “Animal testing shows the antisense molecules take about 4-6 weeks to have an impact on disease symptoms,” Landwehrmeyer says. The effect lasts about four months. And fresh ASO has to be infused around every four weeks.
An RNAi solution? Disadvantages inherent in ASO treatment could be overcome by a next generation of therapeutic concepts for HD. One drug that’s already in the pipeline is applied directly to the brain in a single dose. It was developed by Lisa Stanek, a former Harvard University scientist and the principle investigator at Sanofi Genzyme’s labs in Massachussetts. The company’s HD program grew out of a former collaboration with Ionis. The proof-of-concept, which with Ionis’ anti sense molecules lowered huntingtin and essentially cured mice from HD, has since led to the development of a genetherapy-based approach. Using adeno associated viruses (AAV) as a transport vehicle, Stanek managed to deliver a message to the brain’s nerve cells that in effect instructed them to specifically destroy huntingtin gene transcripts. The message is encoded in an RNAi molecule – a single-stranded nucleic acid with
Picture: Sanofi-Genzyme
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out any adverse events, Stanek expects the US Food and Drug Administration to take an extremely cautious approach. “The FDA is going to put this under a microscope, because this is not a drug you can discontinue if patients do poorly. Once we put it there, the drug will be in their brains forever.” In terms of regulatory hurdles, Ionis’ ASO therapy is easier to develop, because if complications arise, the clinic could just stop infusions.
Trials – not too early, not too late
Picture: P/Weydt/Uniklinik Bonn
MRI of a patient with the first signs of HD. Nerve cell density has decreased.
a sequence that fits huntingtin transcripts. This activates the cell’s transcript shredder – the RNA interference mechanism. It’s able to sort one specific transcript out of a million and destroy it, while leaving all other transcripts untouched. “It can do the same thing as the Ionis drug,” says Stanek. “However, we use gene therapy to deliver it, meaning that we get essentially lifelong suppression of the huntingtin gene with just one dose.” Stanek says Sanofi-Genzyme is developing the AAV/RNAi-based approach together with Boston-based biotech company Voyager. “We’ll file an IND next year, and hope to be in the clinic with it shortly after.” She has faith in her HD gene therapy approach because of her preclinical work with mice and monkeys. “Our HD mouse model recapitulates most of the features of the human disease,” Stanek says. The mice carry the entire human huntingtin gene with 128 CAG repeats. “That’s a lot, because we can’t wait around for years for these mice to get sick,” says Stanek. “We have to really push them to exhibit these disease phenotypes.” With 128 CAG repeats, the mice begin developing motor deficits at just three months. Nevertheless, says the scientist, the therapy cleared the animals of HD symp-
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toms. “But the mouse brain is a thousand times smaller than a human brain. The scale-up problem is enormous.” No injection in a single spot could reach all of the cells in the human brain. “That’s still science fiction at this point,” Stanek says. Luckily, it might not be necessary to treat the entire brain, as HD specifically affects two areas: the striatum and the cortex. And Stanek’s experiments in monkeys show that she can target those regions with current AAV vectors. “So we hope that when we scale-up to human patients, we can achieve the distribution necessary to translate that into a clinical benefit.” Although AAV is known to be a safe vector, and has already been in brains of Parkinson’s patients for seven years with-
Stanek says if Genzyme’s AAV-RNAi trials go ahead, HD patients with earlystage symptoms will be eligible to take part. Although the drug should theoretically also help prevent the outbreak of HD in pre-symptomatic patients, it would be unethical to give them an experimental drug that could fail and harm them while they’re still healthy. On the other hand, “late-stage symptomatic HD patients won’t be eligible for this procedure (either), because their brains are already extremely deteriorated,” Stanek says. Hans Meier is meanwhile eagerly awaiting the results of the Ionis trial. If the evaluation is positive, he’ll have the chance to continue the ASO therapy. Could it possibly stop his disease, or help his battered brain recover? Can he avoid his mother’s fate? Hope springs eternal, even though he’s already planned for the worst. “Doctor Weydt will get my body, so science can learn as much as possible,” Meier says. “After that, they’ll burn me. Everything’s going to be fine.” L s.karberg@biocom.eu
Effect of cytosine, adenine and guanine (CAG) repeats on Huntingtons’s disease presentation
Number of CAG repeats
Presentation of HD
› 9–29
Number of CAG repeats expected to be found in the unaffected population
› 29–34
Individual will not present with symptoms of HD but in very rare cases there is the chance that the gene will expand (genetic anticipation) and future children may develop HD
› 35–39
Some but not all individuals will develop HD; next generation is at risk
› 36–40
HD will develop but often at an older age
› 40 and above
HD will develop at some date in the individual
› 50 and above
HD will develop in childhood or adolescence – juvenile HD
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Genmab reserves the front line
Vaccines Six years after starting the Phase III development for the prostate cancer vaccine Prostvac, an independent monitoring committee recommended the discontinuation of the study. This downer sent Bavarian Nordic A/S’s shares cellarwards in mid-September, cutting the Danish company’s market capitalisation in half. In a 2015 deal, US pharma company Bristol-Myers Squibb licensed Prostvac for an upfront payment of US$80m. Arranged milestone payments of up to US$1bn can be written off almost completely. Despite widespread scepticism in Bavarian’s cancer vaccine technology, their CEO, Paul Chaplin, remains a “steadfast believer” in combining it successfully with other immuno-oncology agents. Back in July, Bavarian had a reason to shine when Johnson & Johnson (J&J) entered a new deal with the Danish biotech worth up to US$879m to develop vaccine regimens. The stock price had reached a multi-year pinnacle at around DKK417. The agreement – signed with J&J’s unit Janssen Pharmaceuticals Inc. – grants the US healthcare group the worldwide exclusive rights to Bavarian’s MVA-BN technology for vaccine programmes targeting hepatitis B and HIV-1. The upfront payment was US$10m (€8.5m) and as part of the package, Johnson & Johnson Innovation JJDC, Inc. subscribed to DKK207.5m (€28m) worth of Bavarian shares. The two companies are already collaborating on vaccines for Human Papillomavirus (since 12/15) and Ebola (since 10/14) employing technologies from both companies. L
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discuss with health authorities the potential for a regulatory submission for newly diagnosed multiple myeloma patients who are not considered candidates for autologous stem cell transplantation. Following the late August news, shares in Genmab jumped 11% in afternoon trading in Copenhagen, as a first-line indication should yield a rise in royalties. The anti-CD38 monoclonal antibody was already hailed as “unprecedented” and “a singular breakthrough in the treatment of myeloma” last year. And that was after being approved as only a second line therapy. Genmab and Janssen teamed up in 2012 in a deal with a total potential value in excess of US$1.1bn. L
Life-saving enzyme convinces Transplantation Hansa Medical AB presented data showing its experimental drug allowed doctors to perform successful kidney transplants in patients with a particularly high risk of organ rejection. The data was published in early August (doi: 10.1056/NEJMoa1612567). Researchers demonstrated that treatment with IdeS, an IgG degrading enzyme of Streptococcus pyogenes, is effective in reducing donor specific antibodies to levels allowing life-saving kidney transplants in highly
sensitised patients. The article addresses three independent clinical Phase II studies with Hansa Medical’s lead candidate. The studies, performed in Sweden and the US, included 25 HLA-sensitised patients who received IdeS immediately before kidney transplantation. All HLA-antibodies were eliminated in all patients after IdeS treatment prior to surgery. Of the 25 treated and transplanted patients, 24 patients had good kidney function at study completion, six months following transplantation. L
IdeS is currently being evaluated in a multi-center study (“Highdes”) in the US, France, and Sweden. Results from this study are expected in 2018.
Picture: Hansa Medical
Hard landing
Myeloma Danish Genmab A/S’ antiCD38 antibody daratumumab (Darzalex) has met the endpoint of progression-free survival in an interim analysis of a pivotal Phase III study aimed at receiving FDA approval as first-line therapy in multiple myeloma. According to the Danish company and licensee Janssen Biotech, Inc./Johnson & Johnson, the Alcyone study of daratumumab in combination with bortezomib, melphalan, and prednisone (VMP) in front line multiple myeloma met the primary endpoint at a pre-planned interim analysis vs VPM alone. The study improved progression-free survival (PFS). Treatment with daratumumab reduced the risk of disease progression or death by 50%. Janssen will
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Äänekoski pulp mill operates
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News Chinese licensee at hand
Metsä estimates that the new factory creates more than 2,500 jobs in Finland. B i o e c o n o my Finnish M e t s ä Group called it a “historical day“ when, in mid-August, it ran up “the world’s first next-generation bioproduct mill.“ The construction started in May 2015 and progressed on schedule and according to the planned budget of €1.2bn. The bioproduct mill in Äänekoski is the largest wood processing plant in the Northern Hemisphere, Metsä states. Pulp deliveries from the new mill to customers began in early September 2017. The bioproduct mill will achieve its nominal capacity approximately a year after start-up. Then, the mill will produce 1.3 million tonnes of softwood pulp per year. The main products are high-quality pulps to be used as raw materials for paper, tissue paper and paperboard. Other products, such as tall oil and turpentine,
are processed as well. Hence, the mill is utilising 100% of its wood raw material as well as production side streams. New bioproducts that already complement the product concept include gas from bark, sulphuric acid from the mill’s odorous gases, and biogas and biofuel pellets from the sludge. Several other processes and product paths are being actively studied. The most important new bioproduct development projects are lignin-based products, textile fibres, and biocomposites. The mill will not use any fossil fuels at all, since it will generate all of the energy that it needs from side streams. The mill’s degree of selfsufficiency in electricity is 240%. That said, the factory is increasing the share of renewable energy in Finland by more than two percentage points. L
Picture: Metsä Group
LEO on the hunt Hot finntech Discovery In a renewed and extended multi-year collaboration with LEO Pharma A/S, Chinese Hitgen Ltd. is poised to discover novel small molecule leads for multiple therapeutic targets chosen by the Danish dermatology specialist. Hitgen of Chengdu will employ its large DNA-encoded library of novel leads, a library that provided Hitgen several discovery partnerships with big pharma, including Janssen, Merck, and Pfizer. The terms of the agreement include an upfront payment by LEO and possibly milestone payments.
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Diabetes Researchers at the University of Tampere have developed a vaccine that could prevent type 1 diabetes. It is designed to provide immunity against coxsackievirus B1, a virus that has been found to trigger the body’s defences into attacking itself. In July, the Finnish start-up Vactech Oy out-licensed the lead asset to Provention Bio, Inc. Now, the US company, backed by MDB Capital Group and Johnson & Johnson Innovation, will forward the vaccine into clinical phase.
Medivir AB has exclusively licenced clinical development, manufacturing, and commercialisation rights for the Greater China region of its preclinical candidate drug MIV-802 to Chinese drug developer Ascletis Bioscience Co. Ltd. Preclinical data indicate that the nucleotide-based NS5B polymerase inhibitor can be used effectively in combination with other classes of antiviral agents for the treatment of hepatitis C virus infections.
Zealand in New York Danish diabetes biotech Zealand Pharma A/S successfully pulled off its initial public offering in the US at Nasdaq Global Select Market. It raised US$91m at US$17.87 per share to fund clinical trials. The company has traded on the Nasdaq Copenhagen under the symbol ZEAL since 2010. Several analyst houses picked up coverage, including Guggenheim, which issued a “buy” rating and a US$28.00 price objective on the stock.
Meeting the challenge Cancer therapy play PCI Biotech Holding ASA announced in September that the first immune response results from a fimaVACC phase I study indicate enhanced overall T-cell responses at tolerable dose levels. FimaVACC is one out of three ways PCI uses to unlock the potential of its photochemical internalisation (PCI) technology. CEO Per Walday said: “Improving immunogenicity of vaccine candidates is a priority in immunotherapy. We believe that the fimaVACC technology may play an important part in solving this challenge.”
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Rich and famous
Brexit Britain’s biggest drug makers, GlaxoSmithKline (GSK) and AstraZeneca (AZ), will pursue different strategies to solve regulatory problems arising from the UK’s Brexit. GSK’s new CEO Emma Walmsle said the company will scale back its presence in the UK, ditch plans for a new production plant in Cumbria, and outsource manufacturing. Inspections of manufacturing sites and approval of new drugs for marketing across Europe are expected to become regulatory challenges for non-EU members after the UK’s EU demission. In September, AZ surprised investors. Following warnings from CEO Pascal Soriot that any UK investment will be put on hold, AZ confirmed a huge investment to ramp up packaging at its biggest manufacturing site in Macclesfield. Some days later, the British government announced it will invest £140m for the creation of four new centres of excellence for drug manufacturing as proposed by the the Medicines Manufacturing Industry Partnership (MMIP). According to Andy Evans, the MMIP chair who heads AZ’s Macclesfield plant, “the UK needs to improve when it comes to manufacturing and packaging.” Specifically, the government announced a £13m funding competition for a medicines manufacturing centre, a £66m investment in a vaccines development and manufacturing centre, a £30m investment in cell and gene therapy centres, a £12m cell and gene therapy investment and £25m to support SMEs and boost innovation. L
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ceive milestone payments of up to €2.4bn plus low double digit royalties on the net sales of every product that reaches the market. Sanofi will be responsible for the development, manufacturing, and commercialisation of the products resulting from the collaboration. Six of Sanofi’s eight clinicical programmes in immune-mediated inflammatory diseases are monoclonal antibody drugs, but only one, SAR156597, is a bispecific antibody. With the deal, Sanofi complements its capacity for multi-targeting, a current hype in lucrative fields such as autoimmunity and cancer. L
Uniqure home alone Gene Therapy Dutch gene therapy specialist uniqure NV (Amsterdam) lost its commercialisation partner Chiesi Farmaceutici in August. Following the commercial end of the Dutch company’s pioneering gene therapy, Glybera, used to treat lipoprotein lipase deficiency (see European Biotechnology, Summer 2017), the Italian drug maker also quit the remaining part of the R&D pact, inked in 2013: uniqure’s hemophilia B factor IX gene therapy AMT-060. Prior to the announcement, which uniqure’s CEO, Matthew Kapusta whitewashed as reacquisition of development and commercialisation rights, the company’s US competitior Spark Therapeutics tabled Phase I/II results of SPK-9001 on 10 patients outperforming those of an ongoing Phase I/II study on AMT-60. While the Dutch company reported a reduction of the annualised spontaneous bleed rate of 84%, Spark reported a 96% drop. Investors seem to be convinced by Spark’s offer. Besides SPK-9001, the company also has gene therapies for hemophilia A (Phase I/ IIa) and retinal diseases (one in Phase I/ IIa another in US registration phase) in its pipeline. In August, the US company closed a US-$380m IPO at Nasdaq.
Under the 2013 collaboration, uniqure shared R&D cost for both programmes with Chiesi, which additionally acquired a €31m equity stake in the successor company of the bankrupt Amsterdam Molecular Therapies (AMT) as part of the deal. Uniqure claimed the end of the alliance was motivated by a change in its strategic priorities and that the transaction will not impact its previous cash guidance. According to financial guidance published in August 2017, the company had US$104.1m in the bank compared with $132.5m as of December 31, 2016. Uniqure said it is financed into 2019. L
Picture: ktsdesign/Fotolia.com
Money boost
Autoimmune diseases Ablynx B.V. (Ghent) has granted French pharma major Sanofi the rights to eight single-chain nanobodies used in the field of immune-mediated inflammatory diseases. The companies did not publish the targeted indications. However, they announced that Sanofi gained exclusive global rights to multi-specific nanobodies, that is antibody fragments targeting multiple antigens, which is expected to increase specificity and potency. Under the deal, Ablynx will sack an upfront payment of €23m and receive initial research funds of up to €8m. Furthermore, Ablynx will be eligible to re-
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News Lift the pressure
Payday from the pharma major cancer Merck Ventures joined the Series A investor syndicate of the British immuno-oncology specialist Macrophage Pharma Ltd at the end of August. The investment arm of pharma major Merck & Co/MSD extended the £9m (€9.8m) Series A investment made by CRT Pioneer Fund, Novo Holdings A/S, and Aglaia Biomedical Ventures BV in January “with an equal size of investment,” according to Macrophage. The company will use the proceeds to initiate Phase I clinical trials of its lead candidate, p38MAPi, a macrophage-targeted p38MAP kinase inhibitor, in 2018, and the development of two further macrophage modulators of the tumour microenvironment, currently in discovery stage.
Macrophage Pharma’s pipeline is based on the acquisition of several drug candidates and a technology license from Chroma Therapeutics Ltd (Oxford, UK), developer of the Esterase Sensitive Motif (ESM) platform. ESM chemically adds specific molecules to active drugs as a means of transporting them into macrophages or monocytes. Following internalisation, the pro-drug is cleaved by cell-specific esterases accumulating the active substance intracellulary, which results in increased potency and half-life. ESM technology is suitable both to modify the tumour microenvironment to reactivate T-cell response, and to use macrophages with high affinity to tumour receptors as drug carriers. L
Picture: fotolia.com/scyrus
Immune blast to cancer Brexit Belgian Oncurious NV acquired an exclusive licence from VIB to commercialise five immuno-oncology assets, which were discovered in the labs of tumour-associated macrophage (TAM) experts Jo Van Ginderachter and Massimiliano Mazzone, as well as paediatric brain cancer specialist Gabriele Bergers. The unnamed modifiers of the tumour micro environment and of tumour infiltration boosted immune responses in cancer cell culture
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and tumour models (C ell M etab, doi: 10.1016/j.cmet.2016.09.008, Cell R ep, doi: 10.1016/j.celrep.2017.07.054, PCT/ EP2013/055427) and paediatric brain cancer (Sci Transl Med, doi: 10.1126/scitranslmed.aak9679). Under the agreement, VIB Discovery Sciences will conduct preclinical development with the option to receive royalties on future sales. VIB increased its stake in Oncurious as main shareholder ThromboGenics NV did (adding €2.1m). L
An analog of the approved diabetes drug exenatide, a GLP-1 agonist, can combat intracranial pressure, reported a team of researchers at the Universities of Birmingham and Copenhagen at the end of August (S ci Transl M ed, doi: 10.1126/ scitranslmed.aan0972). For now, the repurposed drug proved to be effective in rat models for idiopathic intracranial hypertension and hydrocephalus. The new approach, assessed by Hannah Botfield and colleagues, may become an alternative to current invasive treatments that drain excess cerebrospinal fluid (CSF) from the cerebral ventricles. The repurposed diuretic exendin-4 brought down intracranial pressure within 10 minutes of administration, but the effects persisted for 24 hours and had cumulative effects over five days of dosing. Administration of the compound didn’t trigger changes in food, blood-pH, or water intake, said the researchers.
Big data meets cancer Linking up gene expression profiles from the Cancer Genome Atlas with treatment outcomes, researchers headed by Mathias Uhlén at KTH in Stockholm have drafted a Human Pathology Atlas across 17 cancer indications (Sci Transl Med, doi: 10.1126/science.aan2507). The good news is that their self-learning algorithm was able to forecast how altered gene expression would influence patient survival. The bad news is that modulation of 80% of the potential targets would have severe side effects. However, 32 deregulated genes affected tumour growth in 80% of all cancers.
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AMR partnership gathers speed
DMD The European Medicines Agency’s CHMP has rejected a type II extension application to Santhera Pharmaceutical’s coenzyme Q10 analogon idebenone (Raxone) as treatment for patients with Duchenne muscular dystrophy. Raxone was approved under exceptional circumstances in September 2015 to treat visual impairment in patients with the rare eye disease LHON. Thomas Meier, CEO of Santhera, said he plans to appeal this decision and seek re-examination. Shares plunged by almost 60% following the news and recovered a bit afterwards to a level of around CHF40.
Novartis wins CAR-T Cells Swiss Novartis AG has received US market authorisation for its first-in-class CAR-T cell therapy Kymriah (tisagenlecleucel-T) to treat young patients with acute lymphoblastic leukaemia. Albeit based on IP from the University of Pennsylvania (US), the FDA approval is also a huge success for the European advanced therapies community. Besides Novartis, one of the biggest European pharma companies, Oxford Biomedica (UK) and the Fraunhofer IZI (Germany) also contributed to the Kymriah success. As severe cytokine storms seem to be generally linked to CAR-T therapies, the FDA also authorised Roche’s anti-IL-6R antibody Actemra (tocilizumab) as first-in-class treatment to manage them.
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Latest progress on AMR – www.berlin-conferences.com 02 March 2018 Fraunhofer-Forum, Berlin GARDP plans to collaborate with CARB-X, currently the largest private public partnership funded by the US government, and the Wellcome Trust to bolster preclinical antibiotics programmes. The not-for-profit organisation GARDP was founded last summer by the World Health Organisation and the Drugs for Neglected Diseases initiative (DNDi) to fight sexually-transmitted infections, neonatal sepsis, and to develop new antibiotics for adults and children who suffer from bacteria resistant to existing antibiotics. By 2023, the GARDP would need at least €270m in funding to achieve four predefined goals.
The Netherland’s Health Minister Edith Schippers said, “We know that the current business models for the development of new antibiotics do not work. We have to work on new models that result in rel-
A photomicrograph of Gram-stain technique-coloured Neisseria gonorrhoeae
evant and affordable products that are used in a responsible way. Let’s hope that others will join soon: it is time to walk the talk.” Steve Brine, the UK‘s Health Minister, added, “AMR is the biggest global health threat we face and we know infections don’t respect borders, so a united international effort is essential. The UK warmly welcomes Germany’s leadership on AMR through its G20 Presidency, and we will play an active role in supporting these and other initiatives”. Meanwhile, the GARDP had presented its first partner in July. Supporting the US company Entasis Therapeutics, the novel first-in-class oral antibiotic zoliflodacin will enter pivotal clinical trials. The compound is one of only few treatments in development to address drug-resistant gonorrhea. If zoliflodacin receives regulatory approval, Entasis will grant GARDP an exclusive license with sublicensing rights in most low- and middle-income countries, while retaining commercial rights in highincome markets. L
Picture: CDC
Santhera fights
GARDP Six European states, together with the British Wellcome Trust and South Africa, have pledged €56.5m to help develop new antibiotics that break resistance. The ambitious goal of the Global Antibiotic Research and Development Partnership (GARDP) is to develop and deliver up to four new treatments that enter clinical development within the next six years. The candidates can be either improvements on existing antibiotics or new chemical entities. “The fact is that we cannot do without antibiotics,“ said Germany’s Health Minister Hermann Gröhe during a fundraising GARDP event in Berlin in early September. “The funding made available today for the GARDP is a major step forward in the fight against the global health risk that antibiotic resistance presents.” The investment was led by Germany, which will contribute €51.35m, and is cofinanced by the governments of The Netherlands (€2m), the UK (€1.1m), Switzerland (€440,000), South Africa (€390,000), Luxembourg (€100,000), Monaco (N.A.), and the British Wellcome Trust (€1.1m).
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Mundipharma buys €212m asset News Chemotherapy German Cellact Pharma GmbH is eligible to cash in up to US$250m (€212m) from Mundipharma in a licence deal for CAP7.1, a Phase III-ready drug to treat rare biliary tract tumours. According to Cellact’s managing director Nalân Utku, the virtual biotech did not invest more than €10m for bringing the prodrug formulation of the chemotherapeutic etoposide through Phase II proof of concept, offering VC investors Peppermint VC and NRW Bank an excellent exit. CAP7.1 accumulates in tumours as the prodrug is split by esterases primarily produced in the target cells and is, thus, expected to cause fewer side effects than its established originator. Mundipharma did not specify the exact amount of the double digit upfront payment it made for the Phase III development and commercialisation rights for Cellect’s sole clinical asset. In case of market approval, Cellact will also receive double-digit royalties. Mundipharma group has its roots in the US, but CAP7.1 will be taken care of by its subsidiary Mundipharma EDO GmbH
in Basel from now on. Serial entrepreneur Utku is a physician by training. With academic roots in Boston and Berlin, Utku
In July, French-Austrian Valneva SE granted US company Emergent an exclusive worldwide license for its Zika vaccine technology (ZIKV). The deal could be worth up to €50m in milestone payments for Valneva.
AI attracts investors
Chemical structure of etoposide, the therapeutic entity within Cellact’s CAP7.1
founded Genpat77 Pharmacogenetics back in 1998, Cellact Pharma in 2007, and Nekonal Oncology in 2017 – the latter being a joint venture of British Salvarx group and Luxembourg-based Nekonal. L
Immuno-oncology deal sealed
Pictures: Rigontec (bottom), Fvasconcellos/Wikimedia Commons (top)
Cancer US pharma Merck & Co. will acquire German Rigontec GmbH, the companies announced in September. Rigontec is a pioneer in accessing the retinoic acid-inducible gene I (RIGI) pathway, an RNA sensor that is part
RGT100 is Rigontec’s first and only clinical drug candidate
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Valneva finds partner
of the innate immune system, as a novel and distinct approach in cancer immunotherapy to induce both immediate and long-term anti-tumor immunity. Rigontec’s lead candidate, oligonucleotide RGT100, is currently in Phase I/IIb development. Under the the agreement, Merck, through a subsidiary, will make an upfront cash payment of €115m to Rigontec’s shareholders. In addition, milestone payments of up to €349m loom high in the trees. Rigontec finished its series A financing round in 2016, collecting €29.25m from Boehringer Ingelheim Venture Fund, Forbion Capital Partners, High-Tech Gründerfonds, NRW Bank, MP Healthcare Venture Management, Sunstone Capital, and Wellington Partners. Being a University of Bonn spin-off, Rigontec has strong academic roots. L
Artificial intelligence (AI) specialist Sophia Genetics SA from St.Sulpice raised US$30m in a series D round to foster global expansion of its cancer diagnostics annotation platform. The funding round brings the total investment in the 150 employee start-up up to around US$60m.
Platform attracts Lilly Evotec AG’s immunology spinout Topas Therapeutics GmbH from Hamburg inked a multi-year R&D collaboration with US pharma major Eli Lilly in August. Lilly also secured the option to license any interesting candidates discovered with Topas’ nanoparticle platform. Financial details were not disclosed.
Record breaker Roivant Sciences GmbH (Basel) has cashed in a record-breaking US$1.1bn (€937m) in equity financing led by Softbank Vision Fund (Japan) and co-financed by existing investors Viking Global Investors and Dexxon Investor Group. According to the Financial Times, it is the biggest equity financing round in healthcare ever made on the globe. Active mainly in the US, Roivant moved its headquarters to Basel only last December.
28.09.2017 11:40:13 Uhr
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Advertorial
European Biotechnology | Autumn Edition | Vol. 16 | 2017
01–02 November, 2017 Berlin, Germany Sofitel Berlin, Kurfürstendamm
InterNAtional mrna health conference 2017 Hundreds of world-re-
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GREETINGS There is no doubt that each year that we, along with our colleagues from BioNTech and Moderna, host this meeting, we grow substantially closer to realising mRNA as an actual medical application. Academics and industry leaders continue to break new ground
52_EB_Autumn_2017_MRNA-Conference_tg.indd 52
With the conference entering its fifth year, we are delighted to welcome our colleagues in the field to celebrate another successful year of mRNA research and development as we bring our vision closer to realisation. Dr. Ingmar Hoerr CureVac AG CEO and co-founder
› Quick facts Information & Registration www.mrna-conference.com Keynote Adress Reinhold Messner Contact Verena Lauterbach Phone +49 (7071) 9883-1756 organization@mrna-conference.com
Pictures: Curevac AG
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ruptive medical technology may one day be the foundation for treating a range of medical conditions. Participants will have an opportunity to attend scientific presentations given by the most esteemed experts in the field, secure updates on advances in mRNA technology, and network with colleagues. Though there have been many substantial achievements in the past year, the mRNA field is at an important inflection point. Companies and researchers who have helped to establish mRNA as a potentially disruptive force in medicine now need to define the right strategies for product development and interactions within the field and with authorities. In response, the core topics of this year’s conference are proof of concept, clinical development, safety, and efficacy as these factors will be essential for establishing best practices for successful mRNA product development. L
29.09.2017 11:33:28 Uhr
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SOUTHERN EUROPE
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Tandem work
Joining forces CollaBoration In September, Italian biotech Axxam announced the start of a research collaboration with French pharma major Sanofi to optimise a number of leads targeted against different diseases. If the initial evaluation phase is successful, Sanofi has the option to enter into a subsequent licensing agreement.
Neurology The nervous system and the immune system work together, revealed a report in Nature, published inSeptember, by researchers at the Champalimaud Centre for the Unknown and Instituto de Medicina Molecular (both Lisbon) and the EFPL (Lausanne). Most neurons in the body are located in the brain and the central nervous system, and project their axons to every tissue in the organism. Nevertheless, throughout the body there is an abundant number of peripheral nervous cells. The scientists analysed innate lymphoid cells (ILCs) – specifically ILC2 – which are located at the body’s barriers, particularly the gut, to produce immune responses against invading pathogens. According to senior author Henrique Veiga-Fernandes the study bring “two big novelties.” The first
Innate lymphocytes (green) surround the gut (red). “is that neurons define the immune cells’ function. Nobody could have imagined that the nervous system coordinates, commands, and controls the immune response throughout the whole organism.” Second, he says, “it’s one of the fastest and most powerful immune reactions we have ever seen.” Comparatively, the newly discovered neuronal stimulus induces an immune response in a few minutes, while the immune response following vaccination typically takes several weeks to mount.
New funding
Get together Anniversary 3P Biopharmaceuticals celebrated its 10th anniversary by assembling 150 guests in the Pamplone Cathedral. Highlight of the event was the speech by 2005 Nobel Laureate Dr. Barry Marshall on the future possibilities offered by research on the Helicobacter pylori bacteria.
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Start-ups attract investors ASEBIO Investor Day 2017 More than 100 people attended the first ASE-
BIO Investor Day, organised by the Spanish biotech association, at the end of September in Barcelona Science Parc. Around 30 Spanish start-ups presented their businesses to Spanish, French, Swiss, and British investors. “During the last ten years, the Spanish biotech sector has significantly improved in terms of maturity and financing,” said Ion Arocena, CEO of ASEBIO (2nd from right). In terms of key economic indicators, Barcelona is a major driver of this development, said Albert Barberà from the Catalonian government (2nd from left). L
Pictures: Henrique Veiga-Fernandes (above), ASEBIO
Finance The Instituição Financeira de Desenvolvimento (IFD) and healthcare investor Vesalius Biocapital announced the creation of a new joint venture aiming to invest in Portuguese late-stage healthcare companies in September. The financial details haven’t been published yet, but it will be a 50/50 share between the two partners. Vesalius’ recent fund, VBC III, secured over €65m in a first closing in May 2017 and has a targeted size of €150m. Over the next two years, three to five companies should be supported.
28.09.2017 12:33:02 Uhr
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EASTERN EUROPE
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Oncoarendi now on clinical stage
Preclinical Reserach Selvita S.A. (WSE: SLV) and The Leukemia & Lymphoma Society (LLS) will co-fund further preclinical and clinical development of a targeted therapy to treat patients with acute myeloid leukemia (AML). Selvita has discovered and is developing SEL120, a therapy that targets the cyclin-dependent kinase 8 (CDK8) protein, which plays a critical role in gene regulation. Laboratory studies have shown the agent to be effective in certain types of AML cells. The partnership was announced in August. Under the terms of the agreement, LLS will provide up to US$3.25m in funding over four years, through its Therapy Acceleration Program (TAP), in order to help fund further SEL120 Investigational New Drug (IND)-enabling studies and a Phase I trial in AML. Selvita said it initiated IND-enabling studies for SEL120 back in June 2017. The LLS is arguably the world’s largest voluntary health agency dedicated to blood cancer. Founded in 1949 in the US, it has funded over US$1bn in blood cancer research through 4,000 grants to academic institutions and over 50 therapeutic opportunities through the TAP. Back in March 2017, the public company struck its first deal for a proprietary clinical-stage asset when candidate drug SEL24 was out-licensed to German-Italian Berlin-Chemie Menarini. By now, the substance has already been tested in a Phase I/II clinical trial. The indication is AML as well, but SEL24 and SEL120 have different modes of action.
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ily to enter clinical development, Warsaw-based Oncoarendi Therapeutics SA claims. Its main indication is asthma. Earlier this summer, the company also presented its second clinical development candidate: OATD-02. The small molecule inhibitor of two arginase isoforms will be tested in multiple cancer indications. Following the founders’ seed and inkind contributions, Oncoarendi closed investment rounds totalling about PLN34m (€8m). In addition, the 2012 start-up raised non-dilutive grants, exceeding PLN100m (€23m). Among others, the company tapped the EU’s Horizo n 2020 p r o g ra mm e. T h e t o t al cumulative funding should allow Oncoarendi to progress four of its ongoing programmes up to Phase II clinical trials and fill its pipeline with new, early stage exploratory programmes. L
VTAK in shards €15m to care for Cancer The fate of Estonia’s Cancer Research Technology Development Centre (Vähiuuringute Tehnoloogia Arenduskeskus, VTAK) remains uncertain. Last year, Bravo Pharmaceuticals, a member of Indian Bravo Group, became a major shareholder in VTAK. Bravo’s owner Rakesh Pandey had promised to invest up to €5m in Estonia within a few years time – for example in a pharmaceutical plant south of Tallinn that produces generic medicines for the Central Asian market. But now there’s a fight between two shareholders – Bravo on one side and Kevelt AS, part of Russian group Pharmasyntez, on the other – over who will gain control over VTAK. Supported by the Estonian government for ten years, VTAK has worked on two drug candidates against cancer indications. When the funding ran dry last autumn, Bravo stepped in. But as long as the shareholders are in disunity, the development of the drugs-to-be remains stalled.
Healthcare network Regina Maria, a Romanian healthcare provider, will receive support from the European Investment Bank (EIB) in its effort to modernise and expand its ambulatory care network and inpatient facilities outside Romania’s capital Bucharest. The €15m loan is secured by the European Investment Fund (EFSI). Announced in late June, the funding will be used to construct and renovate two hospitals and 15 ambulatory care centres.
Biotech fraud Scandal Beta Biotech is in the headlines in Slovakia after the small company was granted €4m for a project on recycling food industry by-products earlier this year. As Beta Biotech has no experience in this area, the responsible Education Ministry is being accused of fraud. Part of the money are EU funds.
Picture: Oncoarendi Therapeutics SA
Targeting AML
Drug Development Drug developer Oncoarendi has said it filed a Clinical Trial Application (CTA) in Germany to conduct its first ever clinical trial. The Phase I study with OATD-01, a potent dual inhibitor of acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1) is expected to begin in Q4 this year. OATD-01 is the first drug candidate targeting members of the chitinase fam-
27.09.2017 13:48:07 Uhr
European Biotechnology Autumn 2017
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28.09.2017 12:33:45 Uhr
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Special
European Biotechnology | Autumn Edition | Vol. 16 | 2017
59
Preparing for the next generation of biologics Biomanufacturing While the FDA and EMA have for the first time okayed the switch from batch to
continuous manufacture of a pill – Janssen Cilag's HIV protease inhibitor darunavir (Prezista) – the industry is still waiting for such a signal in the biologics field. The FDA wants to boost adoption, and biopharma majors, such as Novartis, Amgen and Biogen, launched a pilot project to lay the groundwork for the next generation of production: continous USP and DSP, and alternatives to CHO cells. While Biogen claims its 4 x 18,500L fed-batch biologics manufacturing plant – set to take up operations by 2019 in Luterbach, Switzerland – is “next generation,” Basel-based pharma major Novartis will be completing a 10-year collaboration with MIT to establish a Novartis-MIT Center for Continuous Manufacturing only a bit later. US and EU regulators have sent out strong signals supporting the shift from fed-batch to continous processes. Apparently, regulators are convinced it would allow more consistent process control and simpler application of process analytical technology, resulting in more reproducible product quality.
previous years. Projections from Bioplan Associates’ 14th Annual Industry Sur vey, however, point to the “optimism” of suppliers that could “translate into investment,” says Eric Langer, the company’s president. Feeling the cost pressure from drug developers, cell line developers and CDMOs are seeking to fur ther improve productivity of CHO cells, the
industry’s working horse for biologics manufacturing, a market that has grown to more than US$70bn in annual sales. In August, Horizon Discovery published the complete annotated DNA sequence of its CHO-K1 cell line in hopes of driving cell line innovation. While 81% of biologics manufactured today stem from mammalian cell culture, companies such as Bio-
Picture: Boehringer Ingelheim
Switch to new processes and production systems Suppliers, such as Pall and Lewa Process Technology, have taken up the idea and most recently launched systems for continous chromatography (see E uropean Biotechnology, Summer edition 2017) expected to overcome the bottleneck in downstream processing capacity the industry has suffered in the past decades of growing yields from mammalian cell-based biomanufacturing. The move could energise the market for bioprocessing equipment, which suffered from a drop to midone-digit-per cent growth in H1/2017 compared to double digit expansion in
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Biomanufacturing of biosimilar adalimumab at Boehringer Ingelheim. The Humira copycat drug received FDA approval at the end of August. Currently, only a fraction of the roughly 650 marketed biologics are biosimilars. To date, six biosimilars have been approved by the FDA and 29 got the green light from the EMA.
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SPECIAL
European Biotechnology | Autumn Edition | Vol. 16 | 2017
2015
2017
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In September, serialization solutions company Adents passed the certification test at the European Medicines Verifi cation Organization (EMVO) for connection to the European Hub. Five hundred days before the EU’s falsified medicines rules will get into application, many companies are far away from uploading their serialisation data through the gateway provider. According to supply chain services provider Tracelink, as many as 400 contract manufacturing organisations (CMOs) will not be ready for upcoming US and EU track-and-trace regulations.
Consolidation of the world’s largest clinical research organisations (CROs) already shows impact on the market of mid-size CROs.
gen and Dyadic International are already testing alternatives. This April, Biogen’s VP of International Manufacturing Operations, Eliana Clark, said CHO cells wouldn’t be Biogen's fi rst choice for cheap production of biologics in the future. Dyadic International, which produces yeast strains, wants to make its C1 expression platform as effective for biologics production as it is for biofuels manufacture, where it yields up to 80g/l. Clark said that Biogen co-funds a project with the Bill & Melinda Gates Foundation and the MIT Center for Biomedical Innovation (led by Biogen's Head of QbD, Rohin Mhatre) that would allow a departure from the safe but costly production in CHO cells. In an 18-month effort, researchers at MIT and Biogen have engineered eight alternative hosts for the production of human antibodies, including fungal (such as yeast and chytrids), algae (diatom) and trypanosome (leishmanial) systems to produce full-length mAbs. Results of the systematic comparison will be presented in Q3/2017. Mark Emalfarb, CEO of Dyadic International predicts that limitations of CHO cells in the production of modern, engineered antibody formats will
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convince producers to select more effective production systems.
Serialisation: 50% of CMOs not prepared Full CDMO service providers such as Polpharma (see p. 64) told E UROPE AN B IOTECHNOLOGY that they have just begun to test alternative cell lines besides its proprietary mammalian cell lines and bacterial expression systems for biologics and biosimilar production. According to Markets & Markets, the Global Healthcare Track and Trace Solutions Market is projected to reach US-$2.81bn by 2021, at a CAGR of 17.3% from 2016 to 2021. However, deadlines for including unique product identifi ers on prescription drugs are putting a strain on biopharma companies and CMOs, many of which are ill-prepared to meet the targets. Accordingly, the US Food and Drug Administration (FDA) extended the deadline this summer for the US Drug Supply Chain Security Act (DSCSA) to November 2018. European companies, however, won’t be able to sell any prescription drugs after 9 February, 2019, unless they meet the serialization requirements set out by EU regulators.
Globally, companies in the contract research market face strong headwinds. Following criticism from Big Pharma about the pricing of CRO services, analysts expected a downturn in bookings. However, as bookings from small and mid-sized biotechs increased in Q2/2017, big shots in the CRO segment, such as INC, seemed to sidestep critics from larger fi rms by increasingly focussing on small biopharma clients. In fact, SMEs contributed to 47% of INC’s sales in H1/2017 vs 41% as of H1/2016. The big CROs’ interest in SME customers puts pressure on mid-sized CROs, which have traditionally made a good deal (70–80%) of their revenues) in the SME segment. In Europe, Brexit puts pressure on UK-based companies. While the UK government announced in September it wants to increase the number of clinical trials by 50%, the expected move of the EMA from London to (most probably) Amsterdam shows that it is totally unclear what will happen after the nation's EU exit in 2019 to CROs located in the UK. According to the CEO of IAOCR, Jacqueline Johnson North, Brexit will have a big impact on about 990 entities related to the contract research sector, which mostly believe that Brexit will have a negative impact on the UK’s CROs. According to EU rules, non-EU drug manufacturers
Picture: fotolia-ciom/ diez-artwork
CROs: Brexit to impact 1,000 companies
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SPECIAL
European Biotechnology | Autumn Edition | Vol. 16 | 2017
will need to import their drugs and cannot participate in the EU's centralised procedure for market authorisation which applies to all biological medicines. After UK's pharma major GlaxoSmithKline announced it will turn away its investments from its home base (see p. 64), the UK government published a position paper calling on it to maintain close ties with the EU's Horizon2020 programme and the EMA.
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Contract Manufacturing You can rely on us.
Real world data integration Another long-term challenge for CROs may come from their clients’ interest in collecting real-world evidence for assessing the safety and effi cacy of drug candidates (see p. 16). “This would bring speed into the system,” Roche Pharma AG's Head, Hagen Pfundner, told EUROPEAN BIOTECHNOLOGY. Real-world evidence could become relevant in drug development very rapidly. In-mid September, FDA Commissioner Scott Gottlieb stressed the development costs of pharmaceuticals had become “unsustainable” and announced that the FDA will modernize the collection of clinical data through adaptive or seamless trials, which would go from first-inman testing through approval in a single continuous trial. Previously, CDER director Janet Woodcock and colleagues had reinforced the FDA’s stance on the incorporation of real-world evidence into clinical trials. According to Woodcock, clinical trials and real-world evidence are complementary and studying electronic medical records (EMRs) can be cheaper than RCTs and help answer questions regarding individual dosing and long-term outcomes and side effects. In June, EMR specialist Flatiron Health announced upcoming collaborations with the FDA and the National Cancer Institute (NCI) to explore how real-world evidence derived from de-identified patient data captured at the point of care can be used for clinical trial design and prospective research studies. The collaboration will explore how real-world evidence derived from Flatiron’s melanoma and non-small cell lung cancer datasets can be used to improve study planning, inform sample size calculations, ease study implementation, better understand current trends in standard of care, and address specific study planning questions.
Cheaper than expected Overall, biopharma companies are apparently searching for partners to help them adapt to increasing costs in order to meet shareholder expectations. A new estimate on the average development cost of cancer meds, published 9/11 in JAMA (doi: 10.1001(jamainternmed.2017.3601), however, could become a earthquake to the sector. Sham Mailankody from Sloan Kettering Cancer Center estimated the median development cost of 10 single cancer meds at US$648m each, while median revenues of every drug almost hit US$6.7.bn t.gabrielczyk@biocom.eu
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Celebrating excellence in Europe Volume 7 Championing scientific diversity in Europe! The European Biotechnology Science & Industry Guide 2017 provides a wealth of information on companies, research institutions, tech parks and providers acting in the life sciences and biotech industry. In addition to the detailed portraits on about 170 pages, this edition contains a summary of BIOCOM‘s latest report “Analysis of European biotech companies on the stock market: US vs Europe”. Discover the many success stories and the current trends in the biotech industry today!
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28.09.2017 16:10:52 Uhr
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Expanding scale and reach PolphARMA BIOLOGICS Flexible and reliable contract manufacturing and development have become the
key success factor in the development of biopharmaceuticals. Due to the long process time and high investment needed to build up production capacities, outsourcing of biologics manufacturing provides both access to advanced technologies and necessary capacity along with flexibility in timing and output.
One-stop shop CDMOs that offer a comprehensive portfolio of services supporting the entire biopharmaceutical development cycle have a clear competitive advantage. Ideally, such CDMOs are located where they can readily support the European and North American markets, which account for most of the consumption of biologic drugs. In 2013, Polpharma Group started to establish state-of-the-art capabilities to support in-house and contract development of biopharmaceuticals. With more than 80 years of experience producing generics and small molecule medicines, and as one of the largest pharmaceutical companies in Central and Eastern Europe, Polpharma has extensive expertise in GMP/regulatory compliance and quality assurance to support such an endeavor in the EMA regulatory environment. Polpharma Biologics, established as a division of Polpharma Group in 2013, today has a biopharmaceutical pipeline in advanced stages. Cell-line development capabilities were added in 2016 with the acquisition of Bioceros in the Nether-
lands. Polpharma Biologics is currently expanding its capability to produce final drug product (5 million vials/syringes per year) at its Gdansk facility. Construction of a commercial manufacturing facility at Duchnice, near Warsaw, is underway, which will eventually have 12 x 2,000-liter production trains and an annual fill-finish capacity of 30 million vials and syringes. Both expansions will be operational for drug substance and drug product manufacturing in 2019.
Committed to quality, pace and cost-efficiency Polpharma Biologics has been specifically structured as a European CDMO that serves global market needs and offers fully integrated solutions along the development and production value chain for biologics and biosimilars. It provides fast, flexible, responsive service with a focus on mammalian cell culture and capabilities, spanning the full-range from cell line, process and analytical development to GMP manufacture of
2019 in operation: large scale cell culture plant (up to 12x2000l) incl. fill&finish (30 million vials/PFS p.a. incl. lyophilsation) at Duchnice close to Warsaw
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drug substance and drug product meeting international quality standards. Low production costs have become compulsory to keep a project successful. High-yielding cell lines allow the use of smaller scale upstream and downstream processing equipment, resulting in reduced capital expenditure and the potential for fewer batches per year for lower operating costs. For more than 25 years, Bioceros has generated high-yield production cell lines for both biosimilar and innovative proteins through its proprietary CHO-BC® platform. It is complemented by a comprehensive toolbox for targeted modulation of posttranslational modifications to accomplish fingerprint biosimilarity, which can be readily analysed using robust in-house bioassays. With its one-stop shop approach, Polpharma Biologics is positioned to provide a comprehensive range of services tailored to each individual project, including de novo process development, process optimisation, and manufacturing of fully developed processes. Clinical manufacturing takes place at the Gdansk site, which houses bioreactors that contain volumes up to 1,000 or 2x1000 liters for cell culture and 500 liters for E. coli fermentation processes. Commercial GMP manufacturing using scaledown models, as well as high-throughput mini- and regular bioreactor systems for parallel screening will be operational at the new Duchnice facility by 2019. With up to 12x2000 liters disposable high-end production set-up, we represent the new benchmark within Europe in terms of cost of production and flexibility. L
Picture: Polpharma Biologics
› Federico Polano, Global Business Development & Contract Manufacturing Director, Polpharma Biologics
29.09.2017 11:35:49 Uhr
Passion for Performance Rentschler Biopharma – A world-class biopharmaceutical CDMO Full�service�from�gene�to�vial�and�from�concept�to�market
Best-in-class formulations provide significant competitive advantages
Complete solutions with state-ofthe-art fill and finish facilites
Strategic�Alliance�with
Strategic�Partnership�with
Rentschler Biopharma SE Erwin-Rentschler-Str.�21�·�88471�Laupheim�·�Germany info@rentschler-biopharma.com�·�www.rentschler-biopharma.com
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Special
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Insight into biomarkers AYOXXA’s LUNARIS™ platform In a case study "Translational proteomics: a new perspective for
ophthalmology research,” Ayoxxa gives insights into the capabilities of its Lunaris multiplex protein analysis platform.
Up to 80% of people who have suffered from diabetes for 20 years or more are afflicted with diabetic retinopathy (DR), which is the leading cause of blindness through damage to the retina. The longer a patient suffers from diabetes, the higher the risk to develop DR. It has been estimated that up to 90% of new cases could be eliminated or reduced in severity, if reliable screening tests were available. By being integrated into routine screenings, such tests could help to identify initial signs of retinopathy as early as possible and help physicians to initiate the right treatment in time. Inflammation and vascularisation play a significant role in ophthalmic diseases and reliable monitoring techniques are required for the analysis of related biomarkers from vitreous and aqueous humor of diabetes patients. However, samples from such sources are limited and current proteomic biomarker detection methods require relatively large sample volumes, which in some patients may be difficult to obtain without having to undergo a vitrectomy. This is where AYOXXA’s innovative automated beadson-a-chip multiplex protein analysis system kicks in. LUNARIS™ assays can be performed with sample volumes as low as 3µl – which represents about 1/10 of the volume required by comparable multiplex technologies.
Assays for translational research But this is not the whole story. Scientists in clinical laboratories who correlate proteomic interactions to pathogenesis in various fields, including ophthalmology
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and immunology, need to build on a robust and reliable platform. To transfer lab findings through to validation in clinical trials, the platform needs to deliver scalability, flexibility and robust data quality. AYOXXA’s LUNARISTM system combines the advantages of a bead-based multiplexing approach plus the reliability and scalability of a plate-based format with the simplicity of image-based analysis. The system is comprised of a dedicated reader, automated analysis software, and a growing portfolio of LUNARIS™ multiplex protein assay kits for the detection and quantification of soluble inflammation and immune-response markers.
Image-based readout combined with the planar beads-on-a-chip format make the LUNARIS™ system very robust and capable of delivering best-in-class data quality. The spatial separation of the individual coated beads in a pre-defined array help to avoid quenching effects and to reduce artifacts due to potential bead clumping, ensuring the best possible accuracy and precision. The readout captures an image of all of the thousands of beads within the reaction well, leaving no bead unread. This exhaustive sampling, combined with robust plate-based workflow, helps achieve coefficients of variation (CVs) in the range of 10% or better.
Highest quality of data through superior accuracy and precision
Flexibility in scalability and formats
AYOXXA offers a variety of disease related panels, including the newly introduced LUNARISTM Human 11-Plex Ophthalmology Kit for the detection of the most important biomarkers for age-related macular degeneration and diabetic retinopathy. Additionally, AYOXXA offers the LUNARISTM Mouse 12-Plex Th17 Kit to help elucidate Th17 cell biology in murine models of autoimmune disorders and immune mediated conditions.
LUNARISTM BioChips have been designed as a modular system with formats from 32- to 384-well density and are compatible with liquid handling system integration, allowing full scalability for low- to high-throughput applications. LUNARIS™ has proven to be highly efficient for multiplex immunoassays – which are the primary format commercially available today. However, the system can potentially also be used for other binding or capture assays in the same modular plate-based format. Researchers in academia and in leading pharmaceutical companies have already tested thousands of samples using LUNARISTM and have found the assays enable their research. The superior features make LUNARIS™ an ideal choice for state-of-the-art biomarker screening and validation. L
Picture: Ayoxxa
› Dr. Matthias Jansen, Senior Product Manager, AYOXXA Biosystems, Germany
29.09.2017 11:36:18 Uhr
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Advanced formulations for biopharmaceuticals Biologics In the past, the role of customised and tailored formulations have been largely
underestimated in the field of biopharmaceutical product development. An advanced formulation strategy can strongly improve the product, leading to significant customer benefits. The growing and increasingly competitive biopharmaceutical market requires individual solutions, particularly for better product stability and prolonged shelf life. › Martin Scholz, CSO, Leukocare AG, and Stefan Schmidt, CSO, Rentschler Biotechnologie GmbH
Customer benefits in focus Advanced biopharmaceutical formulations enhance product stability, allowing the manufacturer to avoid a variety of additional indirect costs, which may include costs related to regulatory issues, brand risk, loss of product efficacy, back office invoicing, packaging,
management time, patent safety, monitoring, and product recovery. Achieving maximum product potential, which requires highest stability, is essential for the biopharmaceutical manufacturer. Improved stability through advanced formulations provides many advantages to manufacturers: i.e. allowing for higher temperature storage with self-applied biopharmaceuticals in pre-filled devices, for high concentrated subcutaneous application, or for the avoidance of lyophilisation steps. For all these approaches the cold chain aspect has to be considered. For example, it is a clear advantage for a manufacturer to provide products with
Molecule design
Host cell selection
Upstream process
Downstream process
Fill finish
› Sequence › Hydro- phobicity
› Proteases › Oxidative stress › Media components › Posttrans- lational modifications
› Stirring › Temperature › pH › Trace metals › Osmolality › Air/liquid interface
› Pressure › Shear forces › Mixing › pH › Air/liquid interface › Light
› Agitation › Shear forces › Excipients › Oxidation › Freeze-thaw › Light
Figure 1: Stress factors during processing
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longer shelf life, either when stored at 2–8 °C or even at ambient temperature. For instance, competitive advantages have been achieved by modified formulations that increased stability of therapeutic antibodies against psoriasis. Specifically, the antibody secukinumab (Cosentyx®) has a shelf life of only 18 months in the EU when stored at 2–8 °C. Advanced formulation by competitors resulted in a 24 month shelf life at 2–8 °C and was approved in the EU for storage up to five days at ≤ 30 °C (Taltz®) and in the US for up to 14 days at room temperature ≤ 25 °C (Siliq®).
Formulation matters Currently, standards do not leverage the strategic opportunities of advanced formulation development and consider formulation too late in product development. This can delay development programmes, if product opportunities are not maximised prior to Phase II trials. Changes of formulations after Phase II may require additional studies, costs, and delays. Early product stabilisation and selection of a commercially viable formulation during manufacturing ensures shorter time lines and greater probability of success later in clinical studies and commercialisation. Multiple processing steps associated with mechanical, chemical, and temperature
Picture: Rentschler
Advanced and customised formulations not only enable the biopharmaceutical manufacturer to be more economical with even a higher product quality compared to competitor products but also help to generate intellectual property and to extend patent life span.
28.09.2017 12:43:44 Uhr
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Figure 2: Example for quality increase by SPS®
stress during drug substance and drug product development result in cumulating molecular changes. Therefore, tailoring the stabilising formulation by considering process-specific stresses should be integrated early in the manufacturing process, i.e. immediately after harvesting the biomolecule.
From gene-to-vial processing Current strategies of biologics manufacturers are aimed at increasing product quality. This already starts with molecule design and the selection of producer cell lines optimising the output while limiting side products such as protein fragments. But it also includes efforts in upstream processes through chemically defined media or tighter online monitoring. Similar efforts have been undertaken for downstream steps focusing on chromatography resins with higher specificity and resolution. Particularly during the downstream manufacturing process, protein molecules are exposed to physical stress factors, such as stirring and mixing in conditioning steps, or shear stress in filtration operations or under high pressure. Chemical stress impacting protein stability is often connected to non-physiological pH values – for instance in low pH elutions from affinity columns at high protein concentrations. Both stress sources (Figure 1) can result in degradation or aggregation of the proteins, ultimately leading to loss of function or causing immunogenic-
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ity problems. High molecular weight aggregates can be eliminated during downstream processing. However, this will reduce the overall yield and the process efficiency by potentially requiring additional unit operations. It has been shown in long-term stability studies that trace amounts of aggregates can act as nuclei for further aggregation thus limiting the shelf life of parenteral drugs in liquid formulation. As low-level product-related impurities are very hard to eliminate completely, other strategies, such as formulation optimisation to prevent the increase of aggregation during the shelf life, are strongly recommended. Currently, most standard formulations are sufficient to support the typical short shelf life in clinical programmes. However, they are often not sufficient to support storage expectations for commercialisation. This means efforts should be undertaken relatively early to establish an advanced formulation and its implementation strategy to facilitate the delivery of competitive formulations. This holds particularly true in crowded indications or for second generation biosimilars where optimised formulations might give the competitive advantage to gain a larger market share.
SPS® in gene-to-vial processing The SPS® formulation technology development platform is a best-in-class formulation platform for the stabili-
sation of proteins, like biopharmaceuticals, to intensify the development of better products. This includes improved product stability during refrigerated or even unrefrigerated distribution and storage, prolonged shelf life, as well as subcutaneous administration of high concentration liquid products etc. The sophisticated backbone of the SPS ® technology platform is a library and database-based rational design approach. By means of this approach more than 100 different, regulatory well-known excipients are combined in order to select the most suitable excipient combinations, concentrations, and ratios for the individual biopharmaceutical product. The strength of the SPS® technology platform lies in the IP-protected amino acid-based formulation strategy in conjunction with the SPS® database, excipient library, and DoE support. All excipients used in SPS ® are listed in relevant pharmacopoeias (USP, EP, JP, etc.) and/or as inactive ingredients by the FDA. According to the principles of preferential exclusion and preferential binding, SPS ® formulations were already shown to be easily adaptable to a broad range of target molecules and requirements for dry and liquid products. The molecular integrity and functionality are the key analytic aspects to monitor the efficacy of the iteratively optimized and finally tailored SPS® formulations. As an example, SPS® significantly improved stability of the therapeutic IgG antibody trastuzumab during different processing stress conditions – i.e. accelerated aging – even in high concentration liquid formulation. SPS®formulations avoided aggregation and fragmentation of trastuzumab even at concentrations ≥ 200 mg/ml and exhibited significantly reduced viscosity versus the original formulation (Figure 2).
Benefits of SPS® The better product quality achieved by SPS® included in gene-to-vial processing and manufacturing helps the customer to realise significant competitive advantages in the market. L
Picture: Leukocare
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AYOXXA Ì&#x201C;s innovative multiplex protein technology for translational proteomics FIND OUT MORE:
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Advertorial
European Biotechnology | Autumn Edition | Vol. 16 | 2017
3P Biopharmaceuticals th celebrates 10 anniversary 3P Biopharmaceuticals 3P Biopharmaceuticals celebrated its tenth anniversary this past September 12
in the Pamplona Cathedral. More than 150 guests had the opportunity to listen to a global leader in biomedicine: Dr. Barry Marshall, Nobel Laureate, who received the award in 2005 for his co-discovery of the bacterium Helicobacter pylori and the role it plays in gastritis and peptic ulcer disease.
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jected the bacteria into his own body, resulting in severe gastritis and confirming his hypothesis. This revolutionary discovery meant ulcers and gastritis could be cured with antibiotics, thereby avoiding surgery and its complications. Professor Marshall also presented future research possibilities on Helicobacter pylori bacteria, a project that he is carrying out alongside the Australian company Ondek, which he founded, and with whom 3P has signed a partnership agreement. As part of this project, a new molecule is being developed and manufactured that will be used in preclinical and clinical research for the treatment of autoimmune diseases.
3P Biopharmaceuticals 3P Biopharmaceuticals, founded in 2007, is a leading European CDMO specializing
Contact 3P Biopharmaceuticals businessdevelopment@3pbio.com phone: +34 (948) 346 480
Pictures: 3P Pharmaceurticals
The company brought together everyone who has participated in its success: clients, suppliers, members of the Board of Directors of ASEBIO (Spanish Bioindustry Association), partners, financial institutions, media outlets, and governmental representatives. The event opened with a speech by Dámaso Molero, General Manager of 3P Biopharmaceuticals. Molero looked back at the past 10 years and thanked everyone for their commitment towards creating the company and making it a success. The main feature of the event was the conference by Professor Barry Marshall, titled “H. pylori: History and Future.” Marshall explained the process that led him and his research partner, Dr. Robin Warren, to confirm what the scientific community had denied: that most stomach ulcers are caused by the Helicobacter pylori organism. Marshall in-
in process development and GMP manufacturing of biologics and cell therapy products. Over the past decade, it has built a top-level facility with a complete GMP Quality System perfectly in line with international regulations. 3P’s commitment is based on a clear objective: to offer each of its clients highquality, cost-effective, flexible, and adaptable solutions to make their projects succeed. A highly qualified team joins their clients as a robust manufacturing partner to offer support at all stages of bio drug development: from initial research to cell-line development to preclinical, clinical and commercial phases. 3P has extensive experience in projects covering all stages of process development and GMP manufacturing in different expression systems: microbial (E. Coli, S. Cerevisiae, H. Polymorpha, P. Pastoris); mammalian (CHO , BHK, HE K, Hybridomas); and New Biological Entities (NBEs), including fusion proteins, vaccines, monoclonal antibodies, and biosimilars. Over the past decade, 3P has served a diverse, international roster of companies: from small biotechs and start-ups to large biopharmaceutical companies with complete pipelines in all stages of development.
28.09.2017 12:44:43 Uhr
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SPECIAL
European Biotechnology | Autumn Edition | Vol. 16 | 2017
A suited approach to rare disease trials Accelerated approval for orphan drugs and the possibility to have market authorisation after a successful Phase II trial have made research in rare diseases more attractive to sponsors. However, challenges and uncertainties remain numerous and designing scientifically robust, patient-centered trials requires proper conceptualisation. OPIS
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cept that can be adjusted for rare disease trials. To be less rigid and allow a greater type 1 error (risk of false positive or α error) makes sense when one definitely does not want to lose the slightest or smallest signs of efficacy of treatment.
DR. ALDO POLI, Founder and CEO of OPIS, is a specialist in clinical research methodology, trial design and biostatistics. With a degree in medicine and surgery from the University of Milan, he has over 30 years of experience in the pharma industry and in clinical research. He regularly collaborates with major academic institutions and serves as an industry consultant in trail design/methodology.
surrogate endpoints, such as biomarkers or composite endpoints, may really help support your proof of concept. Quantification of risk is another con-
EuroBiotech_Many rare disease trials use adaptive trial designs. What are the advantages and disadvantages of adaptive designs? Poli_There are numerous types of adaptive designs. These designs are often based on Bayesian statistical models that focus on estimation, rather than hypothesis testing, and allow a range of possible observed trial results and prior distributions. Adaptive randomisation, sample-size re-estimation, “drop the loser” –i.e. stop the least effective treatment on the basis of predefined criteria – all give one the possibilit y to identif y non-beneficial treatments early and redistribute your valuable resources to more promising treatments. It is also possible to use Bayesian elements in a standard trial design because it would allow an opportunity to include external information in the form of subjective clinician estimation of treatment effect, for example. However, adaptive designs are not always well accepted by ethical and regulatory bodies, and whereas conventional trial designs are well endorsed, adaptive designs are still seen as speculative.
Picture: OPIS
EuroBiotech_You are currently involved in a project for a Phase II study on an ultra-rare disease. That means dealing with extremely low patient populations. How did this fact influence the conceptualisation of the trial? Poli_Rare disease trials imply small and heterogeneous groups of subjects with often very little possibility to select trial subjects through inclusion and exclusion criteria with the aim of getting a more homogenous population. A standard Phase III randomised, controlled trial is not always possible, so it is important to make sure that one optimises and maximises data from smaller trials. The current project in Becker’s disease is based on a classic Phase II design, but there are a few interesting aspects that need mentioning. Being a controlled study, unequal randomisation with a 2:1, 3:1, or 4:1 ratio makes the use of placebo possible and stratified randomisation controls known factors of clinical relevance that might influence the treatment. Building cautions into the protocol to continuously monitor patients and check the primary variable closely eventually safeguards against unethical use of placebo. The concept of endpoints needs mentioning. Apart from the obvious recommendation to define the primary endpoint with signs or symptoms that express the course of the disease best, secondary endpoints can help collect as much information about the disease as possible and setting
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European Biotechnology | Autumn Edition | Vol. 16 | 2017
EuroBiotech_ A low number of trial subjects available does not only influence trial design but it also brings challenges related to recruitment and patient retention. How does one target such small patient populations? Poli_There are quite a number of solutions to help recruitment. Patient networks and close collaboration with patientsâ&#x20AC;&#x2122; families can help design patient-friendly elements directly into a trial. It is more important than ever to approach rare disease trials with a truly patient centered approach. Moreover, the advantages for patients participating in such trials should be underlined clearly. The fact that these patients will be treated with advanced therapies that might cure something yet untreatable, is an opportunity. EuroBiotech_To conclude, your current project is an example of collaboration among academic research institutions, the study sponsor, a CRO and regional funding. How has this combination
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Orphan diseases In Europe, an estimated 30 million people suffer from rare or orphan diseases. A disease is classified as rare when the European Medicines Agency (EMA) estimates that fewer than 5 in 10,000 people suffer from the disease. Around 70% of patients are children. Currently there are between 7,000 and 8,000 diagnosed rare
helped in overcoming some of the obstacles related to rare disease research? Poli_National Health Systems may benefit from clinical trials and their sponsors that absorb costs for treating patients that would otherwise be covered by National Health budgets. However, getting all stakeholders to work together to come up with solutions that consider research
diseases, mostly in oncology, metabolism and CNS indications. Globally, there are an estimated 460 approved orphan drugs on the market. Between 2002 and 2015, the EMA authorised 87 orphan drugs, 15 of them in the last year. In 2015, 23.6% of clinical trials carried out in Europe affected treatments for rare diseases. L
aspects/opinions, patient and patient network aspects/opinions as well as country and cultural aspects can optimise possibilities to have adequate patient numbers to conduct a trial. Looking at all available resources and finding ways to attract attention from a much wider audience, certainly contribute to advancement of rare disease research. L
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Need a contemporary manufacturing strategy? GMP Manufacturing Considering the high development costs of medications and the time invested
before a drug goes from discovery to market, it is critical to develop not only a solid drug development strategy, but a contemporary manufacturing strategy as well. A parallel development strategy could be one possible approach. › Dr. David Brett, Product and Service Manager, Vetter
Beginning with in-human Phase I trials, significant thought is applied to study design, logistics, CRO selection, patient populations, study centers, software and clinical distribution. These are all important considerations, but what is often missing is an equally important, wellthought through manufacturing strategy for the clinical material. Choosing a manufacturing partner with the contemporary manufacturing capabilities and expertise to offer advice on future drug product development is critical. The wrong choice can mean biotech companies must switch partners midstream, resulting in high costs and risks, such as failure to produce, the loss of API, or trial delay.
Plan prior to entering first-in-human studies The best time to involve a manufacturing partner is from the very start. At that time, it is important to have answers to three fundamental questions:
›› What is your commercialisation strategy? Will you license the drug to other companies? If you intend to market it yourself, what markets will you target? This is why the choice of an experienced manufacturing partner and the development of a clinical manufacturing strategy should be considered prior to entering first-in-human studies.
Proven manufacturing strategies for a biologic or small molecule From a CDMO perspective, there are three proven development strategies: full-vial development, parallel-development, and full-syringe or full-cartridge development. Your choice will depend upon your product’s attributes, market requirements, and commercialisation strategy.
The majority of new products are initially filled in vial form since it is easier to carry out dosing studies and the regulatory path is clear. Many biotech companies choose this development path due to their restricted resources, budget, and market-entry strategy. Some exceptions to this rule include accelerated drug development trials or biosimilars. In such cases, the dosing is pre-defined, based on a previous gold standard for a similar compound, and it is known from the start that the final presentation will be a syringe or cartridge. For a new product or biosimilar where an approved treatment for a patented biologic already exists in syringe or cartridge form, there can be a competitive advantage in using a parallel manufacturing development strategy employing a pre-filled syringe or pen and cartridge combination. This is true in less price sensitive markets where there is a need
for your new molecule, i.e. what is the clear unmet need for your target market, the drugs indication, and the market potential? ›› What are the desired product attributes for your drug? For example, what is the clear benefit in the dose scheme/application form?
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Manufacturing is a critical element in the integrated drug development process
Picture: Vetter
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is often sufficient to begin. As soon as your drug product surpasses early clinical phases, however, these partners may have reached their capacities. Thus, you may face issues such as the lack of a plan to limit loss of API in scale up, time delays, and non-cGMP practices, all of which may require additional feasibility, pump and filter studies, and added costs for knowledge and technology transfer to prepare for scale-up.
Proven packaging strategies
to attract patients, and vials offer a price advantage. This is also the case when health care workers are paid per administration step, and receive higher reimbursement from insurance companies when using a vial. The best phase to consider parallel development is following dose-finding studies (Phase IIb). When choosing the parallel development approach, the regulatory pathway can be pursued in parallel. Working with a partner that has strong regulatory experience and is consistently audited to the highest manufacturing quality standards for all clinical phases will help in getting the right answers for submission. Each primary
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packaging material has its specific regulatory requirements. In summary, having different packaging presentations is often a choice made when your commercialisation strategy demands a differing price point.
Choosing the right manufacturing partner There are many local and regional CDMOs and formulation companies with extended small-scale filling services in the market. Many of these companies offer a discount strategy for early phase clinical filling. Their focus is on small-scale preclinical, and early phase filling. This
Headquartered in Ravensburg, Germany, Vetter is a global leading contract development and manufacturing organization (CDMO) with production facilities in Germany and the United States. The company has long-term experience offering services ranging from early development support, including clinical manufacturing, to commercial supply and various packaging solutions for vials, syringes, and cartridges. Vetterâ&#x20AC;&#x2122;s customers range from small and midsize to the worldâ&#x20AC;&#x2122;s top 20 pharmaceutical and biotech companies. As a leading solution provider, the CDMO recognizes its responsibility to support the needs of its customers in developing devices that contribute to increased patient safety, convenience, and enhanced compliance. Learn more about Vetter at www.vetterpharma.com. L
Picture: Vetter
About Vetter
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Rapid implemenation of off-line serialisation Packaging Serialisation of drugs is confronting pharmaceutical companies all over the world
with challenges, especially in relation to data handling and the integration of additional equipment and functions into existing packaging lines. Offline solutions, where secondary packaging is serialized directly by the folding-box manufacturer, combined with sophisticated data flow architectures, are a reliable, flexible, and immediately available alternative to inline serialisation.
Picture: Rondo AG
› Hans-Peter Süsslack, Business Process Manager, Rondo AG, Switzerland
By means of Delegated Regulation (EU) 2016/161, the European Union has drawn up a mandatory standard to prevent the penetration of falsified medicines into the legal supply chain and to increase patient protection. According to this Regulation, all prescription medicines – with the exception of those on the “white list,” and those medicines for self-medication cited on the “black list” – must be provided with an individual distinguishing feature (serialisation) and with protection from manipulation (tamper evidence). In addition to improved patient safety, pharmaceutical manufacturers hope, through serialisation of their drugs, to contain the substantial world-wide increase in economic damage due to product piracy and theft. Apart from economic damage, manufacturers are also afraid that their brand image will be seriously damaged. From an economic viewpoint, pharmaceutical companies can benefit from other aspects of serialisation. For example, recognisability in the event of returns and clear identifiability in the event of recalls – which can be carried out in a more targeted fashion, therefore affecting a smaller quantity of products – reduce costs substantially in some cases. Also, the grey marketing of drugs, particularly the selling of original products outside designated commercial channels, can be better controlled in this way.
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More and more governments throughout the world require the application of an individual distinguishing feature (in this case: China Code) and protection from manipulation (tamper evidence) on all prescription drugs.
Pharmaceutical companies therefore have an interest in promoting serialisation of their products. However, above all they must comply with national standards in order to be allowed to continue to supply after the respective introductory periods. Its introduction confronts pharmaceutical companies with major challenges, in particular with regard to the assignment of data to packaging lines and to the integration of serialisation equipment into existing packaging lines. In the case of retroactive integration, the pharmaceutical contractor is the general contractor, who, however, frequently does not have available the necessary tech-
nical personnel with the qualification required for this.
Challenges for manufacturers Apart from the EU, a large number of governments throughout the world are tackling serialisation of medicines and are in the process establishing standards which differ greatly from each other. Manufacturers who wish to sell their drugs world-wide must, permanently and at short notice, get to grips with and react to new requirements, some of which may change suddenly. Application of the codes on the individual medicine pack requires secure man-
27.09.2017 14:14:28 Uhr
Special
agement within the company of the serial numbers of each individual product and, if necessary, of each individual destination country. During printing using digital print technology there is a requirement for a system at the production machine which prevents duplications, particularly in fault situations and exceptional situations, and which can reliably record the successfully printed codes despite interference factors. Because of the use of Asian fonts, the need to apply specific information to medicine packaging which people can read leads to a large quantity of characters to be processed and to exponentially demanding requirements in terms of data processing.
Outsourcing serialisation The alternative to inline serialisation on the packaging line – offline serialisation by the folding-box manufacturer – spares the pharmaceutical company the cost of integrating printing technology, cameras, and ejection equipment into each individual packaging line, as well as training employees in the use of print technology. The lost production time for the integration and validation period can likewise be saved.
European Biotechnology | Autumn Edition | Vol. 16 | 2017
In the case of inline solutions, print heads for applying the codes with the required print quality and permanence, as well as cameras to check them and software for central control of the new modules, must be integrated into existing installations. In addition, for some countries, aggregation with balancing must be installed. The latter is also necessary for the offline variant, where serialisation is handled by the foldingbox manufacturer. However, any further investment or delicate interventions in systems is not necessary, so their efficiency remains to a large extent unaffected. The basis for offline serialisation is reliable data exchange with the folding-box manufacturer. For the EU, and for most other countries (except China), coding of the expiry date and batch information is required. Depending on the medicine, this data can subject the coding process to time pressure. If serialisation takes place at the folding-box manufacturer, then the latter must have a database system and a quality assurance system that have been proven in practice to guarantee fast, error-free deliveries. Whether inline or offline, serialisation demands the perfect interaction of
At Rondo, all processes and systems required for generation, provision, and exchange of data are fully integrated.
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hardware, software, and reliable, qualifiable processes. Different IT systems must be combined at the equipment level (line ser ver), production level (plant server), and as part of enterprise resource planning (ERP). Serialisation by the folding-box manufacturer provides ultramodern printing techniques combined with reliable data flow architectures and processes which comply with pharma requirements. The offline variant is an attractive option for medium-sized pharma companies in particular, allowing them to avoid additional investment for each individual packaging line and maintain the efficiency of existing equipment – especially if the time for converting all lines is tight. In addition to solutions for tamper evidence and the application of special security features, Rondo also offers its customers this service. The Swiss company has invested in an Atlantic Zeiser DIGILINE Single Pharma 450, which covers all the requirements for reliable offline serialisation. All current codes are applied using OMEGA Drop-on-Demand inkjet technology in high-quality, highcontrast print and codes, using UV-hardening ink, and are therefore resistant to abrasion, water, alcohol and other solvents. The legibility of bundles, which are packed in shrink foil, is significantly improved as a result, and this reduces finishing costs to a minimum. Almost all typical materials can be printed on with a print quality of at least 1.5, according to ISO/IEC 15415:2011 (Grading C). With its extensive format range of 80 x 100 mm to 450 x 500 mm, the system handles all common sheet and cardboard sizes in the pharmaceutical industry. Up to 240 folding boxes per minute can be printed with consistent high-quality, and provided with serial numbers. In this way, Rondo is providing its customers with solutions that can also handle fairly large orders at short notice. All modules of the coding machine, such as the mix-up and inspection cameras, are controlled via central production software. The seamlessly integrated Unique Code Software enables as many sets of numbers as required to be man-
Picture: Rondo AG
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D-Flex . Just One. ÂŽ
Your patient uses more than one injector for different fixed dosages? You miss a variable-dose injection device which prevents the selection of unintended doses? Your new drug is tested in clinical trials or dose escalation studies and you miss a flexible and unique platform for subcutaneous injections?
Q
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You need just one. The new D-Flex.
One pen to deliver doses of one or more pre-set volumes. One pen with a proprietary mechanism to prevent unintended dose selection. One platform designed for easy customisation of pre-set dose volumes. One platform to support you from dose escalation studies to commercial product.
Working together to inspire your patients. haselmeier.com
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aged, and ensures consistent serialisation results. For example, in the event of interruptions in production, whether intended or not, no duplicate serial numbers are assigned. If desired, the list of successfully printed serial numbers can also be made available to the customer. Integration into Rondo’s existing ERP system makes duplicate inputs impossible and guarantees error-free, secure data exchange. The software has been specially adapted for Rondo, in order to enable secure management of print orders and their assignment and distribution across one or more machines for parallel production. In addition to the software, the data flow architecture has also been adapted to the specific requirements of the pharmaceutical industry. Importing of data from the customer is also automated, as is data export of the resulting files. Assignment of serial numbers to the production order is performed using unique naming with automatically generated file names. For production, the data is provided automatically via an enhanced master data management system. For quality assurance, a second camera that checks the correctness and quality of the codes is installed in the equipment. The production results report and the balance file can be generated in different data formats according
European Biotechnology | Autumn Edition | Vol. 16 | 2017
to the customer’s wishes and sent to the customer via electronic data exchange. Outsourcing the serialisation of their medicines to a folding-box manufacturer, such as Rondo, offers pharmaceutical manufacturers a number of benefits.
Secure offline solutions Customers can access the very latest print technologies with high-contrast print images for optimum verifiability and secure software solutions without having to invest several times in production equipment or impair their efficiency. In addition, outsourcing serialisation does not increase the cost of line clearance during the packaging process. With Rondo, pharma companies can rely on secure data handling and relia-
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ble balancing. Data management runs in the background and cannot be influenced by users in any of the individual process steps. Input errors are therefore prevented. Furthermore, pharmaceutical manufacturers can access the expertise of folding-box manufacturers in terms of print, materials, and solutions. For instance, in addition to serialisation of flat cardboard blanks, Rondo also offers its customers reliable, high-quality printing of glued folding boxes, significantly reducing the quantity of serial numbers required by the process. Integration of additional security features and tamper evidence are also possible. This means that Rondo can provide its customers with both standardized and customized solutions for secure packaging which meet all international standards. L
Picture: Rondo AG
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UNLOCK
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BE COMPETITIVE AND VISIT www.vtu-technology.com 79-80_82_EB_Autumn_2017_Special_Rondo_tg.indd 82
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Serialisation using labels Serialisation Every company has its own specific approach to comply with the FMD 2011/62. Those
who are aware of their unique needs should consider the option of pre-serialised labels. Here are a few good examples of how companies can benefit from this technology. › Philip Falkenstein, Product Manager Serialization & Tamper-Verification, Bähren Druck
Pictures: Bähren Druck
Serialisation can be implemented at several stages throughout the manufacturing process: (A) at the folding box manufacturer; (B) at the pharmaceutical company; or (C) in coordination with the label supplier (see graphic). The time-sensitive release of batch and expiry information requires a justin-time packaging coordination. Labels allow a fast and easy supply, and bridge the gap between offline and online/inline serialisation. Drugs using single-dose units or a pouch as sales package provide the most obvious use for pre-serialised labels. The label supplier can combine all required information, including serialisation, in just one label. Such all-in-one labelling is also conceivable for pharmaceutical importers who usually relabel the folding boxes. But there are also drugs on the first market that are packed in blank folding boxes assembled with labels. The majority of drugs are packed in pre-printed folding boxes and serialised inline during the packaging process. However, the inline process reaches its limits
with unusual packaging dimensions. For example, so-called shoe box formats are, in many cases, not suited for inline serialisation processing and need another solution. Using a labeling machine — a lowcost investment compared to stand-alone serialisation systems — the packaged units can be labeled automatically with pre-serialised labels. The level of automation required and speed of the system depend on the batch size and must be decided on a case-by-case basis. Especially in the case of medium and small batch sizes, the set-up times of inline systems and the risk of rejection of faulty products due to misprints should be considered so that pre-serialised labels can be an alternative. This batch range is also characterised by manual packaging processes – the possibility of manual label application is another strength. This is particularly true with regard to a 2-in-1 label solution, which allows two processes to be completed in one step. Furthermore, there may be some scenarios in which pharma companies want to avoid high investment in serialisa-
An example of serialisation implementation: (A) offline at the folding box manufacturer; (B) online/inline at the pharmaceutical company; (C) in coordination with the label supplier
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2-in-1 Label Solution by Bähren Druck. Manual and machine application are possible.
tion equipment. Examples may include smaller companies, and companies with very few prescription drugs (Rx) affected by the legislation. Pre-serialised labels can even allow companies to outsource the entire complex serialisation processes to a packaging specialist, who will guarantee that print quality, data structure, and specific barcode requirements will comply with Regulation 2016/161. Pharma companies can save resources and rely on the manufacturer. Given the fact that the clock is ticking away, plus the fact that some companies have not started their serialisation project at all, pre-serialised labels are also a possible interim solution to fulfil the requirements by February 9th 2019. Of course, the use of pre-serialised labels requires a clear agreement between the pharma company and the packaging manufacturer. Main questions relating to the serial number, data interfaces, and reporting are important tasks, which must be defined in the onboarding process. L www.your-special-case.com
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Injection pens in clinical trials Packaging Due to the high cost pressure in health services, for a product launch to be successful in
the long run, it is necessary for a drug to be not only safe and effective but also more economical than the existing forms of therapy. Haselmeier’s injection pens provide the flexibility and efficiency required to run an effective clinical trial. › Dr. Fred Metzmann, CBO; Konrad Betzler, Chief Pharma Officer, Haselmeier Group, Stuttgart, Germany
the place and time of treatment, thereby greatly reducing therapy costs. A clinical supply manager should demand the following of an injection pen for clinical studies: ›› The form is permitted in the countries in which the studies are being conducted. ›› It is simple and safe to use, and permits a predefined flexibility in the adjustment of the dose. ›› It permits therapy-appropriate labelling, including relabelling for dose adjustment as well as the option of multilingual labels. ›› It can be used continuously or with minimum adjustments for all phases of the clinical study up to the approval of the drug. ›› It can be delivered ready-to-use to the trial participants without having to establish a manufacturing competence in-house. Haselmeier has developed a new product platform, the D-Flex, that is highly suitable for clinical trials. It is a disposable pen for use with 3ml cartridges.
The D-Flex platform can be flexibly configured to suit the desired dose values from the first clinical study to series production, significantly reducing capex and time to market.
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The D-Flex can be configured for several fixed doses, bridging the gap between fixed and variable-dose pens.
D-Flex solution to meet clinical requirements These dose values can be freely selected when designing the pen. This is particularly of interest for dose-escalation studies. The system does not allow any intermediate settings between the set doses. This significantly reduces the risk of an incorrect dose and enhances safety for the patient. The D-Flex pen means that only one device needs to be used throughout the clinical trial, making trials much easier for the pharmaceutical company. Regulatory bodies may also impose a device design that only enables dial-labelled doses. This would disqualify the use of current prefilled pens, which have intermediate dose increments. Using D-Flex for clinical trials and later as serial device enables the customer to decide which set-up he prefers for market introduction. This makes the D-Flex the ideal, flexible platform for adapting to set doses in accordance with the therapy. It has been so well developed and validated that only minimal molecule-specific and customer-specific adjustments are necessary; they can be integrated into the clinical supply chain process seamlessly up to serial production following market authorisation. The D-Flex can also be assembled at Haselmeier’s site up to the drug-device combination product. L
Picture: Haselmeier
Whoever is the first to bring a new therapy to the market determines the price. Therefore, every company will make the best effort to ensure a quick start to, and smooth conduct of, clinical trials. If the drug has to be injected subcutaneously, injection pens offer a great opportunity to control the time factor. Generally, during the clinical phase, medication is stored in vials and administered to the patient through a disposable syringe. However, vials can be inconvenient to use and harbour safety risks, especially with regard to shelf life after opening, contamination, and injury to the staff due to the cannula. An alternative is the prefilled syringe, but this does not permit any dose adjustment and, thus, would mean a substantial additional demand for the trial drug. Moreover, both forms of dosage are unsuitable for use by medical laypeople. Administering the drug once or several times a day would require substantial nursing care and hospital treatment. Self-administration by the patient – for example, with injection pens – is a solution that offers several advantages. The patient has more flexibility to choose
27.09.2017 14:17:14 Uhr
SUPPLY ON DEMAND – PHARMACEUTICAL FOLDING BOXES IN SHORTEST TIME.
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Your requirements: no storage of pharmaceutical packages on your premises and flexible delivery of small quantities in combination with highest product quality and greatest possible process security. Our solution: needs-based delivery of high-quality folding boxes within one week. Supply on Demand is another innovative, GMP compliant solution developed by Rondo, technology pioneers in folding boxes for the pharmaceutical industry. Find out more about Rondo’s Supply on Demand solution on
WWW.RONDO-PACKAGING.COM /SUPPLY-ON-DEMAND
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Products & services
Prepare from the start UGA Biopharma GmbH The company
provides customised cell line development services for biosimilars and New Biological Entities (NBEs), including clone generation, bio-process optimisation, downstream development, and analytics. Their success is based on the choice of an appropriate host cell line, optimized expression vectors, First CHOice® cell culture medium, and longstanding expertise. UGA Biopharma seeks partners to (a) out-license ready-to-use research cell lines (RCB) or (b) start a new development project for a biosimilar/ NBE-expressing cell line together with clients. The portfolio consists of cell lines expressing Adalimumab (Humira®), Aflibercept (Zaltrap®), Anakinra (Kineret®), Bevacizumab (Avastin ®), Certolizumab (Cimzia®), Dupilumab (Dupixent®), Eculizumab (Soliris ®), Imiglucerase (Ce-
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Efficient gene silencing promocell GmbH PromoFectin-siR-
NA is a non-liposomal, cationic transfection reagent designed for an optimized deliver y of siRNA as well as miRNA, oligonucleotides and other ribonucleic acids into a wide variety of cell types, including problematic cell lines and primary cells. PromoFectinsiRNA enables a functional and highly
Contact
PromoCell GmbH Sickingenstr. 63/65 69126 Heidelberg www.promokine.info info@promokine.info
Reduce matrix effects & interferences CANDOR Bioscience GmbH LowCross-
Buffer improves ELISA and immunoassays and replaces HAMA blockers. LowCross-Buffer ® is a substitute for HAMA blockers and prevents matrix effects and interferences. The antibody and sample diluent is applicable for ELISA, EIA, RIA, protein arrays, Western blotting, immuno-PCR, and immunohistochemistr y. False positive or false negative signals and high background can be prevented by using LowCross-Buffer ®. The unique formulation of LowCrossBuffer® helps to shield the specific signal from low or medium affinity cross-reactivities or interferences in immunoassays like an “affinity gate keeper.” Thus quality of detection can be significantly improved. In addition matrix effects – coming from blood sera or plasma specimen, for example – are reduced, and thus no longer exacerbate detection of analytes. Minimising all these negative effects upgrades the quality of the assay and improves the reliability of the results. ®
rezyme®), Ipilimumab (Yervoy®), Laronidase (Aldurazyme ® ), Natalizumab (Tysabri®), Nivolumab (Opdivo®), Omalizumab (Xolair®), Pembrolizumab (Keytruda®), Pertuzumab (Perjeta®), Vedolizumab (Entyvio®). D Contact
UGA Biopharma GmbH Hennigsdorf (Germany) Phone +49 (0) 3302 20 24 900 info@ugabiopharma.com www.ugabiopharma.com
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efficient gene silencing (›90%) with ver y low amounts of siRNA (‹1 nM), avoiding cytoxic and off-target effects. The formulation is compatible with both serum and antibiotics and the fast, easy-to-use protocol is adapted to adherent as well as suspension cell culture. PromoFectin-siRNA shows a very low cytotoxicity for more robust data and excellent cell viability. See our current promotion at http://www. promokine.info/promotion.
LowCross-Buffer ® is ready-to-use and available in bottle sizes of 50 ml, 125 ml and 500 ml. Contact CANDOR Bioscience GmbH Tel.: +49-7522-795 27-0 Fax: +49-7522-795 27-29 info@candor-bioscience.de www.candor-bioscience.de
Pictures: UGA Biopharma (left), Promocell (above), Candor Bioscienc (bottom)
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A RE YOU L OOKI N G FOR EX PERTS I N
MICROBIAL PRODUCTION?
CONTRACT DEVELOPMENT AND MANUFACTURING OF BIOPHARMACEUTICALS Richter-Helm is a Germany-based GMP manufacturer specialized in products derived from bacteria and yeasts, with a proven 25-year track record. ;gmfl gf mk lg Ʈ ]paZdq hjgna\] Y [gehj]`]f% sive range of services and customized solutions. ;da]flk ogjd\oa\] `Yn] Ydj]Y\q Z]f]ƭ l]\ from our commitment to good manufacturing practice and total transparency. Our work focuses on recombinant proteins, plasmid DNA, antibody fragments, and vaccines. Richter-Helm consistently works to the highest standards of pharmaceutical quality.
Contact us +49 40 55290-436 www.richter-helm.eu
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27.09.2017 14:18:10 Uhr
SAVE THE DATE
SWISS BIOTECH DAY 2018
Mark your calendar for next year‘s Swiss Biotech Day, the leading biotechnology conference in Switzerland. Now in its 20th year, the event is not just the place to be for members of the Swiss Biotech Association, who traditionally meet there for the association’s Annual General Assembly. As always, the event targets entre... ONE preneurs, investors, researchers, analysts, political decision makers and industry stakeholders. So, don‘t miss the chance to meet around 600 experts from across Europe.
22
BIOTECH CLUSTER
APRIL 2013 3 MAY 9, 2018
Picture: © Rynacher/ https://commons.wikimedia.org/wiki/File:Basilisk_Wettsteinbrücke.JPG (CC BY-SA 3.0); GNU Free Documentation License
Picture: © Basel Tourismus
The leading Life Sciences Conference in Switzerland and Annual General Assembly of the Swiss Biotech Association
Pre-register online at www.swissbiotechday.ch to be one SIX Swiss Exchange, sector is internationally visible. The project-specific BIOTECHNOLOGY” of the first to receive all information on “WHITE programme, exBasel Congress Center WORKING GROUP participating companies (most of them young and inSWISS BIOTECH... ConventionPoint, Zurich ternationally less savvy) find a comprehensive partner hibitors, sponsoring and the partnering Leading system as soon which is helping to put them in the public window. chemical companies are exploring the op...is an alliance of four leading Biotech regions of portunities that have been opened up by modern bio- The participating Life Science Regions are important Switzerland (Bio Alps, BioPolo Ticino, Basel Area as it is available. internal carriers of the dynamics in the Biotech sectechnology, especially in the field of “white” or indusand Greater Zurich Area). They have combined ef-
Sponsors:
Supporting Partners:
trial biotechnology. And they are also applying these technologies, wherever it makes sense. The SBA takes such initiatives seriously and has formed a working group specifically dedicated to white biotechnology. The Swiss Industrial Biocatalysis Consortium is an important partner in this effort. The group includes leading multinational companies that support white biotechnology as a pillar of economic growth. The planned activities are in agreement with OECD strategies. In partnership with the Swiss Biotechnet (see pages 14/15) the SBA develops training programmes and useful support tools for the industry. It is of importance that the industry specifies its training needs so that the academic side can create tailor-made education. This strategy ensures that the industry gets the right workforce with the right education. The SBA profits from the marketing alliance “Swiss Biotech” (see box) in a multiplied form. Thanks to Swiss Biotech, the
European Biotechnology
NET WORK
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tor, thus enhancing the common understanding of the industry. This and more knowledge is brought into Europa Bio, the European Biotech Association, where the SBA is an active member.
Media Partner:
Domenico Alexakis is Executive Director of the Swiss Biotech Association.
forts to streamline interests of the national biotech sector. The SWX Swiss Exchange holds a leading position in terms of lifescience listings and offers companies from that industry – be they located in Switzerland or abroad – access to an internationally recognised financial marketplace. The initiative was co-founded Organised by:by the SBA which also manages the executive office of Swiss Biotech.
@
For further information please visit www.swissbiotechassociation.ch www.swissbiotech.org
27.09.2017 14:18:20 Uhr
European Biotechnology | Autumn Edition | Vol. 16 | 2017
REGULATORY AFFAIRS
89
EMA’s staff loves London BREXIT The EMA has drafted an initial plan outlining how it might fulfil its most important tasks after significant projected staff loss due to the expected relocation of the agency. The plan, published at the end of September, designates three priority levels for the agency’s activities and defines the workforce required for each:
› Level 1 activities (462 full-time employees required) include all activities needed to evaluate and monitor the safety of medicines, and to uphold the regulatory network’s infrastructure. › Level 2 activities (additional 140 FTEs required) relate to public health issues, such as fighting antimicrobial resistance, improving access to medi-
cines, and establishing collaboration of HTAs. › Level 3 activities (additional 110 FTEs required) cover corporate governance, audits, and participation in conferences and meetings. Additionally, in September the agency performed a staff survey (receiving a 92% response rate) to inform its recruitment strategy to compensate for significant staff losses. It showed that the new EMA location – to be selected from a list of 19 candidate cities – will be a determining factor in whether the majority of employees decide to relocate and remain with the agency. The agency discovered that in a best case scenario it could retain up to
www.ema.europa.eu 65% of its workforce; worst case, below 30% (other estimates range from 50–65% to 30–50%). Even assuming that 65% of the staff remained, the EMA would still require two to three years for full recovery. The priority-level staff requirements clearly demonstrate that a retention rate below 30% would result in permanent damage. However, more than 65% of the EMA staff would be willing to move to five of the potential host cities, in which case the EMA could likely continue full operations.
Recommendations from the EMA: MA (market authorisation); cond. MA (conditional MA); e.c. MA (MA under exceptional circumstances; hybrid MA (MA based preclinical data, results of clinical trials for a reference product and, in part, on new data).
Drug name
Indication
Company
Status
› Maviret (glecaprevir/pibrentasvir)
Treatment of hepatitis C in adults
AbbVie Ltd
MA rec.
› Vosevi (sofosbuvir / velpatasvir / voxilaprevir)
Treatment of hepatitis C in adults
Gilead Sciences International Ltd
MA rec.
› Soliris (eculizumab)
Treatment of myasthenia gravis in patients stratified for ACh receptor overexpression
Alexion Europe SAS
MA rec.
› Kisqali (ribociclib)
Treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer (in first-line setting when combined with aromatase blockers)
Novartis Europharm Ltd
MA rec.
› Fotivda (tivozanib)
Treatment of advanced renal cell carcinoma
EUSA Pharma
MA rec.
› Imraldi (an adalimumab biosimilar)
Treatment of of rheumatoid arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, psoriatic arthritis, psoriasis, paediatric plaque psoriasis, hidradenitis suppurativa, Crohn’s disease, paediatric Crohn’s disease, ulcerative colitis and uveitis
Samsung Bioepis UK Ltd
MA rec.
› Mavenclad (cladribine)
Treatment of relapsing forms of multiple sclerosis
Merck Serono Europe Ltd
MA rec.
› Zafiride (NGR-human tumour necrosis factor alpha)
Treatment of advanced malignant pleural mesothelioma
MolMed S.p.A
MAA withdrawn
› Cuprior (trientine tetrahydrochloride)
Treatment of Wilson’s disease
GMP Orphan SA
hybrid MA rec.
› Rixathon (a rituximab biosimilar)
Treatment of acute lymphocytic leukaemia, non-Hodgkin’s lymphoma, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis.
Sandoz GmbH
MA rec.
› Riximyo (a rituximab biosimilar)
Treatment of non-Hodgkin’s lymphoma, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis
Sandoz GmbH
MA rec.
› Kevzara (sarilumab)
Treatment of rheumatoid arthritis
Sanofi Aventis
MA rec.
› Skilarence (dimethyl fumarate)
Treatment of psoriasis
Almirall SA
MA rec.
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Science
European Biotechnology | Autumn Edition | Vol. 16 | 2017
World Nutrition: Insects will be on every table Bioeconomy It could be a turning point for the fish meal and fish oil dependent animal feed
industry in Europe. Since July, the European Commission has allowed the use of insect-processed animal proteins for aquaculture. According to experts, the use of insect meal as a sustainable alternative opens an US$90bn market.
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In 2050, the world population is expected to reach nine billion people. According the Food and Agriculture Organisation of the United Nations (FAO), humanity will need up to 265 million tons of additional proteins per year. “Probably the most exciting development in global nutrition of the future is the supply of high quality protein from algae, insects and microorganisms,” states Prof. Hannelore Daniel, member of the German Bioeconomy Council, which recently published a background paper on alternative protein sources in the farming industry.
Low footprint guaranteed Insects are abundantly available, with a high nutritional value and a tiny ecological footprint. They can offer a valuable and sustainable addition to soybean and fishmeal – the most common protein sources for aquaculture and livestock. In comparison to other livestock, insects are relatively easy to breed and rear. According to in-
French company Ynsect breeds and processes mealworms (Tenebrio molitor) for mass-scale production of insect protein.
Pictures: Protix, Fair Insects
Imagine your dinner consists of beetles or worms. In Switzerland, insect-eating is now entering everyday life. However, nothing yet crawls on the plate. In August, Switzerland revised its food safety laws and began selling insect products, like burgers or balls made of insect flour, in its second-largest supermarket chain, Coop. But a much larger market is expected in animal breeding. Although the general European human population is not yet eager to introduce the crunchy and nutritious snacks into its diet, insects may soon become a promising source of high-quality, sustainable proteins as an add-on to fishmeal feed formulae for aquaculture. They are rich in proteins and lipids and have a very high content of unsaturated fatty acids, and dietary fiber in the form of chitin and minerals, such as iron or calcium. “It makes them a serious alternative as a high-quality natural diet for fish feed and pet food and opens an estimated US$90bn market,” states Antoine Hubert, president of the International Platform of Insects for Food and Feed (IPIFF).
dustry experts, even on large production scales, they dont need hormones or antibiotics to grow fast or fend off infectious diseases. Some species, like the black soldier fly, can also be fed with organic waste products, such as farming or food waste. Besides that, excrement from the insects can be used as a fertilizer in farming. Larvae require little space and consume low water levels. Furthermore, insects are very efficient in transforming feed into proteins: they need two kilograms of feed to produce one kilogram of mass. In comparison, cattle require 8 kg biomass to produce 1 kg of body weight gain. Concerning the use of insect proteins as animal feed, Europe has reached an important milestone. Since July, the European Commission has allowed the use of insect-processed animal proteins (PAPs) for aquaculture animals. “The green light for the fishing industry is absolutely a huge step forward for the insect industry. It gives insect protein producers high visibility for potential investors for the first time,” says Hubert. The future promise of the insect farming industry was underscored by the recent €45m in funding received by Netherlands-based insect
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company Protix in June – the largest investment in the nascent European insect farming industry to date. In 2009, Protix started their business by developing the first technologies to breed insects. Focusing on scalability and quality, the technologies they devised enabled the industry to take off. The two former McKinsey & Company colleagues and Protix founders, Kees Aarts and Tarique Arsiwalla, built the first demo plant in the Netherlands for producing processed insect proteins, a type of PAP. With current technologies, the whole development chain – from rearing to separation and extraction of proteins – can be run automatically and produce large volumes of insect meal. Protix farms insects predominantly to produce animal and aquaculture feeds – including specialty feeds for pigs, poultry, and pets – and exports its products to more than 12 countries. Its four products are all derived from the black soldier fly. In September, they also acquired the Dutch company Fair Insects BV and diversified their portfolio by adding mealworms, crickets, and locusts.
Reaching the next scale At the beginning of this year, Protix created a joint venture with Switzerlandbased food technology group Bühler named Bühler Insect Technology Solutions. Bühler has developed technologies for milling, one of the key proc-
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the focus of the VC will remain on larvae of BSF.
Current legislations
Antoine Hubert President of the International Platform of Insects for Food and Feed (IPIFF) and CEO of insect company Ynsect.
?
How many kilograms of insect do you need to produce one kilogram meal?
!
The ratio is about four between the living insect to the protein, so for 20,000 tonnes of protein meal you need 80,000 tonnes of live insects. For oil it is 6,500 tons more.
ess steps for extracting proteins from insects, drawing upon their more than 150 years of experience in developing scalable, hygienic plants and processes for food and feed products. The VC is established in Switzerland and has manufacturing plants in Asia, because of the region's long-standing tradition of using insects in the animal industry, and lower barriers to consumer acceptance of insect-based food products. Initially
In many European countries, animal proteins have been banned from use in livestock feeds since 1994, due to the “mad cow disease” crisis triggered by the spread of bovine spongiform encephalopathy (BSE). A legal framework for the use of insect-based feed has consequently yet to be created. In July, the European Commission partially lifted the so-called “feed ban rules” regarding the use of insect-processed animal proteins for aquaculture animals. The authorisation is, however, limited to seven insect species: black soldier fly, house fly, yellow mealworm, lesser mealworm, house cricket, banded cricket, and field cricket. Insects kept in the EU for the production of food, feed, or other purposes are considered “farmed animals” governed by the general EU feed rules. As a consequence, insects cannot be fed with particular materials, such as slurry or manure, catering waste, or processed former foodstuffs containing meat or fish. “Right now, proper communication and guidelines for farming and processing standards in Europe need to be the next steps concerning the use of insect protein in fish feed,“ states Hubert. IPIFF was launched in 2015, combining forces from 40 members of the insect-producing industry from the Netherlands (e.g. Protix, Proti-Farm), France (e.g. Ynsect, Entomo Farm, NextAlim, Micronutris), Germany (Hermetia) and Poland (Hipromine).
Pictures: Ynsect (portrait), Bühler Insect Technology Solutions
Crunchy diet for Europe’s plates
In June, Kees Aarts, founder and CEO of ProtixTM and Andreas Aepli, new CEO of Bühler Insect Technology Solutions in June announced they planned to build the first industrial scale insect processing plant in Europe, situated in the Netherlands. It should be operational in the first half of 2018.
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Although about 1,500 species of insects are consumed in more than 100 countries worldwide, in Europe, they are still very little accepted and food and insect-eating is still in a legal gray zone. But at the beginning of 2018, a new EU regulation will come into force and ensure clarity. Insects will then be recognised as novel foods and need will have to undergo a centralised assessment and authorisation procedure by the European Food Safety Authority. L h.maerzhaeuser@biocom.de
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Science & Technology
News Desired side effect Screening a chemical library for drugs to treat Parkinson’s disease (PD), a team of researchers from Norway, the US, Canada, and Germany has identified b2 adrenergic receptor (b2AR) agonists as a promising new treatment approach (Science, doi: 10.1126/science.aaf3934). Digging through 4 million health records of Norwegian patients, Clemens Scherzer and colleagues found that the asthma therapy salbutamol – a smooth muscle relaxant and short-acting b2AR that blocks expression of the alpha-synuclein gene – decreased PD risk, while propranolol – an anti-hypertensive that boosts a-synuclein expression – increased the probability to develop the neuronal disorder. Aggregation of a-synuclein proteins in the brains of PD patients into socalled Lewy bodies is a known risk factor for the disease.
Halting tumour escape Tracking molecules transported in exosomes, the body’s cell-to-cell communication system, researchers from Luxemburg, Germany, and the US have unraveled a mechanism used by blood cancer cells to turn cells of the innate immune system into cancer-supporting and immunosuppressive puppets (Sci Immunol, doi: 10.1126/sciimmunol.aah5509). Exosomal Y RNA hY4 from malignant chronic lymphocytic leukemia (CLL) blasts reprogrammed monocytes from healthy volunteers in vitro to adopt a CCL phenotype and to express the immunosuppressor PD-L1. Blockers of innate immune receptor TLR7 abolished the effect in mice.
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European Biotechnology | Autumn Edition | Vol. 16 | 2017
Untangling Alzheimer’s Neurodegeneration Australian, US,
and French researchers have taken another step towards a better understanding of the complex processes that lead to neurodegeneration. The group, headed by Sylvain Lesné from INSERM Grenoble, reported that the newly identified amyloid-b oligomer Ab*56 induced specific alterations in neuronal signaling that led to tau phosphorylation and aggregation in mouse neurons (Science Signalling, doi: 10.1126/scisignal.aal2021). Specifi-
cally, Ab*56, but not dimers or trimers, triggered modifications to the tau protein that have previously been implicated in the onset of Alzheimer’s disease. The researchers determined that Ab*56 interacted with the NMDA receptor that controls memory function in aged mouse brains. NMDAR inhibition prevented Ab*56 from causing changes to tau in neurons growing in culture. The authors believe that the amyloids are also relevant in other neurodegenerative disorders.
Mahagoni drug vs. blood cancer Multiple Myeloma A new compound
prevents multiple myeloma (MM) cells from producing proteins that are essential to their growth and survival. In a screening for anti-multiple myeloma activity, French and US researchers led by Salomon Manier identified rocaglate scaffold inhibitors as the most potent blockers of MYC-driven translation initiation, in addition to up-regulation of ribosome biogenesis, a characteristic feature in MM (Science Translational Medicine, doi/10.1126/ scitranslmed.aal2668). The best hit, CMLD010509, killed MM cells grown in a culture, and shrank tumours in three different mouse models
while being well-tolerated and sparing normal blood cells. The derivative of a class of chemicals produced by mahogany trees reduced the levels of 54 proteins in multiple myeloma cell lines, including MYC, MDM2, CCND1, MAF, and MCL1. Analysing the gene expression pattern induced by CMLD01059, the team found that the drug triggered apoptosis. Because protein production in cancer cells is frequently abnormal compared to normal blood-forming cells, the researchers say targeting the MYC-driven translation programme in MM with rocaglates could offer new, nontoxic, therapeutic options.
Mice treated with a new type of targeted cancer therapy (right) had smaller tumours (cooler colours) compared to control animals.
Picture: S. Manier et al., Science Translational Medicine (2017)
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Science & Technology
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The two faces of microglia Alzheimer’s For years, neurologists have hunted for the source of cell toxicity that drives
Picture: Fotolia.com/ralwel
neurodegeneration and cognitive decline in Alzheimer’s disease. An Indian researcher at the University of Zurich might now have solved the mystery. It’s not hidden in amyloid plaques, as researchers previously believed, but in the microglia, the brain’s innate immune system, which triggers loss of synaptic junctions resulting in loss of cognitive functions. Formation of Alzheimer plaques by accumulation of b amyloid proteins are a hallmark of Alzheimer’s disease. Amyloid oligomers and plaques have been considered the primary cause of synaptotoxicity in patients suffering from the neurodegenerative disease that affects 44 million elderly people globally. To determine if and how the brain’s immune system contributes to amyloid clearance and thus preserves neurodegeneration, which is mediated by loss of synapses, Swiss, British, and US researchers, headed by Lawrence Rajendran from University Zurich, conducted loss-of-function experiments in glia cells, knocking out the most common 18 genes linked to neurodegenerative proteinopathies of the brain. As glia cells are known to remove cell debris, such as degenerated proteins, it seemed an attractive hypothesis that b amyloid depletion is driven by factors affecting the phagocytotic activity of the brain’s innate immune cells. In a siRNA screen, post-doc researcher Rosa Chiara Paolicelli, in fact found that genes affecting neurodegeneration sped up b amyloid phagocytosis when silenced in mice. The most pronounced effect was seen with TDP-43, a transcriptional repressor (Neuron, doi: 10.1016/j.neuron.2017.05.037). To her surprise, she made an additional observation. Despite the reduction in amyloid load, she found a significant decrease in synaptic markers in these mice. This points to re-activation of a glia cell function. So far this was only observed in post-natal brain development, during which the brain is rewired including degradation of synapses, the connection between neurons, which is crucial for
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Synaptic loss is a hallmark of cognitive decline, which occurs when the brain can no longer compensate for neurodegeneration.
proper cognitive function. Quantification of the synaptic marker vGlut1 confirmed a drastic reduction in glutamatergic synapses, suggesting that abnormally phagocytic microglia remove not only amyloid but also synapses. Futher experiments showed that TDP-43-mediated synapse degradation occured regardless of the presence of amyloid.
New paradigm of neurodegeneration? “Our data show that abnormal phagocytosis and clearance elicited in microglia following TDP-43 loss is ultimately paradoxical,” the researchers conclude. “These processes are not entirely beneficial in the context of a complex organism, since microglial phagocytic activity
might not only enable clearance of protein aggregates but also synaptic connection loss.” According to Rajendran, “These mixed responses may underlie the failure of many AD drug treatment clinical trials to improve cognitive function, despite the progressive reductions in amyloid burden.” Up to now, it is not known which factors drive TDP-43-driven synaptic degradation. ”Nutrient depletion in the ageing brain might boost phagocytotic activity of the microglia, thus triggering synaptic loss,” speculates Rajendran. Though identification of such metabolic trigger factors seen far off, the new mechanism of TDP-43-mediated neurotoxicity could trigger causative approaches to treat neurodegeneration. L t.gabrielczyk@biocom.eu
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BIOECONOMY
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Archaea were first discovered in extreme environments like hot springs. Depicted is the Grand Prismatic Spring in Yellowstone National Park in the US.
Hot guys in the pool rescue sustainability The renewable energy sector is ramping up in a major way, but a host of infrastructure issues still need to be solved. One is that supply at times now outstrips demand, but there’s no way to store excess power. Turning it into an easy-to-store, energy-rich source like methane could solve the problem. A pivotal aspect of ‘power-to-gas’ technology harnesses some tiny helpers usually found in some of the most extreme regions on the planet.
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Picture: Wikimedia Commons/James St. John
BIOLOGICAL METHANATION
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Picture: Electrochaea
P
ower-to-gas conversion (P2G) is a technology to watch. But does it really have a bright future? “Ultimately, the success of P2G depends on a country’s policy,” says Michael Sterner. As the coordinator of Germany’s ORBIT project, he’s conducting efforts by eight partners to develop better bioreactors in the biotechnological synthesis of methane. Funded with €1m by the German Federal Ministry of Economics and Energy, the project is focused on biological methanation, which uses microorganisms to produce “green” methane from hydrogen. Among the ORBIT partners are three competing companies that are trying to come up with the best technological approach. One of them is Electrochaea. “Power-to-gas was hot in Europe, but not so much then in the US,” recalls Mich Hein, head of the Munich-based firm. “We actually started in St. Louis as a virtual company. After a few initial steps, we were searching for a location with funding and existing infrastructure to develop our technology.” But when Hein couldn’t find that site in the US, he switched gears and headed to Denmark. “The owner of the gas grid Energinet.dk recognised the potential for our technology to feed our renewable gas into their grid and meet long term goals for renewable natural gas in Denmark. With a grant of US$1.2m from the Danish Energy Agency (EUDP), we tested our P2G technology using a 10,000-liter reactor vessel, with raw biogas coming from an on-site agricultural biogas reactor.” After implementing the technology, the system ran continuously for more than 3,200 hours between August 2013 and February 2014 at Aarhus University’s Biogas Research Center in Foulum. “Even though the bioreactor there didn’t have an ideal geometry, the organisms performed better than the rest of the system,” Hein says. “Every other part of the modified system failed at least once during testing, but the biological catalyst continued to work.” All current P2G concepts are in some way based on two fundamental steps (see figure on page 96). Excess electricity is
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Mich Hein CEO of Electrochaea (Germany) and partner at investment firm Focus First (US)
? !
What’s the untapped potential for archaea in biotechnology?
We think several products are possible beyond methane production. To our knowledge, no-one has ever cultivated a monoculture of archaea over 5,000-litres, like we did. Based on this scale, archaea-made molecules for the personal care and lubricant industry, as well as for the medical sector, would make a lot of sense. But those are long-term ideas for Electrochaea. Right now, we’re clearly focussed on gas.
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Archaea also play a central role within the ORBIT project. Constituting the third domain of life (alongside bacteria and eukaryota), these microorganisms have characteristics fitting theories about what very early forms of life on the planet probably looked like. They occur in a wide range of oxygen-free habitats such as marshes and swamps, hydrothermal vents ashore (hot springs, geysers) and at the bottom of the ocean (black and white smokers), but also in the human digestive tract. Within the framework of ORBIT, the interplay between biology, process engineering and unit control is being developed from scratch. Started in mid2017, the project will run three years. Participating companies hope to gain new insights from the project for the operation and further development of their reactors, which should in turn promote uniform comparison standards in engineering new facilities. “So far, most approaches have employed fixed-bed reactors, with gas being introduced from below under high pressure,” explains ORBIT coordinator Sterner. “However, we’re trying to establish the use of trickle-bed reactors, because they’re much more energy efficient.”
No other pigs at the trough used for the electrolysis of water, which produces hydrogen. That’s followed by the reaction of hydrogen and carbon dioxide resulting in methane (methanation), which can be accomplished with or without help from microorganisms. Are bacteria or archaea involved, the process is called biological methanation. The resulting methane – also the main constituent of fossil natural gas – can be fed directly into natural gas networks. “We’re finally creating the link between Denmark’s abundance of wind power and production of eco-friendly gas to the Danish gas grid,” said Kim Behnke, Head of Environment, Research and Development at Energinet.dk back in 2014. That’s when Electrochaea began to take its technology to the next level with the construction of a demonstration plant in the Danish city of Avedøre.
From a process engineering perspective, fixed-bed reactors are possibly less efficient, but so far they’ve been the benchmark in bioreactors that work with archaea. “I’ve been surprised how well we’ve been able to maintain basically an archaea monoculture in this open system....although it’s not exactly a monoculture, as we put raw, unfiltered biogas into the reactor, which contains living organisms,” explains Hein. But according to the trained chemist and expert plant physiologist, there have so far been no signs of ‘predators’ reducing archaea populations. “In a year and four months of operation at full scale in Avedøre, and in seven months of operation in Foulum we have not had an incident of another pig at the trough,” Hein says. “That is to say, there were no other microbes outcompeting our archaea.”
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POWER GRID
GAS GRID
wind energy
– for heating – for transportation – as chemical feedstock wind and solar fuels
gas-fired power plant, block-type thermal power station
solar energy
power generation other renewables
power storage
gas storage O2
electrolysis, H2 reservoir CO2 – atmosphere – geothermal sources – biomass, waste – industry – (fossil fuel power plants)
CO2 reservoir
H2
CO2
CH4 methanation
“wind methane” “solar methane” H2O
renewable energy methane / power-to-gas unit
© Fraunhofer IWES, ZSW Source: Sterner, Specht
To date, the electricity and gas markets have been linked uni-directionally: from gas to power. However, the transition to a 100% renewable energy systems is challenging the status quo of electricity generation. Power-to-gas (P2G) technology reverses this energy flow by converting electrical power into stored chemical energy in the form of methane.
The Avedøre project kicked off in early 2014, construction was completed early last year and soon thereafter, grid quality biomethane was produced. Still running, in thousands of hours of operation, data about the robustness, efficiency, dynamics, productivity, longevity and reliability of the system was collected. In late 2016, Electrochaea – with its headquarters in Munich, Germany, near its key investors – presented plans to build a P2G plant in Hungary. That facility will have a power consumption of up to 10 megawatts of energy – ten times more than the one in Avedøre. When it’s up and running, the Hungarian plant will be the world’s biggest P2G plant, but probably not for long. According to Electrochaea, plants with more than one gigawatt of capacity could become reality around 2025. “The P2G technology is the most advanced commercial technology based on
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archaea. With regard to scale and utility, I think we’re the most advanced of several competitors,” Hein told EURO BIOTECH. Two of those competitors are collaborators in the ORBIT project: Micropyros and Microbenergy/Viessmann. Micropyros has set up an R&D project in its home town of Straubing (Germany), while Microbenergy is already operating its first – and so far only – P2G demonstration facility in Allendorf (Germany). Both small-scale plants have been running for a couple of years, but there are still no clear plans for a scale-up.
Cultivating thermophiles “In microbiology there are two important temperature ranges: the mesophilic range at about 37°C and the thermophilic range above 55°C,” explains Paul Scherer from Hamburg’s University of Applied
Sciences. “The mesophilic area is preferred by both probiotic and pathogenic bacteria. In order to exclude these potentially harmful bacteria, the fermenters in our working group operate in the thermophilic range – where we’re definitely entering uncharted research territory.“ Asked about his experiences cultivating thermophilic archaea, Hein particularly mentions two stages: “One is where the organisms replicate with high rates. Cell division and cell growth are up. After inoculation, we reach full density in the tank within three days, and the doubling time is between two and a half and three hours. The second stage is different. Only a very little amount of provided carbon accumulates in biomass – if any at all. When we for example checked for detritus of cells after months of methane production, we barely found any. The doubling time is at least 100 hours.”
Picture: courtesy of Michael Sterner, OTH Regensburg; elenabsl/fotolia.com (Icons energy grid and power supplies); Edilus/fotolia.com (gas storage tank icon)
H2O
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While the organisms themselves are largely newcomers in commercial biotech, the enzymes archaea produce have been around for some time in the sector. Many play important roles in industrial biotechnology. Nearly all extremophiles are from the archaea domain. In a review, Jennifer Littlechild from the University of Exeter (UK) summarised that some of these biocatalysts are already being used in large-scale industrial processes for the production of optically pure drug intermediates, amino acids and their analogues. One such industrial process, used to produce specific L-amino acids, makes use of an L-amino acylase enzyme. A thermophilic archaeal version of the enzyme has been cloned and over-expressed from Thermococcus litoralis. Another prominent example is an alcohol dehydrogenase enzyme from the hyperthermophilic Aeropyrum pernix. It’s used industrially to make chiral alcohols.
An ancient past, a bright future Many other archaeal enzymes have been characterised at laboratory scale according to their substrate specificity and properties for potential industrial applications. The increasing availabil-
ity of DNA sequences from new archaea species and metagenomes provided by next-generation sequencing technologies is a constantly expanding resource in the race to identify new enzymes of commercial interest. Danish enzyme expert Novozymes knows a lot about the special features of enzymes that have been isolated from archaea. A spokesperson told EuroBiotech: “The main advantage of extremozymes like thermophilic enzymes lies in the high industrial process temperatures during enzymatic conversion. This is the case in processes that need to modify starch and lignocellulose for food or bioenergy.” Littlechild adds that the increased use of enzymes from extremophilic archaea offers the opportunity to access biocatalysts that are naturally stable in a variety of different conditions (temperature, pH, salinity or pressure). She says that makes them suited to different industrial processes than mesophilic microbes. Let’s wrap things up by returning to the energy sector, where some new technologies are focussing on storaging a liquid rather than a gas: methanol. The short alcohol is extremely versatile, and can be stored more easily
Picture: Paul Scherer, University of Applied Sciences, Hamburg
Power-to-gas (P2G) primer Power-to-gas technologies convert electrical power to a gas fuel. All current approaches first use electricity to split water into hydrogen and oxygen through electrolysis. The hydrogen can then be used or stored, but most commonly it’s combined with carbon dioxide to produce methane. Methanation can be via biological or non-biological means (e.g. Sabatier reaction). Most projects realized so far don’t employ microbes, but high temperatures and pressures. A notable exception is the European Union’s €28m Horizon 2020 project Store&Go, which includes a demonstration site in Solothurn (Switzerland) that utilizes Electrochaea’s biological methanation system. A big
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drawback of biological methanation is that it’s slow, but there are also advantages – like the microbes’ ability to cope with impurities in the H2 and CO2 supply chains. Methane- forming microorganisms are called methanogenic archaea, or methanogens. Although some current candidates have names reminiscent of bacteria, all are actually archaea. Electrochaea uses an adapted strain of the thermophilic methanogen Methanothermobacter thermautotrophicus. It was discovered by archaea pioneer Laurens Mets from the University of Chicago (US), and works 20 times more efficiently than strains found in nature. Electrochaea has an exclusive license for this particular strain. L
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Electron micrograph of CH4-producing archaea, which cling to a surface with cell appendages. Within the ORBIT project, scientists from the University of Regensburg‘s Archaea Center are seeking to identify suitable strains for use in the trickle-bed reactors. They want to find strains that grow stably on trickle-bed bioreactor fillers.
than methane. It can be burned to provide heat, generate electricity or power a vehicle. Power-to-liquid (P2L) approaches harness atmospheric carbon dioxide, water, electricity and some special enzymes. European Space Agency spin-out Skytree is now working together with German company Gensoric to develop the world’s first residential P2L system. Its ‘willpower’ system, the company claims, will allow anyone to produce their own fuel at home from surrounding resources. The European Commission is backing the project with a €1.7m grant. Instead of heating a large reactor, the system only brings the immobilised enzymes to the desired temperature. That saves energy. A first pilot plant was installed in Essen (Germany) this year. The firm hopes a crowdfunding campaign that runs into October will provide more money to develop a product for the mass market. Enzyme-driven, CO2-neutral fuel production in the garage – isn’t it a charming vision? m.laqua@biocom.eu
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ASSOCIATIONS
European Biotechnology | Autumn Edition | Vol. 16 | 2017
European Biotechnology is published in co-operation with the following organisations: European Biotechnology NET WORK
Europe: european-biotechnology.net
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Unwind pricing MARKET REVIEW Better access is cru-
cial, tailored solutions essential for EU governments in the biosimilar medicines market. This is the conclusion of the first review on biosimilar medicines policies of 31 European countries from the Medicines for Europe Association (MFEA). The review provides a detailed overview of the status of biosimilar medicines availability, pricing system, tendering, reimbursement, and benefit sharing for physicians, pharmacists, and patients. It demonstrates that “policy-makers need dedicated policies to provide more sustainable access to biosimilar medicines,” according to Adrian van den Hoven, Director General Medicines for Europe. “Benefit sharing with stakeholders has proven to be the most successful approach to improve access and we encourage governments to learn from the best practices around Europe. In their review, MFEA showed that biosimilars need a tailor-made policy framework and have successfully disentangled their pricing policies from those of generic medicines. More at medicinesforeurope.com.
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BIOSIMILARS Switching stable patients
from an original biologic to any of its biosimilars is is still nascent in practice. European Biopharmaceutical Enterprises (EBE), European Federation of Pharmaceutical Industries and Associations (EFPIA), and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) have published a position paper to underscore the central role of the physician when it comes to providing the appropriate treatment. According to the associations, any decision to switch should be made on a case-by-case basis and must be patient, disease, and product-specific. A one-size-fits-all approach is not appropriate. More information at ebe-biopharma.eu
EBE
White Paper on Personalised Medicine 98-103_EB_Autumn_2017_Associations_HM.indd 98
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Members make a difference Leveraging invaluable forums to exchange vital information and support progress on current issues related to health care products, technologies, and services. DIA NETWORK
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UPCOMING EVENTS › 25–26 October, Basel Value, Access and Regulatory Strategy Workshop www.DIAglobal.org/RegulatoryWorkshop › 15–16 November, Barcelona Medical Information & Communication Conference www.DIAglobal.org/MedInfo › 5–6 December, London, UK Clinical Trial Regulation Conference www.DIAglobal.org/ClinicalTrial › 17–19 April, 2018, Basel DIA EuroMeeting www.DIAglobal.org/EuroMeeting
› Through DIA Communities, DIA
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DIA Members & Volunteers Drive Advances in Drug Development
“How do we translate concepts and ideas into reality? How do we drive system-level changes that can be implemented and lead to improvements? We need all stakeholders to convene, align, and commit to change. As DIA, we continue to lead in addressing these critical, multi-stakeholder, global challenges that require a neutral, interdisciplinary forum, and driving the insights gleaned into actions. We are a large global body of individuals, spanning the therapeutic continuum, with one thing in common: We all believe that we can make a difference through our volunteer contributions to DIA,” states Barbara Lopez Kunz, Global Chief Executive of DIA. For 53 years, DIA has collectively brought together regulators, industry, patients, academia, payers, and students globally to advance therapeutic development. Stakeholders convene to discuss the path ahead across various
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disciplines including regulatory affairs, clinical research, pharmacovigilance, patient engagement, medical communications, and the list continues. Serving as an indispensable voice and platform, DIA member and volunteer engagement is a key driver in the decision making process that can affect the product life cycle and the outcomes for patients worldwide. The neutral posture of DIA encourages active participation. Because membership spans all aspects of health care product development and life cycle management, members are free to collaborate fully as they explore fresh ideas and think outside of their traditional fields. › Through Conference Engagement, DIA members both contribute their own insights as programme committee members and speakers, as well as gain new insights from colleagues by workshopping multi-stakeholder solutions.
members support one another by hosting guest speakers on the topic of “Regulator y Considerations for the Use of Social Media.” Or by sharing best practices to answer the question: “What are your thoughts on creating a P2-P4 protocol template to align with the various clinical transparency requirements?” › Through Content Access, DIA members advance their learnings through exclusive subscriptions to the DIA Daily and Therapeutic Innovation & Regulatory Science (TIRS) publications, along with access to thought leadership unique to DIA. DIA Members work together to speed innovation in health care product development. How are you making a difference? To explore more about Membership at DIA visit www.DIAglobal.org/Membership. Holger Adelmann, MD, PhD, Managing Director, DIA Basel
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Report for the economics ministry BIO International Convention The BIO International Conven-
tion, the world’s biggest biotechnology trade show, was held from 19 to 22 June in San Diego. This year’s event drew some 16,000 biotech leaders from 73 countries and broke a new record with more than 41,000 partnering meetings (compared to 35,600 meetings in 2016). The BIO International Convention offered partnering opportunities and a diverse programme featuring more than 400 sessions and company presentations. BIO Deutschland’s Secretary General, Viola Bronsema, participated in the opening panel discussion “What in the World Matters? The Challenge of Spurring Innovation in Global Markets,” which also in-
cluded the heads of the British, Canadian and South African biotech associations. These and other global biotech leaders discussed the challenges that countries are facing as they try to catch up with the prevailing US biotech industry. BIO Deutschland was the official rapporteur of the Federal Ministry for Economic Affairs and Energy (BMWi), which
BIO-Plenum: left: Viola Bronsema, Secretary General BIO Deutschland
Upcoming Events › 18–19 April, 2018, Hannover 9th German Biotechnology Days www.biotechnologietage.de/en/
organises the German Pavilion to support German companies participating in the BIO International Convention. Germany was once again one of the largest international delegations. The German Pavilion showcased some 45 companies and BioRegions – including many members of BIO Deutschland – and around a dozen companies also had their own booths. In addition to its reporting role, BIO Deutschland ran the pavilion’s main information booth and gave the booth’s many visitors comprehensive information on the exhibitors, as well as the German biotech industry and German biotech companies. BIO Deutschland was assisted in this task by Germany Trade and Invest (GTAI), which provided visitors with information on setting up a business in the United States or Germany. In 2018 the BIO International Convention returns to the East Coast: Boston will once again be host to the global event of the biotechnology community from 4 to 7 June this year. L
E vent German Biotech Days 2018 (Deutsche Biotechnologietage, DBT) will take place on 18 and 19 April in Berlin. The conference provides a meeting place for more than 800 representatives from business, science, and government, including partners from funding institutions and public administration. State Secretary Georg Schütte of the Federal Ministry of Education and Research will kick off the event with a welcome address in the opening plenary session and award the biotech
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founders’ prize, Gründungsoffensive Biotechnologie (GO-Bio), to promising German biotech pioneers. In parallel lectures, the topics business environment, medical biotechnology and industrial biotechnology will be presented. One more track is reserved for presentations of companies and research institutes that receive public funding through the federal research and economics ministries. Additionally, there will be company presentations and a start-up challenge, both held entirely in English. If
you are interested in one of the company presentation slots, which are reserved for biotech R&D companies of all stages, please apply by sending an email with a short abstract describing your business model to englbrecht@biodeutschland.org. The DBT day pass costs 250€, including the evening reception. The conference is co-organised by BIO Deutschland and the Council of German BioRegions. Registration is open under www.biotechnologietage.de/en/registration.html. L
Picture: BIO Deutschland
DBT – a successful platform for companies
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“WHITE BIOTECHNOLOGY” WORKING GROUP
sector is internationally visible. The project-specific participating companies (most of them young and internationally less savvy) find a comprehensive partner which is helping to put them in the public window. Leading chemical companies are exploring the opportunities that have been opened up by modern bio- The participating Life Science Regions are important internal carriers of the dynamics in the Biotech sectechnology, especially in the field of “white” or industrial biotechnology. And they are also applying these | Autumn Edition | Vol. 16 | 2017 tor, thus enhancing the common understanding of the Europeantechnologies, Biotechnology wherever it makes sense. The SBA takes industry. This and more knowledge is brought into Europa Bio, the European Biotech Association, where such initiatives seriously and has formed a working the SBA is an active member. group specifically dedicated to white biotechnology. The Swiss Industrial Biocatalysis Consortium is an important partner in this effort. The group includes leading multinational companies that support white biotechnology as a pillar of economic growth. The planned activities are in agreement with OECD strategies. In partnership with the Swiss Biotechnet (see pages 14/15) the SBA develops training programmes and useful support tools for the industry. It is of importance that the industry specifies its training needs so that the academic side can create tailor-made education. Domenico Alexakis This strategy ensures that the industry gets the right is Executive Director with theDay right education. The SBA profits Swissworkforce Biotech of the Swiss Biotech from the marketing alliance “Swiss Biotech” (see box) Association. in a multiplied form. Thanks to Swiss Biotech, the
New CEO announced The 2017 Swiss Biotech Day Fall has focused on current trends within the development of antibodies for therapy and diagnostics towards precision medicine. Executives from the Swiss Biotech Industry gathered at the Swiss Biotech Day Fall in Eysin this year.
The Swiss Biotech Day Fall 2017 in Eysin on Precision Medicine took place within the European Biotech Week, a celebration of biotechnology, including over 100 events across Europe. Hosted by Becton Dickinson Switzerland, inputs featured the current developments and challenges of biologics development and application for diagnostics and targeted therapies. The case presented by Dr. David Hickmann, AC Immune, was complemented by insights into developments in application, clinical research, and intellectual property. The tour through the BD Innovation and Engagement Center sets new standards in interaction with stakeholders. The SBA took advantage of this successful event to announce that Michael Altorfer has been appointed as Chief Executive Officer effective January 1st, 2018.
SWISS BIOTECH...
...is an alliance of four leading Biotech regions of Switzerland (Bio Alps, BioPolo Ticino, Basel Area and Greater Zurich Area). They have combined efforts to streamline interests of the national biotech sector. The SWX Swiss Exchange holds a leading position in terms of lifescience listings and offers companies from that industry – be they located in Switzerland or abroad – access to an internationally recognised financial marketplace. The initiative was co-founded by the SBA which also manages the executive office of Swiss Biotech.
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@
For further information please visit Upcoming Events www.swissbiotechassociation.ch www.swissbiotech.org
› 16 October 2017, Bern NTN Antibiotics Working Group Meeting › 26 October 2017, Sierre Swiss Symposium in Point-of-Care Diagnostics › 8 November 2017, Wädenswil TEDD Annual Meeting
Michael Altorfer, new CEO of Swiss Biotech Association
Dr. Michael Altorfer has more than 20 years of experience in the life science industry, comprising postions at both big pharma and smaller biotech organizations. As a member of the Executive Committee, he supported the build-up of Polyphor Ltd in many different roles (Head BD&L,
CFO, COO and CEO). Michael started his career as a scientist in pharmaceutical research at Sandoz, Ciba-Geigy (Summit, NJ, USA), and Roche. From 1996 to 2001 he held program management and line management roles at the investment bank UBS Warburg. Michael studied Natural Sciences at the ETH and he obtained his Ph.D. in Chemistry under the supervision of Prof. Dr. H.-J. Hansen (University of Zurich) and Prof. Dr. K. Müller (Roche), and holds an MBA degree from the University of Rochester, NY, USA. L
Pictures: Swiss Biotech Association
Stimulate exchange Network The National Thematic Network (NTN) Swiss Biotech™ is a unique network that supports the competitiveness of the biotech ecosystem, fueled by close ties between industry and research and sponsored by the Commission of Technology and Innovation (CTI). The Swiss Biotech Association and biotechnet Switzerland, a network of Universities of Applied Sciences and research institutions, joined forces and applied for CTI funding within the National Thematic Network funding scheme. After successful approval of a first phase from 2013 to 2016, CTI confirmed the value of this network by approving the second phase from 2017 to 2018.
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NTN Swiss Biotech has set ambitious objectives, which are important when it comes to adding value to the technology value chain: ›› combining core competences of innovative companies with academic knowledge and practices; ›› concentrating knowledge and technology around platforms; ›› supporting the building up of important alliances; ›› enabling access to a reliable network.
›› provides platforms; ›› brings together competences and chaperones the phase of partner finding;
›› supports national and international activities;
›› promotes events, workshops, successful R&D projects through publications and website coverage; ›› provides seed money to academic partners to set-up CTI projects with industry partners. L
Furthermore, NTN Swiss Biotech makes use of effective instruments to implement the set objectives. For example it: ›› organises events;
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Mid-term evaluation EU Evaluation The European Union should put innovation-friendly
policies back at the heart of their agenda to benefit from the biotech’s potential to boost jobs and growth. In advance of President Juncker’s State of the Union Speech on 13 September, EuropaBio issued its evaluation of the EU’s progress on creating an innovation-friendly environment, attracting investment, and fostering jobs, growth, and competitiveness. EuropaBio’s Secretary General, John Brennan, noted “critical geopolitical issues, requiring the attention of Europe’s policy makers, have understandably dominated policy discussion and actions. Yet the policy imperative of delivering economic progress is still there, and a strong EU economy is a prerequisite if we are to meet these global challenges. We therefore urge EU policymakers to put ambitious innovation policies and jobs and growth back at the heart of their agenda.” EuropaBio’s evaluation is forward looking, pointing to achievable, and in many instances non-legislative, ways to reach positive results under this Commission’s remaining mandate. At a minimum, these should include:
›› backing at the highest level for an update of Europe’s Bioeconomy Strate-
gy, planned for review in 2017 to create new bio-based markets and ensure cross-policy coherence; ›› a holistic and balanced approach for biotech innovation under the current incentives review preserving, or even enhancing, the incentives that spurred the unique advancements in medicine that innovation in biotechnology has delivered to patients; ›› an efficient implementation of the existing GMO authorisation system avoiding undue delays in the risk assessment and the “comitology” process. Other key barriers to achieving this sector’s full potential are presented in the report, with clear recommendations on how to overcome them. “Bioindustries contribute so much to the EU economy, creating useful products, jobs and growth. If we could couple that with an ambitious EU policy agenda, we can contribute even more to tackling our grand societal challenges in these next two years,” said Mr. Brennan. The report can be downloaded on www. europabio.org. L
Upcoming Events › 25 Sep–1 Oct, Europe European Biotech Week www.biotechweek.org › 9 –11 October, Brussels European Forum for Industrial Biotechnology and the Bioeconomy (EFIB) www.efibforum.com
Crack the record European Biotech Week Over 140 events confirmed in 19 countries means that 2017 is the most successful ever edition of the European Biotech week, with thousands of Europeans engaging with biotechnology! The conference takes place between 25 September and 1 October 2018. ›› Read all about it on www.biotechweek.org. L
Biotech Grant Bio have launched a program to suppor t research visits to laboratories working in areas of Systems Biology and Genomic & Computational Biology. Four fellowships, lasting between one week and six months, will be offered to fund exchanges between laboratories in eligible countries. Applications are open until 31 October 2017. Information under www.embo.org/funding-awards/fellowships. L
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Pictures: Europa Bio
Fellowships . EMBO and Europa-
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European Biotechnology | Autumn Edition | Vol. 16 | 2017
Family Europe! European Union Brexit and the recent elections in heavyweight
member states set the course for the future of European R&D. French President Macron and Commission President Juncker have already outlined their (different) proposals for reforming the EU. After the elections in Germany and Austria, the dispute over the future structure will begin. But where will the journey take us and what impact will this have on the funding of joint European R&D? Europe seems more and
more like a family. There is also everything: the lazy, the hard-working, the greedy and the wasteful, the cheerful and the grumpy. There are often noisy and fierce disputes – but in the end, everyone gets along because they have a common history and, in the end, collective long-term interests. Let’s hope this putty holds our family of states together. L
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European Biotechnology NET WORK
Featured Events › 13–25 October 2017, Paris, France 9th International Conference and Expo on Proteomics › 25–27 October 2017, Krakow, PL 7th Central European Life Science Investment Conference › 28–29 November 2017, Strasbourg, France BioFIT 2017
GLAM in Israel
Picture: BIOCOM AG
Bioeconomy in Champagne expositions EBN corporate member BIOCOM AG is touring Europe with very successful exhibitions showing bio-economic products of daily use. In other words, consumables based on biobased raw materials and/or processes. The exhibition, “The Bioeconomy in Everyday Life,” which included seven regional products, was a great success in Châlons-en-Champagne, France, in September. It was part of the “Foire de Châlons,” a popular agricultural consumer fair. More than 2,000 visitors were counted, among them French Prime Minister Édouard Philippe (right), who visited the bioeconomy exhibition together with Minister of Agriculture and Food Stéphane Travert (left). L
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LEITAT The European GLAM project (Glass-Laser Multiplexed Biosensor) organises a workshop entitled “Key Enabling Technologies for Better Cancer Diagnosis.” It aims at bringing together experts from the field of photonics, nanomedicine, micro-nano-bio systems, and translational medicine and healthcare. Speakers are high-level experts in the field of cancer diagnosis from universities and companies who will present cutting-edge technologies and recent research progress in the field. In addition, GLAM project will present concrete results and the GLAM device that allows to diagnose genitourinary cancer easily and in a non-invasive manner. Large companies and SMEs, universities, research organisations and patient associations from Europe and beyond are highly encouraged to participate. The event will take place in the Museum of the Jewish People in Tel-Aviv, Israel on the 7th of November 2017. It is free of charge. Spanish EBN corporate member Leitat Technological Center, which is part of the GLAM consortium, supplies interested parties with details and the agenda. ›› More information: Maxence Viallon, mviallon@leitat.org
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23&me (USA). . . . . . . . . . . . . . . . . . . . . . . . . . . 20 3P Biopharmaceuticals S.L. (ES). . . . . . . . . . 54, 72 4SC AG (GER). . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Ablynx BV (B). . . . . . . . . . . . . . . . . . . . . . . . 35, 48 Actelion AG (CH). . . . . . . . . . . . . . . . . . . . . . . . 35 AdrenoMed AG (GER) . . . . . . . . . . . . . . . . . 29, 30 Aglaia BioMedical Ventures B.V. (NL). . . . . . . . . 49 Amsterdam Molecular Therapeutics (NL) . . . . . . 48 Aptuit LLC (USA) . . . . . . . . . . . . . . . . . . . . . . . . 35 Ascletis Bioscience Co. Ltd (CN). . . . . . . . . . . . . 47 ASIT biotech (B). . . . . . . . . . . . . . . . . . . . . . . . . 31 AstraZeneca AB (SE/UK). . . . . . . . . . . . . . . . 20, 48 Axxam SpA (IT). . . . . . . . . . . . . . . . . . . . . . . . . . 54 AyoxxA Biosystems GmbH (GER). . . . . . . . . 66, 71 Bardehle Pagenberg (GER) . . . . . . . . . . . . . . . . . . 8 Basilea Pharmaceutica (CH). . . . . . . . . . . . . . . . 35 Bavarian Nordic A/S (DK). . . . . . . . . . . . . . . 35, 46 Bayer AG (GER) . . . . . . . . . . . . . . . . . . . 14, 29, 35 Berlin Partner GmbH (GER) . . . . . . . . . . . . . 38, 39 Berlin-Chemie Menarini (GER). . . . . . . . . . . . . . 54 Beta Biotech (SK) . . . . . . . . . . . . . . . . . . . . . . . . 54 BIOCOM AG (GER) . . . . . . . . . . . 15, 61, 103, CP3 Biontech AG (GER). . . . . . . . . . . . . . . . . . . . . . . 30 Boehmert & Boehmert (GER) . . . . . . . . . . . . . . . 16 Boehringer Ingelheim (GER). . . . . . . . . . . . . . . . 29 Boehringer Ingelheim Venture Fund (GER) . . . . . 51 Bravo Pharmaceuticals (IN). . . . . . . . . . . . . . . . . 54 Bristol Laboratories Ltd. (UK) . . . . . . . . . . . . . . . 46 Bristol Myers Squibb (USA). . . . . . . . . . . . . . 29, 31 Bryan, Garnier & Co. (F). . . . . . . . . . . . . . . . . . . 35 Bühler Insect Technology Solutions (CH) . . . . . . 91 CANDOR Bioscience GmbH (GER) . . . . . . . . . . 86 Cellact Pharma GmbH (GER). . . . . . . . . . . . . . . 51 Cellectis SA (F). . . . . . . . . . . . . . . . . . . . . . . . . . 28 Celonic AG (CH) . . . . . . . . . . . . . . . . . . . . . 62, 63 Celyad SA (F). . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Charles River (USA) . . . . . . . . . . . . . . . . . . . . . . 77 Chiesi Farmaceutici S.p.A. (IT) . . . . . . . . . . . . . . 48 Chroma Therapeutics Ltd. (UK). . . . . . . . . . . . . . 49 CureVac AG – mRNA Conference 2017 (GER). . 53 DECHEMA Ausstellungs-GmbH (GER). . . . . . . . 25 Deutsche Bank AG (GER). . . . . . . . . . . . . . . . . . 35 Dexxon Investor Group (IL) . . . . . . . . . . . . . . . . 51 EBD Group (GER). . . . . . . . . . . . . . . . . . 28, 32, 33 Elektrochaea GmbH (GER). . . . . . . . . . . . . . 95, 96 Eli Lilly & Co Ltd (USA) . . . . . . . . . . . . . . . . . . . 51 Emergent Biosolutions (USA) . . . . . . . . . . . . . . . 51 Entomo Farm (F). . . . . . . . . . . . . . . . . . . . . . . . . 91 Eppendorf AG/Bioprocess Center Europe (GER) . 43 EuropaBio (B). . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 evocatal GmbH (GER) . . . . . . . . . . . . . . . . . . . . 14 Evotec AG (GER). . . . . . . . . . . . . . . . . . . . . . 35, 51 Fair Insects BV (NL) . . . . . . . . . . . . . . . . . . . . . . 91 Faron Pharmaceuticals Oy (FI) . . . . . . . . . . . . . . 35 FGK Clinical Research GmbH (GER) . . . . . . . . . 78 FibroGen Inc. (USA). . . . . . . . . . . . . . . . . . . . . . 29 Flatiron Health (USA). . . . . . . . . . . . . . . . . . . . . 20 Focus First (USA) . . . . . . . . . . . . . . . . . . . . . . . . 95 Fördergesellschaft IZB (GER). . . . . . . . . Supplement Forbion Capital Partners (NL) . . . . . . . . . . . . . . . 51 Foundation Medicine Inc. (USA). . . . . . . . . . 20, 24 Freenome (USA). . . . . . . . . . . . . . . . . . . . . . . . . 20 FUJIFILM Diosynth Biotechnologies (USA). . . . . 67
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European Biotechnology | Autumn Edition | Vol. 16 | 2017
Galapagos NV (B). . . . . . . . . . . . . . . . . . . . . . . . 29 Genentech Inc. (USA). . . . . . . . . . . . . . . . . . . . . 30 GeNeuro S.A. (CH). . . . . . . . . . . . . . . . . . . . . . . 35 Genmab A/S (DK). . . . . . . . . . . . . . . . . . . . . 30, 46 GenPat 77 Pharmacogenetics AG (GER). . . . . . . 51 GenSearch Consulting (GER) . . . . . . . . . . . . . . . . 7 Gensoric (GER). . . . . . . . . . . . . . . . . . . . . . . . . . 97 Gilead Sciences Internation Ltd. (USA). . . . . 35, 89 GlaxoSmithKline (UK) . . . . . . . . . . . . . . . . . . . . 48 Google Inc. (USA) . . . . . . . . . . . . . . . . . . . . 19, 24 Hansa Medical AB (SE). . . . . . . . . . . . . . . . . 35, 46 Hermetia (GER) . . . . . . . . . . . . . . . . . . . . . . . . . 91 High Tech Gr√ºnderfonds GmbH (GER) . . . . . . . 51 HiProMine SA (PL). . . . . . . . . . . . . . . . . . . . . . . 91 Hitgen Ltd. (CN). . . . . . . . . . . . . . . . . . . . . . . . . 47 I&L Biosystems GmbH (GER). . . . . . . . . . . . . . . 21 IBM Corp. (USA). . . . . . . . . . . . . . . . . . . . . 19, 24 Illumina Inc. (USA). . . . . . . . . . . . . . . . . . . . . . . 20 Incyte Corporation (USA). . . . . . . . . . . . . . . . . . 28 INOFEA Ltd. (CH). . . . . . . . . . . . . . . . . . . . . . . . 14 Ionis Pharmaceuticals (USA). . . . . . . . . . . . . 42, 45 Janssen Biotech Inc. (USA). . . . . . . . . . . . . . 20, 46 Janssen Pharmaceutica N.V. (NL). . . . . . 31, 35, 47 Johnson & Johnson (USA). . . . . . . . . . . . . . . 35, 46 Kiadis Pharma BV (NL). . . . . . . . . . . . . . . . . . . . 36 Kite Pharma (USA). . . . . . . . . . . . . . . . . . . . . . . 35 LEO Pharma A/S (DK). . . . . . . . . . . . . . . . . . . . . 47 Les Laboratoires Servier S.A. (F) . . . . . . . . . . . . . 28 Leukocare AG (GER). . . . . . . . . . . . . . . . . . . . . . 68 Life Science Austria LISA . . . . . . . . . . . . . . . . . . 25 Lipotype GmbH (GER). . . . . . . . . . . . . . . . . 38, 39 M+W Central Europe GmbH (GER) . . . . . . . . . . 73 Macrophage Pharma Ltd (UK). . . . . . . . . . . . . . . 49 MediGene (GER) . . . . . . . . . . . . . . . . . . . . . . . . 28 Medivir AB (SE). . . . . . . . . . . . . . . . . . . . . . . 30, 47 Merck & Co. (USA). . . . . . . . . . . . . . . . . . . . 49, 51 Merck KGaA (GER). . . . . . . . . . . . . . 20, 22, 24, 47 Merus B.V. (NL) . . . . . . . . . . . . . . . . . . . . . . . . . 28 Metsäs Group Coop. (FI). . . . . . . . . . . . . . . . . . . 47 MicrobEnergy GmbH (GER). . . . . . . . . . . . . . . . 96 Micronutics (F). . . . . . . . . . . . . . . . . . . . . . . . . . 91 MicroPyros GmbH (GER). . . . . . . . . . . . . . . . . . 96 Microsoft Corp. (USA) . . . . . . . . . . . . . . . . . 19, 24 MLM Medical Labs GmbH (GER). . . . . . . . . . . . 11 Mologen AG (GER). . . . . . . . . . . . . . . . . . . . . . . 31 MorphoSys AG (GER). . . . . . . . . . . . . . . . . . . . . 29 MP Healthcare Venture Management (USA). . . . 51 Mundipharma EDO GmbH (CH) . . . . . . . . . . . . 51 Myriad Genetics (USA). . . . . . . . . . . . . . . . . . . . 22 Nekonal Oncology (LU). . . . . . . . . . . . . . . . . . . 51 NextAlim (F). . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Nordea Bank (DK) . . . . . . . . . . . . . . . . . . . . . . . 35 nova-Institut GmbH (GER) . . . . . . . . . . . . . . . . . 15 Novartis AG (CH). . . . . . . . . . . . . 8, 20, 28, 35, 50 Novo Holdings A/S (DK). . . . . . . . . . . . . . . . . . . 49 Novozymes A/S (DK) . . . . . . . . . . . . . . . . . . . . . 14 NRW Bank (GER). . . . . . . . . . . . . . . . . . . . . . . . 51
Oxford BioMedica plc (UK) . . . . . . . . . . . . . 35, 50 Palantir Technologies Inc. (USA). . . . . . . . . . . . . 20 PCI Biotech AS (N). . . . . . . . . . . . . . . . . . . . . . . 47 Peppermint Financial Partners (GER). . . . . . . . . . 51 Pfizer (USA). . . . . . . . . . . . . . . . . . . . . . . . . 35, 47 Pfizer CentreOne (USA). . . . . . . . . . . . . . . . . . CP4 PharmaMar S.A. (ES). . . . . . . . . . . . . . . . . . . 14, 30 Pieris Pharmaceuticals Inc. (USA). . . . . . . . . . . . 28 polpharma biologics (PL) . . . . . . . . . . . . . . CP2, 64 Promocell GmbH (GER). . . . . . . . . . . . . . . . . . . 68 ProScience Polska/BioInnovation Int. Summit. . . 55 Proti-Farm (NL). . . . . . . . . . . . . . . . . . . . . . . . . . 91 Protix BV (NL) . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Rentschler Biotechnologie GmbH (GER). . . . 65, 68 Richter-Helm BioLogics GmbH & Co. KG (GER). 87 Rigontec GmbH (GER). . . . . . . . . . . . . . . . . . . . 51 Roche AG (CH). . . . . . . . . . . . . . . . . . . . 19, 20, 29 Roche Diagnostics Deutschland GmbH. . . . . . . 58 Roivant Sciences GmbH (CH). . . . . . . . . . . . . . . 51 Rondo AG (CH) . . . . . . . . . . . . . . . . 79, 80, 81, 85 Rx Securities (UK). . . . . . . . . . . . . . . . . . . . . . . . 35 SalvaRx Group (UK). . . . . . . . . . . . . . . . . . . . . . 51 Sanofi SA (F) . . . . . . . . . . . . . . . . . . 20, 35, 48, 54 Sanofi-Genzyme (USA). . . . . . . . . . . . . . . . . 44, 45 Santhera Pharmaceuticals (CH). . . . . . . . . . . . . . 50 Selvita sp. z o.o. (PL) . . . . . . . . . . . . . . . . . . . . . 54 Sobi AB (SE). . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 Softbank Vision Fund (JP) . . . . . . . . . . . . . . . . . . 51 Sophia Genetics S.A. (CH) . . . . . . . . . . . . . . 20, 51 Spark Therapeutics (USA). . . . . . . . . . . . . . . . . . 48 Summit Therapeutics plc (IRL). . . . . . . . . . . . . . . 35 Sunstone Capital (DK). . . . . . . . . . . . . . . . . . . . . 51 Swiss Biotech Association (CH). . . . . . . . . . . . . . 88 Thermo Fisher Scientific (UK). . . . . . . . . . . . 22, 24 ThromboGenics NV (B) . . . . . . . . . . . . . . . . . . . 49 Tiziana Life Sciences plc (UK). . . . . . . . . . . . . . . 35 Topas Therapeutics GmbH. . . . . . . . . . . . . . . . . 51 Transgene SA (F). . . . . . . . . . . . . . . . . . . . . . . . . 31 Trianni, Inc. (USA) . . . . . . . . . . . . . . . . . . . . . . . 23 UCB S.A. (B). . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 UGA Biopharma GmbH (GER). . . . . . . . . . . . . . 86 uniQure BV (NL) . . . . . . . . . . . . . . . . . . . . . . . . 48 Valneva (F/A) . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Vectron Biosolutions AS (N). . . . . . . . . . . . . . . . 69 Veeva Systems Inc (USA) . . . . . . . . . . . . . . . . . . . 3 Verily Life Scienes (USA) . . . . . . . . . . . . . . . 19, 20 Verona Pharma plc (UK). . . . . . . . . . . . . . . . . . 106 Vesalius Biocapital Partners S.a.r.L. (LU). . . . . . . 54 Vetter Pharma-Fertigung GmbH (GER) . . 31, 76, 78 VIB Discovery Sciences (B). . . . . . . . . . . . . . . . . 49 Viessmann GmbH (GER). . . . . . . . . . . . . . . . . . . 96 Viking Global Investors (USA). . . . . . . . . . . . . . . 51 Voyager Therapeutics (USA). . . . . . . . . . . . . . . . 45 VTU Technology GmbH (AT) . . . . . . . . . . . . . . . 81 Wellington Partners (GER). . . . . . . . . . . . . . . . . . 51 Wilhelm Bähren GmbH (GER). . . . 83, Supplement Wilhelm Haselmeier GmbH (GER). . . . . . . . 83, 84 Xell AG (GER). . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Oncurious NV (B). . . . . . . . . . . . . . . . . . . . . . . . 49 OPIS s.r.l. (IT). . . . . . . . . . . . . . . . . . . . . . . . 29, 74 Orion Corporation (FI) . . . . . . . . . . . . . . . . . . . . 61 ORPEGEN Peptide Chemicals GmbH (GER). . . . 34
Ynsect (F). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Zealand Pharmaceuticals A/S (DK). . . . . . . . 31, 47
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EVents
European Biotechnology | Autumn Edition | Vol. 16 | 2017
Bioinnovation Summit 19.–20.10.2017, Gdansk At Bioinnovation International Summit 2017, researchers can have their innovations checked by technology brokers and top-class experts. Technology transfer experts will present their latest innovations and ongoing projects. www.bioinnovation.pl/en/
23.–25.10.17
13.–17.11.17
International Conference & Expo on Proteomics, Paris (F) Info: Conference Series LLC, www.proteomicsconference.com
PEGS Europe – Protein & Antibody Engineering Summit, Lisbon (PT) Info: CHI – Cambridge Health Institute, www.pegsummiteurope.com
24.–27.10.17
21.–22.11.17
EMBL Conference: Mammalian Genetics and Genomics: From Molecular Mechanisms to Translational Applications, Heidelberg (GER) Info: EMBL, www.embl.de
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Biosimilars Europe Congress 2017, London (UK) Info: Graviton International, www.biosimilarseurope.com
30.10.–1.11.17
Clinical Proteomics.Postgenome Medicine, Moscow (RU) Info: Russian Proteome Organization/EuPA, www.clinprot2017.org/
Pharmalab Congress 7.–8.11.2017, Düsseldorf In six
1.–2.11.17
5th International mRNA Health Conference, Berlin (GER) Info: Verena Lauterbach, CureVac AG, www.mrna-conference.com/
6.–8.11.17
BIO-Europe 2017, Berlin (GER) Info: Thomas Voigt, EBD Group, www.ebdgroup.com/
9.–11.10.17
EFIB 2017, Brussels (BE) Info: Adriana Lobo, EuropaBio/Smithers Rapra, www.efibforum.com
10.–11.10.17
European Business Development Conference 2017, Heidelberg (GER) Info: BIO Deutschland, www.biodeutschland.org/.html
8.–9.11.17
7th Annual European Biomass to Power Conference, Aarhus (DK) Info: ACI, www.wplgroup.com
conferences, experts from various lab areas, authorities, and industrial quality control will report on the qualification of devices and systems, the validation of analytical methods and microbiological tests, as well as their optimisation for routine use in daily lab operations. www.pharmalab-congress.com
9.–11.11.17
4th European Biopharma Congress, Vienna (AT) Info: Conference Series LLC, http://biopharmaceutics.pharmaceuticalconferences. com/europe/
10.–12.10.17
World Vaccine Congress Europe, Barcelona (ES) Info: Tayyab Abbass, Terrapinn, www.terrapinn.com
Pictures: Popova Olga/fotolia.com (left, modified by BIOCOM); Pharmalab (middle); Bioinnovation (right)
11.–13.10.17
BioJapan 2017, Yokohama (JP) Info: JTB Communication, www.ics-expo.jp/biojapan
16.–19.10.17
25th International Conference on Materials and Technology – 25 ISM&T, Portorez (SI) Info: Institute of Metals and Technology, IMT, www.imt.si
17.–19.10.17
LABCompLEX, Kiew (UKR) Info: National Academy of Sciences of Ukraine/ LMT Company, www.labcomplex.com
17.–19.10.17
Rethink Ag & Food Innovation Week, London (UK) Info: Rethink Events Ltd., www.rafiweek.com/london/
18.–20.10.17
BioMicroWorld 2017, Madrid (ES) Info: Formatex Research Center, http://biomicroworld2017.org/
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OPTIBIOCAT 2017 22.11.17 7.11.2017, RIMINI Market demand
is steadily increasing for cosmetics that are produced with natural enzyme-based conversions. With the OPTIBIOCAT Final Conference, European researchers present a major initiative that is sifting through the genomes of fungi and bacteria for appropriate biocatalysts. www.optibiocat.eu
13th Dutch Life Sciences Conference, Oss (NL) Info: Willy Tukker, Iventus, www.dutchlifesciences.com
27.–28.11.17
EuroPLX 65 – European Pharma License Exchange, London (UK) Info: Dr. Norbert Rau, RauCon, www.europlx.com
27.–29.11.17
3rd Annual European Microbiome Congress, London (UK) Info: KISACO Research, https://microbiomecongress.com
28.–29.11.17
12 th European Bioplastics Conference, Berlin (GER) Info: European Bioplastics e.V., www.european-bioplastics.org
4.–8.12.17
Zdravookhraneniye 2017, Moscow (RU) Info: Elena Gureeva , www.zdravo-expo.ru/en/
29.09.2017 11:42:52 Uhr
Encore
Winners & losers
European Biotechnology | Autumn Edition | Vol. 16 | 2017
I’m in biotechnology because …
Open Innovation
Danish enzyme maker Novozymes launched an open innovation venture to kickstart global collaboration to solve pestering problems. First on the list of helloscience.io: a rapid E. coli detection device. Closed innovation In the patent
battle over the CRISPR technology, Millipore Sigma (part of German Merck KGaA) turned up as a new party that filed early CRISPR claims with the European Patent Organisation. All in all, there are now six players with substantially overlapping rights.
David Ebsworth Non-Executive Chairman of the Board, Verona Pharma plc
“… companies like Verona Pharma can improve the lives of patients with rare diseases such as cystic fibrosis as well as very common killers such as COPD.”
Big Pharma in 2026 A recent report from Pharma Intelligence reveals some farreaching trends in the pharma industry. The outlook into 2026 is based on in-house sales forecasts from ten major companies. One outcome: Swiss pharma company Roche will replace Pfizer (US) on the top spot regarding prescription drug sales. Furthermore, the companies will have less blockbusters than at the moment (left). The oncology sales will increase from US$62.3bn (2016) to US$96.7bn in 2026 (top).
US$96.7bn 36 new blockbusters Big Pharma will have BUT
33 products will lose blockbuster status
Platelet promise Diagnostics An interesting new idea in liquid biopsy got some traction this summer. Analysis of tumour RNA carried in platelets may prove to be more useful than other technologies for diagnosing cancer and determining its primary location and potential therapeutic approaches. A new study showed that a blood test based on these nucleus-free cells can determine with 91% confidence if someone has advanced, non-small cell lung cancer – and still with 81% confidence if someone has early-stage lung cancer (doi: 10.1016/j.ccell.2017.07.004). Lead author Tomas Wurdinger from the VUmc Cancer Centre Amsterdam said he expects that in the future, mammographies and coloscopies will be less necessary – if this technology lives up to its promise.
in Big Pharma prescription sales in 2026; oncology will be the No. 1 sector then the Big Pharma infectious diseases sector remains stagnant; estimated annual growth rate:
–0.1% the immunology and inflammation sector will grow modestly; major biosimilar threats are thwarted by innovative product launches
Source: Informa Pharma Intelligence
106
Evotec & Abivax enter into strategic #collaboration to develop novel antiviral agents. http://bit.ly/2wITbdP @EvotecAG French @Lesaffre_Group acquires an equity stake for more than €15.5m in US biotech @Intralytix #bacterio phage #AMR http://bit.ly/2yGUVDu @EuroBiotechNews We are deeply disappointed by the MINDSET results and are saddened for the
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millions impacted by #Alzheimers disease: http://bit.ly/2yFkR1Y @axovant
Please follow us @EuroBiotechNews @Novartis' new CEO, @VasNarasimhan looks to cut drug development costs by 25% #digital_technology http://bit.ly/2xL7cIL @BosBioJosh
Next Magazine European Biotechnology will bring you news and stories again on 14 December. The deadline for advertisements in the winter edition of the magazine is 27 November. Please give some special attention to our Euro Biofairs Compass which will cover the most relevant life sciences events in winter and spring 2017. Questions can be directed to Andreas Macht (+49-30-264921-54) and Oliver Schnell (+49-30-264921-45), or drop us an email at marketing@biocom.de.
Picture: Europabio/Veldemanphoto; FARBAI/fotolia.com (bacteria icons)
axovant #AMR @VasNarasimhan Event preview
29.09.2017 12:25:31 Uhr
UI #FSMJO $POGFSFODF PO -JGF 4DJFODFT
Picture: Dimitar Marinov / fotolia.com
/PWFM "OUJNJDSPCJBMT BOE ".3 %JBHOPTUJDT
2 March 2018, Berlin, Germany Over it’s ten year’s history, the Berlin Conference has become a must-attend event for Life Science decision makers, business developers, investors and legal experts. The 11th conference will explore the exciting market for the development of novel antimicrobials and AMR diagnostics. › › › › › ›
Antimicrobial Market – Industry overview, SME engagement & financial insights Technology Perspective – New approaches to efficiently combat antimicrobial resistance Diagnostic Challenge – Promising molecular methods of detecting multiple drug resistance Legal Environment & Reimbursement – The challenges of bringing antimicrobials to the market R&D Trends – Research and development beyond antibiotics & public-private partnerships Start-up Pitch – Investors’ talk & new business models in the field of therapeutics and diagnostics
Find a preliminary programme and more information at: www.berlin-conferences.com
Supporting Partners:
Media Partner:
European Biotechnology NET WORK
Organisation: BIOCOM AG | Lützowstraße 33–36 | 10785 Berlin events@biocom.de | Tel. +49 (0)30 264921-53 | Fax +49 (0)30 264921-66
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27.09.2017 15:48:29 Uhr
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