Social and Analysts, Join Us! @Scripnews /Scripintelligence Contents/Editor’S Letter

January 8th 2016 No 3784 scripintelligence.com

Top Five Deals Of 2015 (And A Few That Fell Apart) It’s obvious which transaction (or pending transaction) is deal of the year for 2015 even without being told, right? Of course, it’s the $160bn merger between Pfizer Inc. and Allergan PLC, not just because it will create the biggest pharma company and the biggest health care company in the world, but also because of the deals that had to occur for the merger to make sense and because of the deals that may follow on its heels in 2016. There is no doubt that big pharma, specialty biopharma and small biotech companies felt pressure from investors to EKS/shutterstock.com close a deal in 2015 and they will continue to feel the heat in 2016, especially the world’s biggest pharma players now that Pfizer has PFIZER SETTING THE BAR: Companies will all feel the heat now arranged the type of deal its shareholders that Pfizer has arranged the type of deal its shareholders wanted have wanted for quite a while – an acquisition that relocates the corporate headquarters overseas to reduce the company’s tax rate. So were mergers and acquisitions all went beyond financial maneuvering. Pharma It also doesn’t hurt that Pfizer will about bulking up in 2015 and will that be and big biotech need to look beyond tax gain established blockbusters, including the case for M&A in 2016 as companies breaks to boost earnings by filling their Botox (onabotulinumtoxinA) and Restasis face increased pressure to grow through commercial portfolios and R&D pipelines (cyclosporine) as well as a potentially high transactions? Hardly, because many with valuable assets, like AbbVie Inc. with value research and development pipeline. companies made strategic deals in 2015 that Turn to page 7 Actelion’s Uptravi Approval To Shake Up Market Watch out United Therapeutics! Actelion has could upset a market that is already dominated combination of long term-efficacy, safety finally garnered approval for its oral PAH drug by therapies form United Therapeutics. and convenience,” said Actelion CEO Jean- from FDA, making it the 44th approval in 2015 “Uptravi will significantly expand the Paul Clozel, noting the other offerings in the and giving the company a swath of offerings options to delay disease progression after company’s portfolio that serve patients at a in the space. initiation of therapy with a baseline treatment different point on the continuum of care. The Swiss firm confirmed early Dec. 22 that like Opsumit and well ahead of Veletri for PAH is a form of high blood pressure in the the regulatory agency had given the greenlight the late disease stage. Actelion now has an arteries connecting the heart and the lungs for Uptravi (selexipag) to treat adults to unparalleled portfolio of treatments across that causes added stress to the right side of pulmonary arterial hypertension (PAH). The drug the continuum of care in PAH that offer a Turn to page 10

We are tweeting, chatting, liking and Let’s get sharing the latest industry news and insights from our global team of editors Social and analysts, join us! @scripnews /scripintelligence contents/editor’s letter

1 Top Five Deals Of 2015 16 Amgen: No Proof Apotex (And A Few That Fell Apart) Biosimilar Approval Looming 1 Actelion’s Uptravi Approval 17 Apotex: Amgen’s Arguments To Shake Up Market Miss The Mark, Hypocritical 3 Bayer And CRISPR Form 18 Infographic: Pfizer-Allergan, Cutting Edge Gene Editing JV The Deal In Numbers Eleanor Malone, , 4 What Will 2016 Hold For Pharma? 20 Buccal Drug Delivery: Editor Opportunities And Evolution Scrip Intelligence 5 Creabilis Itching To Start Chronic Pruritus PhIII 20 BI Third Generation Lung Cancer Happy New Year to all our readers! Drug A ‘Breakthrough’ If pharma news flow over the last week AML Drug Is Next Big Thing For 6 R&D Bites of December was anything to go by, a vast Seattle Genetics 21 swathe of the industry’s workforce took the 22 Orbimed Closes $950M Fund 8 10 Pharma Movers And Shakers As Biotech VC Surge Continues opportunity to switch off and rest. After a Who Stood Out In 2015 mad rush of deals and regulatory decisions in 23 BMS’s Sale Of HIV Pipeline the weeks leading up to Christmas, the sector 9 Supreme Court Review Of Biosimilars Signals Tightened Focus Law Closer? pretty much went into hibernation after the 24 Karolinska Development winter solstice, with only the slow drip of 10 Sanofi Files Lixilan For Diabetes, Relationship ‘No Longer Exclusive’ bad news to punctuate the silence at the Gambles Expensive Priority Review very end of the year. While most slumbered Voucher 24 AbbVie: Hearing Needed On Biosimilars Interchangeability peacefully, Valeant, Chimerix and anything to 11 Head Of Bayer LifeScience Center: do with Martin Shkreli suffered nightmarish Expect More JVs 25 Commentary: A Life In Genes: Scrip Award contortions (see p12, 14 & 15 and further Winner Sir Gregory Winter’s Speech coverage on www.scripintelligence.com). Chimerix Crashes On PhIII 12 Pharma’s Experiment With As always, Scrip kicks off the year with a Brincidofovir Flop 26 India’s Borrow And Treat Model double issue. Pharma people may have been lying low recently, but that doesn’t mean our 13 Whatever Happened To 27 Novartis Consolidates Indian Industry’s Interest In Ebola? Service Operations journalists have been twiddling their thumbs. We’ve taken the opportunity both to look Business Bulletin 14 28 Policy & Regulation Briefs back and distil the pharma essence of 2015 15 Bionor To Prove ‘Shock And Kill’ 29 That Was The Year That Was: Scrip’s for your delectation, and to look forward and Could Lead To HIV Cure Biggest Stories Of 2015 consider what we have in store. We’ve also put together a splendid 15 Valeant CEO Hospitalization Ebola, Childhood Cancers, And Chronic 30 double-page spread in which we highlight Vexes Investors Pain: IMI’s New R&D Ventures the key points of the deal of the century, the 16 Adamas Readies NDA 31 Expert View: Indian Essential Drugs List planned merger between Pfizer and Allergan Heralds Price Caps On Hep C Products (p18-19). 32 Stockwatch: A Brief History Of So if you’re looking for a recap of the Asset Swaps biggest deals of 2015 (see p1 & 7); a round- up of the year’s US drug approvals (p33); Scrip US Capitol Capsule: Cancer Therapies, 33 the cast list for 2015’s multifaceted pharma Editor: [email protected] Orphan Drugs Dominated 2015 Managing Editor: [email protected] Approvals; PCSK9s Arrived drama (p8); or just want to reminisce over News Editor: [email protected] the biggest stories of the year (p29), grab a South Asia Editor: [email protected] 34 Pipeline Watch coffee, pull up a chair and read on. Washington Editor: [email protected] US West Coast Editor: [email protected] 36 Appointments If you were wondering what had Features Editor: [email protected] happened to all those experimental Senior Reporter: [email protected] treatments for Ebola now that the brouhaha Principal Analysts: [email protected]; has died down, see p13. [email protected]; [email protected] We would love to hear your comments about Reporter: [email protected] Scrip’s coverage. Feel free to tweet us or post And although we don’t do horoscopes, we [email protected] Reporter: a discussion on our LinkedIn group, for your did ask a number of industry visionaries to Creative Content Reporter: [email protected] chance to interact with editor Editorial Assistant: [email protected] Eleanor Malone gaze into their crystal balls and tell us what Production: [email protected] and the rest of the Scrip Intelligence team. they see being the next big thing in 2016. Pharma Data Editor: [email protected] See p4-5 for their prophecies. Global Content Director: [email protected] Follow us at: @scripnews All stock images in this publication courtesy of www.shutterstock.com unless otherwise stated. Join us at: linkd.in/scripintelligence Customer Services Tel: +44 (0)20 7017 5540 or (US) Toll Free: 1 800 997 3892 Email: [email protected] To subscribe, visit scripintelligence.com To advertise, contact [email protected] Scrip is published by Informa UK Limited. ©Informa UK Ltd 2016: All rights reserved. ISSN 0143 7690.

2 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Bayer And CRISPR Form Cutting Edge Gene Editing JV A big pharma has entered the fray, teaming Therapeutics for $35m in cash. Newly created include Intellia Therapeutics, Eligo Bioscience, up with a biotech to create the first long- know-how from the collaboration around the and Editas Medicine. term stand-alone joint venture exploring the CRISPR-Cas9 system beyond the three disease CRISPR Therapeutics is already lending gene-editing technology Crispr-Cas9. German areas will be exclusively made available to its CRISPR-Cas9 gene editing technology conglomerate Bayer AG and Switzerland- CRISPR Therapeutics for human use, and to to Vertex Pharmaceuticals Inc. as part of based CRISPR Therapeutics have created Bayer for non-human use, such as agricultural a four-year research collaboration aimed a joint venture (JV) that will explore the applications. All technology development at discovering treatments to address the technology in three therapeutic areas. and future IP developed by the JV will also be underlying genetic defects that cause or The pair announced on Dec. 21 their exclusively available to the parent companies contribute to certain diseases, including cystic London-based JV will develop therapies using Bayer and CRISPR Therapeutics. fibrosis and sickle cell disease. new technology for “editing” defective genes The JV will be led by Axel Bouchon, who Novak says the joint venture with Bayer will to treat blood disorders such as hemophilia, heads the BLSC as interim CEO while Rodger be very different. blindness, and congenital heart disease – Novak, CEO and co-founder of CRISPR “Our Vertex arrangement is more of a three key therapeutic areas for the German Therapeutics, will be interim chair of the classical, target-only licensing deal. With company. The JV will use privately-held newly formed JV Board. Bayer, we decided a JV would be best as it CRISPR Therapeutics’ proprietary CRISPR-Cas9 “It’s the first time that a big pharma would ensure independence and depth of gene-editing technology and intellectual company is investing big bucks in an open- expertise. This JV is totally focused on actually property, while Bayer will provide its protein ended joint venture to research this problem. developing delivery technologies for systemic engineering expertise and relevant disease It will offer unique R&D freedom because applications of the Crispr-Cas technology,” know-how. it hasn’t been sucked in-house, but rather Novak told Scrip. The idea is to develop therapies to home will operate outside Bayer,” CRISPR CEO and A former vice president at Sanofi’s infectious in on a specific gene causing a disease, then co-founder Novak said in an interview. disease group, Novak will serve as the interim snip it out and, if necessary, replace it with a “The $300m is just the start. If we are chair of the newly formed JV Board. The deal healthy segment of DNA. Drug companies successful, we can add more money. And we will ensure CRISPR Therapeutics continues to have only recently begun exploring how to think we’ll need five years to burn through the be well funded going forward, he said. make drugs using Crispr-Cas9 gene-editing initial $300m,” Novak said. “This is a 50-50 joint venture so we keep a technology, so any resulting therapies from Bouchon in an interview agreed the JV 50% ownership in the high-risk, high-reward the JV will likely be years in the making. plan was effectively “open-ended” and said areas of blood disorders, blindness, and CRISPRs (clustered regularly interspaced its scientific operations would be based in congenital heart diseases, but also retain full short palindromic repeats) occur in the Cambridge, Massachusetts. access to target delivery technologies and the genome of certain bacteria. The associated “Our ramp-up plans at the moment IP created by the JV, which we intend to fully Cas9 enzyme, bound to RNA, which guides it for this JV see us employing something leverage in support of CRISPR Therapeutics’ to the exact site of the mutation, acts on the between 40 to 60 people, but we will wholly owned core strategic disease areas,” disease-related DNA within the cell to cut and also immediately tap into Bayer’s research Novak said. He likened the relationship edit it using the cell’s own mechanisms. resources as well,” said Bouchon, 42, who has to that between Sanofi and Regeneron Crispr-Cas9 isn’t the only technology been with Bayer since 2002. Pharmaceuticals Inc., while ensuring freedom capable of editing genes, but many The Crispr-Cas9 technology has two basic to explore other therapeutic areas on its own. researchers believe it is easier to use than elements. One part is the Cas9 protein, which other methods. Initial research outlining cuts out a defective gene. This molecular knife IP Issue the therapeutic importance of Crispr-Cas9 is guided to its genetic goal by the second There is a cloud hovering over the complex was first published in a Science paper only component, a single molecule of RNA. intellectual property landscape of Crispr-Cas9, three years ago, and the first experimental As an example, a hemophilia drug based however. treatments based on it haven’t even been on the technology would consist of a guide In 2014 the Broad Institute in Cambridge, tested yet in humans. Still, the idea offers RNA molecule programed to find the mutated Mass., the Massachusetts Institute of huge potential for developing new therapies gene behind that disease. Then the Cas9 Technology and the president and fellows of for diseases caused by a mutated gene. protein would cut both strands of DNA around Harvard College received the first US patent The yet-to-be-named JV is the first that gene. The drug would also include a rights related to Crispr-Cas9 technology. But investment by the newly established Bayer piece of DNA with a healthy genetic sequence, that is being challenged by the University LifeScience Center (BLSC), which operates as a which cells could copy as they go about of California, the University of Vienna and by novel strategic innovation unit in Bayer directly repairing the break in their chromosomes. For Emmanuelle Charpentier of Umea University reporting to Bayer’s Board of Management. some diseases, however, the defective gene in Sweden. Charpentier is co-founder of Its mission is to “uncover, encourage and won’t need to be replaced with healthy DNA. CRISPR Therapeutics. unlock fundamental scientific and medical Since its inception 20 months ago, CRISPR CEO Novak says the Swiss company breakthroughs more rapidly by enabling has been evaluating this technology to use is confident about its IP position on the innovative partnerships with entrepreneurial in vivo – by removing the diseased cells from underlying technology. best-in-class biotechnology companies like the body, modifying the gene causing the “In these IP situations there are always CRISPR Therapeutics” the company said. disease, and delivering the cells back to the people trying to get a piece of the cake. Suffice Bayer will inject a minimum of $300m in patient - in immune therapies, blood disease it to say that our partners at Bayer are very R&D investments over the next five years. treatments, and immuno-oncology. Other comfortable with our IP position,” Novak said. Bayer is also buying a minority stake in CRISPR start-ups also developing CRISPR-Cas9 drugs [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 3 headline news What Will 2016 Hold For Pharma? With the New Year almost upon us, Scrip is significant in that it indicates that number of challenges of course. Sanghera asked a number of movers and shakers across customized therapies may not be required acknowledged that regulatory systems will the pharma and biotech spectrum for their for each patient, he noted. have to keep up with the technology in this expectations for 2016. “This could change the course of what area. Individuals will become able to use is currently seen as personalized medicine. technologies to monitor DNA information Jane Osbourn, This is as yet uncharted territory but gains in different environments such as a food incoming chair of significance for researchers in the field.” production line or environmental setting. the UK BioIndustry Shahani refers to modifying a patient’s “It follows that it will become technically Association, was T-cells, an approach known as CAR-T, being feasible for people to analyze their own among several industry pursued by several companies including blood to monitor what might be changing. leaders who picked Novartis. CARs are proteins that allow the There is a need to keep on top of the ethics immuno-oncology T cells to recognize a specific antigen on and regulations in this time when self- as the big thing for tumor cells. Engineered CAR-T cells are quantification is becoming the ‘new normal,’ in 2016: “One of the most grown in the laboratory and then infused a way that seizes the opportunity rather than exciting things that has happened in my into the patient. stifles innovation.” time in drug discovery and developments is “If things go to plan, the engineered T cells seeing these immuno-oncology checkpoint recognize and kill the cancer cells that have inhibitor approaches bringing patient benefit, the antigen on their surfaces,” he adds. ‘There is a need to keep on top and there’s a whole area of opportunity there, of the ethics and regulations as in understanding the biology and looking at Going beyond the pill some of these approaches in combination as in his crystal ball gazing self-quantification is becoming well,” she says. “There’s a lot of demonstration was Darren Carroll, Eli out there now of the benefits of that Lilly & Co’s senior vice the new normal’ approach in terms of biological therapies; president of corporate how we combine that with small molecules - business development. David Williams is CEO of Discuva Ltd., that has to be a really exciting area.” “In 10 years, I think a UK-based antimicrobial developer. He the delivery system described two developments to look out Johnson & Johnson’s will matter almost for in 2016. The first will come from the Jim global oncology chief, as much as the drug, certainly for large O’Neill Review being published Spring/ Peter Lebowitz, told molecules. The way a patient can self- Summer 2016. Scrip: “We’re going to administer a medicine is going to be as “Whilst this review will focus on see more sophisticated important as anything else,” he said. “We suggesting real-life solutions to encourage approaches to immuno- are already seeing the beginning of great the creation of new much–needed oncology which is utilization of electronic medical records, antibiotics to counter the current where we can very but it’s just beginning. We will understand antimicrobial resistance problem, it will selectively target tumors far more about how behaviors such as explore concepts which will ‘bleed’ into and bring the immune system in - such as compliance to medication, diet or other other therapeutic areas,” said Williams. T-cell redirection approaches with bi-specific therapies, impact health. These are things I “Such concepts will be around methods antibodies. There’s a number of those coming expect to really change the nature of how to reward companies for therapeutic focus in. There will be approaches that add tumor we invest in the coming years because to in specific areas in terms of discovery and antigens in vaccines to checkpoint inhibitors or impact something in five years I should development incentives, but possibly immune checkpoints, and I think that is going already be doing it; to impact something in more importantly it will explore price/ to change how these things act. We’re going 10 years I need to be thinking about it and reimbursement models.” to see more activity and less toxicity with this. preparing to act.” The second innovation Williams discussed So it is really beginning to address immuno- was the more general application of newer oncology in a more comprehensive way by Gordon Sanghera, CEO of sequencing machine learning algorithms in drug honing in on issues with specificity for tumors specialist Oxford Nanopore, told Scrip about discovery to process and understand the and tumor antigens. That’s what is coming next.” the potential opening up of applied markets increasingly large datasets being generated. for DNA information. Current technologies “This field has recently blossomed with the Ranjit Shahani, vice performing DNA sequencing are relatively application of method refinements especially chair and managing complicated, said Sanghera. As a result, most in the application of neural network ‘deep director of Novartis of the DNA analyses being performed are still learning.’ There are enormous opportunities India, also believes that relatively clustered into specialist centers. for this technology both in drug discovery there will be a paradigm “We are working to disrupt this model and development in ‘seeing things’ that we shift in the way cancer by making DNA sequencing much more humans invariably miss.” is treated through the simple, mobile, and financially accessible. increasing use of cancer The ultimate aim is to open up completely “Integrating patients into every phase of immunotherapy. The new types of consumers of DNA information clinical research will transform how we do recent news report of a baby girl being beyond science into education, industry and trials in the near future,” said Duke Clinical cured of cancer through cell therapy eventually consumers.” This will result in a Research Institute Director Eric Peterson,

4 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news who is currently working with patients on provincial public drug plans. This means the all aspects of the ADAPTABLE trial, a patient- last significant payer left out of the mix is the Creabilis Itching To centric trial assessing the benefits and federal Non-Insured Health Benefit (NIHB) long-term effectiveness of daily aspirin in program, which provides coverage to First Start Chronic patients with heart disease. Patients serve Nation and Inuit. “Given cost savings offered on the executive leadership committee by the inclusion in the pCPA, it is likely the Pruritus PhIII as well as the data and safety monitoring NIHB will also join, which would signal the Keen to make up for lost time, dermatology committee, Peterson explained. The consent start of a new era of collaboration on pricing specialist Creabilis Ltd is using positive and data collection forms were developed among all levels of government in Canada, Phase IIb data to advance its lead anti-itch based on participant feedback, and a patient including federal, provincial and territorial product CT327, a novel topical TrkA kinase advisory group will serve as the voice of the authorities,” says Mani. inhibitor, on to Phase III trials in psoriasis participant every step of the way. Patients The increasing importance of the pCPA in patients which, if successful, should open also serve as the primary means of collecting negotiating the actual reimbursement price the way for regulatory filing in mid-2018 follow-up outcomes assessment. “Studies for public payers hangs a question mark over for a condition where there is no approved like ADAPTABLE are rewriting the chapter on the relevance of the Patented Medicine Prices standard of care. patient engagement,” he told Scrip. Review Board. The PMPRB’s executive director The company, based in Canterbury, has mentioned on numerous occasions over England, hopes to build on momentum The BIA’s Osbourn, meanwhile, sees the past year that the board is working on a generated after results of Phase IIb clinical bioprocess and manufacturing developing strategic plan aimed at, among other things, data on CT327 were published in Acta apace, “particularly in the UK, and I think making the organization more “relevant”. The Dermato-Venereologica, a peer-review that’s an area where we’re going to start Liberal government has clear intentions to journal in dermatology, in March 2015 seeing some very innovative approaches to explore this matter, which makes it likely that which outlined clinically and statistically manufacturing biologics for tailored patient this strategic plan will be squarely aimed at significant reductions in pruritus, or populations” – although she acknowledges making a meaningful impact on drug prices itching, in patients with mild to moderate that the full benefits are unlikely to be seen in Canada, says Mani. psoriasis treated with the therapy. as early as 2016. In emerging markets, the next big thing The biotech’s recently-installed CEO said for the pharmaceutical industry will probably the latest data builds on previous work A shift in Canada’s be focused around more basic issues such as published in May 2013 demonstrating political landscape improving access and diagnosis, especially in a lack of correlation between psoriasis could impact the areas like oncology. disease severity and pruritus severity, pharma sector there, highlighting the need for targeted anti- said Arvind Mani, Alexander Hardy, itch treatments for patients with psoriasis director of market regional head asia- and other dermatological conditions. access and policy pacific, Roche Pharma, At the same time the company also research at PDCI told Scrip access to wanted to assess the validity of the data Market Access, innovation remains the in another dermatology condition and a Canadian pricing and reimbursement key topic in the Asia chose to undertake a different Phase consultancy. In October the Liberal Party won Pacific as countries IIb trial of CT327 in September 2013 in a majority in October’s federal election after meet their population’s pruritus in atopic dermatitis, for which nine years of Conservative Party leadership. growing desire for new results proved inconclusive. Mani highlights two items from the treatments against diseases such as cancer Asked in an interview with Scrip what Liberal party’s election platform focused that are becoming relatively more important Creabilis had been doing in the interim on drug purchasing and pricing that could in the region. between May 2013 and now to advance signal the type of change that may be in He referred to the ACTION (ASEAN Costs in CT327’s prospects, CEO Alex Leech replied, store. Firstly: “We will join provincial and Oncology) study conducted by the George “We certainly weren’t sitting on our hands. territorial governments to negotiate better Institute for Global Health, wherein 75% of the We ran an atopic dermatitis study and prices for prescription medications and patients experience death or financial harm also got in to see regulators, and had a full to buy them in bulk – reducing the cost within one year of diagnosis. Type C meeting with the FDA, the minutes governments pay to purchase drugs;” and “The current level of cancer diagnosis in of which we received in February 2015. We secondly “We will consult with industry South East Asia is disastrous.” then looked at various financing options for driving our business forward, and we’ve and review the rules used by the Patented Access, he underscored, is not just about also been focusing on the rest of our Medicine Prices Review Board [PMPRB, affordability but needs to consider awareness, portfolio and moving that ahead.” which sets a drug’s basic list price] to accessibility and infrastructure including Leech, who was appointed CEO in ensure value for the money governments the increasing importance of testing and October 2015, originally joined Creabilis and individual Canadians spend on brand diagnosis to drive the correct treatment in 2010 as chief operating officer. The name drugs.” choice. “I do believe that public-private- company wants to start Phase III trialling Greater collaboration on pricing is already partnerships can be further utilized and Roche of CT327 in 2016 in pruritus of psoriasis happening and more could be on the cards. with our unique presence in personalized alone, as well as take two other molecules Quebec has now joined the pan-Canadian healthcare is well positioned to play an into clinical development for psoriasis and Pharmaceutical Alliance (pCPA), which active role in improving healthcare across the atopic dermatitis, respectively. negotiates reimbursement prices for drugs region,” Hardy added. [email protected] and it is now comprised of all of Canada’s This article was jointly compiled by the Scrip editorial team

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 5 headline news AML Drug Is Next Big Thing For Seattle Genetics Seattle Genetics’ “next opportunity for a Siegall noted that while it has been response or complete remission with commercial product” – following on from rumored Pfizer may reintroduce Mylotarg to incomplete platelet or neutrophil recovery the success of its Takeda-partnered Hodgkin’s the market the chances of this happening are (Cri). Responses were observed in higher- lymphoma drug Adcetris (brentuximab lower as time goes on. risk patients, with remission achieved in vedotin) – will move into Phase III trials in 2016. eight of 10 patients (80%) with underlying President and CEO of Seattle Genetics Dr. Competition In AML myelodysplasia and eight of nine patients Clay Siegall told Scrip in a recent interview A new therapy for the treatment of AML (89%) with adverse cytogenetics. that while “Adcetris is spectacular on so many has not entered the market in more than Furthermore, 96%of patients (22 of 23) fronts,” he believes excitement is building for two decades, so the opportunity for Seattle had reduction in bone marrow blasts, with the company’s next big product to reach the Genetics if SGN-CD33A is successful in Phase 87% (20 of 23) experiencing a reduction of market – acute myeloid leukemia therapy III could be momentous. According to The 50% or greater. SGN-CD33A. American Cancer Society there have been “It is a drug with very strong anti-leukemic SGN-CD33A (or vadastuximab talirine) is about 20,830 new cases of AML diagnosed in activity,” Siegall said. an antibody drug conjugate targeting the 2015 and around 10,460 deaths. Regarding the Phase III study in this patient CD33 receptor, which is almost ubiquitously The company also has the benefit over population, the design and details of which expressed in patients with myeloid diseases competitor AML drugs in development that have not yet been disclosed, Siegall said: “We such as AML and myelodysplastic syndrome its product targets CD33, which is expressed have been working with the FDA and EMA to (MDS). It was designed in a specific manner, on leukemic blasts in nearly all AML patients design a global trial and we have been making Siegall said, to be a better version in every and expression is generally not influenced strong progress with these regulatory bodies.” way of an old Pfizer-owned AML therapy, by subtype, cytogenetic abnormality or He added, “I feel confident that we will go Mylotarg (gemtuzumab), which was voluntarily underlying mutations. forward in 2016 with a Phase III that will be withdrawn from the US market in 2010. There are other CD33-targeting AML drugs an international trial. We are going to try to Siegall said that while Mylotarg (also an in development but according to data from redefine how older patients with AML are ADC) was a pioneering drug and regularly Sagient Research’s BioMedTracker Seattle treated. We are excited to take this first step, sought after by AML doctors even after its Genetics’ drug appears to be the most advanced not the last step, into Phase III; I imagine withdrawal from the market, it had a number – sliding ahead of Actinium Pharmaceuticals’ there will be many Phase III trials and this of issues. However, Siegall said, the drug, product, Actimab-A, which is in Phase I/II, will be the first and in the setting with the which was developed more than 20 years following its Phase III trial announcement. biggest unmet need in AML.” ago, “picked a target, CD33, that is fantastic Seattle Genetics’ CEO said the trial will and despite its flaws Mylotarg had activity.” Moving Into Phase III begin “as soon as possible” in the New Year. The main issues with Mylotarg, Siegall said, At the American Society for Hematology’s He highlighted that the company will work was that the antibody and the drug were (ASH) annual meeting held last month in closely with regulators to ensure that when linked with an unstable linker, which caused Orlando, Florida, Seattle Genetics’ presented the time comes for registration of SGN- non-specific toxicity in patients. Also, he said, updated Phase I/II data for SGN-CD33A in CD33A, the company has all the data it needs the product used an antibody that had “only a combination with hypomethylating agents for an approval. modest ability to internalize into its receptor, in frontline AML; and as monotherapy in “We are developing a dozen products developers used a conjugation technology primarily relapsed AML. The company is and not all of them are successful and that was not very productive, and the drug also current running a clinical trial of the winners,” Siegal said. “We know when we used was sensitive to the known multi-drug product in patients with newly diagnosed have something and historically we have resistance (MDR) pathway blockade – so if myelodysplastic syndrome MDS)for which it closed programs, we have closed four or five a patient had MDR, which more than half of has not yet presented any data; and it plans programs in the last 10 years, so it’s not like AML patients have, the drug was ineffective.” to launch a trial soon in younger patients, every one of our programs is a success story. “So we looked at all this and said: we testing SGN-CD33A in combination with 7+3 Once we can really sense that the totality of need an antibody that internalizes better; chemotherapy (seven days of standard-dose the data we have in different settings is there we need a linker that is more stable; we cytarabine, and three days of an anthracycline and we have talked to enough doctors who need a powerful drug that is not blocked antibiotic or an anthracenedione). have used the drug, we work very closely by MDR; and we need a conjugation system The company announced at the ASH with regulators.” that conjugates to homogeneity so that meeting that a Phase III trial will begin in “Sometimes the differences in needs for everything you have is fully conjugated and 2016 evaluating SGN-CD33A in combination the various regulators are small things like there is no free antibody in the drug product,” with hypomethylating agents in previously how many scans you do or how often you Siegall said. After around four years of untreated older AML patients. do them, things that Wall Street doesn’t really development on these specific areas, Siegall Data were reported from 25 frontline look at, these are just the nuts and bolts,” says SGN-CD33A is “the best of the best.” unfit AML patients with a median age of 77 he said. “But it’s about making sure we are SGN-CD33A, which was recently granted years and predominantly intermediate or looking at the exact correct endpoints with orphan drug designation by the US FDA, adverse cytogenetic risk who had declined the correct safety profile that regulators want.” uses Seattle Genetics’ newest technology, intensive therapy. Of 23 efficacy-evaluable “I am really excited for this drug, and while comprising an engineered cysteine antibody patients treated with hypomethylating agents not a commercial product today, I think it (EC-mAb) stably linked to a highly potent DNA azacitidine or decitabine in combination represents our next opportunity to get a binding agent called a pyrrolobenzodiazepine with SGN-CD33A, the best clinical response commercial product after Adcetris,” Siegall said. (PBD) dimer. included 15 patients (65%) with a complete [email protected]

6 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news

Top Five Deals Of 2015 (And A Few That Fell Apart) (Continued from page 1) its $21bn acquisition of Pharmacyclics Inc. negotiated under the business development Beyond Scrip’s top five transactions of 2015, leadership of George Golumbeski. we’ve highlighted some deals that didn’t Celgene is a leader in the treatment of happen in 2015 despite months-long efforts hematological malignancies, but the company by the proposed acquirers. is not satisfied to diversify its portfolio strictly in the oncology field. The Receptos deal Number One 4zevar/shutterstock.com expanded Celgene’s relatively small, but The first stepping stone toward Pfizer’s growing, immunology and inflammation Allergan deal was laid when Actavis PLC portfolio with ozanimod, a selective (before its name change to Allergan) sphingosine 1-phosphate (S1P) receptor completed its $28bn acquisition of Forest modulator that is expected to win US FDA Laboratories in July 2014, giving the company approval for relapsing multiple sclerosis in the brand name drugs that it needed to be 2018 and for ulcerative colitis in 2019. known as more than a generics maker and for ViiV and the deal sharpens BMS’s focus sparking speculation that Actavis may be a on key therapeutic areas, such as immuno- Number Five good buy for Pfizer. oncology, heart failure, thrombosis, fibrosis, The past year shook up the US generics When Forest-turned-Actavis-CEO Brent certain genetically defined diseases and industry with Actavis, one of the world’s Saunders engineered the $66bn buyout immunoscience. largest generics makers, becoming the brand of Allergan and Actavis took on the Botox name-focused company Allergan via the maker’s name, the company’s brand name Number Three eventual divestment of its generics business fate was sealed. And if any doubt remained, AbbVie’s $21bn Pharmacyclics buy was a big to Teva. Meanwhile, Mylan attempted to bulk Allergan agreed to sell its legacy Actavis bet for the Chicago-area big pharma, but up its mostly generics business by acquiring generics portfolio to Teva Pharmaceutical bold moves probably are needed to fill the Perrigo, but failed to convince shareholders it Industries Ltd. for $40.5bn, making the gap that AbbVie will feel as its blockbuster was a worthwhile deal. company even more attractive for a product Humira (adalimumab) – the top- Through it all, Hikma Pharmaceuticals buyer like Pfizer. Allergan’s Dublin, Ireland selling biopharma product in the world right stayed above the fray and managed to headquarters and lower ex-US corporate tax now – falls victim to biosimilar competition. become the sixth largest generics player rate is the cherry on top of a sweet deal. It remains to be seen whether the in the US (by revenue) through its July Pharmacyclics pipeline, including the two- acquisition of Roxane Laboratories for $2.65bn Number Two year-old chronic lymphocytic leukemia (CLL) from Boehringer Ingelheim. The company’s The Pfizer-Allergan deal’s understudy isn’t a drug Imbruvica (ibrutinib), will be a major or CEO Said Darwazah said at the time that single transaction, but a dealmaking trend minor contributor to the company’s future London-based Hikma would continue to that makes a lot of sense: big companies sales regardless of the potential Humira grow globally through acquisitions. trading portfolios of assets that don’t belong revenue losses. in their main therapeutic areas for products However, AbbVie’s faith in Imbruvica’s Deals That Died and pipelines that are better strategic fits. potential won some validation recently when The road to major business combinations in The trend gained traction when Novartis AG AstraZeneca PLC agreed to pay $4bn for a 2015 also was paved with a few deals that agreed to pay $16bn for GlaxoSmithKline majority stake in Acerta Pharma BV, which didn’t happen and a couple of others that PLC’s oncology portfolio while GSK bought is developing a next-generation Bruton’s could be side-lined in the new year. the Novartis global vaccines business for tyrosine kinase (BTK) inhibitor that could Mylan ended the seven-month slog of $5.25bn. The deal closed in March of 2015. take sales from Imbruvica. The approved attempting to buy Perrigo for $26bn without The trend continued in 2015 with two drug, which Pharmacyclics developed and purchasing its fellow generic drug maker in high-profile, year-end swaps. First, Sanofi commercialized with Johnson & Johnson, November. The mea culpa came just days agreed to exchange its animal health showed promise as a first-line treatment for before Horizon Pharma PLC gave up its businessMerial that’s worth €11.4bn for CLL earlier last year, which could expand unwanted $1.7bn pursuit of Depomed Inc. Boehringer Ingelheim’s consumer healthcare Imbruvica’s label beyond the second-line The jury’s still out on two potentially large business that’s worth €6.7bn. Boehringer will setting and boost sales for AbbVie. deals. First, Shire PLC reportedly is still in pay Sanofi €4.7bn to make up the difference. negotiations to potentially buy Baxalta in Sanofi believes it will have the leading Number Four a $34bn deal that the Baxter International consumer health business and Boehringer Summit, New Jersey-based Celgene biotech spinout originally rejected on July 31. could have the world’s second largest Corp.’s growth is largely dependent on its Also, Astellas Pharma Inc. signed a $379m animal health business after the deal closes. multiple myeloma blockbuster Revlimid deal to buy the cell therapy developer Ocata In the second year-end swap, ViiV (lenalidomide), which is why the big biotech Therapeutics Inc. in November, but Ocata’s Healthcare, a majority of which is owned company spends so much of its time and investors reportedly have urged the US by GSK, paid Bristol-Myers Squibb Co. resources scouring the biopharma landscape company to reject the Japanese pharma $350m up front and committed up to for drug candidates that it can license or firm’s offer of $8.50 per share, and the tender $587m in milestone fees plus other sales- companies that it can buy, as it did with offer period during which Astellas must buy based payments for Bristol’s early and late- the $7.2bn acquisition of San Diego-based a majority of outstanding Ocata shares has stage HIV R&D pipeline. The transaction Receptos that was announced in July. It is been extended to Jan. 21. diversifies and provides revenue growth one of the largest deals that Celgene has [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 7 headline news 10 Pharma Movers And Shakers Who Stood Out In 2015 Who were the individuals who dominated pharma industry headlines in 2015? Who achieved great things and reflected glory on the sector, and who cast a dark shadow? Here Scrip casts its eyes over the year’s dramatis personae.

Number One First up is Ian Read, Pfizer Inc.’s CEO, who sealed his reputation as one of the great deal-

makers of the pharmaceutical industry when amasterphotographer/shutterstock.com he launched a $160bn bid for Allergan in November, the largest in health care history. Pfizer is a company built on acquisitions and mergers stretching back decades, and Read could so easily have been disheartened when its $100bn bid for AstraZeneca PLC hit the rocks in 2014 amid harsh criticism of the potential tie-up from the UK’s political/ business establishment. But the quietly spoken Read persevered with the M&A strategy and, as a chartered accountant, only partly thanks to his firm’s pursuit of KaloBios Pharmaceuticals Inc. and Retrophin must be particularly pleased with the tax acquisitions. The company lurched out of the Inc. The controversy around the price rise savings likely to be associated with a merger long drawn-out, vituperative and ultimately for Daraprim generated a political storm with Dublin, Ireland-based Allergan PLC. The futile hostile bid for Allergan in late 2014 and triggered a broader investigation into Allergan deal may well be Read’s crowning but less than a year later it stumbled into drug pricing in the US that will carry on into achievement before retirement, but don’t fresh controversy over its dealings with 2016. The chair of PhRMA branded Shkreli an rule out further moves just yet. He has shown specialty pharmacies, and the pricing of “aberration.” Say no more. he is a master of the art of unexpected and its drugs. For the man who told Scrip in audacious corporate maneuvers. early 2014 that he was aiming to make his Number Five company “one of the top five most valuable In contrast to those who have might be Number Two pharmaceutical companies by the end of viewed as the sector’s pantomime villains Read’s counterpart at Allergan PLC, CEO Brent 2016” with a market cap of around $150bn, – or rather its whipping boys, depending Saunders, soon-to-be president and chief the drop in Valeant’s market cap from nearly on your perspective – stands David Pyott, operating officer of Pfizer Inc., arguably had $50bn at the beginning of 2015 to less than fomer CEO of Allergan. He fended off a the best year of anyone in biopharma in 2015 $35bn as of Dec. 29, 2015 after it peaked hostile acquirer and then did the best for and joins our line-up of movers and shakers. at $89bn in August will be particularly shareholders by completing the sale of When his company was still known as Actavis painful. But Pearson needs to prioritize his company to Actavis during 2015. He PLC, Saunders got to play the hero by rescuing his own health over that of his company: handled the pursuit by Valeant and the Allergan from a hostile takeover attempt by Valeant announced on Dec. 28 that the CEO following acquisition with grace. Unlike Valeant Pharmaceuticals International. And role would be covered by a triumvirate of some CEOs, he didn’t resort to name-calling after Actavis closed the $66bn acquisition and executives following Pearson’s hospitalization or bad behavior during the back and forth changed its name to Allergan, Saunders with severe pneumonia. The news triggered with Valeant – although he did continue boldly agreed to sell the company’s generics another 10% share price drop. to push for an investigation into possible business – the legacy business of Actavis breaches of securities regulations during and its predecessor Watson Pharmaceuticals the takeover bid by Valeant and its hedge – to Teva Pharmaceutical Industries Ltd. for No list of pharma headline- fund backer, Bill Ackman’s Pershing Square. $40.5bn. The two transactions gave Allergan a makers in 2015 could omit Once recognized by the Harvard Business singular focus on brand name drugs, including Review as one of the world’s 100 best blockbusters like Botox (onabotulinumtoxinA) Martin Shkreli who became ‘the performing CEOs, Pyott stood down from and Restasis (cyclosporine), and set the Allergan after it was bought by Actavis. His company up for acquisition by a major most hated man in America’ latest board appointment was to Alynlam pharma. Within four months, Saunders more Pharmaceuticals, Inc, announced Dec. 18. than doubled his two-year, $152bn deal- making tally when Allergan and Pfizer revealed Number Four Number Six their plans for a $160bn merger. No list of pharma headline-makers in 2015 Christopher Viehbacher went through a very could omit Martin Shkreli, whose audacious public firing by the Sanofi board of directors in Number Three exploits in price-hiking and alleged October 2014 and slowly, but not necessarily Michael Pearson, CEO of Valeant fraudulent activities have done far more quietly, re-emerged in 2015 with various new Pharmaceuticals International, Inc., has than merely wreak havoc at firms he has roles in the biotechnology world, ushering spent much time in the limelight too, and helmed, namely Turing Pharmaceuticals AG, start-ups and pre-commercial companies ➤

8 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news through the drug development process. with a second grilling by the European Viehbacher’s first new role announced in Parliament, he got it for another five years, Supreme Court February was a seat on the board of directors on top of the three he had served before his for Boston-based PureTech, which incubates untimely demotion. Now there’s a lesson in Review Of new technology and spins it out in new tenacity – and, for the complainant, in being companies. By June, he was named managing careful what you wish for. Biosimilars director of Gurnet Point Capital, a $2bn fund focused on life science and health care Number Nine Law Closer? investments. Gurnet Point invested $600m In a year when cancer breakthroughs Novartis AG unit Sandoz Inc. is mulling to get Boston Pharmaceuticals going in dominated the news, Richard Pazdur, over whether to seek an appeal to the US November, naming Viehbacher chair of the director of the FDA’s Office of Oncology and Supreme Court of an appeals court ruling company, which will acquire drug candidates Hematology Products, has to feature in any list in a case involving the firm’s biosimilar from other companies, de-risk the assets of key movers and shakers. Zarxio (filgrastim-sndz) – a lawsuit brought through R&D, then sell or find a partner for Over much of the previous decade, by Amgen Inc. each program. Pazdur, who joined the FDA in 1999 after But really, the case is about the spending many years at MD Anderson Biologics Price Competition and Number Seven Cancer Center at the University of Texas, was Innovations Act (BPCIA) – the law that Robert Califf and Margaret Hamburg share ridiculed for rejecting cancer drugs – called gave the FDA the authority to approve their place in the Scrip Mover and Shaker list. a “”Dr. No,” a “one-man death panel” and even biosimilars. Even before Califf, a former Duke University a “murderer by some critics and hotheaded Sandoz submitted a request to the professor and researcher, had joined the patient advocates. In the past year, however, Supreme Court on Dec. 23 seeking an FDA in early 2015, he’d long been rumored Pazdur and his team of 150 oncologists, extension of the deadline to file a writ to be in line to take the reins at the agency toxicologists and other specialists have for certiorari – asking Chief Justice John – a buzz that started before President been highly praised for facilitating rapid Roberts to move the date from Jan. 14, Barack Obama selected Hamburg, who was development of cancer medicines and 2016 to Feb. 16, 2016. installed into the job in 2009. Hamburg, a approving numerous products well-ahead On Dec. 29, Roberts granted that former commissioner for the New York City of their user fee action dates, particularly request, although Sandoz is under no Department of Health and Mental Hygiene, treatments for non-small-cell lung cancer. obligation to actually file the cert petition. where she helped to curb the spread of Pazdur, who recently lost his wife to ovarian Chances are, the Supreme Court would tuberculosis, was only the second women to cancer, said in November it’s time for the big wait until another decision is rendered by lead the FDA and the first African-American question to be answered of whether survival the US Court of Appeals for the Federal women to hold the title of commissioner, or time-to-progression should be used to Circuit before the high court would take a job she left in early April. While Califf is approve oncology medicines. up any case involving the BPCIA. expected to be confirmed in January after In July, a three-judge panel from the getting an easy pass at a November Senate Number Ten Federal Circuit ruled 2-1 that the so-called hearing, there have been some critics who Over in India, Sun Pharma’s billionaire boss “patent dance” disclosure and negotiation have charged he’s too well connected to the Dilip Shanghvi was clearly among the top procedure requirements under the BPCIA drug and device industries. Others, however, newsmakers in 2015. From the closure of were optional and biosimilar makers could have called Califf the disruptor the FDA the merger with the troubled Ranbaxy choose not to disclose their application needs and someone well-suited to lead the and handling plant compliance issues to and manufacturing details. agency as it struggles with regulating ever- making a string of niche buys including But the court also ruled 2-1 that when increasingly complex therapies. the US ophthalmology firm InSite Vision a biosimilar applicant does not dance, 180 and GSK’s opiates business in Australia, days notice of commercial marketing of Number Eight the unassuming Shanghvi has rarely been biosimilars is mandatory and may only be Almost a year after being ousted as executive off the radar of both news-hounds and given after FDA licensure. director of the European Medicines Agency, investors. He also invested in the Indian Amgen and Sandoz both had sought Guido Rasi bounced back into the job after wind turbine maker Suzlon Energy in his a rehearing of their arguments by the full running the full EU recruitment gauntlet for a personal capacity during the year. And Federal Circuit en banc, but on Oct. 16, second time. if market watchers are to be believed the court denied the companies’ petitions. Rasi had to step down in November 2014 Shanghvi isn’t done yet: Long listed meds The companies had 90 days to submit a after a disgruntled co-candidate for the job, in Japan are believed to be on the canny writ for certiorari to the Supreme Court – Emil Hristov, complained that the procedure businessman’s watch list; subsidiary Taro, meaning they had to act by Jan. 14. used to select Rasi in 2011 was marred by sitting on a cash pile of $1bn, has been But a second case has now made conflicts of interest. The EU’s civil service candid about its intent to evaluate the its way to the Federal Circuit – an tribunal agreed, so Rasi had to go. But he right acquisitions and there’s a lot riding appeal by Apotex Inc. of a lawsuit it is was kept on at the EMA in the specially on Sun’s late stage asset for chronic plaque fighting against Amgen, which has been created position of principal adviser in psoriasis, tildrakizumab, acquired from Merck trying to prevent the biosimilar maker charge of strategy, and when the European & Co. Meanwhile, it’s always useful to have from bringing its version of Neulasta Commission advertised the position vacant, mega deal maker and Teva’s former CEO (pegfilgrastim) to the US market (see he re-applied and fought off 35 other Israel Makov as Sun’s chair. All in all 2016 p16 & 17). hopefuls to get his job back. Not only that, as looks exciting. [email protected] it was a fresh recruitment process complete This article was jointly compiled by the Scrip editorial team

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 9 headline news Sanofi Files Lixilan For Diabetes, Gambles Expensive Priority Review Voucher Sanofi has filed a new drug application (NDA) daily injection for the treatment of adults with growth to a number of reasons: “Lack of payer with the US FDA for LixiLan, its investigational type 2 diabetes. Zealand receives a $20m interest, coming to the market late; but we fixed-ratio combination of insulin glargine milestone related to the US filing of LixiLan. always knew that outside the US was never (Lantus) and the GLP-1 receptor agonist “Sanofi’s decision to redeem a PRV on going to be a major market for us. But still, we lixisenatide (Lyxumia). Sanofi also revealed LixiLan is a sign to us of how valuable they hoped for more. However, we are confident that it redeemed a priority review voucher consider the product to be,” said Zealand CEO that LixiLan is going to be a major product.” (PRV) with the filing, giving the NDA an Britt Meelby Jensen. Sanofi’s US NDA for Lyxumia is currently expedited 6-month review if the submission under review, although an FDA action date is accepted by the FDA, instead of the has not been disclosed. The product had standard 10-month review. ‘Sanofi has been through a lot been filed previously but Sanofi voluntarily Sanofi paid $245m for the PRV, which it of change but it has continued withdrew the original submission in 2013. The bought from Retrophin in early 2015. The new filing included data from the recently- voucher allows for a priority review on an to demonstrate its commitment completed ELIXA cardiovascular outcomes application that would not otherwise qualify trial (CVOT). for one. to LixiLan’ The NDA submission for LixiLan is based The pharma giant has been struggling on data from the LixiLan-O and LixiLan-L with its US diabetes franchise for some Speaking to Scrip a few weeks ago, Jensen Phase III studies, which both reported time, and recently projected that its global said, “Obviously a big part of our valuation is positive top-line results earlier in 2015. These diabetes sales will decline at an average related to Sanofi. Sanofi has gone through a lot studies enrolled more than 1,900 patients annualized rate of between 4% and 8% of change over the last 12 months, but it has worldwide to evaluate the safety and efficacy between 2015 and 2018, as Lantus succumbs continued to demonstrate its commitment to of the fixed-ratio combination when used in to biosimilar competition amid changing LixiLan through everything that has gone on.” patient populations uncontrolled after oral diabetes market dynamics. Lixisenatide is marketed outside the US antidiabetic agents (OADs) and after basal Zealand Pharma, the originator for as Lyxumia, and Jensen explained that the insulin therapy, respectively. lixisenatide, said it expects a European filing of product’s ex-US sales are her “only single Sanofi noted that a name for the fixed-ratio LixiLan by Sanofi in Q1 2016. If approved, the frustration,” since joining Zealand as CEO combination is still under consideration. product would be administered as a single about a year ago. She attributes this lack of [email protected]

Actelion’s Uptravi Approval To Shake Up Market (Continued from page 1) the heart. The condition can result in difficulty trial, first reported in June 2014, showed the These factors significantly differentiate Uptravi breathing during exercise, as well as more drug could reduce the risk of mortality and from the only other approved orally available severe symptoms like shortness of breath and morbidity. About 80% of patients in the trial prostanoid therapy, United Therapeutics heart failure. were also treated with either an endothelin Orenitram and should help accelerate uptake Uptravi is a pill taken twice daily that targets receptor antagonist, a phosphodiesterase-5 by physicians,” the analyst added. the prostacyclin pathway. The approved label inhibitor or a combination of the two. The Pricing for the drug has not yet been recommends a 200mcg starting given twice 39% decreased risk in mortality/morbidity announced, but will likely be revealed in early daily, increased by 200 mcg on a weekly basis shown in GRIPHON was on top of a base rate January when the company intends to launch. up to a maximum dose of 1600 mcg. The for these treatments. Side effects of the drug Actelion intends to hold a conference call with drug is not recommended for use in breast included headache, diarrhea, jaw pain, nausea, investors during the first week of the new year feeding mothers or patients with severe muscle pain, vomiting and flushing. where the subject will likely be addressed. hepatic impairment. The label recommends “Uptravi was shown to be effective in The approval of Uptravi could be bad that Uptravi not be taken with an older class of reducing hospitalization for PAH and reducing news for Orenitram (treprostinil), which cholesterol drugs known as CYP2C8 inhibitors the risks of disease progression compared to gained approval in late-2013 after twice that could increase the effects of Uptravi. placebo,” according to a statement from FDA. being rejected and has only gained about It is the first selective oral IP prostacyclin 20% of the market share. Currently, the receptor agonist. Unlike the older prostacyclin A Leg Up market is dominated by older intravenous analogs, Uptravi is selective for the IP receptor Analysts agree that the label for Uptravi and subcutaneous drugs, including United over the other four prostanoid receptors, holds little surprises and could be helpful in Therapeutics’ Remodulin (treprostinil). allowing for reduced side effects while establishing pricing for the drug in the US. Analysts have not had much faith in maintaining efficacy. The drug acts by dilating Deutsche Bank analyst Richard Parkes called Orenitram, projecting at the time of approval blood vessels and decreasing the pressure on it a “strong and broad label” in a Dec. 22 note that it would have peak sales of $250m, while the heart. to investors. most have projected sales of over $1bn for The approval of Uptravi, which was “The latter should help in pricing/access Uptravi. United Therapeutics reported sales submitted to both FDA and European negotiations. In addition, the label seems to of $34m for Orenitram for the three months regulators in December 2014, was based on be broad in terms of both disease etiology/ ended Sept. 30. the phase III GRIPHON study. The 1,156-person severity and use with background therapy. [email protected]

10 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Head Of Bayer LifeScience Center: Expect More JVs our first joint venture project for the BLSC. “The seeding of this new company will This is perfectly suited to fully leverage need to be done very properly so the next Bayer’s expertise in protein engineering and year will mainly be spent on ensuring this knowledge in the targeted disease areas of new joint venture gets a successful launch, this JV,” Bouchon said, adding that “There will after which we’ll then start working on the be others.” next technology platform.” Bayer’s new breakthrough R&D unit is The JV’s scientific operations would be keen to explore cell therapy, stem cell based in Cambridge, MA, while the corporate therapies and regenerative medicine. “So headquarters will be in London. we will be exploring RNA [ribonucleic acid] “Our ramp-up plans at the moment for activation and RNA inhibition as well as this JV see us employing between 40 to the microbiome where you use symbiotic 60 people, but we will also immediately bacteria in the body to cure disease, but can tap into Bayer’s research resources as well,” also make agricultural treatments which are said Bouchon, 42, who has been with Bayer much more natural and sustainable,” he said, since 2002. “We will also tap into Bayer’s without elaborating. research resources. The protein engineering The BLSC, based in Berlin, has been set work will be done in our Bayer facilities in up at a transformative time for the German Cologne; a lot of the hematological work at conglomerate. Bayer recently announced the start will be done in our research labs plans for a new organizational structure in [the Alexandria Center for Science and starting in January 2016, which will see the Technology near the University of group become a “life sciences” business California’s campus at] Mission Bay. And focused on pharmaceuticals, consumer then cardiology and ophthalmology work Axel Bouchon health and crop science. Under this will be supported out of our research centre reorganization Bayer spun out its material in Wuppertal Germany. So there will be 40 The head of Bayer AG’s new “breakthrough” science business – which in the third quarter people in Cambridge MA supported by R&D unit expects to form more joint ventures floated on the Frankfurt Stock Exchange service and know-how capabilities from the with cutting-edge biotechnology start-ups under the name Covestro. Bayer platform.” like the one announced with Switzerland- “Our three core therapeutic areas are Regarding the intellectual property based CRISPR Therapeutics aimed at blood disorders, blindness, and congenital landscape underlying Crispr-Cas9, Bouchon harnessing their technologies and linking heart disease, as well as agricultural is taking a relaxed view despite ongoing them with Bayer’s expertise. business. We at Bayer focus on proteins, legal issues. Axel Bouchon, who heads the newly chemicals and classical breeding Last year, the Broad Institute in Cambridge, established Bayer LifeScience Center (BLSC), technologies, so the BLSC will be looking Mass., the Massachusetts Institute of told Scrip the unit’s purpose reflects the times. for partners to form other joint ventures,” Technology and the president and fellows of “Innovation is under pressure everywhere. said Bouchon, who has been head of global Harvard College received the first US patent We needed a new model and dynamic business development and licensing at rights related to Crispr-Cas9 technology. But approach,” said Bouchon when explaining Bayer HealthCare since April 1, 2015. that is being challenged by the University why Bayer decided to set up the BLSC. Fresh JVs involving the BLSC won’t be of California, the University of Vienna and by “Doing incremental innovation along with announced soon, however, as Bouchon Emmanuelle Charpentier of Umea University occasional disruptive things with classical and his team want to ensure the yet-to-be- in Sweden. Charpentier is co-founder of technologies is not ambitious enough today. named stand-alone partnership with CRISPR CRISPR Therapeutics. So In early 2015 we in Bayer Healthcare Therapeutics gets launched correctly. “The fight over innovation IP is happening asked ourselves what would be the “We don’t yet know how many joint everywhere. It’s the nature of our business. ultimate products in the areas where we ventures we actually need. It might be just Therefore for me it was and is much more are strategic leaders and identified a set of five, or we might need to respond when we important to actually get the best secondary these ultimate products and associated with see something new coming. But it will be IP – meaning what comes next – and we’ve them technologies that we need to enable all aimed at solving these big breakthrough seen the scientific type with CRISPR and realization of these.” ideas and be partnering with biotech start- knowing Bayer’s scientific team on the The joint venture with closely-held CRISPR ups, venture capital firms and academia.” protein engineering front, I was intrigued Therapeutics, announced Dec. 21, aims to Bouchon said the joint venture exploring to combine these two teams because that find new drugs for conditions including how to make drugs using the gene-editing is how I see the secondary IP will make hemophilia, heart disease in infants and a technology Crispr-Cas9 with CRISPR the fundamental difference. So whatever form of blindness called Stargardt disease. Therapeutics is open-ended. “We haven’t set happens with the foundational IP, this They will pursue treatments by linking CRISPR an end date and at some point the initial battle will continue no doubt, but there will Therapeutics’ gene-editing technology, money will run out and I believe we would eventually be a settlement, at which point known as Crispr-Cas9, with Bayer’s expertise in continue beyond that initial five-year period. I’m confident that the next level IP which engineering proteins. So the first $300m that Bayer is investing in our joint venture will generate will be the “It was obvious to us that CRISPR is a this are for the first five years – but we left it differentiating one.” key breakthrough technology, so this was open as we don’t want to cap the future.” [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 11 headline news Chimerix Crashes On PhIII Brincidofovir Flop Shares of Chimerix Inc. crashed on Dec. effect of the compound seen in the Phase II brincidofovir and placebo received the correct 28 – plummeting as low as 82% – on word study, Berrey explained. blinded study drug. the firm’s Phase III SUPPRESS trial of its oral But unlike the Phase II study, CMV infections Nichols said the rate of CMV infection for antiviral brincidofovir failed to achieve its in the brincidofovir arm continued to occur patients on the placebo arm also was in line primary endpoint of preventing clinically during the 10 weeks off treatment between with Chimerix’ past studies and historical significant cytomegalovirus (CMV) infection weeks 14 to 24, she said. trial data. in patients through week 24 after undergoing “We, of course, questioned whether He said the number of patients lost to hematopoietic cell transplantation (HCT). there were errors in randomization or other follow-up in SUPPRESS was low – under 10% – The stock closed the day at $6.62, a loss of elements of the study,” Berrey said. and the rate of study drug discontinuation for 28.95, or 81.4%. But, she said, “All available data point gastrointestinal events also was less than 10%, The news of the top-line results stunned to a well-conducted trial with a balanced “and thus comparable to our observations in Wall Street analysts, who had anticipated a randomization.” the Phase II trial.” positive outcome of the study. “We do have some evidence of successful “While the results of the SUPPRESS are Indeed, UBS Securities analyst Andrew demonstration of brincidofovir’s effectiveness disappointing, there is no option available for Peters said the failure was “clearly surprising” at individual site and then some specific the prevention of CMV infection in these high since he and his colleagues – “and consensus” populations,” Berrey said. But Berrey said the risk allogeneic stem cell transplant recipients,” – had viewed the prior Phase II dataset as preliminary analysis suggested the primary Nichols insisted. “We remain committed to supportive of a favorable clinical profile ahead endpoint failures in the prevention of CMV assessing the potential for brincidofovir to of a similarly designed Phase III. infections and death in the brincidofovir arm help meet this unmet need,” he said. The trial’s flop leaves many questions were driven by confirmed cases of graft- unanswered, including whether there’s a future versus-host-disease (GVHD), which resulted Promise Of Other Indications for brincidofovir in CMV in HCT, Peters said. in a significantly higher use of corticosteroids Even with a clear explanation behind the “Unfortunately, without additional data than in the control group. SUPPRESS study results, any near-term progress from the study, it is too early to conclude one She also acknowledged there was a non- in CMV seems difficult, UBS’ Peters said. He said way or the other,” he said. statistically significant increase in mortality in the next steps beyond the data presentation While most investors had assumed the the brincidofovir arm, versus the control. “We’re from that trial will be the full dataset in the primary endpoint would be positive, a still in the early stages of working through the second half from the open-label AdVise trial handful had started to turn their attention full data set to understand the reasons for this of brincidofovir in patients with disseminated to key secondary endpoints recognizing the disparity,” Berrey said, noting Chimerix already adenovirus infection, “which will help inform any devil would be in the details of the results, has started reaching out to the SUPPRESS potential path to approval” in that indication. noted Piper Jaffray analyst Joshua Schimmer. investigators and additional experts in the field The firm this past February reported a “Unfortunately, the devil was in the primary “to help us understand these findings.” mortality rate of under 40% at a mean of 10 endpoint, too, as a year punctuated by rude The company has also been in weeks of observation in the AdVise trial. awakenings finished with one more doozie,” communication with the FDA and other In an updated preliminary analysis of the Schimmer said, calling the failed Chimerix regulatory bodies and said it would share any full cohort B population of HCT recipients study “disastrous.” updates on the brincidofovir program when with disseminated adenovirus infection, all- A full analysis of the SUPPRESS trial results the firm is able. cause mortality at day 90 remained less than is ongoing and is expected to be presented Chimerix officials pointed out that GVHD and 40%, which Chimerix officials said continued in February at the BMT Tandem Meeting in use of corticosteroids are risk factors for late to support a potential positive risk-benefit for Hawaii, said Chimerix president and CEO CMV infection that occurs after discontinuation the treatment of adenovirus infection. Michelle Berrey. But pending the availability of the antiviral in HCT recipients. of complete data from SUPPRESS, including “Graft-versus-host-disease is a common Ebola Use Abandoned secondary endpoints in other dsDNA viral complication of allogeneic stem cell In 2014 the company had pursued infections, Chimerix has elected to pause transplantation and occurs due to the brincidofovir as a treatment for Ebola, but further enrollment in the Phase III SUSTAIN and transplanted immune system, attacking the abandoned that program this past February. SURPASS trials in kidney transplant recipients. body of the recipient,” said Garrett Nichols, Brincidofovir burst onto the Ebola scene in a Berrey, however, said Chimerix plans to Chimerix’s chief medical officer, noting big way in October 2014 after the FDA cleared continue the programs testing brincidofovir in those type of transplant recipients are it for use in the first patient ever diagnosed with serious adenovirus infections and smallpox. “heterogeneous and complex.” the virus inside US borders, Thomas Eric Duncan. He said the company would be evaluating Mr Duncan, however, received the drug What Happened? the subgroups of patients within SUPPRESS, too late in his disease and died of Ebola on Brincidofovir is an oral nucleotide analogue such as T-cell depleted transplant recipients who Oct. 8, 2014. But brincidofovir was used on that has shown in vitro antiviral activity have a lower risk of GVHD, to better understand an emergency basis in other Ebola-infected against all five families of DNA viruses that the results and inform the firm’s next steps. patients, including Ashoka Mukpo, a freelance affect humans, including herpesviruses and “Given that we only have top-line results to journalist who was in Liberia working as a adenovirus, Chimerix said. date, we have much work to do to understand cameraman for NBC News and Craig Spencer, During the on-treatment period through why this trial was not successful,” Nichols said. a doctor who was the first person to be week 14 after HCT in SUPPRESS, fewer The randomization appeared to have diagnosed with the virus in the US after patients in the brincidofovir arm had a CMV been effective in balancing baseline risks, returning from West Africa. Mukpo and Spencer infection, consistent with the positive antiviral he said, adding that patients randomized to both recovered. [email protected]

12 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Whatever Happened To Industry’s Interest In Ebola? The story of the year for the biopharmaceutical By the end of 2014, investigational drugs He noted that when the three new Ebola industry in 2015 was most certainly the like Mapp’s ZMapp, Fujifilm Holdings Corp.’s cases were reported in November in Liberia, rumpus over drug prices – whether it was favipiravir and Chimerix Inc.’s brincidofovir and the PREVAIL researchers amended the study’s the uproar over the jacked up costs of older experimental vaccines from the NIH’s National protocol to provide the Merck-NewLink products by Turing Pharmaceuticals AG Institute of Allergy and Infectious Diseases vaccine to the contacts of those patients and and Valeant Pharmaceuticals International (NIAID) and its collaborator GSK and NewLink the contacts of contacts. Inc. or the deals the new kids on the block, Genetics Inc. and its partner Merck looked “Public health experts thought that was a the proprotein convertase subtilisin/kexin promising and offered new hope against the prudent thing to do,” Lane said. 9 inhibitors, Sanofi SA’s and Regeneron Ebola epidemic. Pharmaceuticals Inc.’s Praluent (alirocumab) Where Do We Go From Here? and Amgen Inc.’s Repatha (evolocumab), had Is Industry Still Committed? For now, the NIH and the PREVAIL team are to make with payers to get past the fray. With a lot of quick work and collaboration, 2015 in discussions about potentially conducting Indeed, the drug price debate in 2015 started off with much excitement that large- additional trials under a regional effort in quickly muted the big biopharmaceutical scale testing of the experimental medicines and West Africa, working in partnership with the industry conversation that dominated a year vaccines would soon be underway. three health ministries and other entities, like earlier – Ebola, which was driven mostly by But while the work moved forward on the the London School of Hygiene and Tropical public fear and the fact the World Health vaccines throughout 2015, that wasn’t the Medicine and the French Institute of Health Organization (WHO) had almost nothing case for some of the investigational drugs – and Medical Research, or INSERM, to see about good to say about drug and vaccine makers, with Tekmira bowing out of Ebola R&D this doing some additional work, Lane explained. putting manufacturers under the microscope past July and changing its name to Arbutus “That’s not really well-defined yet. It’s just in to prove their worth in a crisis. Biopharma Corp. and Chimerix halting its the discussion stage,” he emphasized, noting The most recent Ebola outbreak is responsible work on brincidofovir’s use against the virus, the path forward for further administering for killing about 11,300 people, mostly in West returning to its key focuses for the drug, the experimental vaccines and getting them Africa, and sickening nearly 29,000. adenovirus and cytomegalovirus, although licensed or available under expanded access The WHO on Dec. 29 declared Guinea – the there’s some question now about its future in will depend on what the data currently being nation where the original chain of transmission the latter indication. gathered show. started in late 2013 – free of Ebola. The US government has continued to pour Lane also pointed out that it will be up to Neighboring Sierra Leone was deemed money into ZMapp and similar antibodies the vaccine sponsors to decide on whether free of the virus in November, while Liberia from Regeneron. Fujifilm also recently they want to pursue licensure of the products has twice been designated done with the reported more positive news about its in the US or elsewhere. disease, only to have it return – most recently antiviral in Ebola. Meanwhile, another study testing the the week of Nov. 22, when three new cases In July, researchers reported in the medical Merck-NewLink vaccine run by the CDC has were reported. If there are no other cases journal The Lancet that the Merck-NewLink completed its immunizations against Ebola confirmed, Liberia could again be declared Ebola vaccine, known as rVSV-ZEBOV, was of more than 8,000 study participants, with all Ebola-free on Jan. 14, 2016. 100% effective in protecting humans against vaccination sites now closed, spokesperson While WHO has admitted it made several the virus in the Phase III ring study. Ian Branam told Scrip. mistakes in dealing with the crisis, one top The results of the study, supported and led The study, known as STRIVE, which got official from the global agency in August 2014 by WHO, suggested the rVSV-ZEBOV vaccine underway in April, was being conducted at declared Ebola a “market failure” – putting protected adults potentially exposed to Ebola seven sites in five districts in Sierra Leone – all much of the blame for the out-of-control as early as 10 days after being vaccinated. of which were opened by June 18, Branam outbreak in West Africa at industry’s feet. Another trial, known as PREVAIL – the said in an email response to questions. But industry stepped up – with firms like Partnership for Research on Ebola Vaccines In the study, participants were Merck & Co., GlaxoSmithKline Plc , Johnson & in Liberia – being run by the NIH and testing randomized to receive the vaccine Johnson Inc. and others jumping in to ensure rVSV-ZEBOV and the NIAID-GSK vaccine cAd3- immediately or in six months. drug and vaccine companies had a seat at EBOZ, reported positive Phase II results in Enrollment in the STRIVE trial closed on the table, whether it was at the emergency March and met its enrollment goal of 1,500 Aug. 15, with 8,680 participants vaccinated. WHO-convened meetings to figure out what in May. Efficacy data from STRIVE are pending. to do to address the situation or working with But because the virus had waned in West J&J in October also started a trial of its the National Institutes of Health (NIH) and the Africa, the trial has been unable to move prime-boost vaccine regimen in Sierra Leone, Centers for Disease Control and Prevention into Phase III and determine efficacy of the which was initiated on parallel track with (CDC) on accelerating the development and products, said Cliff Lane, deputy director for multiple ongoing Phase I and II studies across testing of investigational products that were, clinical research at NIAID and the lead for US, Europe and Africa as part of accelerated at the height of the Ebola panic in the fall of the US-Liberian clinical research partnership development plan for the product. 2014, at the very early stages. overseeing the PREVAIL studies. The study, dubbed EBOVAC-Salone, is Suddenly, small companies like Nonetheless, the PREVAIL study has testing the uses of a combination of two Tekmira Pharmaceuticals Corp. and Mapp “continued to run quite well and follow-up vaccine components based on AdVac Biopharmaceuticals Inc. were all the rage – has been quite good,” Lane told Scrip. “We technology from J&J subsidiary Crucell with everyone wanting to get the funding continue to generate data on the level of Holland BV and the MVA-BN technology from attention those tiny firms were getting from antibody responses and how long those its partner Bavarian Nordic. investors and government agencies. antibody responses persist.” [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 13 business bulletin Business Bulletin programs as president of the Johnson & Johnson Halozyme Lands Latest Partner In Lilly AstraZeneca Links subsidiary Janssen Biotech. As Epizyme’s CEO, he Halozyme Therapeutics Inc. has added to its roster Up With Lion will lead the company based on his experiences of large pharma partners with a late-2015 tie-up as a patient and as an executive who’s worked in with Eli Lilly & Co. that will focus on developing five AstraZeneca’s MedImmune inked its latest all phases of drug development, from early-stage new drugs using the biotech’s technology platform. immuno-oncology collaboration with Lion research through commercialization of therapies Lilly will pay Halozyme $25m upfront, as well as Biotechnologies Inc. for its PD-L1 inhibitor that treat cancer, autoimmune disorders and rare $160m per target – resulting in the potential for durvalumab. Lion will conduct two Phase IIa diseases. “I’m excited to be at this company, which is $800m in total payments – related to development, clinical trials of durvalumab in combination at a big inflection point. We’re a preclinical and early regulatory and sales milestones. The biotech with its tumor-infiltrating lymphocytes (TIL) clinical company that’s going into registrational also has the potential to earn mid-single digit in patients with metastatic melanoma and Phase II trials,” Bazemore said. Epizyme is developing royalties on any products developed as well. Lilly is small molecule inhibitors of chromatin-modifying neck cancer in order to establish safety and dishing out the cash to use Halozyme’s ENHANZE proteins (CMPs), such as histone methyltransferases efficacy of the combined drugs. Further technology platform, which allows for more rapid (HMTs), which are involved in gene regulation delivery of drugs through subcutaneous injection. preclinical research, funded by MedImmune (or epigenetics) and control gene expression. and conducted by Lion, will use the TIL and The company’s drug candidates target genetic Buzzing Indian M&A/IPO Counter MedImmune’s checkpoint inhibitors to find alterations that can change the activity of CMPs and In 2016? other therapeutic combinations. Financial terms cause cancer. 2016 could see an uptick in M&A deal flow in of the agreement have not been disclosed. India and more than half a dozen healthcare/ AstraZeneca, as well as other big pharmas, have Aveo Licenses Tivozanib To EUSA pharma firms may consider going public, buoyed been inking partnership after partnership for If Aveo Oncology’s lead cancer drug candidate by a clutch of successful recent IPOs, according tivozanib was a cat, it would be on its eighth out their respective PD-1/PD-L1 inhibitors. Clinicians to experts in the deal advisory/private equity of nine lives by now, the latest of which involves believe that combination therapies are going to space. Sanjiv Kaul, managing director of the India- an ex-US partnership with EUSA Pharma that offers focused investment firm ChrysCapital, said that be the future of cancer treatments. a small $2.5m upfront payment, but potentially the perceptions about India and Indian companies lucrative milestone fees totaling as much as KaloBios Seeks Appeal Of had improved significantly in the last 12 months $394m. Cambridge, Massachusetts-based Aveo Nasdaq Delisting relative to emerging markets and 2016 would see licensed its vascular endothelial growth factor “major traction” in deal flow. KaloBios Pharmaceuticals Inc. on Dec. 29 said it (VEGF) tyrosine kinase inhibitor (TKI) to EUSA for is appealing the Nasdaq’s decision to delist the the treatment of advanced renal cell carcinoma Anavex Thumped On SEC Subpoena company’s securities from the stock market. A (RCC) in Europe and certain markets outside of Shares of Anavex Life Sciences Corp. were smacked hearing has been set for Feb. 25, 2016. The firm North America, including South America and South on Dec. 29 – tumbling as low as 21.2% in morning revealed on Dec. 23 it had received a letter from Africa, with the potential to extend the license trading – after the company revealed it had the Nasdaq listing qualification staff about the beyond kidney cancer. Aveo could earn royalties in been hit with a subpoena from the Securities decision to delist the company, citing among the various territories ranging from a low double- and Exchange Commission (SEC) declaring it was its reasons the Dec. 17 criminal indictment and digit percentage to the mid-20% range, assuming conducting a formal investigation of the firm. arrest of the firm’s controlling shareholder and tivozanib wins approval in those markets – a task Anavex said it believes the subpoena, which former chair and CEO Martin Shkreli on charges that’s proven difficult in the US. actually came on Dec. 22, and investigation are of defrauding investors in his former hedge funds, related to the recent “unusual” market activity of its MSMB Capital Management and MSMB Healthcare, Intrexon Researching Diabetes shares. The New York-based company said it was and misappropriating more than $11m in assets For Janssen “fully cooperating” with the SEC in its investigation. from Retrophin Inc. – a publicly traded firm he Maryland-based biotech Intrexon Corp. inked Piramal Builds GI Play With OTC Acquisitions founded and then ultimately was fired from. an early research collaboration with Janssen Piramal Enterprises’ consumer products unit has KaloBios filed for chapter 11 bankruptcy protection Pharmaceutica NV to develop treatments for type 2 acquired five brands from Organon India Pvt Ltd on Dec. 30. diabetes and other metabolic disorders, including and MSD BV for INR920m ($13.8m), as it expands obesity. The deal was brokered by the big pharma’s its offering in the fast growing gastrointestinals Epizyme CEO Brings Patient Perspective recently established business development engine segment in India. Key brands in the deal include Epizyme Inc. president and CEO Robert Bazemore’s Johnson & Johnson Innovation. The Centers of Naturolax, Lactobacil and Farizym, which Piramal first thought when he was diagnosed with Stage Innovation were established in 2013 and has will market through the OTC route in the GI 4 diffuse large B-cell lymphoma (DLBCL) – an a presence in Boston, London, Shanghai and segment. Piramal already has Polycrol - the largest advanced form of non-Hodgkin lymphoma (NHL) California. The teams at the J&J Innovation centers antacid brand in eastern India. with a 50-50 chance of survival – was that his work to facilitate young companies and new young children wouldn’t remember him when he technologies with the goal of eventually signing Shkreli’s Empire Collapses was gone. Twelve years later at Epizyme, where the deals for the big pharma. Financial details of the In just a few short weeks, Martin Shkreli’s empire has lymphoma survivor took over the CEO role from Dec. 22 announcement were not disclosed. collapsed. The publicly traded company for which Robert Gould in September, Bazemore is thinking Shkreli became the controlling shareholder just of NHL patients who were not cured after first-line Mallinckrodt Splurges On last month, KaloBios Pharmaceuticals Inc., filed for Rituxan (rituximab) plus chemotherapy – people Hemostasis Drugs chapter 11 bankruptcy protection on Dec. 30, while who may have gone through as many as seven Mallinckrodt PLC is buying three commercial-stage the firm he started in 2015, Turing Pharmaceuticals courses of treatment before enrolling in clinical trials topical hemostasis drugs – Recothrom Thrombin AG, has laid off staff and is searching for a new for Epizyme’s lead drug candidate tazemetostat. topical (recombinant), PreveLeak Surgical Sealant, CEO. KaloBios said it would continue to manage Prior to joining Epizyme, Bazemore was chief and Raplixa (Fibrin Sealant) from The Medicines and operate its business and assets as a “debtor- operating officer at the rare disease specialist Company for an initial payment of $175m that in-possession” under the jurisdiction of the US Synageva BioPharma until its $8.4bn acquisition by includes existing inventory. However, the value of the Bankruptcy Court for the District of Delaware and Alexion Pharmaceuticals Inc., which closed in July. deal could rise by $235m subject to future milestone in accordance with the applicable provisions of the Before that, he oversaw oncology and immunology payments and the total could reach up to $410m. bankruptcy code and the orders of the court.

14 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news

Bionor To Prove ‘Shock And Kill’ Valeant CEO Could Lead To HIV Cure Hospitalization Bionor Pharma ASA has met the primary What Now? endpoint of its REDUC HIV ‘shock and kill’ Bionor is currently planning BIOSKILL, a Vexes Investors trial, which tested a potential vaccine to cure Phase II, randomized, double blind, placebo Shares of Valeant Pharmaceuticals HIV/AIDS. controlled clinical trial in around 160 patients International Inc. sank about 11% on Dec. The REDUC study is a Phase I/II trial as the next step in the development program. 28 over concerns about the hospitalization and the first step in Bionor’s strategy to The primary endpoint will be viral load during due to a “severe case of pneumonia” demonstrate that its Vacc-4x vaccine cART after each of three romidepsin infusions and subsequent medical leave of the component can potentially form part of a in Vacc-4x treated patients compared to company’s CEO Michael Pearson. functional cure for HIV. placebo controlled patients Shares of the Canadian drug company The REDUC trial’s objective was to The first patient is expected to be dosed closed at $102.14 on Dec. 28, down address one of the core issues with clinical by August 2016, CEO David Solomon told $11.97, or 10.5%. management of HIV infection, which is that Scrip. To date, Bionor has filed clinical trial Just the fact the company’s board has some HIV infected cells remain hidden in applications for BIOSKILL in the UK, Germany created an “Office of the Chief Executive latent reservoirs. The reservoirs are unaffected and Denmark. Officer” consisting of three people – Robert by conventional HIV medication and invisible However, the company first needs to Chai-Onn, general counsel; Ari Kellen, to the immune system. Histone deacetylase secure funding for the BIOSKILL trial. Solomon company group chairman; and Robert inhibitors such as romidepsin (Istodax, declined to comment further on the potential Rosiello, chief financial officer – to serve Celgene) have the potential to activate structure of this fundraising or the amount in an interim capacity, plus a committee (“shock”) these latently infected cells to being sought. to oversee and support those executives, produce virus. This “shock” will make the HIV The REDUC results “confirm that we are speaks volumes to the magnitude of filling infected cells visible to the immune system; on the right track toward a cure for HIV,” Pearson’s shoes while he’s away. the immune responses generated by Vacc-4x commented Professor Lars Østergaard, the Valeant was just on its way back can then attack and eliminate (“kill”) these principal investigator of the REDUC trial. from digging out of a scandal involving infected cells. He noted several highlights of the study: its sketchy relationship with specialty Bionor’s Vacc-4x has shown it can “The statistically significant decrease of pharmacy Philidor Rx Services Inc. – significantly reduce HIV viral load and the viral reservoir as measured by Total hoping a new distribution deal with generate a long-term immune response HIV DNA, and of utmost importance is the Walgreens Boots Alliance Inc. would in infected patients. It has been designed highly acceptable short-term safety data. It improve its image. to elicit a cell-based immune response by is also very positive that we see consistency Philidor has been accused of using generating T-cells which can recognize and with the interim results reported earlier “phantom” pharmacy accounts to destroy infected HIV cells. in 2015. While no patient is yet cured as a mask the Valeant’s price increases and In REDUC Part A (reported in May 2014), consequence of the REDUC trial, it is a step circumvent the traditional insurance patients received romidepsin infusions on the way to a cure for HIV, and further reimbursement process. without preceding vaccination with Vacc-4x, research and development based on the There’s also been reports Valeant and the size of the latent reservoir was not Shock & Kill principle is urgently needed.” employees were instrumental in affected. launching Philidor’s business in 2013, were In Part B of the REDUC trial, Vacc-4x and Third Element? involved in questionable billing practices romidepsin were combined to reduce the Solomon anticipates that a third agent and used fake emails to hide their size of the latent viral reservoir in HIV infected capable of further strengthening immune connections with the specialty pharmacy patients on anti-retroviral treatment, which reactivity is needed as part of a combination – assertions Rep. Elijah Cummings (D-MD), could significantly contribute to a functional treatment in addition to Vacc-4x and a latency ranking member on the House Oversight HIV cure. In addition, the ability to control viral reversing agent. and Government Reform Committee, has load during a treatment interruption of cART “We’re not saying that Vacc-4x and been investigating. was investigated. romidepsin alone cannot be the answer, we Meanwhile, Valeant has been at the The headline results were: are just saying that adding a third agent could center of the firestorm over drug prices • The latent HIV reservoir was reduced by 40% well strengthen our hand and that it’s worth – sharing the disdain on Capitol Hill with • Viral load remained below the level of exploring,” he explained. Turing Pharmaceuticals AG over hiked detection in 11 out of 17 patients on Bionor has some ideas for a third candidate, prices of older medicines. combination antiretroviral therapy (cART) “maybe a neutralizing antibody,” suggested Valeant and Turing are among the despite reservoir reactivation. Four patients Solomon, but his immediate priority is to get companies being investigated by the had measureable but low viral load and only the larger trial started. “BIOSKILL will be key in Senate Committee on Aging and by at one of the three romidepsin infusions proving the shock and kill approach,” he said. Cummings and Sen. Bernie Sanders (I-VT). • The pharmacodynamic effect of romidepsin, “Nobody has put these two together, and that Robert Ingram, lead independent director i.e., reactivation of the latent HIV reservoir, gives us fist mover advantage.” on Valeant’s board, said the firm was was confirmed by increases in histone Bionor intends to conduct two exploratory keeping the status of Pearson’s condition acetylation levels and viral expression clinical trials in parallel with BIOSKILL private at the request of his family. • The combination of Vacc-4x and to select the optimal components in a [email protected] romidepsin was safe and well tolerated. combination regimen. [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 15 headline news

Adamas Amgen: No Proof Apotex Biosimilar Readies NDA Approval Looming Adamas Pharmaceuticals soared in On Dec. 9, Judge James Cohn of the US midday trading on Dec. 23, giving the gift District Court for the Southern District of of positive late-stage results to investors Florida, sided with Amgen and imposed the PI. for its Parkinson’s disease treatment. But Apotex immediately appealed, and a The California biotech said its few days later, called on the Federal Circuit to extended-release version of amantadine expedite the case because the company said HCl, ADS-5102, was able to reduce it was awaiting the FDA’s decision “within the the involuntary muscle movements next several months” and asserted the PI was associated with the use of levodopa in causing “immediate harm” by preventing it Parkinson’s disease patients at 12 weeks from putting the product on the market right gst/shutterstock.com by 23% compared with placebo and that away once the firm got regulators decision the effects were maintained at 24 weeks. in hand. The drug was also able to increase “On” Apotex insisted that even under an Amgen declared Apotex’s motion to time without dyskinesia for patients by speed up its appeal should be denied expedited court schedule, the FDA could 2.7 hours compared with placebo. Further approve the firm’s biosimilars before the results will be presented at an upcoming Federal Circuit issued an opinion. medical meeting. There’s no need to expedite Apotex Inc.’s But Amgen argued “Not so.” Levadopa is a commonly used appeal of a Florida district court’s decision What is currently preventing Apotex treatment for the disease, but often to impose a preliminary injunction (PI) on from marketing its pegfilgrastim biosimilar, causes severe side effects that get worse the firm preventing it from marketing its along with its other product under review, a with prolonged exposure to the drug. pegfilgrastim biosimilar for 180 days after biosimilar of Amgen’s Neupogen, is the fact Adamas has developed an extended- FDA approval because there’s no evidence the FDA has not approved either one of those, release version of a drug already sold by the agency’s verdict on the product is the latter company said in its opposition to Endo Pharmaceuticals. looming, Amgen Inc. said in court documents the motion for the expedited appeal. “Parkinson’s disease patients have no filed on Dec. 18. “Right now, no one knows when, or even if, approved medicine for this potentially Amgen, whose long-acting human any approval will come,” Amgen contended. serious complication of levodopa granulocyte colony-stimulating factor While Apotex “speculates” a US approval therapy. With these data in hand, we Neulasta is the reference drug on which could come as soon as “the next several look forward to talking with the FDA Apotex’s product is based, told the US months,” the company has provided “no about our planned NDA submission for Court of Appeals for the Federal Circuit the evidence to support that conjecture,” Amgen ADS-5102,” said Adamas chair and CEO biosimilar maker has not shown good cause said, adding that it has repeatedly requested Gregory Went. to suspend the “ordinary rules,” which the proof through the discovery process and The company is also conducting another California innovator said should provide it a again in consideration of whether to oppose Phase III study of the drug that completed “full and fair opportunity” to prepare its brief the motion to expedite the case. enrollment of 77 patients in December. and argument. “Apotex has refused to provide Amgen Analysts estimate the drug could Therefore, Amgen declared, Apotex’s motion with any discovery into the status of its FDA bring in as much as $500m for Adamas, to speed up its appeal should be denied. applications,” the California biotech giant said. a major boon for a company that only Amgen has accused Apotex of violating the “Because Apotex has made no fact-based has a market capitalization of $315m. disclosure and negotiation procedures of the showing of good cause, its motion to shorten BioMedTracker estimates that the drug Biologics Price Competition and Innovations Amgen’s time to file its brief and prepare for has a 60% likelihood of approval, 8% Act (BPCIA) – the so-called patent dance. oral argument should be denied.” higher than average. Amgen has been insisting that companies The case is significant because it provides another opportunity for the Federal Circuit to According to BioMedTracker, there that want to copy an innovator’s biologic must provide the referenced product sponsor further interpret the BPCIA. are several other drugs in development with a 180-day notice before first commercial A three-judge panel from the Federal Circuit for levodopa-induced dyskinesia, marketing of the biosimilar and must wait to this past July gave Sandoz Inc. and other including a Phase III drug from Osmotica give that notice until after the FDA approves biosimilar makers a win by declaring in a 2-1 Pharmaceutical Corp. and Phase II the biosimilar. decision they could choose not to disclose compounds from Vanda Pharmaceuticals Amgen and Apotex actually had engaged their application and manufacturing details. and Addex Therapeutics. in the patent dance – agreeing that through The court also sided with Amgen, ruling 2-1 “We think having this positive data their exchanges to include two Neulasta that when a biosimilar applicant opts out in hand significantly de-risks their key patents, known as ‘138 and ‘784, in their of the patent dance, notice of commercial product ahead of its NDA filing (expected litigation process. marketing of biosimilars is mandatory and may in 2016) and boosts their position against But Apotex sent its notice of commercial only be given after FDA approval. competitor Osmotica in the race to FDA marketing in April, which Amgen said was That case involved Sandoz’s biosimilar of approval,” wrote Credit Suisse analyst Vamil too early and a violation of the BPCIA’s Neupogen, known as Zarxio (filgrastim-sndz) – Divan in a Dec. 23 note to investors. requirements, since the FDA has not yet even the first biosimilar approved in the US. [email protected] licensed the pegfilgrastim biosimilar. [email protected]

16 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Apotex: Amgen’s Arguments Miss The Mark, Hypocritical California-based Amgen Inc.’s arguments opposing a motion by Apotex Inc. to expedite its appeal of a Florida district court’s decision to impose a preliminary injunction (PI), which would block the Canadian firm from marketing its yet-to-be approved pegfilgrastim biosimilar in the US until six months after licensure, miss the mark and are hypocritical, the latter company asserted in court documents on Dec. 22. Apotex still isn’t saying whether it received a complete response letter from the FDA on the company’s 351(k) application for its pegfilgrastim biosimilar or if the agency delayed its decision – a verdict that was sergign/shutterstock.com expected this past October. What Apotex did reveal in court documents on Dec. 22 is that the company said it has “no way of knowing exactly when FDA will approve” the pegfilgrastim biosimilar application for the US market. In late December Apotex declared it expedite resolution of an analogous issue panel from the Federal Circuit this past July expected the FDA to act on the 351(k) “within involving interpretation of the BPCIA,” Apotex ruled 2-1 the “patent dance” disclosure and the next several months.” said. “Amgen’s argument is thus hypocritical negotiation procedure requirements under No matter when the FDA acts, Apotex said and should be discounted.” the BPCIA were optional and biosimilar it would “suffer immediate harm” because “Like the issue presented to this court in makers could choose not to disclose their it could not launch the product until 180 the Amgen v. Sandoz case, this appeal has application and manufacturing details. days later unless the US Court of Appeals for implications that reach beyond the present But the court also ruled 2-1 that when a the Federal Circuit overturns the PI on the parties,” Apotex told the Federal Circuit in biosimilar applicant does not dance, 180 days application for the pegfilgrastim biosimilar, the firm’s reply to Amgen’s opposition to the notice of commercial marketing of biosimilars which is referenced on Amgen’s long-acting expedited appeal. is mandatory and may only be given after human granulocyte colony-stimulating factor FDA licensure. Neulasta (pegfilgrastim). But, said Apotex, the majority in that July Therefore, Apotex said, it could not wait No matter when the FDA acts, 2015 ruling “explicitly stated that its holding until it receives an FDA approval to request Apotex says it will ‘suffer was limited to scenarios in which a biosimilar an expedited appeal of the PI – disputing applicant elects not to follow the BPCIA Amgen’s arguments there was no need for immediate harm’ pathway” and does not provide its 351(k) to the Federal Circuit to act quickly. the reference product sponsor at the outset. Apotex said it also was surprised Amgen The Canadian company noted there are Apotex argued that in its case, it had provided would contend the issues in the appeal two other ongoing biosimilars lawsuits its application and manufacturing information do not warrant a speedy review by the – Amgen v. Hospira Inc. at the US District to Amgen by the statutory deadline. Federal Circuit, given the latter company Court for the District of Delaware; and “Therefore, the Federal Circuit’s had sought an expedited appeal from the Janssen Biotech Inc. v. Celltrion Healthcare holding in [Amgen v. Sandoz] does not same court in its lawsuit against Sandoz at the US District Court for the District of control, but instead is only instructive,” Inc. – which involved a similar issue of Massachusetts – which involve a similar, if not Apotex contended. statutory interpretation of the Biologics Price identical, question of statutory interpretation In its request for an expedited appeal, the Competition and Innovations Act (BPCIA) – concerning the notice of commercial biosimilar maker had asked the Federal Circuit arguing the issues in that case were “of great marketing provision of the BPCIA. in December to set a quicker schedule, which importance to the biopharmaceutical industry “Expeditious resolution of the present would involve the firm submitting its opening as a whole.” appeal will likely facilitate prompt resolution, brief by Dec. 30, with Amgen responding by Amgen has been insisting that companies or at the very least be instructive, of this issue Jan. 19, 2016, followed by Apotex’s reply by that want to copy an innovator’s biologic in those cases as well,” Apotex said. Jan. 27, 2016, with finally the joint appendix must provide the referenced product sponsor The firm also disputed Amgen’s assertions deadline at Jan. 29, 2016. with a 180-day notice before first commercial the issues in Apotex’s appeal were addressed The court is expected to act quickly on marketing of the biosimilar and must wait to in the Amgen v. Sandoz case. whether to grant or deny Apotex’s motion for give that notice until after the FDA approves “This is simply not true,” Apotex declared. the expedited appeal – a decision that could the biosimilar. In Amgen v. Sandoz, which involved the come before the firm files its opening brief in “Now, presumably because it was successful latter firm’s Zarxio (filgrastim-sndz) – the first the case. at the district court, Amgen sees no need to biosimilar approved in the US – a three-judge [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 17 INFOGRAPHIC

PFIZER-ALLERGAN EMPLOYEES TOP DEALS The deal in numbers Pfizer Allergan 1999 Vodafone AirTouch acquires Mannesmann $203bn ~30,000 ~10,000 This deal included in top five deals US WORKFORCE US WORKFORCE 2000 AOL acquires Time Warner $182bn POST TEVA TRANSACTION globally ever

$160bn 30% 2016 Pfizer Allergan merger $160bn Acquisition Cost: Premium to Allergan shareholders based on Pfizer share price before based on Allergan and Pfizer share prices Verizon buys Vodafone's stake deal was announced before deal was mooted in October 2014 in Verizon Wireless $140bn

98,734 15,858 2008 Philip Morris International GLOBAL WORKFORCE GLOBAL WORKFORCE spun out of Altria $113bn ~56% OWNERSHIP ~44% current Pfizer shareholders BREAKDOWN current Allergan shareholders COMBINED COMPANY 2016 Pfizer acquires Allergan $160bn ~40,000 114,592 ~5,730 This deal included in top five pharma US WORKFORCE: 35% GLOBAL WORKFORCE IRISH WORKFORCE: <5% 2000 Pfizer acquires Warner-Lambert $90bn Allergan shareholders must own at least 40% for tax inversion to be permitted deals ever GlaxoWellcome merges with 2000 SmithKline Beecham $72bn SHARE PRICE DYNAMICS TOP 5 2015 Actavis acquires Allergan $71bn DEALS Pfizer Allergan

2009 Pfizer acquires Wyeth $68bn Friday 20 November close: $32.18 last day before announcement $312.46

$31.33 Monday 23 November close: $301.72 following deal announcement (-2.6%) (-3.4%) PFIZER TAX 2015 ESTIMATED $32.79 Friday 27 November close $319.76 Pfizer's total tax provision for 2014 was $3.12bn, of which it actually paid $2.8bn (+1.9% on 20 Nov price) (+2.3% % on 20 Nov price) PRO FORMA SALES

Pfizer CFO Frank D'Amelio Allergan CEO Brent Saunders ~$48bn ~$16bn 2014 2013 2012 PFIZER ALLERGAN

$36m $995m Currently from expected in first three years - just under 2/3 Selling, $478m US tax actually paid Reported net tax $2bn SI&A; just under 1/3 R&D; tiny amount: Cost of Goods Sold (COGS) US tax actually paid SYNERGIES Out of total $2.13bn in deferred benefit in US Out of total reported US and current US income tax deferred and current income tax of $948m PRO FORMA >100 $40.5bn “This combination will ADJUSTED TAX RATE 17-18% “This deal gives us access Adjusted tax rate vs. effective Number of mid to late stage clinical Amount Teva is paying for significantly expand AFTER CLOSING: to more than 70 additional tax rate of 25.5% in 2014 programs in the combined company Allergan generics business Pfizer's access to cash.” markets where we don't operate today.” Pfizer reportedly holds tens of billions of dollars in overseas earnings that an inversion Break fee: up to $3.5bn for either party could help release $$$ © Informa UK Ltd 2015

18 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 INFOGRAPHIC

PFIZER-ALLERGAN EMPLOYEES TOP DEALS The deal in numbers Pfizer Allergan 1999 Vodafone AirTouch acquires Mannesmann $203bn ~30,000 ~10,000 This deal included in top five deals US WORKFORCE US WORKFORCE 2000 AOL acquires Time Warner $182bn POST TEVA TRANSACTION globally ever

$160bn 30% 2016 Pfizer Allergan merger $160bn Acquisition Cost: Premium to Allergan shareholders based on Pfizer share price before based on Allergan and Pfizer share prices Verizon buys Vodafone's stake deal was announced before deal was mooted in October 2014 in Verizon Wireless $140bn

98,734 15,858 2008 Philip Morris International GLOBAL WORKFORCE GLOBAL WORKFORCE spun out of Altria $113bn ~56% OWNERSHIP ~44% current Pfizer shareholders BREAKDOWN current Allergan shareholders COMBINED COMPANY 2016 Pfizer acquires Allergan $160bn ~40,000 114,592 ~5,730 This deal included in top five pharma US WORKFORCE: 35% GLOBAL WORKFORCE IRISH WORKFORCE: <5% 2000 Pfizer acquires Warner-Lambert $90bn Allergan shareholders must own at least 40% for tax inversion to be permitted deals ever GlaxoWellcome merges with 2000 SmithKline Beecham $72bn SHARE PRICE DYNAMICS TOP 5 2015 Actavis acquires Allergan $71bn DEALS Pfizer Allergan

2009 Pfizer acquires Wyeth $68bn Friday 20 November close: $32.18 last day before announcement $312.46

$31.33 Monday 23 November close: $301.72 following deal announcement (-2.6%) (-3.4%) PFIZER TAX 2015 ESTIMATED $32.79 Friday 27 November close $319.76 Pfizer's total tax provision for 2014 was $3.12bn, of which it actually paid $2.8bn (+1.9% on 20 Nov price) (+2.3% % on 20 Nov price) PRO FORMA SALES

Pfizer CFO Frank D'Amelio Allergan CEO Brent Saunders ~$48bn ~$16bn 2014 2013 2012 PFIZER ALLERGAN

$36m $995m Currently from expected in first three years - just under 2/3 Selling, $478m US tax actually paid Reported net tax $2bn SI&A; just under 1/3 R&D; tiny amount: Cost of Goods Sold (COGS) US tax actually paid SYNERGIES Out of total $2.13bn in deferred benefit in US Out of total reported US and current US income tax deferred and current income tax of $948m PRO FORMA >100 $40.5bn “This combination will ADJUSTED TAX RATE 17-18% “This deal gives us access Adjusted tax rate vs. effective Number of mid to late stage clinical Amount Teva is paying for significantly expand AFTER CLOSING: to more than 70 additional tax rate of 25.5% in 2014 programs in the combined company Allergan generics business Pfizer's access to cash.” markets where we don't operate today.” Pfizer reportedly holds tens of billions of dollars in overseas earnings that an inversion Break fee: up to $3.5bn for either party could help release $$$ © Informa UK Ltd 2015

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 19 headline news Buccal Drug Delivery: Opportunities And Evolution Buccal drug delivery holds significant Firms developing oral mucoadhesive buccal when it comes to innovation in buccal promise and the next generation of buccal delivery systems include BioDelivery Sciences technology and KyuKyu of Japan for product designs could evolve to potentially (BDSI), Meda Pharma, Generex Biotechnology manufacturing such products could draw more include options for controlled release of Corporation and Teijin while sublingual attention to the buccal delivery space in future. drugs up to 12-24 hours, according to a technology has been used by frontline “Grünenthal is one of the best integrated report by MP Advisors, an Indian strategic companies such as Teva, Actavis and Sandoz, firms [combining] R&D, manufacturing and business advisory firm. among others. Perrigo and Insys Therapeutics marketing of buccal technology-based The ease of administration and improved and Generex are among those that have products,” Shah added. compliance provided via the buccal route offers deployed sublingual spray technology to He also noted how European private equity advantages for patients and physicians over develop potential drugs, the report noted. and venture capital (VC) funds and Japanese other invasive routes and oral ingestion and will In September 2015, Generex announced VCs allot a “decent” amount in the segment drive the market in the “positive direction,” it said. the commencement of R&D on buccal already. He expects such funding to go up, “Pain management is one of the leading leuprolide. In 2014, Endo Pharmaceuticals and albeit not a “big jump.” uses of buccal delivery. Besides, patients BDSI released positive top-line Phase III data The report also indicates that the next whose gastrointestinal systems are weak may for chronic pain drug BEMA buprenorphine. generation of buccal product designs will find buccal delivery very helpful. Compliance The product blends the opioid analgesic evolve to include controlled release options, in GI-challenged patients would increase buprenorphine with BDSI’s BioErodible but refers to the general challenge for when the buccal route is made available,” MucoAdhesive (BEMA) drug delivery controlled release applications of designing Tarun Shah, founder of MP Advisors, told Scrip. technology, whereby a small piece of polymer systems that slowly erode over time without MP Advisors noted that novel buccal film is applied to the buccal mucosa. becoming dislodged or being swallowed as delivery such as soluble thin films, Endo/BDSI’s Belbuca (buprenorphine HCl result of eating and drinking. mucoadhesive films and RapidMist spray also buccal film) was approved by the FDA in “Increased residence times of new buccal offer newer routes of delivery for generics that October, 2015. delivery devices may make it possible to have low patient compliance. Products like Reckitt-Benckiser’s Suboxone deliver sensitive biological compounds that Generex’s RapidMist drug delivery (buprenorphine and naloxone orally dissolving would otherwise be deactivated in the GI platform technology administers the active sublingual film), a maintenance therapy tract and thereby can only be dispensed pharmaceutical ingredient via aerosolized for opioid dependence, garnered US sales currently through an injectable dose,” MP said. metered dose spray into the mouth for rapid of about $1.3bn in 2014; BDSI’s Bunavail The advisory firm, though, underscored absorption by the buccal mucosa. (buprenorphine and naloxone buccal film) that product developers must be mindful of The report, shared with Scrip, underscores received FDA approval in 2014 while Subsys an increased potential for irritation to occur how buccal formulations can potentially be (fentanyl sublingual spray) developed by Insys for longer wearing drugs -some of these protected from degradation by GI enzymes Therapeutics was cleared in the US for the concerns, though, can be addressed through and the acidic environment – it avoids the treatment of cancer pain. proper mucoadhesion ingredient selection. first pass hepatic metabolism. MP believes that firms like LTS Lohmann [email protected] BI Third Generation Lung Cancer Drug A ‘Breakthrough’ Boehringer Ingelheim won a breakthrough for Hanmi’s drug candidate. could delay rociletinib’s potential approval. therapy designation from the US FDA for The South Korean company retained Beating out both Clovis and Boehringer its lung cancer drug candidate BI 1482694 commercialization rights for BI 1482694 in in the US, AstraZeneca PLC received a (HM61713), a third generation epidermal its home country, China and Hong Kong, breakthrough designation in the treatment of growth factor receptor (EGFR) tyrosine kinase and Hanmi recently submitted a new drug T790M-positive NSCLC patients in April 2014 inhibitor (TKI) that the German firm licensed application (NDA) for BI 1482694 (HM61713) to for its EGFR inhibitor Tagrisso (mereletinib; from Hanmi Pharmaceutical Co. Ltd. in July, the Korean Ministry of Food and Drug Safety. AZD-9291), which was approved in the US in which will face stiff competition from several The FDA’s breakthrough therapy program November and won preliminary EU approval other EGFR-targeting therapies. allows for a faster review and approval process on Dec. 18. The breakthrough designation was for promising treatments that address serious Eli Lilly & Co.’s EGFR inhibitor Portrazza awarded to BI 1482694 based on Phase I/ diseases. But in the case of T790M-positive (necitumumab) – a biologic and a second- II clinical trial results that showed a 62% NSCLC, breakthrough designations previously generation version of the company’s Erbitux objective response rate and a 91% disease were awarded to two next-generation EGFR (cetuximab) – also was approved in the US in control rate among advanced and pre- inhibitors that will hit the US market before November and received a recommendation treated EGFR mutation-positive non-small cell Boehringer’s and Hanmi’s drug. for approval in the EU in December. lung cancer (NSCLC) patients with a T790M Clovis Oncology’s rociletinib (CO-1686) Even Boehringer already has an EGFR mutation. The data were first reported during won the designation in May 2014 and an inhibitor on the market – the oral drug Gilotrif the American Society of Clinical Oncology NDA for the drug is under FDA consideration. (afatinib), which was approved in the US (ASCO) annual meeting, nearly two months However, a decision on the application in 2013 to treat metastatic NSCLC patients before Boehringer agreed to pay up to $690m recently was delayed by three months until whose tumors express EGFR exon 19 deletions in upfront and milestone fees plus royalties for June 28 after Clovis said it submitted new and or exon 21 L858R substitution mutations. global rights, excluding certain Asian markets, slightly less positive data to the agency that [email protected]

20 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 R&D bites R&D Bites data supporting the marketing authorization treatment, while only 18% of Medidur patients AZ’s Gout Drug Gets applications of both products. Kovaltry and needed the systemic treatment. It also offers Iblias will be available individually as 250 IU, 500 a strong safety profile. Results from the study FDA Go-Ahead IU, 1000 IU, 2000 IU and 3000 IU powders and showed that only 10.9% more Medidur-treated The US FDA has approved AstraZeneca’s solvent for solution for injection. The products will patients experienced an increase in intraocular Zurampic (lesinurad) to treat treat high levels work as replacement therapy and help prevent pressure above 21 mmHg through six months, of uric acid in the blood associated with gout. and control bleeding by increasing levels of which was reduced to 6.1% through the most The approval, for its use in combination with factor VIII. The active molecule in the products is recent follow-up visits, said the company. a xanthine oxidase inhibitor (or XOI, such antihemorrhagic octocog alfa, which is a blood as allopurinol or febuxostat, which reduce coagulation factor VIII. Evgen’s CEO Shares 2016 Plans uric acid production), is conditional upon Sulforaphane, a potential anticancer agent and GeNeuro Phase IIb Launch neuroprotectant found in brassica vegetables, AstraZeneca completing a postmarketing And Investment is the basis of newly listed Evgen Pharma’s study to further evaluate the drug’s renal and GeNeuro SA. has begun its proof-of-concept Phase technology, Sulforadex. Evgen has created cardiovascular safety. Zurampic has a boxed IIb study, CHANGE-MS, with lead product GNbAC1, a synthetic version of the molecule with its warning about the raised risk of acute kidney an antibody targeting the protein MSRV-Env technology, which it believes will be successful failure when Zurampic is used without an expressed in multiple sclerosis (MS). Servier, the in treating types of cancer, multiple sclerosis XOI and with higher than approved doses. company’s development partner, has also exercised (MS) and subarachnoid hemorrhage. Scrip’s An FDA advisory committee was tested its equity investment option to become a minority Lubna Ahmed spoke to Evgen’s CEO Dr. Stephen when considering whether to approve the shareholder in GeNeuro by buying shares from Franklin to find out more about where the drug because of the fact that the minimum existing shareholder Eclosion2. GeNeuro entered company started, its technology and what we should expect from Evgen moving into 2016. dosage of the drug needed for it to work is into a strategic partnership with Servier late 2014, to develop GNbAC1 and under the terms of the Evgen was founded by Franklin in 2007 with also the maximum tolerated dose (200 mg). agreement, GeNeuro will receive $40m from funding from venture capital investors Enterprise In the end, the panel voted 10-4 in favor Servier for the completion of the Phase IIb study. In Ventures and Imprimatur Capital. A few years later, of approval, with unanimous agreement addition, depending on whether Servier exercises Franklin secured intellectual property rights to that the drug had been shown to provide its option for a licensing agreement, it will fund commercialize sulforaphane from PharmAgra Labs clinically meaningful benefit. However, the global Phase III program and pay GeNeuro up Inc., a chemical synthesis company that discovered only seven agreed that its safety profile to an additional $355m, in future development a method for synthesizing and stabilizing the supported approval, with six disagreeing and sales related milestones along with royalties molecule in a sugar lattice. The company branded and one abstaining. The panel called for on futures sales. The Phase IIb study will enroll 260 the technology Sulforadex and moved forward. postmarketing studies. Despite the drug’s patients in 68 clinical centers in the EU and Eastern A series A funding in 2011 supported the Europe and preliminary results are expected by the company’s preclinical and clinical development imperfect profile, it is recognised that there end of 2017. The study aims to show the benefit and by 2014, Evgen’s lead product SFX-01 had is a significant level of unmet need in gout, of the lead product in neutralizing the MSRV-Env passed through preclinical and toxicology and a factor that influenced the agency in its protein in relapsing-remitting multiple sclerosis completed two Phase I trials. Franklin explained decision to approve Zurampic. Zurampic is (RRMS) patients. This protein is said to fuel the that these Phase I studies were carried out in a first in class oral non-nucleoside reverse inflammatory and neurodegenerative components healthy human volunteers, giving the company transcriptase inhibitor (NNRTI) that inhibits of MS. Efficacy will be determined by various a platform to continue to Phase II trials in any URAT1 transporter-mediated uptake of uric magnetic resonance imaging brain scans with the indication. The company is close to delivering the acid, leading to greater excretion of uric acid first endpoint analysis after six months followed by data for synthesized sulforaphane that it believes in the urine. The European Medicines Agency a six-month extension. “big pharma is waiting for.” It expects pivotal trial data to open up several avenues in terms of Committee for Medicinal Products for Human pSivida Moving Forward With partnerships for the product. The sulforaphane is Use (CHMP) last month recommended Late-Stage Eye Drug synthesized in the presence of alpha-cyclodextrin, approval of the drug as an adjunctive Massachusetts drug developer pSivida is ready which stabilizes it by allowing sulforaphane to therapy, putting it on track for approval in to move its latest eye drug/device combo to embed itself in its pores, once the molecule is fully Europe in February. the next stage now that Phase III results show formed, therefore creating a stable 3D structure, overwhelming efficacy. The results from a late- which can be formulated into pills. SFX-01 is based CHMP Greenlight For Bayer’s stage study of Medidur were announced on Dec. on this technology and is being investigated for Hemophilia A Product 22, showing the implant was more effective than three indications: metastatic breast cancer and The European Medicines Agency’s Committee for a control in treating the rare eye disease posterior subarachnoid hemorrhage, for which the company Medicinal Products for Human Use (CHMP) has uveitis. The 129-patient trial lasted six months and is looking to start Phase II trials, and MS, for which adopted a positive opinion for Bayer’s Kovaltry showed that only 18.4% of patients on Medidur there is pre-clinical work being done. Evgen (octocog alfa) and Iblias (octocog alfa). The had a recurrence of the condition compared with completed an IPO on London Stock Exchange’s products, which have also been referred to as 78.6% in the control group. Medidur is an implant (LSE) Alternative Investment Market (AIM) on Oct. BAY 81-8973 by the company, are intended for that is injected into the back of the eye that 21, 2015, raising £7m (before expenses) to fund the treatment of bleeding in patients of all ages allows a corticosteroid to be released slowly over the two upcoming Phase II trials. Franklin said with congenital factor VIII deficiency, hemophilia time. It is similar to pSivida’s recently approved that the reason for joining the LSE in October was A. Having been registered with two brand names, drug/device for diabetic macular edema Iluvien, mainly to raise capital needed for the Phase II trials once approved Bayer will market BAY 81-8973 which entered the market in early 2015 and hasn’t and enhance the company’s profile by so that in under the brand name of Kovaltry and under performed well. While Medidur would be entering future talks with big pharma Evgen is “deemed as a a supply agreement CSL Behring has rights to a highly competitive market, the long-term more credible entity.” Franklin also highlighted that market the molecule under the submitted trade nature of the product could be an advantage that the company had received positive data on SFX-01 mark Iblias. The applications were duplicate, allows for better compliance. More than 54% of as adjunct to hormonal therapy in cancer tissues meaning Bayer provided the same clinical the control group had to continue with systemic taken from breast cancer patients.

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 21 headline news Orbimed Closes $950M Fund As Biotech VC Surge Continues The healthcare-focused venture capital firm VC funding total. Between late November and a 55% stake in the Dutch company for $4bn OrbiMed has raised its largest VC fund to date mid-December alone, 18 drug developers and gained an option to buy the other 45% totaling $950m and if prior investment patterns raised $472m in venture capital, including 11 for $3bn. are repeated as much as $760m of that could Series A rounds. “There has been a tremendous pace be invested in companies focused on the As the year drew to a close, another five of M&A,” Neild said. “It seems like a very development of drugs or gene therapies. biopharma firms raised $139.5m: eFFECTOR healthy environment. Small companies are “Where we’ve seen many of our most Therapeutics, Navitor Pharmaceuticals Inc., developing things that larger companies exciting opportunities has been in Gelesis and Novan Therapeutics plus tiny are willing to acquire and drop in to their biopharmaceuticals,” OrbiMed partner Carter Aquinnah Pharmaceuticals, which closed a strategic gaps.” Neild told Scrip, noting that about 75% to small big pharma-backed Series A round (see Other recent M&A transactions in OrbiMed’s 80% of the VC firm’s capital in recent years has table below). portfolio include the early November sale of been invested in biopharma from startups to Cardioxyl Pharmaceuticals Inc. to Bristol-Myers growth-stage companies. The new fund called OrbiMed Optimistic About IPO, Squibb Co. for $300m up front and up to OrbiMed Private Investments VI LP will make M&A Exits $1.8bn in milestone fees, which was preceded $10m to $75m investments in about 30 North Venture capital investors are not deterred by by the sale of cCAM Biotherapeutics of Israel American and European biopharma, medical the recent slowdown in biotech initial public to Merck & Co. Inc. for $95m up front and up device, diagnostic and health care information offerings. Indeed, while the IPO window seemed to $510m in milestone fees in July. technology companies. to close in November for drug developers – the “One thing that we see is the need to be Led by investments in therapeutics last therapeutics company to go public in the increasingly globalized and I think we set up companies, US venture capital for US last year was Axsome Therapeutics on Nov. our firm in a way to take advantage of that,” biotechnology is booming with $5.8bn in VC 21 – Neild said there still are biopharma firms Neild said. “We’re one of the few firms that’s cash invested in the industry during the first in the queue even if the pace of IPOs may slow not just in North America, but we’re in India, nine months of 2015, putting last year just compared with the past few years. China and Israel as well. We see faster market $500m behind the industry’s record-breaking “I think maybe the IPO market slowed down growth in places like China and India with $6.3bn total for all of 2014 before 2015’s compared to the crazy, torrid pace, but I think good opportunities in Israel.” fourth quarter frenzy began. it’s still around. Both mergers and acquisitions, In terms of therapeutic areas, OrbiMed sees Even without an official tally from the and IPOs, exist as exits,” he said. “There are still good investment opportunities in oncology, MoneyTree Report assembled by the lots of reasonable ways to monetize these especially in immuno-oncology; gene therapy National Venture Capital Association exciting innovations going.” and gene editing; and orphan diseases. The (NVCA), PricewaterhouseCoopers (PwC) and OrbiMed recently monetized a significant VC firm recently recruited Stephen Squinto, Thompson Reuters, it appears that 2015 is portion of its investment in Acerta Pharma co-founder and former chief operations officer well on its way to beating the 2014 biotech BV when UK-based AstraZeneca PLC acquired and research head at Alexion Pharmaceuticals ➤

Late December Venture Capital Deals Company Investors Use Of Proceeds eFFECTOR Therapeutics; San Altitude Life Sciences led a $40m Series B round for eFFECTOR with participation The company has now raised $95m, including a $45m Series A round, for the Diego from AbbVie Biotech Ventures and BioMed Ventures as well as prior investors development of small molecule cancer drugs that restore translational control to Abingworth, Novartis Venture Fund, GlaxoSmithKline’s SR One, The Column Group, halt underlying disease mechanisms while preserving healthy physiological US Venture Partners, Astellas Ventures, Osage University Partners and Mission Bay processes. The new VC cash will support a Phase I/II clinical trial in the treatment of Capital. solid tumors with eFT508, an inhibitor of MNK1 and MNK2, which effect multiple oncogenes, as well as clinical development for a second drug candidate. Navitor Pharmaceuticals Inc.; Brace Pharma Capital LLC, a strategic investment company formed by Brazil’s largest Navitor will use its new money to take its first program into the clinic and to Cambridge, Massachusetts pharma firm EMS SA, led a $33m Series B round in partnership with unnamed high continue research for additional programs from its pipeline of selective modulators net worth individuals that also was supported by new Navitor investors Remeditex of the mTORC1 pathway, which plays a key role in chronic metabolic, Ventures, Sanofi-Genzyme BioVentures, and an undisclosed individual. Prior neurodegenerative, immune and autoimmune, and musculoskeletal diseases investors Polaris Partners, Atlas Venture, Johnson & Johnson Innovation – JJDC Inc., related to aging as well as rare disorders. The company raised a $23.5m Series A and GSK’s SR One also participated. round in June 2014. Gelesis; Boston After giving up on an IPO in May, which could’ve raised about $60m from stock The company has raised $90m to date for its weight loss and glycemic control market investors, Gelesis announced $31.5m in private growth capital from new therapies. Lead product candidate Gelesis100 is an oral capsule containing hydrogel institutional investors, including Cormorant Asset Management. Prior backers particles with multiple mechanisms of action along the gastrointestinal tract. Invesco Asset Management, PureTech and the Pritzker/Vlock Family Office also Gelesis recently expanded its GLOW pivotal trial and anticipates completing supported the funding round. enrollment in 2016 so that the company can seek US FDA approval in 2017. Novan Therapeutics; Durham, Novan will follow its $50m private financing in March with a $31m funding round in Novan reported positive Phase IIb data in September for SB204, a topical nitric oxide North Carolina which the company has raised $30.4m to date, according to a filing with the US drug candidate, for the treatment of acne. The company said at the time that it Securities and Exchange Commission (SEC). Investors were not listed in the SEC planned to initiate two Phase III clinical trials enrolling 1,300 patients each during filing on Dec. 16. the first quarter of 2016. Aquinnah Pharmaceuticals; Aquinnah raised $5m from Teva Pharmaceutical Co. Ltd. in the startup’s first-ever The company will use the money and its grant funding to advance novel compounds Cambridge, Massachusetts private equity financing. that slow or reverse the progression of amyotrophic lateral sclerosis (ALS) by breaking down protein complexes found in the brains of most people with ALS.

22 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news BMS’s Sale Of HIV Pipeline Signals Tightened Focus Bristol-Myers Squibb Co. on Dec. 18 took space. Sales of its integrase inhibitor Tivicay another step in narrowing its therapeutic (dolutegravir) and combination drug Triumeq focus by selling its pipeline of HIV candidates, (dolutegravir/abacavir/lamivudine) were cited including novel Phase III and Phase IIb assets, by GSK as high points in a second quarter to ViiV Healthcare in a pair of deals bringing performance that saw the company’s overall $350m in upfront cash and significant earn- pharmaceutical sales decrease by 6% year- out potential back to the US-based pharma. over-year. BMS has been pivoting away from “GSK is not going to depend solely on primary care for several years now, making Tivicay/Triumeq for ViiV’s growth, but will its biggest splash as one of the leaders in continue to bolster its combo portfolio to immuno-oncology with PD-1 inhibitor Opdivo include novel mechanisms with potential in (nivolumab). But the Princeton, N.J., pharma treatment-resistant patients,” Fernandez said. is aiming more broadly to be a leader in Lightspring/shutterstock.com While encouraged by the deal from GSK’s specialty care. perspective, he noted it “fails to add near-term While continuing some development needle-movers for GSK.” efforts in hepatitis C, Bristol exited virology The attachment inhibitor from Bristol discovery roughly two years ago, and the would address about 5% of the global HIV divestment of the HIV pipeline furthers that population, the analyst added, making it a nice process. The company in future will especially portfolio complement to Tivicay and Triumeq, seek out innovation in five non-cancer which combines an integrase inhibitor with therapeutic areas, including virology, where Phase IIb maturation inhibitor BMS-955176. two nucleoside reverse transcriptase inhibitors. a number of clinical development programs The latter is being developed for both GSK has indicated it plans to investigate a continue despite the end of discovery efforts. treatment-naïve and treatment-experienced combination regimen of Tivicay and the This includes new areas of focus for Bristol patients. Each has a novel mechanism of attachment inhibitor from Bristol. in genetically defined disease and fibrotic action and would be a first-in-class agent if But the maturation inhibitors may comprise disease, as well as continuing efforts in approved, Bristol said. the more compelling opportunity as they cardiovascular and immunological medicine. ViiV is paying $317m up front for the address a different stage of the HIV lifecycle “These agreements with ViiV Healthcare clinical assets, which also include a backup than anything Gilead currently markets, represent another important step toward maturation inhibitor, BMS-986173. The firm is Fernandez said. focusing Bristol-Myers Squibb’s research and also gaining active preclinical and discovery “None of the approved agents act on viral development efforts in areas we believe assets through a separate deal, for an upfront assembly/maturation,” he pointed out. “Safe we can best deliver future transformational payment of $33m. Bristol also could earn and effective assembly/maturation inhibitors, advances – oncology, immuno-oncology, development and first commercial sale alone or combined with other agents heart failure, thrombosis, fibrosis, milestones of up to $518m, along with tiered with different mechanisms, could provide certain genetically defined diseases and royalties, on the clinical compounds. The additional benefit compared to existing immunoscience,” a Bristol spoksperson said. earlier-stage portfolio transaction is structured treatment mechanisms.” “At the same time, the sale of our HIV R&D with up to $587m in development and In May, GSK dropped plans for a ViiV portfolio … puts the development of these commercial milestones. initial public offering. Japan’s Shionogi & Co. novel assets in the hands of a global specialist During a transitional period, Bristol will Ltd. bought into the JV in 2012, with Pfizer company exclusively dedicated to delivering provide, at ViiV’s expense, R&D support, and reducing its stake in ViiV to 13.5%. GSK holds a advances in treatment and care for people approximately 20 Bristol employees are being 76.5% interest in the firm. living with HIV,” the spoksperson added. offered an opportunity to transition over to [email protected] The most advanced assets going to ViiV, ViiV, which is headquartered in Brentford, UK. a joint venture of GlaxoSmithKline PLC and In a same-day note, Leerink Partners’ analyst A longer version of this article was also published Pfizer Inc. founded in 2009, are the Phase III Seamus Fernandez called the deal “a step in in “The Pink Sheet” DAILY. Scrip Intelligence brings attachment inhibitor BMS-663068 for heavily the right direction” for ViiV as it competes with selected complementary coverage from sister treatment-experienced HIV patients and the Gilead Sciences Inc. for top status in the HIV publications to our subscribers.

Orbimed Closes A $950M Fund As Biotech VC Surge Continues (Continued from page 22)

Inc., as a venture partner who can help guide as few as nine and as many as 16 OrbiMed- and Foresite Capital in July with $550m and the operations of orphan disease therapeutics backed startups launched during the next $450m funds, respectively. companies. three or four years. OrbiMed generally invests in three or Other recent VC firms that raised new Recent VC Funding Rounds four startups each year, which could be a venture capital for biopharma investments Aquinnah was the only startup among a significant number of companies under last year include Sofinnova Ventures with a group of five private drug developers that the VC firm’s new fund, which will begin €300m fund that closed last month, Frazier revealed new funding rounds between Dec. its 10-year life with a three- to four-year Healthcare Partners with a $262m fund in 16 and 22. investment period. That means there could be November, and Deerfield Management [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 23 headline news

Karolinska AbbVie: Hearing Needed On Development Biosimilars Interchangeability While the FDA had pledged to provide Epogen (epoetin alfa) and Enbrel (etanercept) Relationship ‘No biosimilar makers a guidance in 2015 – that have been chased by biosimilar makers outlining what is needed for products to (see P16 & 17). Longer Exclusive’ demonstrate interchangeability – a promise Indeed, it was Novartis AG unit Sandoz Karolinska Development AB and it did not keep considering 2016 has arrived Inc. that won the first approval in the US of a Karolinska Institutet Holding AB (the and there is still no sign of a document – biosimilar of Neupogen, which is marketed as technology transfer company of the AbbVie Inc. is arguing a public hearing is Zarxio (filgrastim-sndz). Karolinska Institute) have renegotiated needed before the agency acts on that vow. But now it’s Amgen that’s in hot pursuit – their relationship into a new non-exclusive A public hearing on interchangeability, with AbbVie’s product in its sights. deal flow agreement. The move follows which would also examine the implications So AbbVie’s had a lot to say lately. the appointment of new Karolinska of determinations where multiple biosimilars It submitted an earlier petition in June Development chief executive Jim Van may have been found to be interchangeable calling for the FDA to ensure there is a clear heusden earlier last year. He immediately with a single reference product, but not statement in the labeling of a biosimilar began implementing a new strategy each other, would help “protect patients by declaring the product is, indeed, a biosimilar, for the chronically underperforming ensuring that all viewpoints are heard,” AbbVie and if it is licensed for fewer than all of the Karolinska Development by positioning it insisted in a new citizen petition. reference product’s approved indications, it as a venture capital company. must acknowledge such. The deal will give the Karolinska AbbVie also said a biosimilar’s labeling must Institute access to a broader range of ‘Interchangeability raises acknowledge the licensed indications were funding sources and allow it to build questions fundamentally based on extrapolation, if applicable. stronger links with industry partners. In addition, AbbVie said the labeling of While Karolinska Development was not different from those presented biosimilars that have not been determined limited to only backing companies from to be interchangeable with the innovator the Karolinska Institute, Van heusden is by biosimilarity’ referenced product must include a clear convinced this new agreement is good statement of that fact. Karolinska Development too. The company said it supports the entry The company said there also should “Both parties have been involved of biosimilars into the US market and be a concise description of the pertinent in shaping the plans that have been acknowledged it would be possible “at some data developed to support licensure of the announced,” Van heusden told Scrip. “I point in time” for a manufacturer to provide biosimilar, along with information adequate believe it will benefit both the Karolinska sufficient scientific support to demonstrate to enable prescribers to distinguish data Institute and Karolinska Development its product is interchangeable with the derived from studies of that product from and will lead to more success in building innovator’s referenced medicine under the those derived from trials of the referenced successful life science business based on Biologics Price Competition and Innovation innovator drug. Karolinska Institute discoveries.” Act – the law that gave US regulators the The FDA notified AbbVie in early “Karolinska Development will be able authority to approve biosimilars. December the agency has not yet made a to increase its focus on building a more But, AbbVie said, “Interchangeability raises decision on the firm’s June petition about balanced investment portfolio by sourcing complex questions that are fundamentally labeling “because it raises complex issues opportunities from other academic different from those presented by biosimilarity.” requiring extensive review and analysis by institutions across the Nordic region,” he said. The company contended that because agency officials.” As part of the new agreement, the interchangeability determinations will facilitate In its latest petition, AbbVie said that Karolinska Institute plans to establish automatic substitution of biological products, like therapeutic equivalence ratings a new incubator fund focused on the standards for evaluation the FDA will use assigned to generic small molecule drugs, innovations at an early pre-seed stage, “are of major public health importance.” the interchangeability determinations are providing project management and In assessing interchangeability, the FDA must intended to facilitate pharmacy substitution funding. Karolinska Development will be a ensure applicants meet the safety standards for of lower-cost follow-on medicines for their cornerstone investor in the new incubator “each” condition of use for which the reference respective referenced therapies without the fund alongside a select group of other product is licensed – “regardless of whether the intervention of prescribers. specialist life sciences investors. applicant intends to label its product for every Unlike small molecules, however, biologics By investing in the new pre-seed fund such condition of use,” AbbVie demanded. present significant risks of immunogenicity, affecting both patient safety and product “we will continue having access to new The firm’s tumor necrosis factor (TNF) blocker Humira (adalimumab) has become the target efficacy, AbbVie said. And, the company said, high-quality opportunities based on the of Amgen Inc. to be copied as a biosimilar. one biologic cannot be the “same as” another. world-class innovation originating at Amgen is awaiting the FDA’s decision on So, AbbVie said, the FDA should clarify Karolinska Institute… This new incubator whether it will accept the company’s 351(k) that the statutory standard for establishing fund will provide these opportunities with application, submitted in November, for its interchangeability differs in both kind and exposure to a broader group of experienced adalimumab biosimilar, dubbed ABP 501. scope from the standard for establishing life science investors,” said Van heusden. It’s mostly been Amgen’s products – biosimilarity. [email protected] Neupogen (filgrastim), Neulasta (pegfilgrastim), [email protected]

24 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 commentary A Life In Genes: Scrip Award Winner Sir Gregory Winter’s Speech The 2015 Scrip Lifetime Achievement Award was given to Sir Gregory Winter, Master of Trinity College, Cambridge (UK). Founder of Cambridge Antibody Technology (acquired by AstraZeneca), Domantis (acquired by GlaxoSmithKline) and Bicycle Therapeutics, he is best known for his pioneering research into humanizing antibodies. His findings led to the development of the first human antibody, Humira (adalimumab), until very recently the world’s top-selling drug. See below for Sir Greg’s acceptance speech, delivered at the Scrip Awards ceremony at the Grosvenor House Hotel in London on Dec. 2, 2015.

Acceptance Speech “This is my first Lifetime Achievement Award, at least in this life. On behalf of myself I am grateful to accept it and to thank the sponsor Medidata, Scrip Awards, those who made the decision and those of you who have made me feel so welcome this evening. However I have been instructed to say a few more words than this…so please bear with me. Many years ago, before the days of rapid DNA sequencing, my PhD project involved sequencing a protein by digesting it into fragments, fractionating them and sequencing each peptide. I had already used Of course Brian was right. As I look back Again with hindsight of 25 years, I was just a range of different digests and procedures over a lifetime, I realize just how lucky I have so lucky that no established UK company was for peptide fractionation but was missing been. I was lucky to work for the Medical interested in working with me to develop my many of the overlap peptides needed to zip Research Council, lucky to work at the MRC ideas of making human antibodies from gene the sequences together. My PhD funding Laboratory of Molecular Biology, and lucky to repertoires. Otherwise I wouldn’t have had the was coming to an end, and I only had time have had Brian Hartley, Fred Sanger and Cesar experience of setting up Cambridge Antibody and material for one last throw of the dice. Milstein as mentors. But sometimes Lady Luck Technology with David Chiswell, or of raising I favoured one strategy for producing the presented herself in strange ways... money from the other side of the planet, or overlap peptides and my supervisor, Professor With the hindsight of 30 years I now realize of engaging with all those Australian horse- Brian Hartley, strongly advised another. how very fortunate I was to be attacked by a racing investors. At the time it really didn’t Inevitably I did it my way, and less inevitably criminal in 1984, and to suffer a nerve injury seem so lucky, but it all turned out for the it worked. that paralyzed my right arm and took me from good. Perhaps the lesson it is that extreme I went to tell Brian the good news and the bench as an experimentalist. This forced adversity can provoke innovation, which in was too polite to mention that I had ignored me to spend several months immersing turn can strike lucky. his advice, at least until he said: “Well lad, I myself deeply in the structures of enzymes A Lifetime Achievement Award may am so glad that you came round to my way and antibodies using an early computer suggest to some of you that I am finished – of thinking.” graphic system. I worked from dawn to a line drawn. Hard luck! And then on being corrected, he said “You dusk and then into the night to the point of As you know I have helped to found a were very lucky.” total exhaustion. I didn’t really want to do new company, Bicycle Therapeutics, based He might as well have thrown oil on a fire, it, I would much rather have been working on inventions relating to the creation and I found myself explaining angrily why on the bench had I been fit, but it was only and selection of bicyclic peptides as my strategy had been both intellectually and by complete mental immersion that I could pharmaceuticals. We think that “bicycles” practically superior to his. Each time I made a dull the intense pain from the nerve injury. combine many of the advantages of point, Brian said in his bluff Yorkshire accent It was during this time, and due to the deep antibodies and small molecules, and I “Luck” or “You were lucky,” like something immersion in protein structure, that I came up am hopeful that, after a sufficient dose of out of that Monty Python sketch. Finally as I the insight of humanizing mouse antibodies adversity, we will strike lucky and the platform started to froth at mouth, he totally disarmed by transplanting the antigen-binding loops will make it big-time. And perhaps in 25 me, by saying “Lad, calm down: it’s much from rodent monoclonal antibodies into a years’ time I will be invited back for the Scrip more important to be lucky.” human antibody. Resurrection Award!

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 25 headline news Pharma’s Experiment With India’s Borrow And Treat Model When a 52-year-old Indian cart-seller of Early Movers Arogya says it has taken a step to bridge plastic toys was hospitalized because of a MSD (as Merck & Co is known outside the this gap by offering loans at reasonable terms cardiac condition the first time, his family US and Canada) was perhaps among the to those who lack formal income proof, in the decided against going through with the first drug firms to ensure that its hepatitis C process creating a “lifeline” for people pushed treatment. They simply could not afford the therapy, interferon alfa 2b, can be accessed into poverty as a result of unexpected health costs involved. in India at “cash flow” levels that a patient, shocks. It uses innovative risk assessment tools But the second time round, when he was typically with average means, may possibly that allow it to finance people outside the back in hospital, Arogya Finance, which be comfortable with, though the arrival of formal banking system and its business model offers medical loans to the “traditionally sofosbuvir is believed to have seen a scale is structured in a way, that it directly pays the un-bankable” in India, ensured that he could back of the initiative. medical bills of an individual to the hospital or not only go through with the required Others like Roche and Boehringer the healthcare service provider. procedure but also need not be plunged Ingelheim have also indicated that they are Close to 800 patients across four regions into poverty after paying for his treatment. keen on financing models for their oncology and 10 Indian states have so far availed The vendor could repay Arogya in small products in India, while Medtronic offers themselves of Arogya’s services. monthly instalments. financial assistance for its heart devices. Such financing alternatives also trump Pharmaceutical companies are closely Roche said that with 80% of Indians paying the much publicized tiered pricing model, monitoring examples such as these as they out of pocket for healthcare, and cancer according to Peter. The latter he argues is “very link up with firms like Arogya to experiment being the third-highest cause of mortality good on paper” and starts off very well, but has with unique financing schemes in both among non-communicable diseases currently, not really been able to penetrate and scale. the drugs and devices segment in India. it recognizes that one of the key hurdles in “It ends up with everyone getting the Importantly, the trend appears set to spread access to optimal standard of care for cancer lowest price in the market.” to other Asian markets and potentially patients is the availability of funds. pockets of the developed world too. It expects to launch a pilot program Reliable People Typically, under such financing schemes, with a leading financial institution in India Peter also highlighted some interesting trends patients can stagger payment of the actual to create a financing option for Herclon that the Arogya model has seen. therapy cost over a specified period via equal (trastuzumab) as a part of its “The Blue Tree” Critically, payback is almost certain in the monthly instalments (EMIs) – along the lines patient support initiative. case of such medical loans. of similar schemes for consumer durables. “The aim is to reduce the monthly cash “Our limited experience shows us that these The chief of a US drug firm in India outflow and increase flexibility as much as are a very reliable people, although many explained that there is a difference between possible for the applicant. We hope that such people feel and think otherwise. About 90% the “ability” and “willingness” to pay for novel an offering will greatly increase access to of collections happen automatically, without therapies and that more and more firms have treatment,” Roche told Scrip. our intervention; may be a little telephonic begun to recognize the nuances. More recently Dr Reddy’s Laboratories intervention. I see no reason why this cannot “EMI schemes define the ability to pay linked up with Arogya to roll out a financing scale….it’s just that somebody needs to be much better and willingness to pay is about initiative for its hepatitis C therapy, Resof successful first.” whether you are really convinced about the (sofosbuvir). Arogya finances up to 100% of The Arogya model, he said, is also moving therapy. If you combine both well you get the drug cost in this case and the maximum beyond Indian shores. Financing efforts under much better results. People have begun to tenure allowed is 36 months, with the Medtronic’s successful ‘Healthy Heart for All’ understand this and you’d probably see more maximum loan up to INR200,000 ($3,009). initiative is now available in a “limited manner” of such efforts,” he told Scrip. Resof is priced at INR 20,000 for a 28s pack. in the South East Asian region. Optimal reach of such finance schemes Jose Peter, co-founder and CEO of Arogya “In the Philippines, we ran a pilot in Manila; for specialty products in a large and diverse Finance, a unique social healthcare venture, there are conversations going on about a market like India, some experts say, would said that currently most of the expensive similar one in Malaysia. They are talking about require the involvement of large banks as well treatments reach only 10-20% of patients doing something in the US,” Peter said. as non-banking financial companies. who could benefit from the therapy, Launched in 2010 in India, the Healthy Heart Dr Ajit Dangi, president and CEO of mainly because of challenges in awareness, for All initiative provides financial assistance Danssen Consulting and a former director availability and affordability. to implant heart devices such as stents, general of the Organization of Pharmaceutical “While all these issues need to be pacemakers and heart valves by partnering Producers of India, told Scrip that while India addressed, affordability is the single most with hospitals. More than 100 Indian hospitals has a large under-banked population (only important aspect in the decision-making are part of Medtronic’s access initiative 40% of the population hold bank accounts, process of the patient and the doctor/care that includes screening camps and patient he notes referring to a Reserve Bank of India giver,” Peter, a former CFO of the retail finance counselling, besides financial assistance. report) things have significantly improved firm, Tata Motor Finance, told Scrip. The initiative is said to have screened more recently after the Government’s concerted Arogya also noted how millions of Indians than 100,000 patients, treating over 14,000 efforts to incentivize the rural population to are unable to pay out-of-pocket for medical and disbursing in excess of 500 loans. open bank accounts. emergencies and often money is borrowed In addition, India’s massive postal at high interest rates or is organized by selling Gilead Model network, the largest in the world, should personal assets or simply ignoring much needed Some experts, however, believe that a be roped in for medicine and healthcare medical attention. This, it estimates, leads to 40m hybrid approach, including the “Gilead financing, he adds. people falling into poverty every year. model,” is the way forward to improve access ➤

26 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Novartis Consolidates Indian Service Operations Novartis has consolidated its largest global service operations at Hyderabad, underscoring the Swiss multinational’s long- term commitment in the segment in India. The new state-of-the-art office, Novartis Knowledge City in Hyderabad, is the largest of five Novartis Global Service Centers; the other sites are in Kuala Lumpur, Prague, Dublin and Mexico City. The new site combines Novartis’ mamong w/shutterstock.com operations in Hyderabad from two existing offices and can house 3,500 employees.

This is a very important Novartis Knowledge City in Hyderabad is the largest of five Novartis Global Service Centers element for Novartis given the ‘vibrancy of India’ marketing graduates with deep knowledge produce abstracts etc. of a particular therapeutic area are able to Emmanuel Puginier, head of product “Going ahead this is going to be a very support countries and the global organization lifecycle services, Novartis AG, underscored important element for Novartis given the with analysis of a particular launch, what that access to a pool of highly qualified demographics and the vibrancy of India,” price the launch can be made, competitor professionals across many disciplines, Ranjit Shahani, vice chair and managing comparisons etc. together with availability of key infrastructure, director of Novartis in India said at a recent “Things that really help the onsite made Hyderabad an outstanding location for interaction in Hyderabad. organization to make decisions on whether a Novartis Global Service Center. The new site provides a gamut of services we launch; how we launch. Hyderabad being The reference to scale up plans of the five including information technology, financial the oldest and largest, we will lead the way global service centers in Novartis’ Q3 2015 reporting and accounting, market analytics, within our organization as a global service results, he clarified, was related to the other data management, biostatistics, medical center,” Gullapalli said. centers such as the ones in Prague and communications and scientific support Approximately 10% of personnel at the Mexico, which are new and relatively small. services among others. Hyderabad site are medical doctorates, The Novartis Knowledge City was Naveen Gullapalli, Head of the new Novartis medics or PhDs, allowing it to also leverage inaugurated by KT Rama Rao, minister of Global Service Centre in Hyderabad told Scrip scientific knowledge and generate information technology of Telangana state. that in areas such as marketing analytics, appropriate content for medical conferences, [email protected]

Pharma’s Experiment With India’s Borrow And Treat Model (Continued from page 26) to breakthrough, pricey therapies in the government abdicate its responsibility to a He also referred to how Gilead is probably developing world and point to the limited private commercial entity?” Micro finance the first company to break this paradigm with impact microfinance firms can have in moving companies can help, Shah added, but he noted Sovaldi and hoped that many others follow the access needle. that they do not resolve the issue of access and the lead and that financing schemes “do not Last year Gilead entered into licensing affordability, given their limited reach. end up becoming the way forward” in India. deals with several India-based firms Others note how naysayers accuse The industry pundit also believes that including Cipla, Zydus Cadila, Hetero, pharma of profiteering and appeal to it for debt-financing schemes for breakthrough Strides, Ranbaxy and Mylan Labs to develop “compassion and understanding” while doing drugs are not a win-win for stakeholders sofosbuvir and the single tablet regimen of “precious little” themselves to control spiralling and merely address the “symptoms” without ledipasvir/sofosbuvir for distribution in 91 costs across the spectrum of health care. addressing the “malaise.” He had some radical developing countries. They underscore that medicine prices are suggestions to “build” access by reducing Dilip Shah, secretary general of the Indian a small subset of and directly proportional the cost of medicines, including pressurizing Pharmaceutical Alliance, which represents to the overall health care costs and that governments around the world to de-regulate leading domestic firms, says that a combination multinationals in India are caught between “a and liberalize the health sector, reducing of both government financing and the “Gilead rock and a hard place” because this rationale patent life and devising new ways to model” is the way forward in India. makes little sense in an out-of-pocket market. incentivize pharma R&D. “For the rich, one can add co-payment as “That is why financing schemes were “The more the sector is opened up to the third element for access to expensive deemed as a clever way to encourage market forces, the quicker we will see prices medicines,” he told Scrip. caregivers to buy these medicines whose fall and service improve. Until then, we can He does not favour debt-financing for prices cannot be reduced for a variety of only hope to come up with cleverer financing breakthrough pharmaceutical products and reasons such as reference pricing and parallel options for prices that are, in the long run, believes that it would leave patients at the trade,” an industry pundit with a foreign firm unsustainable,” he maintained. “mercy” of the patent holder. “How can a told Scrip. [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 27 policy & regulation briefs Policy & Regulation Briefs infectives, though finer price details on products Court Speeds Up will only become clearer once India’s pricing regulator sets out caps on the NLEM 2015 products. Apotex Appeal In Valeriy/shutterstock.com Evlakhov Industry experts, however, told Scrip that it was not Amgen Biosimilar Suit immediately clear how many formulation packs The US Court of Appeals for the Federal the AIOCD AWACS data covered and whether it included all the products whose ceiling prices Circuit granted Apotex Inc.’s motion – or were set under Para 19 of the Drugs Prices Control at least, in part – for an expedited appeal Order. “The span of control could probably be 3-4% of a Florida court’s decision to impose a more than is being suggested. It is also not very preliminary injunction (PI) that prevents the clear if the data takes into account certain drugs firm from marketing its yet-to-be approved under Para 19 which will go outside price control,” pegfilgrastim biosimilar until 180 days after oncology active pharmaceutical ingredients site in an expert said. India’s National Pharmaceutical FDA licenses the product. The biosimilar Ahmedabad (Zyfine). This is the second time that Pricing Authority (NPPA) had in 2014 capped is referenced on Neulasta, a long-acting the Moraiya unit is under the FDA scanner – it was prices of certain drugs under Para 19, which deals human granulocyte colony-stimulating previously pulled up in 2011 but received a FDA with fixation of ceiling prices of drugs under “extra-ordinary circumstances”. The NPPA while factor marketed by Amgen Inc., which filed close out letter in 2012 after violations there were addressed. The Moraiya site accounts for about invoking Para 19 then claimed that there existed the lawsuit, in which it accuses Apotex of 60% of Zydus Cadila’s US formulation revenues and huge inter-brand differences in branded-generics/ violating the disclosure and negotiation roughly 40% of the firm’s oral solid dosage filings off patent drugs which was indicative of a severe procedures of the Biologics Price Competition for the US. The Ahmedabad-based firm, however, market failure, as different brands of the same drug and Innovations Act (BPCIA) – the so-called clarified that there were no products in the US formulation are identical to each other. Industry patent dance. Amgen has been insisting that market that use APIs of the Zyfine facility. Zydus has challenged these price caps. AIOCD AWACS biosimilar makers must provide innovators Cadila chairman and managing director, Pankaj has indicated that its data calculations have been with a 180-day notice of commercial R Patel, explained that the API facility had good done without factoring in “special dosage / unique marketing after, and not before, FDA licensure manufacturing practice (GMP) issues and the firm delivery mechanisms.” The data includes the Para 19 – even if they’ve engaged in the patent had taken action to “correct people and processes” molecules under the NLEM 2015 (see p31 for more). dance, like Apotex did with the California and suspended activity there. While remediation work was ongoing, the site underwent an FDA FDA Warning Eclipses Sun And SPARC biotech giant. On Dec. 9, Judge James Cohn inspection and certain observations were made. Shares of Sun Pharmaceutical Industries Ltd and of the US District Court for the Southern Sun Pharma Advanced Research Company Ltd District of Florida sided with Amgen and New Indian Price Caps Loom (SPARC) were pounded in early trade Dec. 21 on imposed the PI. But Apotex quickly appealed, India’s national list of essential medicines (NLEM) Indian bourses after the weekend announcement and a few days later, called on the Federal 2015 is estimated to cover an additional INR77.84bn of an FDA warning letter for Sun’s Halol site, though Circuit to expedite the case – declaring the PI ($1.17bn) worth of drugs across therapy segments, analysts appeared cautiously optimistic about the would cause “immediate harm” by preventing extending the scope of price controls to certain firm’s bounce-back prospects despite the short- the Canadian company from putting its new products while bringing significant savings term pain. Some analysts claimed that Sun had biosimilar on the market immediately after to patients. Early estimates provided by AIOCD more than 40 sites and hence the larger picture AWACS, a market research agency that tracks wasn’t as alarming, though they had an eye out regulators issued their decision on the retail sales, suggest that frontline Indian firms like for any caustic content in the warning letter that product. Apotex had asked the Federal Cipla, Sun Pharma, Lupin, and Zydus Cadila will may point towards a probability of an escalation Circuit to set a quicker schedule – putting the bear the brunt of the extended NLEM coverage, of compliance issues at Halol. On Dec. 19, Sun said deadline at Dec. 30 for the firm to submit its with foreign firms such as Pfizer, Novartis and that it had received a warning letter from the US opening brief, with Amgen responding by Janssen far less impacted. Overall “patient benefits” FDA as a result of the agency’s September 2014 Jan. 19, 2016, followed by Apotex’s reply by accruing from NLEM 2015 has been estimated at inspection at its facility in Halol, Gujarat, but Sun’s Jan. 27, 2016, with the deadline for the joint INR7.47bn. Company reactions to the data could management, in an investor call later that evening, appendix by Jan. 29, 2016. The Federal Circuit not immediately be got owing to the holiday clarified that the FY16 guidance stood unchanged. moved swiftly with an order on Dec. 15 – period. India had on Dec.23 announced its NLEM Sales to the US from Halol represent a “high single telling Amgen it had until Dec. 18 to submit 2015, which covers a total of 376 drugs across 30 digit number” in percentage terms to total FY16 therapeutic segments, including those such as revenues and the site is the only one from which its brief in opposition to Apotex’s motion to sofosbuvir, pegylated interferon alfa 2a and 2b, the Indian firm has filed injectable products for expedite and setting Dec. 22 for any reply raltegravir, trastuzumab, and rituximab, as against the US. “Our initial reading of the warning letter in support of the motion. It also set Dec. 30 348 medicines across 27 segments listed in NLEM indicates that it is based on the 483 observations as the due date for Apotex’s opening brief – 2011. While the key objective of the NLEM is to issued in Sept 2014. Over the next few days we giving the company what it had requested. promote the rational use of drugs and optimum will try to understand this in further detail,” Dilip use of resources available for health care delivery, Shanghvi, managing director, Sun Pharma said at Zydus Cadila Reels Under Double medicines on the NLEM are typically subject to the investor call. Sun has responded to the FDA FDA Warning price caps. India’s Drug Prices Control Order 2013 inspection observations with a remediation process Shares of Cadila Healthcare were pounded on had capped the prices of over 600 formulations that is still ongoing, with significant investments Indian bourses on New Year’s eve after the FDA across 27 therapeutic segments specified in the in automation and training to enhance its quality issued warning letters against two of the firm’s NLEM 2011. AIOCD AWACS data indicates that systems. To a query on typical timelines for sites, though the company’s top brass stressed new additional coverage under the NLEM 2015 resolution of warning letters being in the region of that de-risking efforts, by way of site transfers for is higher in segments such as anti-infectives, 12-15 months , Shanghvi said: “I don’t think we will critical products, were underway. Cadila on Dec. cardiology, neurology and CNS, with dermatology have to redo all the remediation…. we may have 31 announced that it had received warning letters seemingly the least impacted. Patient savings are to augment some of the remediation, so it may not against its Moraiya formulation facility and its also expected to be highest in segments like anti- take 12-15 months is what is our sense.”

28 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news That Was The Year That Was: Scrip’s Biggest Stories Of 2015 possible combinations of IO strategies and settings ahead. Expect this to continue well into 2016 and beyond.

Biosimilars Hit The US At the other end of the R&D life cycle, 2015 finally saw the arrival of the first biosimilar on the US market. In January, Dr Janet Woodcock, director of the FDA’s Center for Drug Evaluation & Research, described the meeting of the FDA’s Oncologic Drugs Advisory Committee as an “historic

Pixelbliss/shutterstock.com occasion” – referring to the fact it was the first time ever one of the agency’s advisory committees had assessed a so-called 351(k) biosimilar application. The filgrastim biosimilar in question, Zarxio from Novartis and its Sandoz unit, duly won the panel’s unanimous support. It was approved in March but launch had to wait until As the effects of too much seasonal feasting led to similar levels of ink being spilt on September following a legal dispute with begin to fade, what better way to kick back this question. Talk of a biotech bubble has the innovator Amgen. Still, the precedent and relax than with a quick review of the been rampant since US Federal Reserve was set, and around six other applications year? For your delectation, Scrip has surveyed Chair Janet Yellen made comments last year are now in the offing. Meanwhile in Europe – the stats to see which stories kept our readers about the industry, with high valuations, pioneering territory for biosimilars – a recent clicking in 2015: a wide-open IPO window, and a constant slackening in approvals has picked up again stream of M&A activity, lending weight to with a spate of filings. Seven biosimilars Mergers And Acquisitions the theory. But others say that things are are now under active review at the CHMP: Really there is no other theme to beat it. not the same as they were 15 years ago, and etanercept (one product), infliximab (one), News of the industry’s whirlwind courtships, that history is not destined to repeat itself: pegfilgrastim (two), rituximab (one) and failed pursuits and tricky threesomes are the good times for the market are more enoxaparin sodium (two). perennial favorites, and 2015 made its fair likely to normalize gently. Well, we shall see For more information on the year’s big share of riveting reading. The royal wedding what happens in 2016. news at the FDA, see US Capitol Capsule: of them all was of course Pfizer’s and Washington’s 2015 Biopharma Game Changers. Allergan’s record-breaking $160bn tie-up (a soothing balm for any lingering wounds from When do you know you are in a Oh No It Isn’t! AstraZeneca’s most public rejection), but bubble? Once it bursts, maybe? ‘Tis the season and every pantomime needs AbbVie’s $21bn purchase of Pharmacyclics, someone to play the villain. Hiking the price and Celgene’s $7.2bn acquisition of San for a toxoplasmosis medicine, Daraprim Diego-based Receptos also made headlines. Immuno-Oncology Progress (pyrimethamine), by more than 5,000% was But there was no happy ending for those While the captains were busy minding their bound to get some people booing. The who perhaps pushed a little too hard: steps in the M&A dance, pharma’s R&D engine Martin Shkreli story has kept readers clicking Mylan’s Perrigo hunt, and Horizon Pharma’s rooms have been at full speed churning ever since his unapologetic response to unwanted $1.7bn suit for Depomed both out more and more research in immuno- criticism in September. But it was the Turing failed. Meanwhile, we await the dénouement oncology, making it the major science Pharmaceuticals AG’s CEO activities at his of two further sizeable potential deals theme of the year. Merck & Co’s Keytruda previous drug firm, Retrophin Inc., that got between Shire PLC and Baxalta, and between (with a great testimony from Jimmy Carter) the 32-year-old former hedge fund manager Astellas Pharma Inc. and the cell therapy and Bristol-Myers Squibb’s Opdivo solidified arrested for securities fraud early on Dec. company Ocata Therapeutics. their positions as the key IO drugs, for now 17; he was seen being escorted out of his For more details of these and other major anyway, while new data poured forth from midtown Manhattan apartment by law deals of the year see The Top Five Deals Of meetings such as ASCO and ASH without any enforcement officials. He promptly resigned 2015 (And A Few That Fell Apart). real dampening of enthusiasm for the field. as Turing CEO and was sacked as CEO of Still, many questions remain, especially over KaloBios Pharmaceuticals Inc. a firm he had Biotech Bubble the commercial viability of autologous CAR-T only joined in November after acquiring a When do you know you are in a bubble? therapies in the light of highly promising 70% stake. Shkreli has pleaded not guilty to Once it bursts, maybe? Whatever, the (albeit very early) data for Cellectis’ “off-the- the fraud charges against him, setting the amount of investment and deal-making that shelf” allogeneic product. There is also the stage for Act Two in 2016. has gone on in this sector this past year has Herculean task of teasing out the myriad [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 29 headline news Ebola, Childhood Cancers, And Chronic Pain: IMI’s New R&D Ventures Europe’s Innovative Medicines Initiative (IMI) readiness to respond to future outbreaks.” March 16, 2016, Sept. 15, 2016, March 16, has launched two calls for proposals, one Proposals may address various aspects of 2017, Sept. 24, 2017, and March 15, 2018. The of which allots €70m ($76m) for research preclinical or clinical development of Ebola whole of the €70m budget will be available as into Ebola, specifically the development of and other vaccines (in particular multivalent), of the first cut-off date. vaccines, treatments and diagnostic tests to treatments and diagnostic tests, as well as improve responses to future outbreaks of manufacturing strategies, vaccine stability in Other Topics Ebola or related diseases. transport and storage, and deployment of IMI2 call No 7 is a standard call that includes The other call covers a total of seven topics, vaccines and treatments in situ. the following topics (for each topic the including childhood cancers, chronic pain, Partners in any proposed consortia funding figure is the amount provided by both degenerative brain diseases, and the use of must be able to develop the results into the IMI and EFPIA, the latter mostly in the form “big data” to improve clinical outcomes. validated treatments, preventive measures or of in-kind contributions by the EFPIA member Pierre Meulien, IMI executive director, said accurate and rapid diagnosis that will result companies in the relevant consortium): the latest calls demonstrated the added in increased preparedness in case of future Big data: this comprises two separate value of collaboration as enabled by the outbreaks. Collaboration with international topics: projects to help coordinate and IMI. “Excellent science exists in all of these organisations that were involved in managing support the entire “Big Data for Better research areas, but only by bringing together the 2014/2015 Ebola epidemic is encouraged, Outcomes” (BD4BO) program, and those experts from industry, academia, small the IMI says. aimed at improving clinical outcomes for biotechs, patient groups, and others can we The key deliverables of funded projects people with heart disease through better hope to translate world-class science into include the following: access to and use of high-quality data. The improved health for patients,” he declared. • Progression of a novel vaccine candidate, contributions for the first topic will be €3.55m, Under the IMI process, pharmaceutical diagnostic or treatment up to a stage ready and for the second a maximum of €9.672m companies, public bodies, patient organizations for testing in an outbreak setting. (the EFPIA in-kind contribution for the second and so on are invited to assemble consortia • New tools to assist preclinical and clinical topic will include access to placebo data from to tackle projects in the areas in question. development of vaccine candidates and existing and concurrently collected clinical Successful consortia gain access to the benefits treatments (including proof of concept trial data, capped at a maximum of €4m). of collaborative working as well as to funding testing of existing platforms for screening Childhood cancers: the IMI says that and in-kind benefits through the IMI, which is compounds for Ebola and other filoviruses). despite significant advances in treatment and co-financed by the European Commission and • Development and/or validation of a novel survival over the past 20 years, more than the European Federation of Pharmaceutical diagnostic test that is sufficiently sensitive, 20% of pediatric cancers are still incurable Industries and Associations. rapid, user-friendly, cheap, and usable in and survivors often experience long-term side resource-limited settings. effects. The prospect of molecular targeted Ebola Project • Novel strategies to improve the stability therapies could lead to cures for many The new calls for proposals are being made of vaccines against Ebola and other filoviral intractable pediatric tumors, and promises under the second phase of the IMI (IMI2). infections during transport and storage, safer, less harmful treatment options for Ebola (call No 8) is an open call, meaning for example allowing allow storage at 8°C tumors that are responsive to conventional that it will remain open for two years, with a or ambient temperatures for prolonged therapy but will likely suffer debilitating long- number of cut-off dates for the submission of durations. term side effects, the IMI says. Unlike research proposals. The IMI says that the collaborative • Novel manufacturing and delivery for adult cancer, pediatric research is severely approach is “a necessity” in this area because strategies. limited by a lack of disease-relevant preclinical on the one hand the expected return on • New learning and strategies for optimal models capable of generating effective investment into research on Ebola and other deployment and adherence to vaccination patient-tailoring hypotheses to guide the filoviral hemorrhagic fevers is low, but on programs. clinical development of pediatric drugs. the other hand the diseases pose a “great An important expected impact of projects Alzheimer’s and Parkinson’s diseases: the threat to nations worldwide” and dealing with funded under this call and the Ebola+ focus of this topic is on how protein tangles, outbreaks is difficult in countries where the program in general is to maximize the benefit which are hallmarks of both diseases, spread healthcare infrastructure may be limited. to the people in the countries at risk from throughout the brain. Projects should be This is in fact the second call under the future outbreaks of filoviral hemorrhagic aimed at identifying druggable targets that Ebola+ program, which was launched in fevers, the IMI says. “In order to achieve this, modulate these misfolded proteins in order response to the 2014 disease outbreak in successful applicant consortia should have to develop treatments with the potential to West Africa and which has so far funded eight the capability to accelerate their project delay or halt disease progression (€4.685m). projects that are now up and running. The IMI results into health care interventions.” Chronic pain: neuropathic pain (NP) affects says the latest call provides “an opportunity Moreover, any project funded under the 6-8% of the population, causes great misery, to capture emerging scientific advances and Ebola+ program is expected to synergize with incurs “huge” costs to society and is extremely to progress those rapidly into health care the other EU-funded projects that have been hard to treat, the IMI observes. Current therapies interventions.” Projects funded under this call launched under the EU Horizon 2020 program. address only the symptoms, not the causes, of should ensure “fast development, uptake and/ The call for proposals is continuously open the pain, and so are not curative. Moreover, the or wide deployment of sustainable innovative for a period of two years, with the following aetiologies of the disease are poorly understood, solutions that will result in an increased cut-off dates for submission of proposals: and this hinders the development of new, more

30 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 expert view Indian Essential Drugs List Heralds Price Caps On Hep C Products diseases as public health problems in India. across 27 therapeutic segments specified The list could be called as a best-fit list,” the in its NLEM 2011, in line with its previously

Kunal Mehta/shutterstock.com report of the core committee chaired by Dr announced national pharmaceutical pricing VM Katoch, former secretary, department of policy. In 2012, India announced its new health research and director general, Indian market-based pricing policy as against the Council of Medical Research, noted. Dr YK previous cost-based one. Gupta, professor and head, department of pharmacology, All India Institute of Medical NLEM 2015 Sciences (AIIMS) was the vice chair. The core committee report also notes that the Industry experts say that an early read of essentiality of a medicine in NLEM 2015 has NLEM 2015 indicates that the span of price been considered in terms of its dosage form India has announced its national list of control would increase, though it may not be and strength too. essential medicines (NLEM) 2015, which dramatic. It, however, clarified that any dosage form of a covers a total of 376 drugs across 30 “We are glad that the expert committee medicine, other than the dosage form included therapeutic segments, including those such has remained consistent with the criteria for in NLEM, but in the same strength and route of as sofosbuvir, pegylated interferon alfa 2a and selection of medicines in the NLEM and also administration, which does not have significant 2b, raltegravir, trastuzumab, and rituximab, as that it has been more explicit so that there difference in terms of pharmacokinetics/ against 348 medicines across 27 segments is limited scope for the pricing regulator to pharmacodynamics/ efficacy-safety profile over listed in NLEM 2011. interpret what can be brought under price the dosage form mentioned in the list will be While the key objective of the NLEM is control,” Dilip Shah, secretary general of considered as included. to promote the rational use of drugs and the Indian Pharmaceutical Alliance, which “However, such different dosage forms optimum use of resources available for health represents leading domestic firms, told Scrip. should be considered differently for purposes care delivery, medicines on the NLEM are An Indian parliamentary standing such as procurement policy, pricing etc. typically subject to price caps in India. Early committee on chemicals and fertilizers This principle also applies to all other estimates, however, suggest that the broad had earlier stirred up a hornet’s nest after it dosage forms e.g. oral liquid dosage forms, industry-wide impact of NLEM 2015 may not suggested that “all medicines are essential” injectables, topical dosage forms etc,” it said. be drastic, though there may be significant and taken only when needed by patients and It also notes that in cases where an active winners and losers among individual firms. that these medicines including life-saving moiety is available as different isomers/ NLEM 2015 is also categorical about drugs should be available in the market at analogues/ derivatives, they are considered as inclusion/ exclusion of different salts of a “affordable cost.” separate entities, and inclusion of one does medicine, leaving little room for interpretation Asked about the inclusion of new drugs not imply inclusion of all. by India’s price regulator, industry experts said. such as sofosbuvir in the NLEM, Shah said NLEM 2015 also underscores the role Details in the report of the core committee that there may be no reason to be “unduly of innovation in medicine. It specifies that for revision of the NLEM made public Nov.23, worried” given the market-based pricing formulations developed through incremental note that a total of 106 medicines have been policy followed by India. innovation/ novel drug delivery systems added, and 70 medicines have been deleted “It must interpreted as being consistent like lipid/liposomal formulations, sustained to arrive at NLEM 2015. Eight molecules with the objective of the NLEM,” Shah said. release/controlled release etc. should be find mention across different therapeutic A clutch of players including Cipla, Zydus considered as included only if specified in the segments, industry experts said, explaining Cadila, Natco Pharma, Strides Arcolab and list against any medicine. the mismatch in numbers. Mylan have launched sofosbuvir in India “Such different formulations should be “The NLEM 2015 has been prepared following licensing deals with Gilead. considered differently for purposes such as adhering to the basic principles of efficacy, India’s Drug Prices Control Order 2013 had procurement policy, pricing etc,” it adds. safety, cost-effectiveness; consideration of earlier capped the prices of formulations [email protected]

Ebola, Childhood Cancers, And Chronic Pain: IMI’s New R&D Ventures (Continued from page 30) effective analgesics. This topic will use cutting- macular degeneration (dry AMD), which is one Medicines safety: this topic aims to edge techniques and technologies to deepen of the leading causes of blindness worldwide. advance the use of imaging in assessments understanding of clinical NP at the cellular and This topic will focus on the development of of medicines safety. Among other things, genetic levels, and the knowledge gained will novel endpoints for clinical trials of new drugs, this would help to improve drug safety, “greatly improve the chances of identifying and looking particularly at functional impairment add to our understanding of why developing curative analgesic therapies for in intermediate AMD and progression to late- medicines sometimes cause toxicity, and chronic NP which would enhance the quality stage diseases, the development of structural reduce the use of animals in research, of life for millions of patients” as well as bringing imaging biomarkers as surrogate markers according to the IMI. Information on these substantial cost savings in healthcare (€1.5m). of functional vision impairment, and the and other aspects of the IMI can be found at Eye diseases: there are currently no development of measures of patient-reported www.imi.europa.eu. effective treatments for dry age-related outcomes (€8.025m). [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 31 stockwatch A Brief History Of Asset Swaps Even with the proposed acquisition of Allergan Plc by Pfizer Inc., 2015 was not so much the year of life science M&A or even the bursting of the biotech bubble but the rise in the asset-swapping imperative. The jury is almost certainly still out for this development amongst big pharmaceutical companies so unlike the pharmaceutical mega-merger there Hein Nouwens/shutterstock.com is at least one reason why we may continue to see asset swap transactions in 2016. At the JP Morgan Healthcare conference almost two years ago I was interested in the Novartis AG fireside chat, which highlighted a preference for scale and a disdain for underperforming divisions (especially if they were small, like its OTC, vaccines and diagnostic divisions). This sounded like a & Co. into clinical diagnostics and pharmacy to be one of those rare asset swaps where no corporate finance 101 class, in which the benefit management have only resulted in the losers have yet been identified. margins of a conglomerate are scrutinized to divestment of those divisions a few years after The financial and corporate imperative identify divisions with lower profitability that their acquisition and not, like CSL’s vaccine for asset swaps between pharmaceutical might be divested so that the proceeds can business acquisition, as a result of competition companies in order to avoid sub-scale be used to bulk up higher margin businesses. authority concern. Perhaps it is partly the operations and promote therapeutic focus Nevertheless, the Novartis strategy was scale and complexity that defeats the lofty might appear logical. However, at least the prefaced by a statement of satisfaction with aims of achieving critical mass. The string of largest and most complex of such transactions its low margin but sufficiently large generic smaller scale respiratory-focused acquisitions seems to have been accompanied with a pharmaceutical business, Sandoz. by AstraZeneca Plc, which included divisions bitter financial aftertaste. GSK was supposed to That aspirational corporate re-organization from Almirall SA and Actavis PLC, have a more distribute a special £4bn dividend as a result was finally enacted last year with the sensible “sticking to the knitting” approach. of the cash generated from its asset swap principal transaction involving Novartis and AstraZeneca has not always been on the with Novartis but this investor pay-off was GlaxoSmithKline PLC (GSK) as the two lead right end of an asset swap transaction. Its later cut by three quarters. It is also illogical proponents, with a number of other companies $4.3bn acquisition of the other half of its to believe that a sub-scale division with years such as Eli Lilly & Co., Perrigo Co. PLC and CSL diabetes joint venture with Bristol-Myers of underperformance either in one company Limited playing supporting roles. The main swap Squibb, Co. demonstrated that an “also or under joint ownership will suddenly be was GSK’s oncology drugs portfolio (but not ran” therapeutic franchise owned by two transformed into a jewel under changed its development pipeline) for Novartis’ vaccine pharmaceutical companies does not become ownership. In this respect, there may be more business, while the OTC businesses of both any better when controlled by just one. This losers than winners in pharmaceutical asset companies were combined. At the same time, had been aptly demonstrated in the same swap transactions. However, there is always Novartis’ $5.4bn animal health business was sold therapeutic area a few years previously when one guaranteed winner – the investment to Lilly. Subsequently, some of GSK’s consumer Pfizer took full control of the inhaled insulin bankers – who earn juicy fees from both sides brands were sold to Perrigo and the Novartis franchise from Sanofi only to write off the on every transaction. influenza vaccine business sold to CSL to satisfy whole investment when the product was The Magna Biopharma Income fund the competition authorities. As a poster boy for eventually withdrawn. Sanofi initially came holdings include Allergan, Pfizer, Novartis, CSL, the pharmaceutical asset swap this transaction out of the transaction with honor, but it went Merck and BMS. was initially billed as a win-win-(win) depending on to license the spectacularly unsuccessful Andy Smith on how many participants were included. To inhaled insulin developed by MannKind, Andy Smith is chief investment officer of Mann judge by GSK’s and Novartis’ first full quarterly Corp., indicating that the lesson of inhaled Bioinvest. Mann Bioinvest is the investment results following the closing of the transaction, insulin appeared not to have been learned. adviser for the Magna BioPharma Income however, there may not have been any winners. Smaller scale asset swaps, or complete fund which has no position in the stocks The losing streak even extended to CSL, whose exits from a therapeutic area – in contrast to mentioned, unless stated above. Dr Smith gives acquisition of Novartis’ influenza business for GSK’s oncology asset swap – appear to have an investment fund manager’s view on public just over half its annual revenues turned into been more successful. The $4.1bn divestment life science companies. He has been lead fund another loss as the extent of the associated of the BMS wound care business amongst manager for four life science– specific funds, restructuring costs came to light. other non-pharmaceutical assets in order to including International Biotechnology Trust and Asset swaps have punctuated the recent focus on oncology, like the later divestment the AXA Framlington Biotech Fund, and was history of the pharmaceutical sector and of the diabetes business to AstraZeneca, has awarded the Technology Fund Manager of the it might appear that, like the Novartis- not appeared to have done the remaining year for 2007. GSK transaction, the more revolutionary company any harm. Likewise, the $14.2bn the transaction, the less successful the divestment of Merck’s consumer business to For all Stockwatch articles visit combination. Thus the previous forays of Bayer AG – executed like BMS to sharpen a scripintelligence.com/stockwatch pharmaceutical companies like GSK and Merck focus on immuno-oncology – so far appears

32 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 US capitol capsule Cancer Therapies, Orphan Drugs Dominated 2015 Approvals; PCSK9s Arrived Cancer therapies dominated US drug approvals Patients with multiple myeloma also were Other new therapies cleared by the in 2015, with the FDA’s Center for Drug big winners in 2015, with the FDA’s OHOP FDA’s OHOP in 2015 included Taiho Evaluation and Research (CDER) also giving its granting NME or novel biologic approvals Pharmaceutical Co. Ltd.’s Lonsurf (trifluridine/ nod to a record number of medicines that had for Novartis’ Farydak (panobinostat), Janssen tipiracil), which is indicated as a treatment gained orphan drug designation. Biotech Inc.’s and Genmab AS’ Darzalex for patients with metastatic colorectal cancer Indeed, of the 45 new molecular entities (daratumumab), Takeda Pharmaceutical Co.’s who have been previously treated with (NMEs) and novel biologics CDER approved in Ninlaro (ixazomib) and Bristol-Myers Squibb fluoropyrimidine-, oxaliplatin- and irinotecan- 2015 – which was four more than 2014 and Co.’s and AbbVie Inc.’s Empliciti (elotuzumab). based chemotherapy, an anti-VEGF biological the most since 1996 when there were 53 – 21 Two new skin cancer drugs also secured therapy and if RAS wild-type, an anti-EGFR had orphan status. approvals from OHOP in 2015: Genentech’s therapy; and Janssen’s Yondelis (trabectedin) The year also was a game changer for and Exelixis Inc.’s Cotellic (cobimetinib), a MEK as a treatment for metastatic or unresectable patients with extremely high cholesterol – inhibitor, which was cleared as a therapy in liposarcoma and leiomyosarcoma. with the arrival of the proprotein convertase combination with Zelboraf (vemurafenib), OHOP also approved Boehringer Ingelheim subtilisin/kexin 9 inhibitors onto the US market. a kinase inhibitor marketed in the US by GmbH’s Praxbind (idarucizumab) this part Sanofi SA’s and Regeneron Pharmaceuticals Genentech and Daiichi Sankyo Co. Ltd., to October under an accelerated approval as Inc.’s Praluent (alirocumab) was first to clear treat patients with unresectable or metastatic the first agent available to reverse the blood- the FDA’s bar, gaining approval in July 2015, melanoma with a BRAF V600E or V600K thinning effects of the company’s highly while Amgen Inc.’s Repatha (evolocumab) mutation; and Novartis’ Odomzo (sonidegib), popular anticoagulant Pradaxa (dabigatran) in followed close behind about a month later. an oral selective smoothened inhibitor, which emergency surgery or urgent procedures or The two PCSK9s have been in a fierce was approved as a treatment for adults with in situations when there’s life-threatening or competition to be placed on payers’ formularies, locally advanced basal cell carcinoma that uncontrolled bleeding. although Express Scripts Holding Co., the largest has recurred following surgery or radiation Tesaro Inc. was another firm given the pharmacy benefit management company therapy, or those who are not candidates for FDA’s go-ahead in 2015 to market a new in the US, decided to put both Praluent and surgery or radiation therapy. drug: Varubi (rolapitant), which is indicated Repatha on its “national preferred formulary.” On Feb. 3, 2015, the OHOP approved Pfizer in combination with other antiemetic CDER also gave its blessing to two new heart Inc.’s Ibrance (palbociclib) in combination agents for use in adults to prevent delayed failure drugs: Amgen’s Corlanor (ivabradine) with letrozole as a first-line treatment for nausea and vomiting associated with initial and Novartis AG’s Entresto (sacubitril/valsartan). postmenopausal women with estrogen and repeat courses of emetogenic cancer Schizophrenia patients also have new receptor positive, human epidermal growth chemotherapy, including, but not limited to, options, with three first-of-their-kind factor receptor 2 negative advanced breast highly emetogenic chemotherapy. medicines given the FDA’s OK to enter the cancer who have not received previous Other NMEs or novel biologics approved in US market: Otsuka Pharmaceutical Co. Ltd.’s systemic treatment for their advanced disease. 2015 by CDER included Daiichi Sankyo’s Savaysa and H Lundbeck AS’ Rexulti (brexpiprazole), Ten days later, Eisai Co. Ltd. nabbed a US (edoxaban), Novartis’ Cosentyx (secukinumab), Allergan PLC’s Vraylar (cariprazine) and approval for its receptor tyrosine kinase inhibitor NPS Pharmaceutical Inc.’s Natpara (parathyroid Alkermes PLC’s Aristada (aripiprazole lauroxil). Lenvima (lenvatinib) as a treatment for locally horomone), Astellas Pharma Inc.’s Cresemba By far, the most controversial approval recurrent or metastatic, progressive, radioactive (isavuconazonium sulfate), Retrophin Inc.’s by the FDA in 2015 was for Sprout iodine-refractory differentiated thyroid cancer. Cholbam (cholic acid), The Medicine Co.’s Pharmaceuticals Inc.’s female libido pill Addyi United Therapeutics Corp. had an Kengreal (canegrelor), Vertex Pharmaceuticals (flibanserin), which was acquired, along important approval in March 2015 with the Inc.’s Orkambi (lumacaftor 200mg/ivacaftor with the company, just days later by Valeant FDA’s nod for Unituxin (dinutuximab), a GD2- 125mg) and BMS’ Daklinza (daclatasvir). Pharmaceuticals International Inc. for $1bn – a binding monoclonal antibody indicated in The agency also cleared Novo Nordisk AS’ decision the latter firm may be regretting, combination with granulocyte-macrophage Tresiba (insulin degludec injection), Relypsa given the drug’s slow sales. colony-stimulating factor, interleukin-2 and Inc.’s Veltassa (patiromer for oral suspension), Over this past year, the FDA’s Office 13-cis-retinoic acid as a treatment for pediatric GlaxoSmithKline PLC’s Nucala (mepolizumab), of Hematology and Oncology Products patients with high-risk neuroblastoma who Gilead Sciences Inc.’s Genvoya (elvitegravir/ (OHOP) approved 14 NMEs or new biologics achieve at least a partial response to prior cobicistat/emtricitabine/tenofovir alafenamide), for various forms of cancer – lung, breast, first-line multiagent multimodality therapy. Merck & Co.’s Bridion (sugammadex), Actelion thyroid, colorectal and skin cancers; multiple With that approval, United Therapeutics Pharmaceuticals Ltd.’s Uptravi (selexipag), myeloma; neuroblastoma; and liposarcoma also won a rare pediatric disease priority AstraZeneca’s Zurampic (lesinurad), Alexion and leiomyosarcoma – with the agency acting review voucher – making history by garnering Pharmaceutical Inc.’s Strensiq (asfotase alfa) and on many of those applications well-ahead of the highest amount ever paid for a voucher Kanuma (sebelipase alfa) and Allergan’s Avycaz their user fee goal dates. when it sold it to AbbVie in August for $350m. (ceftazidime-avibactam), Kybella (deoxycholic Of the six drugs OHOP approved in 2015 The vouchers, however, have been a acid) and Viberzi (eluxadoline). to treat non-small-cell lung cancer, three particularly sore issue for the FDA’s John Jenkins, [email protected] were NMEs or novel biologics: AstraZeneca director of the Office of New Drugs, who has PLC’s Tagrisso (osimertinib), Eli Lilly & Co.’s called the program flawed because it places the For all Capitol Capsule articles visit Portrazza (necitumumab) and Genentech agency’s “limited resources” in a situation where scripintelligence.com/capitolcapsule Inc.’s Alecensa (alectinib). they are “for sale to the highest bidder.”

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 33 pipeline watch

Scrip’s weekly Pipeline Watch tabulates the most recently reported late-stage clinical trial and regulatory developments from the more than 10,000 drug candidates currently under active research worldwide.

Late-stage clinical developments for the week 18-24 December 2015 Lead Company Partner Company Drug Indication Market Comments REGULATORY APPROVAL Actelion – Uptravi (selexipag) pulmonary arterial US Uptravi is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Pharmaceuticals hypertension Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Ltd. AstraZeneca PLC – Zurampic (lesinurad) gout US In combination with a xanthine oxidase inhibitor (XOI) for the treatment of 200mg tablets hyperuricemia associated with gout in patients who have not achieved target serum uric acid (sUA) levels with an XOI alone. Amgen Inc. – Imlygic (talimogene melanoma EU For the treatment of adults with unresectable melanoma that is regionally or laherparepvec) distantly metastatic (Stage IIIB, IIIC and IVM1a), with no bone, brain, lung or other visceral disease. This approval grants a centralized marketing authorization in the 28 countries that are members of the EU. Sanofi – Dengvaxia Dengue fever Philippines The Philippines’ Food and Drug Administration approved Dengvaxia, tetravalent Dengue vaccine, for the prevention of disease caused by all four Dengue types in individuals from 9-45 years of age living in endemic areas. Mitsubishi Tanabe – Radicut (edaravone) amyotrophic lateral South Mitsubishi Tanabe Pharma announced that its consolidated subsidiary Mitsubishi Pharma sclerosis Korea Tanabe Pharma Korea has received import and marketing permission for Radicut Corporation inj. 30mg and Radicut Infusion inj. 30mg for an indication of progress delay of functional disorder in patients with amytrophic lateral sclerosis. Valeant Hyupjin / Pharming Ruconest (recombinant hereditary angioedema South Pharming and its partner, HyupJin, announced that Hyupjin has received the Pharmaceuticals human C1 inhibitor) Korea marketing authorisation for Ruconest in South Korea for the treatment of acute International Inc angioedema attacks in adult patients with hereditary angioedema HAE. HyupJin will now seek reimbursement for Ruconest in South Korea. SUPPLEMENTAL REGULATORY APPROVAL Bristol-Myers Pfizer Erikyusu (apixaban) Eliquis venous thromboembolism Japan Bristol-Myers and Pfizer announced the approval of Erikyusu for the treatment Squibb Company (VTE) recurrence suppression of pulmonary thromboembolism. The approval was supported from the AMPLIFY-J test of Phase III AMPLIFY study. Celgene – Revlimid (lenalidomide) multiple myeloma Japan Revlimid has been granted full marketing authorization by Japan’s Ministry of Corporation Health, Labour and Welfare (MHLW) for use in combination with dexamethasone as a treatment for patients newly diagnosed with multiple myeloma. Johnson & Mitsubishi Tanabe Remicade (infliximab) Kawasaki disease Japan Mitsubishi Tanabe Pharma announced that it has received approval for an Johnson additional indication for Remicade for I.V. Infusion 100, an anti-human TNFa monoclonal antibody. The additional indication is for acute-stage Kawasaki disease for which existing treatments are not sufficiently effective. Merck & Co. Inc. – Keytruda (pembrolizumab) melanoma US The FDA has approved an expanded indication for Keytruda to include the first- line treatment of patients with unresectable or metastatic melanoma. Merck & Co. Inc. – Keytruda (pembrolizumab) melanoma US The FDA has approved an update to the product labeling for Keytruda for the treatment of patients with ipilimumab-refractory advanced melanoma. REGULATORY FILING ACCEPTED Vanda – Fanaptum tablets schizophrenia EU Vanda Pharmaceuticals announced that its MAA for oral Fanaptum tablets has been Pharmaceuticals (iloperidone) Fanapt accepted for evaluation by the EMA for the treatment of schizophrenia in adults. Inc. ORPHAN DRUG DESIGNATION OXiGENE, Inc. – OXi4503 acute myelogenous EU The European Commission has granted orphan drug designation to OXi4503 for the leukemia (AML) treatment of AML. OXi4503 has previously received US orphan drug designation. HUYA Bioscience – HBI-8000 peripheral T-cell Japan HUYA Bioscience announced that the Ministry of Health, Labour and Welfare has International lymphoma granted HBI-8000 orphan drug designation in Japan for peripheral T-cell lymphoma. BREAKTHROUGH THERAPY DESIGNATION Boehringer Hanmi Pharmaceutical BI 1482694 (HM61713) non-small cell lung cancer US Boehringer Ingelheim announced that the US FDA has granted Breakthrough Ingelheim GmbH (NSCLC) Therapy Designation for its epidermal growth factor receptor (EGFR) mutation- specific tyrosine kinase inhibitor, BI 1482694. CHMP COMMUNICATION Merck & Co. Inc. – elbasvir/grazoprevir FDC hepatitis C EU The CHMP has responded to Merck’s MAA for elbasvir/grazoprevir for the (50mg/100mg) treatment of adult patients with chronic hepatitis C (HCV) infection. The CHMP advised Merck that the application will now be reviewed on a standard timetable, rather than the accelerated assessment timeline previously announced. Under the revised timeline, Merck anticipates a EC decision in mid-2016. CHMP NEGATIVE OPINION Lucane Pharma – Dropcys (mercaptamine cystinosis EU On Dec. 17, the CHMP adopted a negative opinion, recommending the refusal of SA hydrochloride) the marketing authorisation for the medicinal product Dropcys, intended to prevent and treat the build-up of the amino acid cystine in the cornea. CHMP POSITIVE OPINION ON FIRST APPROVAL AstraZeneca PLC – Tagrisso (AZD9291, non-small cell lung cancer EU For the treatment of adult patients with locally advanced or metastatic epidermal osimertinib) 80 mg once- (NSCLC) growth factor receptor (EGFR) T790M mutation-positive NSCLC. This indication daily tablets includes NSCLC patients whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) and patients with a T790M mutation who have not been treated with an EGFR-TKI.

34 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 pipeline watch

AstraZeneca PLC – Zurampic (lesinurad) gout EU As adjunctive treatment of hyperuricaemia in combination with a xanthine 200mg tablets oxidase inhibitor in adults with gout. Zurampic will be available as 200 mg film- coated tablets. Bayer AG – Iblias / Kovaltry (BAY hemophilia A EU The CHMP has recommended BAY 81-8973, submitted under the trade names 81-8973) Iblias and Kovaltry, for approval in the EU for the treatment and prophylaxis of bleeding in patients with hemophilia A for all age groups. Eli Lilly & – Portrazza (necitumumab) non-small cell lung cancer EU For the treatment of epidermal growth factor receptor (EGFR)-expressing Company (NSCLC) squamous non-small cell lung cancer. Shield – Feraccru (ferric maltol) anemia EU For the twice-daily oral therapy for use in the treatment of adults with iron Therapeutics capsules (ST10) deficiency anaemia in patients with inactive to moderately active inflammatory bowel disease. CHMP POSITIVE OPINION ON SUPPLEMENTAL APPROVAL Amgen Inc. – Nplate (romiplostim) immune EU The CHMP adopted an extension to the existing indication as follows: “Nplate is thrombocytopenic indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) purpura splenectomised patients who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) Nplate may be considered as second line treatment for adult non-splenectomised patients where surgery is contra-indicated.” Astellas Pharma Chugai / Roche Tarceva (erlotinib) non-small cell lung cancer EU The CHMP adopted a change to one of the existing indications of Tarceva as Inc. (NSCLC) follows: “Tarceva is also indicated as monotherapy for switch maintenance treatment in patients with locally advanced or metastatic NSCLC with EGFR activating mutations and stable disease after 4 cycles of standard platinum- based first-line chemotherapy.” AstraZeneca PLC Medicines Company Brilique (ticagrelor) Brilinta acute coronary syndrome EU Brilique 60mg for patients with a history of heart attack and at high risk of (ACS) having a further atherothrombotic event. The opinion states treatment may be started as continuation therapy after an initial one-year treatment with dual anti platelet therapy. Eli Lilly & AstraZeneca Cyramza (ramucirumab) non-small cell lung cancer EU The CHMP adopted two new indications as follows: “Cyramza in combination Company (NSCLC) with docetaxel is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with disease progression after platinumbased chemotherapy.” And “Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine.” Novartis AG Ligand Promacta (eltrombopag immune EU The CHMP adopted a change to an existing indication as follows: “Revolade is olamine) thrombocytopenic indicated for adult chronic immune (idiopathic) thrombocytopenic purpura (ITP) purpura (ITP) splenectomised patients who are refractory to other treatments (e.g. corticosteroids, or immunoglobulins) (see sections 4.2 and 5.1). Revolade may be considered as second line treatment for adult non-splenectomised patients where surgery is contraindicated.” REGULATORY FILING Sanofi Zealand Pharma LixiLan (insulin glargine/ type 2 diabetes US Sanofi has submitted a US NDA for its investigational fixed-ratio combination of insulin lixisenatide) glargine 100 Units/mL and lixisenatide, which if approved would be administered as a single daily injection for the treatment of adults with type 2 diabetes. Portola – andexanet alfa drug toxicity US Portola Pharmaceuticals announced completion of the submission of a BLA for Pharmaceuticals andexanet alfa, an FDA-designated breakthrough therapy specifically designed to Inc. reverse the anticoagulant activity of both direct and indirect Factor Xa inhibitors. CSL Limited – CSL627 hemophilia A EU CSL Behring has submitted its MAA for its novel investigational recombinant factor VIII single-chain (rVIII-SingleChain) for the treatment of hemophilia A. CSL Limited – rIX-FP hemophilia B Japan CSL Behring announced that the company has submitted its new drug application to Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) for its investigational fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP). Cardiome Pharma – Brinavess (vernakalant atrial fibrillation / flutter Canada For the rapid conversion of recent onset atrial fibrillation (AF) to sinus rhythm in Corp. hydrochloride) adults with AF for up to 7 days. Health Canada’s target duration of NDS review is 300 days. REGULATORY REVIEW EXTENSION BioMarin – Kyndrisa (drisapersen) muscular systrophy US BioMarin announced that the US FDA has notified it that it had not yet completed Pharmaceutical their review process and would be unable to take an action by the PDUFA action date Inc. for Kyndrisa of Dec. 27, 2015, and anticipate taking action in early January 2016. Intercept Sumitomo Dainippon INT-747 obeticholic acid primary biliary cirrhosis US Intercept Pharmaceuticals announced that the FDA has extended the PDUFA date Pharmaceuticals Pharma (OCA) for its Priority Review of obeticholic acid in primary biliary cirrhosis, recently Inc. renamed primary biliary cholangitis (PBC). The original PDUFA date of February 29, 2016 has been extended by three months. ROLLING NDA COMPLETED Exelixis, Inc. GlaxoSmithKline (GSK) Cometriq (cabozantinib) renal cell cancer US Exelixis has completed the submission of its rolling US NDA for cabozantinib as a treatment for patients with advanced renal cell carcinoma who have received one prior therapy. Exelixis has requested Priority Review as part of the NDA filing. PRODUCT LAUNCH Relypsa Inc. – Veltassa (patiromer) for hyperkalemia US Relypsa announced that Veltassa is now available for prescription to patients oral suspension with hyperkalemia in the US, following FDA approval on Oct. 21, 2015 for the treatment of hyperkalemia. Source: BioMedTracker

© Informa UK Ltd 2016 @scripnews scripintelligence.com January 8th 2016 35 appointments

BioMarin Pharmaceutical Inc. has appointed Scholar Rock, a company focused on drugs Inovio Pharmaceuticals Inc. has appointed former chair and CEO of Allergan, David Pyott, to targeting growth factors in the disease Prakash Bhuyan vice president of clinical its board of directors. Pyott was CEO of Allergan microenvironment, has appointed fibrosis expert development. He will lead the clinical development from 1998 to 2015 and was recognized by the Scott L. Friedman to its scientific advisory board of Inovio’s programs to treat HPV-related pre- Harvard Business Review as one of ‘The 100 Best (SAB). Friedman is professor of medicine, dean for cancers. Bhuyan joins the company from Pfizer Performing CEO’s in the World.’ Prior to Allergan therapeutic discovery and chief of the division where he was senior director of vaccine research. he was a member of the executive committee of liver diseases at the Icahn School of Medicine Prior to this he directed the development and for Switzerland-based Novartis AG and head of at Mount Sinai Hospital. He has also previously execution of clinical trials for vaccines at Merck. Novartis’s nutrition division. Currently Pyott is lead undertaken research into the underlying causes of director and board member of Avery Dennison fibrosis linked to chronic liver disease. Friedman has Ardelyx Inc., a company focused on Corporation and a board member of Alnylam received various awards for his work including the gastrointestinal and cardio-renal disease, has Pharmaceuticals, Inc. China Friendship Award in 2014, the International appointed Paul Korner to the newly created Achievement Prize of the Europe Association for position of executive vice president and chief PLx Pharma Inc. has appointed Natasha Giordano the Study of Liver Diseases in 2012 and the Hans medical officer. Most recently Korner was president CEO replacing Ronald R. Zimmerman, who will Popper International Liver Research Prize in 2003. of the Ferring International Pharmascience Center remain on the company’s board of directors and US Inc., and senior vice president of US clinical continue in his role as founder and senior advisor. Evgen Pharma Plc., a company focused on development for Ferring Pharmaceuticals. Prior to Giordano has also been appointed president and cancer and neurological conditions, has appointed this, Korner was vice president of medical affairs for member of the board and brings over 25 years’ Hamina J. Patel chief medical officer. She brings female health at Bayer Healthcare Pharmaceuticals. experience to the company. Before PLx, she was over 15 years’ experience to the company having president and CEO of Clear Point Learning and prior previously been director of drug development, NEMUS Bioscience Inc. has appointed Donald to this she held the same positions at Healthcare oncology at Johnson and Johnson. Patel has also Abrams to its scientific advisory board (SAB). Abrams Corporation of America. Previously, Giordano was also worked in the development of biopharmaceuticals is currently professor of clinical medicine at the president and CEO of Xanodyne Pharmaceuticals. at Celltech and at Chugai. University of California and chief of the hematology- oncology division at San Francisco General Hospital. Achillion Pharmaceuticals has appointed Joel Padlock Therapeutics, a company focused on He is also an integrative oncologist at the U.C.S.F. Barrish chief scientific officer and executive vice autoimmune diseases, has appointed one of its Osher Center for Integrative Medicine and was president – effective Jan. 4, 2016. Barrish has scientific co-founders, Kerri Mowen, to the newly co-editor of the Oxford University Press textbook over 30 years’ experience in the pharmaceutical created position of director of biology. Mowen is an of Integrative Oncology. Previously, Abrams was industry and most recently was vice president expert in the biology of protein-arginine deiminase president of the Society of Integrative Oncology and head of discovery chemistry at Bristol-Myers (PAD) enzymes and will direct a team of biologist in a and he is currently a member of the National Cancer Squibb (BMS). He has also co-authored more than Padlock location as a resident company at the Johnson Institute’s (NCI) Physician Data Query: Complementary 120 peer-reviewed publications. and Johnson Innovation JLABS incubator in San Diego. and Alternative Medicine editorial board.

Let’s get Social

We are tweeting, chatting, liking and sharing the latest industry news and insights from our global team of editors and analysts, join us!

@scripnews /scripintelligence

36 January 8th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016