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March 18th 2016 No 3794 scripintelligence.com

New Active Substance Launches Plummet The number of new active substances launched in 2015 fell by nearly a third compared with the previous year. But there is no need for despair – beating 2014’s record- breaking year of 63 new active substance (NAS) launches was always going to be a tall order, and 2015’s tally actually came in at a very respectable 46. This makes 2015 the second-best year for launches of new active substances (i.e., Kristensen/shutterstock.com Rodrigo new chemical and biological entities, and excluding generics, new formulations and new combinations of old products) for some time, and it is a close third in terms of overall numbers. In fact, the past three years were the best on record, and looking at the graph an HIGH STANDARDS: Drop in 2015’s NAS launches upward trend can be discerned stretching back more to do with 2014 being anomalously high to 2007. That’s almost a decade of growth. As such, it appears that the drop in NAS launches last year was more to do with 2014 reaching the market for just one indication: the SGLT2 inhibitor class were launched for being anomalously high than anything that hepatitis C. No fewer than seven NASs were diabetes in 2014, but none this year. went wrong in 2015, and it was apparent launched for this disease in 2014 as the The full alphabetical list of NASs for 2015 early on that these heights would not be explosion of R&D for direct-acting antivirals is found in Table 1. Included in the table are reached again anytime soon. As we explored came to fruition.No NASs were launched the drugs’ generic and trade names, their last year, there was a glut of products for HCV in 2015. Similarly, four products in Turn to page 10 Boehringer Hopes To Tap AbbVie’s ‘Humira Magic’ Boehringer Ingelheim and AbbVie Inc. have of clinical development for a number of as Crohn’s Disease and colitis ulcerosa, the launched a global collaboration to develop immunology indications. companies announced March 7. two of the German group’s most advanced BI 655066, a monoclonal anti-IL-23 antibody biologic compounds in immunology, a is the most advanced and will be tested in AbbVie Expertise Key therapy field where the US-based group psoriasis, Crohn’s Disease, and psoriatic arthritis. Both compounds have been discovered and has acquired extensive insight from its TNF BI 655064, a monoclonal anti-CD-40 developed in-house by the family-controlled inhibitor Humira (adalimumab). antibody which is currently in Phase I being German drug maker, at its Ridgefield The investigative two compounds - BI studied for Lupus Nephritis, also has potential Connecticut labs in the US. 655066 and BI 655064 - are in various stages for treating inflammatory bowel diseases such Turn to page 8

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Eleanor Malone, Editor, 7 Scrip Intelligence

2014 was an extraordinary year for pharma 1 New Active Substance 14 A Life Sciences Fortuitous Opportunity: Launches Plummet NASA’s Twins Study and biotech. There were record numbers of new drug approvals, biotech investment 1 Boehringer Hopes To Tap 15 Pharma’s Space Frontier: boomed and the tax inversion gold rush AbbVie’s ‘Humira Magic’ Come On And Take A Free Ride intensified M&A. Last year saw the biotech 3 Biotech IPOs: Will There Be 16 R&D Bites boom continue for several months while M&A activity was buttressed by Pfizer and A March Miracle? $1.14bn For Xtandi Royalties: How 18 Allergan agreeing the biggest deal the UCLA Cut Risk, Diversified Its Assets 4 Amgen: Sandoz Seeks To industry has ever seen towards the end of Circumvent Biosimilars Law 19 Using Patient Biology the year. But everything on Earth is subject to 5 Schizophrenia Overview: Doctors To Shepherd Clinical Trials gravity, and what goes up must come down. Highlight Pipeline Voids 19 Has FDA Lost Its Grip? Sure enough, our headlines reflect a new reality. Last year, the launch of new active PhRMA Condemns Medicare B Rx The Amarin Deal 6 substances “plummeted” (see this week’s Drug Payment Experiment Business Bulletin 20 cover story for Alex Shimmings’ analysis of 6 Medicare Chief: Engage With Us 20 Policy & Regulation Briefs 2015’s drug debuts). On Payment Experiment 21 Expert View: Can Premium-Priced In the second half of 2015, the decline 7 Zydus’ Humira Biosimilar: Trulicity Prickle Victoza In India? in biotech stock values began the “is the The Story So Far In India bubble bursting?” debate, and this year, 22 Stockwatch: Pharmaceutical Fight Club biotechnology stocks have been “in freefall”, Sanofi Pasteur, Merck Part Ways 8 23 Pipeline Watch as Mandy Jackson reports in her analysis of On European Vaccines Venture the current IPO landscape on p3. Appointments 9 PhRMA Chief: Time To Play Offense 24 Even drug pricing, which has resisted the On Price Debate law of gravity for so long (at least in the US), is struggling to maintain its upwards trajectory, 13 Opdivo Reimbursement Rejected In Scotland and is coming under constant pressure now from US politicians, pharmacy benefit managers and competitive challenges alike. On p6 Donna Young digs into the detail of the US government’s redesign of the Medicare Scrip Part B reimbursement system that is aimed at removing incentives for doctors to prescribe Editor: [email protected] Managing Editor: [email protected] more expensive drugs. She reports on the new News Editor: [email protected] president and CEO of PhRMA’s determination South Asia Editor: [email protected] to go on the offensive over the pricing debate, Washington Editor: [email protected] US West Coast Editor: [email protected] which he argues unfairly characterizes the Features Editor: [email protected] pharma industry as adding to the cost of Senior Reporter: [email protected] healthcare, on p9. With this debate making the Principal Analysts: [email protected]; headlines on a regular basis, the post-patent [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 cliff uplift that the sector has enjoyed for a [email protected] Creative Content Reporter: a discussion on our LinkedIn group, for your while now thanks to important new drug Editorial Assistant: [email protected] chance to interact with editor Production: [email protected] Eleanor Malone launches feels vulnerable. Pharma Data Editor: [email protected] and the rest of the Scrip Intelligence team. Gravity isn’t necessarily a bad thing for the Global Content Director: [email protected] industry, though. Bubbles burst, but being All stock images in this publication courtesy of Follow us at: @scripnews grounded enables us to distinguish true value www.shutterstock.com unless otherwise stated. Customer Services Join us at: linkd.in/scripintelligence from hype, and build on stronger foundations. Tel: +44 (0)20 7017 5540 or (US) Toll Free: 1 800 997 3892 Still, if that sounds depressingly mundane, Email: [email protected] NASA is offering space on its rockets for To subscribe, visit scripintelligence.com biomedical R&D projects looking to get away To advertise, contact [email protected] from gravitational pull (p15). It might be your Scrip is published by Informa UK Limited. ©Informa UK Ltd 2016: All rights reserved. best bet right now. ISSN 0143 7690. Astute readers may have experienced déjà vu when reading this column last week. We apologize for any confusion caused when we accidentally republished an item from March 2014.

2 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Biotech IPOs: Will There Be A March Miracle? Biotechnology stocks have been in a freefall since the start of 2016, keeping firms with plans for initial public offerings on the sidelines. But with values up 5% since the start of this month, will IPO hopefuls take advantage of a Miracle March or will drug pricing concerns again push share prices lower? The Nasdaq Biotech Index (NBI) closed March 7 with a 5.15% gain versus where the index started the month, which feels like it could be the start of a recovery after investors watched the NBI fall 22.39% blackboard1965/shutterstock.com between the start of January and the end of February. However, the credit rating agency Moody’s Investors Service lowered its outlook for the global pharmaceutical industry from positive to stable on March 3, Good news for venture capitalists as M&A noting that drug makers are posting more will help pharma companies grow in 2016 moderate price increases in response to the ongoing debate about high prescription medicine costs in the US. treatments. If the government steps in, “that’s share price was 122% above of its IPO value Moody’s senior vice president Michael probably the worst case scenario at this point as of March 4 and the Chinese immuno- Levesque said in a statement that the rating in time,” he said. There’d be no flexibility in oncology drug developer BeiGene Ltd. was agency’s pharma outlook changed, “because negotiating outcomes-based pricing and trading 35% above its US offering price. of a modest reduction in our expectations for reimbursement agreements, which reward However, Proteostasis Therapeutics Inc., the industry’s earnings growth.” Earnings are drug makers for therapies that improve AveXis Inc. and Syndax were trading 31%, 2% expected to increase across the board by 3% outcomes and cut healthcare costs. and 1% below their IPO values, respectively, to 4% versus a prior forecast of 4% to 5%, due noted the IPO-tracking firm Renaissance to pharma companies’ less aggressive pricing IPOs Wait For Good Signs Capital LLC. actions as well as foreign currency impacts On the positive side, Levesque of Moody’s Unfortunately, the Proteostasis, AveXis and slower than expected adoption of some noted that mergers and acquisitions will help and Syndax offerings mirror more closely the new products. pharma companies grow in 2016, which is performance of the 2015 IPO class, which Griffin Securities analyst Keith Markey good news for venture capitalists looking to generated an average return of 3.6% versus noted in an interview with Scrip that, “As the exit investments in private firms as well as for the offering price at year-end with last year’s pressure builds on the industry, we’re going to stock market investors seeking big paydays IPO companies generating a 21.3% loss on see greater and greater emphasis on the value from publicly traded biotech holdings. average by the end of January 2016. for the dollar. If there are great products, but “Pharmaceutical companies will remain Recent biotech IPO performance has not only a few people can afford them, they’re not active in the M&A market as they try to cut swayed new companies from announcing going to do very well.” costs, achieve greater scale and diversification, their intentions to become publicly traded Markey said drug pricing has become and acquire pipeline drugs with high entities, but some firms have withdrawn their a political hot potato during an intensely potential,” Levesque said. names from contention. competitive US election cycle, with Moody’s issued its new outlook on global Hutchison China MediTech could become presidential hopeful Hillary Clinton shining a pharma a day before Syndax Pharmaceuticals the second Chinese immuno-oncology light on the issue in September. However, he Inc. launched the fifth biotech IPO of 2016 on company to list shares on the US stock market noted, there will always be pressure on the March 2 at $12 per share, which was below in 2016 after BeiGene’s successful IPO. The cost of medicines when there’s a view that the $14 to $16 offering price that Waltham, company said on March 4 that it may offer certain products aren’t priced appropriately Massachusetts-based Syndax proposed in 6.1m American Depository Shares (ADSs) at relative to the value that they provide. late February. The Syndax IPO, which grossed $16.33 each to raise $100m, but that was a “If there’s something truly innovative, $52.8m for the cancer drug developer, tentative price for the forthcoming offering. and if it’s replacing an existing intervention, was a big risk based on recent biotech IPO On the other hand, PLx Pharma withdrew whether it’s surgical or pharmaceutical, you performance. its plan on March 7 to raise up to $68m to can look at the cost savings and use that as Biotech IPOs that launched in 2015 commercialize a delayed-release aspirin a guide for what the pricing ought to be,” provided such bad returns by year-end, and product. Also, there were no IPOs – not for Markey said, although he noted that different stock prices for therapeutics companies biotech or among companies in any other organizations have different ideas about how performed so poorly in January, that the industry – that were expected to price during to value pharmaceutical innovation. first four drug developers to price an IPO in the week of March 7 to 11, according to He noted that the biopharma industry and 2016 didn’t do so until February and they Renaissance Capital, suggesting that investors health insurance provides are best-placed to generated mixed results for investors. in first-time offerings of any kind remain on look at the value of new or existing medicines Of those four offerings in February, the the sidelines. versus the cost of – or lack of – available gene editing company Editas Medicine Inc.’s [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com March 18th 2016 3 headline news Amgen: Sandoz Seeks To Circumvent Biosimilars Law its rights and to obtain an order compelling By refusing to participate in a “timely and Sandoz to comply with the BPCIA’s provisions. complete manner” under the BPCIA, including The California biotech giant also disagreed by seeking to extinguish the innovator’s with Sandoz’s assertion that filing a ability to consider and respond to Sandoz’s patent infringement lawsuit after March 4 contentions about the patents the innovator deprived Amgen of its entitlement to other had “properly identified” and “entirely evading” infringement relief provided by the BPCIA, the negotiations, the biosimilar maker has such as a permanent injunction. “repudiated” its obligations under the BPCIA, Amgen already is tied up in two other Amgen charged. lawsuits with Sandoz – one involving the After beginning the statutory exchange latter firm’s biosimilar of filgrastim, Zarxio process, Sandoz is unwilling to complete (filgrastim-sndz), which it wants the Supreme the BPCIA’s procedures and has sought to Court to settle – and the other involving its “circumvent” the law’s process by refusing copycat of Enbrel, which also is before the to participate in the patent dance and Lightspring/shutterstock.com New Jersey district court. threatening to seek penalties that limit Like the Enbrel biosimilar suit, Amgen Amgen’s relief for infringement to a accused Sandoz in the latest case of reasonable royalty – rather than the full “piggybacking on the fruits” of the complement of remedies available, the latter innovator’s “trailblazing efforts” and of trying company argued. to “once again” “reap the commercial benefits Amgen has asked the court to issue a provided to biosimilar manufacturers judgment declaring that that Sandoz failed to under the BPCIA while seeking to avoid the comply with the “mandatory” requirements Amgen Inc. has filed another lawsuit obligations” Congress established to protect of the BPCIA patent dispute resolution involving the Biologics Price Competition and branded companies. provisions, and that its attempt to “waive” Innovation Act (BPCIA) at the US District Court In the new lawsuit, Amgen noted the BPCIA the rest of the exchanges and negotiations for the District of New Jersey against Novartis created an intricate and carefully orchestrated preceding the “immediate litigation” phase of AG unit Sandoz Inc., accusing the biosimilar set of procedures for biosimilar applicants the law “means there can be no immediate maker again of violating certain aspects of the and reference product sponsors to engage patent infringement action, Herrmann Blais law’s patent-dispute-resolution provisions – in a series of information exchanges and pointed out. commonly called the patent dance. good-faith negotiations between parties Amgen said that although it has not yet This suit involves Sandoz’s biosimilar of before filing a patent infringement lawsuit – filed an action for patent infringement, that pegfilgrastim, a product Amgen markets as provisions aimed at avoiding burdening the does not mean it is thereby barred from later Neulasta. courts and parties with unnecessary disputes. seeking the full scope of remedies available Elaine Herrmann Blais, a partner and head The FDA accepted Sandoz’s 351(k) for patent infringement claims, including lost of litigation in the Boston office of Goodwin biosimilars application for its version of profits and injunctive relief, she explained. Procter LLP, noted that Amgen’s latest pegfilgratim this past October, although the Herrmann Blais noted Amgen also asked complaint does not allege patent infringement company didn’t reveal that action until a few for an order compelling Sandoz to comply claims, but rather seeks a declaration from the weeks later. with the rest of the BPCIA patent dance, and court that Sandoz is wrong. On Nov. 13, 2015, Sandoz provided to compensate the innovator for “damages It also alleges and that Amgen would not Amgen with a file transfer link to electronic incurred as a results of biosimilar maker’s be limited to seeking reasonable royalties if it files in which the biosimilar firm said actions or inactions. later brings a patent infringement suit against constituted its application and information “As Amgen notes in its complaint, this is not Sandoz concerning its pegfilgrastim product, relating to the manufacturing process for its the first time a district court has been asked she pointed out. pegfilgrastim product. to consider whether biosimilar applicants can Sandoz has indicated it does not intend Amgen said it provided Sandoz on Jan. agree to immediate litigation on the patents to follow the patent dance provisions and 12 a list identifying two patents for which listed by a reference product sponsor, instead has insisted Amgen file an immediate patent the innovator believed a claim of patent of engaging in negotiations on which of the infringement action before the conclusion infringement could reasonably be asserted listed patents will be the subject of the first of the BPCIA dispute-resolution process and against the pegfilgrastim biosimilar. wave of immediate litigation contemplated has threatened to seek penalties under law if Sandoz argued in its Feb. 2 reply the by the BPCIA,” said Alexandra Lu, an associate the innovator failed to do so, the latter firm patents were “invalid, unenforceable or in the litigation group at Goodwin Procter’s contended in a complaint filed on March 4. will not be infringed by the commercial Boston office. Sandoz asserted that Amgen must file its marketing” of the biosimilar and said it no Indeed, she said, the same question patent infringement lawsuit by March 4 or longer wanted to follow the strictures of also has been raised in two other lawsuits such lawsuit would be untimely and its patent the BPCIA – cutting the patent dance short pending at other district courts: Janssen infringement damages would be limited to a and telling Amgen to move forward with a v. Celltrion at the US District Court for the “reasonable royalty.” patent infringement lawsuit “Otherwise, the District of Massachusetts, and and Amgen Amgen, which insisted Sandoz was wrong penalty for an untimely suit – that the ‘sole v. Hospira, at the US District Court for the about having to file a patent infringement suit and exclusive remedy’ for any infringement be District of Delaware. by March 4, said it filed its action to protect limited to a ‘reasonable royalty’ – applies.” [email protected]

4 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Schizophrenia Overview: Doctors Highlight Pipeline Voids The top unmet needs in schizophrenia drug of safety, including motor, metabolic and monitored and managed for severe neutropenia therapy are medicines for the management cardiovascular side effects associated with events, under the Clozapine Risk Evaluation and of negative symptoms, new treatments for other schizophrenia drugs. Sagient Research’s Mitigation Strategy (REMS) Program. refractory-positive symptoms and improved BioMedTracker expects ITI-007 to reach the There are currently no late-stage pipeline tolerability of drug treatment, according to a market late in 2017 or early 2018 if the company candidates that appear to have the potential Datamonitor Healthcare survey of more than is successful in gaining market approvals. to alleviate refractory positive symptoms, but 200 psychiatrists. Meanwhile, encenicline’s recently between 10% and 30% of patients show little Negative symptoms in schizophrenia discovered gastrointestinal safety issues symptomatic improvement after multiple remain largely untreated, despite being (noted in Alzheimer’s trials of the drug) could trials of typical antipsychotics. present in nearly 50% of patients and pose a risk to its development program. despite the sizeable number of approved Positive symptoms of schizophrenia, such Oral Therapies Lead Charge antipsychotics available for the disease overall as hallucinations and/or delusions, are more Datamonitor Healthcare found that in every – most of which focus on positive or cognitive widely treated by current therapies. However, surveyed market, the most commonly symptoms. This treatment gap was marked the issue of drugs for refractory patients was prescribed treatments for acute schizophrenia as the greatest unmet need by 236 surveyed among top concerns for doctors surveyed by included oral formulations of olanzapine, physicians. Even with this need, the current Datamonitor Healthcare. risperidone, and aripiprazole. However, of these pipeline for new antipsychotics contains The most commonly used option in 15 leading therapies, no single medication few products specifically targeting negative treatment-resistant patients is clozapine, is recommended for first-line use in the US, symptoms. an atypical antipsychotic that improves the UK, Germany, Spain and Italy. This is Schizophrenia presents itself in various schizophrenia symptoms in patients who do not likely because of the lack of differentiation forms, with patients suffering different sets of respond adequately to standard antipsychotic between the clinical profiles of the available symptoms. Certain subtypes of the disease treatments. Nevertheless, Datamonitor antipsychotics. are associated with negative symptoms, Healthcare analyst Ines Guerra highlighted that To view a table online of all products in such as avolition, blunted affect, and slower while clozapine is a “useful therapeutic option, clinical development for the treatment of movement patterns. the drug can cause severe neutropenia.” In schizophrenia, Phase I to NDA submission, go to: Minerva Neurosciences is one company the US, clozapine-treated patients need to be http://bit.ly/1Uwqoy7 [email protected] advancing development of a new drug, MIN- 101, specifically targeting negative symptoms Leading Schizophrenia Therapeutics of schizophrenia. MIN-101, currently in Phase IIb clinical trials, functions primarily by Drug Name Company Most Commom Therapeutic Role Administration targeting the 5-HT2A receptor and Sigma- Abilify Otsuka/Lundbeck Acute and maintenance treatment of schizophrenia Oral, tablets 2 receptor as an antagonist. It is thought Abilify Maintena Otsuka/Lundbeck Acute and maintenance treatment of schizophrenia Intramuscular, long-acting that the blockade of 5-HT2A may improve (aripiprazole) injection negative symptoms of schizophrenia by Clozaril (clozapine) Novartis Acute and maintenance treatment of schizophrenia Oral, tablets cultivating mood without carrying significant side effects. Minerva believes MIN-101 will Fanapt Vanda Treatment-resistant schizophrenia, reduction in Oral, tablets (iloperidone) Pharmaceuticals risk of suicidal behavior in schizophrenia improve negative symptoms, cognitive symptoms, and correct sleep abnormalities in Geodon/Zeldox Pfizer/Meiji Seika Acute and maintenance treatment of schizophrenia Oral, tablets schizophrenia patients. (ziprasidone) ITI-007 from Intra-Cellular Therapies and Invega J&J Acute and maintenance treatment of schizophrenia Oral, tablets encenicline from Forum Pharmaceuticals/ (paliperidone) in adults and adolescents Mitsubishi Tanabe, both of which are in Phase Invega Sustenna J&J Acute and maintenance treatment of schizophrenia Intramuscular, long-acting III trials, are two other candidates being injection developed to help address negative and Latuda Dainippon Acute and maintenance treatment of schizophrenia Oral, tablets cognitive symptoms. (lurasidone) Sumitomo ITI-007 also appears to address doctors’ Lonasen Dainippon Acute and maintenance treatment of schizophrenia Oral, tablets concerns around improved tolerability (blonanserin) Sumitomo of drugs for schizophrenia. Intra-Cellular Risperdal J&J Acute and maintenance treatment of schizophrenia Oral, tablets Therapies reported positive Phase III data in (risperidone) in adults and adolescents September 2015 for ITI-007, which showed a Risperdal Consta J&J Acute and maintenance treatment of schizophrenia Intramuscular, long-acting potentially differentiated safety profile relative (risperidone) injection to approved antipsychotic drugs. As such the Saphris/Sycrest Allergan/Lundbeck/ Acute and maintenance treatment of schizophrenia Oral, tablets company is pursuing a first-line indication for (asenapine) Meiji Seika ITI-007, which combines serotonin 5-HT2A Seroquel AstraZeneca/ Acute and maintenance treatment of schizophrenia Oral, tablets receptor antagonism, dopamine receptor (quetiapine) Astellas in adults and adolescents phosphoprotein modulation (DPPM), glutamatergic modulation and serotonin Zyprexa Eli Lilly Acute and maintenance treatment of schizophrenia Oral, tablets (olanzapine) in adults and adolescents reuptake inhibition in a once-daily pill. Intra-Cellular reported that ITI-007 did not Zyprexa Relprevv Eli Lilly Acute and maintenance treatment of schizophrenia Intramuscular, long-acting differ significantly from placebo in terms injection

PhRMA Condemns Medicare Chief: Engage With Us Medicare B Rx On Payment Experiment Centers for Medicare & Medicaid Services The Biotechnology Innovation Organization Drug Payment (CMS) acting administrator Andy Slavitt said it was “gravely concerned” CMS’ proposed entered the lion’s den on March 9 and model “threatens to disrupt the successful Experiment faced about 300 hundred drug company reimbursement framework” already in place. The Pharmaceutical Researchers executives and other healthcare stakeholders But Slavitt contended that “These are not and Manufacturers of America at a meeting in Washington the day after ideas we’ve made up.” (PhRMA) wasted no time in condemning releasing a controversial proposal to overhaul Rather, he said, the concepts in CMS’ Part B the Obama administration’s plans the way the government pays for outpatient payment proposal have been “long discussed” to launch a new experiment testing prescription medicines, which had some and were “long-brought forward,” and should whether alternative payment designs industry leaders up in arms before it was even help people to want to connect with the may lead to reducing Medicare Part officially revealed. But Slavitt was conciliatory, agency – eventually getting to the “substance B expenditures, while preserving and declaring at the annual meeting of the of what will make good policy.” potentially even enhancing beneficiaries’ Pharmaceutical Research and Manufacturers “My ask of everyone is that we engage on quality of care. of America (PhRMA) that “I don’t think we feel this together, and we engage on it seriously “Proposing sweeping changes to like we have the monopoly on good policy.” and collaboratively,” the CMS chief declared. Medicare Part B drug reimbursement He insisted, however, there was “nothing Slavitt said the agency’s goal with the without thoughtful consideration we proposed to do or intend to do or Part B experiment is to determine what and stakeholder input is not the right should do that, in any way, prevents a works well and what doesn’t and “adjust.” He approach and puts Medicare patients patient from getting the prescription acknowledged that before CMS could even who rely on these medicines at risk,” medicine that they need.” get the proposal out the door, there already PhRMA spokesperson Allyson Funk told were efforts to stop it in its tracks. Scrip in a statement. Kenneth Frazier, chair and CEO of Merck & She insisted the current drug Doctors encouraged to prescribe Co. Inc. and PhRMA’s chair, said the industry payment methodology for Part B, which expensive drugs over lower-cost was concerned about CMS making a “major covers prescription medicines that are shift in the healthcare delivery system.” administered in physician’s offices or comparators with same benefits “People want to make sure we are thinking hospital outpatient departments, such as about this very carefully,” Frazier said. cancer therapies, injectables antibiotics Slavitt said CMS’ March 8 proposal to test Frazier told Slavitt to expect to hear and eye care treatments, is “an effective, whether alternative payment designs may lead “constructive reactions” from drug makers over market-based pricing mechanism that to reducing expenditures for Medicare Part B, the next few weeks. works to control costs.” But Patrick Conway, which covers prescription medicines that are “Do I think we’ve thought of everything and chief medical officer at the Centers for administered in physician’s offices or hospital every consequence? Absolutely not,” Slavitt Medicare & Medicaid Services (CMS), outpatient departments, such as cancer responded. But he defended CMS’ actions – argued the current structure provides therapies, injectables antibiotics and eye care insisting it is a “process that invites the most “perverse incentives” that encourages treatments, would allow the agency to engage public input possible.” doctors to prescribe the most expensive with stakeholders and the public and “invite He reminded drug makers at the PhRMA drugs over lower-cost products that are people” to look at six “substantive” ideas. conference “We are in early innings still” just as effective. The centerpiece of the experiment involves with the Part B payment experiment, which Currently, Medicare Part B generally changing the Medicare Part B reimbursement actually won’t get underway until this fall, pays physicians and hospital outpatient rate doctors and outpatient facilities are paid with the second stage not launching until facilities a drug’s average sales price for prescription drugs. Currently, the payment early next year. (ASP) plus a “statutorily mandated” add- covers a drug’s average sales price plus a Slavitt admitted that often a “policy on of 6%. “statutorily mandated” add-on of 6%. But CMS that sounds great in Washington” may But in a Federal Register notice posted wants to test whether changing the add-on actually end up being burdensome when online on March 8, CMS contended the payment to 2.5% plus a flat fee payment it’s put to the test in the real world, which ASP methodology “may encourage the of $16.80 per drug would strengthen the is why Slavitt said it’s important to use of more expensive drugs because the financial incentive for physicians to choose experiment with new models like CMS is 6% add-on generates more revenue for higher value drugs and improve quality. attempting to do with the Medicare Part more expensive drugs.” CMS officials argued the current system B program, rather than simply instituting the plan. Slavitt said he believes industry “The Part B payment method provides encourages doctors to prescribe the most expensive drugs over lower-cost products that and government already are “past the point weak incentives for physicians to consider are just as effective. But the plan was swiftly of finding the big ideas” on payment and value – that is choose the lowest cost condemned by the big brand-name drug reimbursement issues. therapy to effectively treat a patient,” lobbying groups – with PhRMA warning that “We are at the really interesting and the agency said in a separate document making “sweeping changes” to the Medicare difficult part of the nitty-gritty of rolling up posted on its website. Part B drug reimbursement rate “without our sleeves and making the world better for Read full story at: http://bit.ly/1U0HuFX thoughtful consideration and stakeholder people,” he said. [email protected] input” would put beneficiaries “at risk.” [email protected]

6 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Zydus’ Humira Biosimilar: The Story So Far In India One dose of AbbVie’s blockbuster biologic, Humira (adalimumab), in the US equals around six doses of Zydus Cadila’s cut-price biosimilar version in terms of the cost of therapy and the Indian firm’s product appears to have triggered interesting shifts both in treatment dynamics and the competitive landscape on the domestic market. Zydus Cadila’s Exemptia (adalimumab) costs INR11,000-14,000 ($163.4-208) per dose, a fraction of Humira’s international price, singh_lens/shutterstock.com estimated at around $1,000 per vial, and the Indian firm now has around 2,000 patients on the product since its debut in December 2014, it told Scrip. Zydus had at the time of launch claimed that Exemptia was a “fingerprint match” with the originator product in terms of safety, purity and potency. top Indian physicians are said to be focused Exemptia has been approved for the Experts suggest that the relevance of on rheumatology as a discipline and they are treatment of auto immune disorders such the biosimilar’s price advantage is probably largely based in metro cities and Class A towns. as rheumatoid arthritis, juvenile idiopathic more important in an out-of-pocket market “There is the question of awareness arthritis, psoriatic arthritis, ankylosing like India, where physicians generally try to and access in terms of medical expertise. spondylitis, ulcerative colitis and Crohn’s economize and prescribe adalimumab for Besides, unfortunately, though patients may disease in India. around six months to bring down/control have medical insurance, typically in India, Zydus, whose pipeline comprises 24 the severity of the symptoms after which the insurance covers only in-patient treatments. biosimilars under development including four patient can be tapered off the biologic and This is a chronic disease that has a significant novel biologics, expects to take products such maintained on oral/conventional therapies. economic/health burden, but our insurance as Exemptia to international markets. “Physicians may want the patient to system is not geared to support this,” the “The plan is to launch all the molecules continue on the product for longer but the expert added. first in India, then in the emerging markets patient’s economic condition may not permit and finally selected molecules globally in that in India,” an industry expert told Scrip. the more regulated markets (the US and Significantly, the arrival of biosimilar Zydus claimed Exemptia was a the EU). Three molecules are already in adalimumab is also believed to have ‘fingerprint match’ in terms of global development for the more regulated triggered price cuts in therapies such as markets,” Zydus said. etanercept and infliximab – the latter is said safety, purity and potency On AbbVie’s reference to limited studies to have seen dramatic reductions in the with Exemptia in India, Zydus indicated that average monthly treatment costs over the Zydus, though, maintains that it is on its product has a finger print match with the past 15 months, though specifics could not course to developing Exemptia into an innovator product – one of the most difficult immediately be got. INR1bn brand in around three years. It is things to achieve and that once achieved the “In the last six months there has been a believed to be experimenting with an equal assumption generally is that all that has been reduction of about 40% in the prices of other monthly instalment (EMI)-based financing proven with the innovator brand should be biologics,” Zydus Cadila said. model for the product. The model has replicable with the fingerprint like biosimilar. Earlier this year, competitor Torrent currently been rolled out on a pilot basis, Zydus also said that its study was Pharma had followed Zydus onto the though the absence of a “pre-defined hard statistically powered, significantly enough for domestic market with its adalimumab stop” for treatment adds to complexities of the regulator to give an approval. biosimilar (marketed as Adfrar). The product expanding such models. The company added that it expects to is part of the biosimilars portfolio covered India has seen such EMI-based financing take its product to other markets and its under Torrent’s 2014 exclusive licensing models for hepatitis C therapies and in the dossiers would be “robust” to withstand those pact with the local firm Reliance Life devices space, among others. Typically, under guidelines and pass through. Sciences, wherein the latter was to develop such financing schemes, patients can stagger AbbVie had earlier noted that Exemptia’s and supply these products to Torrent post payment of the actual therapy cost over a Phase III study included only 120 patients in regulatory approvals. specified period via EMIs – along the lines of India and in a single indication, rheumatoid similar schemes for consumer durables. arthritis. “As a result, it is unclear whether it is a Challenges Zydus had, at the time of launch, also biosimilar by the standards of other regulatory While Exemptia’s patient base may still be indicated that it was putting in a place an agencies, such as the FDA,’’ AbbVie said then. relatively small compared with the patient Exemptia Care program, which aims to provide Humira raked in 2015 revenues of $14bn pool, expanding access in India for such important support and information regarding (+11.7%), accounting for more than half of products, though, comes with significant access, adherence, awareness and help AbbVie’s $22.8bn in total sales for the year. challenges given that only an estimated 400 patients to appropriately manage their disease. [email protected]

Boehringer Hopes To Tap Abbvie’s ‘Humira Magic’ (Continued from page 1) Sanofi Pasteur, Boehringer Ingelheim says it now needs the positive data seen in a Phase II head-to- Merck Part Ways a well-placed, experienced partner to head psoriasis study that showed it having ensure that the medicines are developed superior efficacy over Johnson & Johnson’s On European and commercialized as best and as quickly successful IL-12/IL-23 blocker Stelara as possible. (ustekinumab). Last October, Boehringer Vaccines Venture “We have entered this collaboration Ingelheim released nine-month data from to ensure that these two very promising that study, dubbed NCT02054481, which compounds can be progressed to benefit investigated the efficacy and safety of BI all patients directly from the moment of 655066 versus ustekinumab in 166 patients launch,” according to Jan Poth, who heads and which after nine months showed 69% immunology at Boehringer Ingelheim of patients with moderate-to-severe plaque “We have been active in immunology for psoriasis maintained clear or almost clear skin quite some time already but we don’t have any as measured by the Psoriasis Area Severity product on the market yet so we don’t have a Index (PASI 90) with BI 655066, compared to commercial organisation for that therapeutic 30% of patients on ustekinumab. Patients also area yet. AbbVie on the other hand has achieved this skin clearance significantly faster extensive experience in the immunology field,” - around eight weeks versus approximately 16 Poth said in an interview, noting as an example weeks, and for more than two months longer AbbVie’s blockbuster Humira, currently the than those on ustekinumab. Completely biggest selling drug in the world. “So they clear skin (PASI 100) was maintained after are the ideal partner for us [and Boehringer nine months in nearly triple the percentage Ingelheim’s aspirations in immunology].” of patients on BI 655066 compared with

“This collaboration positions BI 655066 ustekinumab, or 43% versus 15%, Boehringer retrorocket/shutterstock.com as AbbVie’s lead investigational compound Ingelheim said at the time. in psoriasis, complementing our robust “We hope to repeat these kinds of results Sanofi Pasteur MSD - the joint venture in immunology pipeline,” said AbbVie’s chief in Phase III and, based on that, expect these Europe between Sanofi SA’s vaccine arm and scientific officer, Michael Severino. “Our compounds to have very good potential,” Merck & Co – is ending after 22 years as the expertise in developing and commercializing Poth said. duo believes they can better manage their the world’s leading biologic, combined The abnormal immune response in product portfolios independently. with Boehringer Ingelheim’s clinical success psoriasis is driven by immune cells and Founded in 1994 and owned 50/50 by to-date will enable us to offer patients a proteins that are released, known as cytokines. the French and US drugmakers, Sanofi new treatment option with the potential to A cytokine known as interleukin-23 (IL-23) is a Pasteur MSD was formed to combine their meaningfully improve the standard of care,” key driver in psoriasis, Poth explained. geographic footprints and vaccines offerings. Severino said in a statement. More than 100 It had sales of €824m in 2015, but revenues million people suffer from psoriasis, a chronic, AbbVie To Lead Regulatory Pathway have flattened recently. systemic, immune-mediated disease. Asked about the likely regulatory pathway for The companies on March 8 said The two companies will work together in the two investigation biologics, BI 655066 and the decision to dissolve their vaccines clinical trials comprising various indications BI 655064, Poth replied: “that’s a little down partnership reflected changing times for the two compounds. BI 655066 is entering the road but the plan is for AbbVie to lead in international markets and within the four Phase III trials in psoriasis, two of which the registration process. The current timeline companies themselves. have already been initiated. “And probably in foresees a launch of BI 655066 sometime in “Merck and Sanofi have reviewed their the late 2016 or early next year, we will begin late 2019 or early 2020.” strategic priorities for vaccines operations and Phase III trials [of BI 655066] in Crohn’s Disease. Boehringer Ingelheim has already had an determined that operating independently This compound is currently in Phase II testing end-of-Phase II meeting with the FDA on would benefit both by giving them better for psoriatic arthritis,” Poth told Scrip. The last BI 655066.”The program has already been control and flexibility, execute more efficiently, of the four Phase III trials is expected to end in evaluated by the FDA as well as the EMA accelerate growth within their businesses and late 2019 or early 2020, he added. BI 655066 [European Medicines Agency] and we have optimise global access to their vaccines,” Merck is also in Phase II trialling for Ankylosing taken their advice into account with these & Co spokesperson Lainie Keller told Scrip. Spondylitis as well as for asthma. coming Phase III studies,” he said. Eventual The new collaboration’s second focus, BI commercialization of the two compounds will 655064, is a bit earlier in clinical development be done solely by AbbVie. Reflects New Sanofi CEO’s Priorities and will start Phase II testing in Lupus Nephritis The immunology space is particularly fertile The arrival of Sanofi’s new chief executive within the next few months, Poth said. for me-too drug and biologic development. Olivier Brandicourt has also played a part. Under the deal, AbbVie will make an initial With multiple, relatively common diseases The French executive, who is reshaping upfront payment of $595m. Boehringer including rheumatoid arthritis, psoriasis, France’s biggest pharmaceuticals group, Ingelheim will be eligible to receive ankylosing spondylitis and inflammatory has been in the role less than a year but additional development and regulatory bowel disease sharing the same or similar served notice last November that its vaccines milestone payments and royalties on net biological pathways, immunology products business was a core activity. Sanofi Pasteur sales, the terms of which are not disclosed. like AbbVie’s Humira have become mega- believes its experience developing Dengvaxia, The partners hope BI 655066 can replicate blockbusters. [email protected] the first vaccine to prevent dengue fever, as ➤

8 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news well as vaccines against Chinese encephalitis “The joint venture had a very good Merck will create a new vaccine division for and yellow fever, gives it clear competitive rationale when formed, and was very Europe, located in Lyon, France, the same city advantages going forward. successful. Now, not all Sanofi Pasteur MSD that Sanofi Pasteur has its vaccines base. products are being promoted at the level Both Sanofi Pasteur and Merck said they that they could or should be, however, so intend to keep investing in vaccines R&D and The decision to dissolve the customers are not getting the optimum will continue efforts to commercialize Vaxelis, vaccines partnership reflected options for our respective vaccines. a combination vaccine designed to protect Separating should improve business for each infants and toddlers against diphtheria, changing times in international of the companies,” Bernal said. tetanus, pertussis, hepatitis B, poliovirus types Merck and Sanofi said they would integrate 1, 2 and 3, and invasive disease caused by markets and within the their respective European vaccines businesses Haemophilus influenzae type B, giving it the companies themselves into their existing operations, independently unwieldy nickname DTaP5-IPV-Hib-Hep. manage their product portfolios and pursue Sanofi Pasteur and Merck said they will Asked by Scrip whether Brandicourt’s plans distinct growth strategies. ensure that any impact on employees for the overall group were the catalyst for the “We understand that one time cost of as a result of the proposed changes to decision, spokesperson Alain Bernal replied: “The restructuring for Sanofi should be around the business model “will be managed decision was taken, it is true, at a point where €100m, with eventual revenue synergies of responsibly. We are also focused on a we at Sanofi are looking for more simplification €60m driven by Sanofi being able to provide smooth and orderly transition while and clarity within the organization, so it should more sales effort behind their own products,” achieving our public healthcare goals be seen in conjunction with optimizing our commented analysts at Credit Suisse in a and upholding our commitments to our vaccines businesses, but I don’t think one thing note. They added that “Merck should see a customers and business partners.” triggered the other.” small boost to their revenues as they begin Sanofi Pasteur and Merck expect dissolution Bernal said each company in the joint to book sales for their own vaccines, but this of their joint venture to complete by the end venture now had adequately large vaccine is expected to generally be offset by loss of of 2016. portfolios to proceed alone. equity income from the JV.” [email protected] PhRMA Chief: Time To Play Offense On Price Debate Drug makers have played defense long presidential candidate Hillary Clinton about outgoing chair, Kenneth Frazier, CEO of enough in the debate over skyrocketing her plan to take on “price gouging, which Merck & Co. Inc.,took the day before. “It prices of medicines and it’s time to go led to a $132bn drop in market cap in the would usher in a new era of government on the offense and drive the discussion, industry, as how vulnerable drug makers are deciding what seniors can get. We believe declared the new president and CEO of the to the debate over the costs of medicines. these are the wrong ways to solve the Pharmaceutical Research and Manufacturers But Ubl argued “the debate is healthcare cost problem.” of America (PhRMA). Stephen Ubl asserted misinformed because it focuses on list prices The new PhRMA chief, who stepped in to the debate over drug prices in the US has and ignores increasingly consolidated and John Castellani’s shoes this past December, said largely been “myopic and misinformed.” sophisticated purchasers with enormous “No one should doubt our resolve to fight price It’s myopic, he said during a March 10 marketplace leverage.” controls in whatever shape they may take.” address at PhRMA’s annual meeting in “We know from experience,” he said, Washington, because it focuses on a “small” “mandating prices leads to reduced access share of healthcare spending and “not the ‘Critics are basing all of and choice for patients.” true cost driver, chronic disease, which is 80% their policy solutions on At PhRMA’s conference, Ubl also outlined of US healthcare spending.” a new policy framework, which he said Ubl noted the lion’s share of healthcare the anomaly’ consisted of four commonsense proposals: costs are being borne in the institutional modernizing the FDA; moving towards value- settings, like hospitals, skilled nursing facilities He contended that “critics are basing all based healthcare; engaging patients; and and physician office visits, where he insisted of their policy solutions on the anomaly” addressing market distorting policies. “Our products stand the best chance of or 2014, when there were record FDA “Now is the time for PhRMA to play a ameliorating those costs.” approvals, a Medicaid expansion and the leadership role in advancing pragmatic, pro- Ubl reverberated what’s become PhRMA’s entrance to the US market of new, and consumer policies that enhance the private standard argument – the debate over drug expensive, hepatitis C medicines, “and not market and address costs holistically,” he said. prices “ignores the value our products bring to the long-term trend.” Also at the meeting, the board elected patients, the healthcare system and the broader Ubl criticized the Centers for Medicare & its new directors, naming Biogen Inc. CEO economy” – pointing to hepatitis C medicines, Medicaid Services’ proposal to overhaul the way George Scangos as the lobbying group’s new which have been at the center of much of the government pays for outpatient prescription chair, succeeding Frazier. the firestorm, as actually avoiding costly medicines as “sweeping” and radical. Joaquin Duato, worldwide chair of complications, like liver disease or transplants, “This proposal would apply to vast pharmaceuticals at Johnson & Johnson and therefore saving the system money. majority of the country, violating definition Inc., also was voted chair-elect and Joseph Value, he charged, is “barely a footnote.” of demonstration and the spirit of the Jimenez, CEO at Novartis AG, assumed the Ubl pointed to the tweet sent out last authority outlined in the statute,” Ubl said, role of board treasurer. September by former Secretary of State and taking more of a hard-line tone than PhRMA’s [email protected]

New Active Substance Launches Plummet (Continued from page 1) mechanisms of action, the companies which at 30.4% and 28.2%, respectively. Thirteen output relatively steady over the years, have launched them, the diseases they are novel anticancers made their market debuts were Boehringer Ingelheim’s Praxbind and launched for, and the country and month during 2015, making this the most successful Novartis’s Entresto. Praxbind (idarucizumab) of first launch. Also noted is an indication of therapeutic group by some way. And when is the first specific reversal agent for an whether or not they have received orphan compared with oncology performance for the oral anticoagulant, in this case Boehringer drug status, and whether or not they can be past 15 years a clear trend can be discerned. Ingelheim’s Pradaxa (dabigatran etexilate) considered novel in terms of whether a drug Five of the new anticancers are first-in- in cases where surgery is required or with the same mechanism(s) is already on class products, and three of these also fit into uncontrolled bleeding occurs. The company the market. the rapidly expanding immuno-oncology expects Praxbind to be used minimally, These are some of the key metrics by which area. These include AbbVie and Bristol- but its existence should boost Pradaxa’s to measure pharma’s R&D performance over Myers Squibb’s Empliciti (elotuzumab), the use, as doctors will be more confident the year. Arguably for innovation, the most first SLAMF7 antagonist. It’s one of nine using it knowing its effect can be reversed important is the number with previously monoclonal antibodies on the list this year, when necessary. Entresto contains unseen mechanisms of action, and here four of which are for cancer. SLAMF7 is a the widely-prescribed angiotensin II 1 the list makes for encouraging reading. An CD2-like receptor involved in the activation antagonist valsartan along with new drug impressive 14 of the NASs listed are first-in- of cytotoxic cells, and the drug was launched sacubitril and is an important improvement class products, up from 12 (19.4%) in 2014 for the treatment of multiple myeloma. in the treatment of symptomatic chronic and therefore making up an even greater In another first for multiple myeloma, heart failure. percentage of the whole at 30.4%. Genmab and Johnson & Johnson’s Darzalex (daratumumab), the first CD38 antagonist, Other novel entries Orphans was launched in the US, while the final The respiratory arena has not benefitted One striking feature of the 2015 NAS list is how immuno-oncology MAb anticancer NAS from much in the way of new mechanistic many of the drugs which feature are orphans: on the list is United Therapeutics’ Unituxin approaches in recent years, but in 2015 at 24 this was more than half. The final column (dinutuximab). This chimeric MAb targets GlaxoSmithKline produced Nucala in the NAS table shows (see p11 & 12) whether ganglioside antigen GD2 in the treatment (mepolizumab), the first interleukin-15 or not each of the NASs has orphan drug of pediatric Neuroblastoma, and has orphan antagonist to reach the market. This is the first status in at least one market for at least one drug designation in both the EU and the US. of a new wave of products focusing on severe condition (it may not always be the country/ By contrast, there were far fewer anti- refractory eosinophilic asthma. Another novel disease for which it received its first launch, infectives hitting the pharmacies for the first NAS MAb which targets an interleukin, this although this is mainly the case). A comparison time last year – eight, compared with 21 in the time 17A, Novartis’ Cosentyx (secukinumab) with recent years shows a dramatic increase previous 12 months. But this was partly due was one of the Japanese first launches, in the proportion of NAS launches with an to the previous year’s HCV bubble, while 2015 debuting there back in January 2015. orphan drug status, showing a real shift in was also light on new vaccine introductions. Another notable entry is Sprout’s drug development towards rare diseases. There is only one first-in-class anti-infective (Valeant’s) Addyi (flibanserin), which gained Interestingly a large proportion of these are this year, and this is just a component of approval at the third attempt for acquired for cancer indications (particularly multiple an antibiotic combination. AstraZeneca generalized hypoactive sexual desire disorder myeloma) rather than the relatively easier-to- and Allergan added the novel specific in premenopausal women. But side-effect develop enzyme replacement therapies. lactamase A and C inhibitor avibactam to limitations and a lack of marketing mean that, the previously-marketed cephalosporin far from being the “female Viagra,” the drug Company Performance ceftazidime to form Avycaz for abdominal has thus far been a commercial flop. Once again, Novartis led the way with four and urinary tract infections. One thing that hasn’t changed over the NAS first launches, and in 2015 the Swiss firm And it was yet another disappointing year years is the US’s dominance of first launches. shared top-billing with Allergan (it was with for neurologicals. Despite being once again It was the market of choice for 29 of the Merck & Co and Eli Lilly the year before). But the second-largest area in terms of number of NASs, well over half at 63%, and up from Merck still did well in 2015 with three NAS pipeline products, it fared poorly in delivering 2014’s 56%. Japan again performed well, its launches to its name. Indeed, each of the top just two new drugs to the market, continuing eight launches this year beating the whole 10 companies managed at least one launch a run of poor years for this difficult area. of Europe combined; its recent push to last year. But six of them were outplayed The cardiovascular class performed better. accelerate approval timelines is having the by relative minnow Alexion, which enjoyed Two new PCSK9 inhibitors, Regeneron/ desired effect. Within Europe, Germany was a stellar year with two product launches, Sanofi’s Praluent (alirocumab) and Amgen’s the most popular European market for a first both in its core area of expensive enzyme Repatha (evolocumab), reached the market launch, despite some companies’ ongoing replacement therapies. Early sales data have for hypercholesterolemia, with Praluent just reimbursement problems there. been disappointing, though. pipping its rival to the market after a very [email protected] One of the most notable features of the close race. These injectable therapies are now list is the further evidence it provides that at the forefront of pricing and reimbursement With thanks to Ian Lloyd senior director for the revolution in cancer R&D is now bearing battles, a reminder if any were needed that Citeline’s Pharmaprojects for help in compiling, NAS fruit. In 2014, products in the oncology getting a product to market is not the final refining and analysing the NAS list. area accounted for 29.3% of drugs in the hurdle to market success. pipeline, but only 14.5% of NAS launches. In Also boosting the year’s tally to five, Click here to access the full version of this story, the year just closed, this gap had narrowed and keeping the cardiovascular NAS including interactive charts and tables.

10 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news

Table 1: New Active Substance Launches 2015 Generic Name Trade Name Company Indication Mechanism Of Action Country Of Month Of First First In Orphan Drug First Launch Launch? ↕ Class? Status? afamelanotide Scenesse Clinuvel Erythropoetic protoporphyria Melanocyte stimulating Italy and July Yes Yes hormone A receptor agonist Switzerland alipogene Glybera uniQure/Chiesi Lipoprotein lipase deficiency Lipase clearing factor Germany September No Yes tiparvovec stimulant alirocumab Praluent Regeneron/Sanofi Heterozygous familial PCSK9 inhibitor USA July Yes No hypercholesterolemia & mixed dyslipidaemia anthrax immune Anthrasil Emergent BioSolutions Anthrax infection Immunostimulant USA September No Yes globulin, Emergent asfotase alfa Strensiq Alexion Perinatal, infantile and Alkaline phosphatase Japan August Yes Yes juvenile-onset stimulant hypophosphatasia avibactam* + Avycaz AstraZeneca/Allergan Complicated abdominal and Lactamase A/C inhibitor, Cell USA April Yes No ceftazidime urinary tract infections wall synthesis inhibitor brexpiprazole Rexulti Otsuka Major depressive disorder and Dopamine D2/D3 receptor USA November No No schizophrenia agonist, 5-HT1A receptor agonist, 5-HT2A receptor antagonist cangrelor Kengrexal The Medicines Adjunctive therapy to Purinoreceptor P2Y12 EU and USA September No No tetrasodium Company percutaneous coronary antagonist, Platelet intervention aggregation inhibitor ceftolozane Zerbaxa Cubist/Merck & Co Complicated,intra-abdominal Cell wall synthesis inhibitor, USA February No No sulfate** + & urinary tract infection Lactamase inhibitor tazobactam chidamide Epidaza Shenzhen Chipscreen Peripheral T-cell lymphoma Histone deacetylase inhibitor China January No Yes Biosciences cobimetinib Cotellic Exelixis/Roche Melanoma MEK inhibitor USA November No Yes daratumumab Darzalex Genmab/Johnson & Multiple myeloma CD38 antagonist; Anticancer USA November Yes Yes Johnson immunotherapy deoxycholic acid Kybella Kythera (Allergan) Submental fat reduction Membrane integrity inhibitor USA June No No dinutuximab Unituxin United Therapeutics Neuroblastoma Ganglioside antigen GD2 USA October Yes Yes antagonist, Anticancer immunotherapy DTP + polio vaccine, Squarekids Daiichi Sankyo Pertussis, diphtheria, tetanus Immunostimulant Japan December No No Kitasato Daiichi and poliomyelitis prophylaxis Sankyo elotuzumab Empliciti AbbVie/Bristol-Myers Multiple myeloma SLAMF7 antagonist; Anticancer USA December Yes Yes Squibb immunotherapy eluxadoline Viberzi Furiex (Allergan) Diarrhoea-predominant Opioid mu receptor agonist, USA December No No irritable bowel syndrome Opioid delta receptor antagonist erismodegib Odomzo Novartis Basal cell carcinoma Hedgehog pathway inhibitor USA October No Yes evolocumab Repatha Amgen Heterozygous familial PCSK9 inhibitor UK and USA September No Yes hypercholesterolemia & clinical atherosclerotic cardiovascular disease flibanserin Addyi Sprout Acquired generalized 5HT1A receptor agonist, USA October Yes***** No Pharmaceuticals hypoactive sexual desire 5-HT2A receptor antagonist, (Valeant) disorder in premenopausal Dopamine D4 receptor agonist women idarucizumab Praxbind Boehringer Ingelheim Anticoagulant reversal Chelating agent USA October No Yes isavuconazonium Cresemba Basilea/Astellas Invasive aspergillosis & Cell wall synthesis inhibitor USA April No Yes chloride mucormycosis

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ixazomib citrate Ninlaro Takeda Multiple myeloma Proteasome inhibitor, USA December No Yes Transcription factor NF-kappaB inhibitor lenvatinib Lenvima Eisai Metastatic thyroid cancer VEGFR-1,2,3 tyrosine kinase USA February Yes****** Yes inhibitor, FGF receptor 1,2,3,4 tyrosine kinase inhibitor, Platelet-derived growth factor receptor beta kinase inhibitor, RET tyrosine kinase inhibitor, C-kit inhibitor lumacaftor*** + Orkambi Vertex Cystic fibrosis CF transmembrane USA September No Yes ivacaftor conductance regulator agonist lusutrombopag Mulpleta Shionogi Thrombocytopenia Thrombopoietin agonist Japan December No No mepolizumab Nucala GlaxoSmithKline Severe asthma Interleukin 5 antagonist USA December Yes Yes myoblast cell HeartSheet Terumo Congestive heart failure Not applicable Japan September No Yes therapy, ACT necitumumab Portrazza Eli Lilly Non-small cell lung cancer EGFR antagonist USA December No Yes nemonoxacin Taigexyn Warner Chilcott/ Community-acquired DNA topoisomerase II/IV Taiwan December No No TaiGen pneumonia inhibitor omarigliptin Marizev Merck & Co Type 2 diabetes Dipeptidyl peptidase 4 (DPP Japan December No No IV) inhibitor osimertinib Tagrisso AstraZeneca Non-small cell lung cancer EGFR kinase inhibitor USA November No Yes palbociclib Ibrance Pfizer/Amgen Breast cancer Cyclin-dependent kinase 4/6 USA February Yes No inhibitor panobinostat Farydak Novartis Multiple myeloma Histone deacetylase inhibitor USA March No Yes patiromer Veltassa Relypsa Hyperkalaemia Potassium antagonist USA December Yes No polmacoxib Acelex Aestura Musculoskeletal and Cyclooxygenase 2 inhibitor, South Korea September No No (AmorePacific)/ osteoarthritic pain Carbonic anhydrase inhibitor CrystalGenomics rolapitant Varubi OPKO Health/Tesaro Chemotherapy-induced nausea Neurokinin 1 receptor USA November No No and vomiting antagonist rotavirus vaccine, Rotavac Bharat Biotech Rotavirus infection prophylaxis Immunostimulant India March No No Bharat sacubitril**** + Entresto Novartis Chronic heart failure Angiotensin II 1 antagonist, USA July No No valsartan Membrane metallo endopeptidase inhibitor safinamide Xadago Newron/Zambon Parkinson’s disease Monoamine oxidase B Germany May No No mesylate inhibitor, Sodium channel antagonist, Calcium channel antagonist, Glutamate release inhibitor, Dopamine reuptake inhibitor sebelipase alfa Kanuma Synageva BioPharma Lysosomal acid lipase Lysosomal acid lipase Germany October Yes Yes (Alexion) deficiency stimulant secukinumab Cosentyx Novartis Psoriasis & psoriatic arthritis Interleukin 17A antagonist Japan January Yes Yes talimogene Imlygic Amgen Melanoma Granulocyte macrophage USA November No Yes laherparepvec colony stimulating factor agonist, Anticancer immunotherapy trelagliptin Zafatek Takeda/Allergan Type 2 diabetes Dipeptidyl peptidase 4 (DPP Japan May No No IV) inhibitor, Insulin secretagogue vonoprazan Takecab Takeda/Otsuka Ulcer and oesophagitis Potassium-competitive acid Japan February No No fumarate antagonist 9-valent HPV Gardasil 9 Merck & Co Human papilloma virus Immunostimulant Canada April No No vaccine, Merck infection prophylaxis Source: Scrip Intelligence, Citeline’s Pharmaprojects *avibactam is the NAS here **ceftolozane sulfate is the NAS here ***lumacaftor is the NAS here ****sacubitril is the NAS here *****Dopamine D4 antagonist is the novel mechanism here ******FGF-2 and -4 tyrosine kinase inhibition are the novel mechanisms here ↕Some months may be approximations

12 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Opdivo Reimbursement Rejected In Scotland Bristol-Myers Squibb’s skin cancer therapy, more flexible for novel oncology products, A spokesperson for the SMC told Scrip that Opdivo (nivolumab), has been rejected for approving medicines that NICE has rejected. BMS’s submission for Opdivo contained a use on the Scottish National Health System For example, in December 2014 the SMC complex economic model involving treatment – an unusual decision considering the drug’s reimbursed two cancer products that NICE naïve and pre-treated melanoma patients with recent approval for use in England and Wales. had already turned down – Eli Lilly’s Alimta more than one possible comparator. “There The Scottish Medicines Consortium issued (pemetrexed)as a monotherapy for the were a number of uncertainties in the analyses guidance not recommending the use of maintenance treatment of locally advanced and some assumptions, for example around Opdivo – a PD-1 immune checkpoint inhibitor, or metastatic non-small cell lung cancer; treatment duration, that the committee felt a new class of cancer medicines – as a and Celgene’s Imnovid (pomalidomide) in were unlikely to reflect clinical practice,” the monotherapy for the treatment of advanced combination with dexamethasone for the SMC said. (unresectable or metastatic) melanoma in treatment of adult patients with relapsed and BMS said it presented the same evidence adults. The health technology appraisal body refractory multiple myeloma. Furthermore, to both NICE and the SMC, including the said it was disappointed about returning a in April 2015, Scotland gave the green light same drug list price that NICE found cost- negative verdict, but said “weaknesses” in the to three anticancers that England had at the effective. In England Opdivo costs £439 health economic case presented by BMS led time rejected – Ariad’s Iclusig (ponatinib), per 4ml vial and £1,097 per 10ml vial, to “considerable uncertainty” about the drug’s Boehringer Ingelheim’s Vargatef (nintedanib) excluding VAT and any local procurement cost-effectiveness. and Bayer’s Stivarga (regorafenib). Some of discounts. NICE’s appraisal committee in However, BMS’s product was accepted, these products have since been accepted for January decided that the incremental cost uncharacteristically quickly, by the SMC’s reimbursement by NICE. effectiveness ratio for the drug, compared neighbor NICE for use on the NHS in England The assessment for Opdivo in Scotland also with BMS’ Yervoy (ipilimumab), Roche’s and Wales in January this year. It is not included views from a Patient and Clinician Zelboraf (vemurafenib) and Novartis’ Tafinlar uncommon for the two devolved HTAs in Engagement (PACE) meeting, but doctors’ (dabrafenib), would be less than £30,000 per Britain to come to opposing verdicts for new opinions emphasizing the need for new quality adjusted life year gained. products and in the past the groups have therapies like Opdivo, which have fewer side In Scotland BMS now has the option to returned differing opinions on the use of a effects and can be used in patients who don’t submit further data analysis to the SMC for number of expensive new cancer therapies. have BRAF mutations, were not able to sway consideration. Nevertheless, the SMC has usually been the SMC. [email protected]

SPONSORED BY SOCIAL MEDIA SPONSOR CATEGORY SPONSORED BY

HUYA BIOSCIENCE’S BEST NEW DRUG AWARD WINNER: NOVARTIS’S COSENTYX

This human monoclonal antibody is the first and only approved IL-17A inhibitor for plaque psoriasis, offering an important new treatment option, and a better chance of achieving clear skin. The judges said: “IL-17A has been an interesting target in psoriasis and this drug has shown selective binding that has translated into excellent clinical activity. The superiority of Cosentyx (secukinumab) against two of the most widely used drugs is impressive and the long-term data confirm its potential to transform treatment.”

Novartis is honored that Cosentyx has been named the Best New Drug of 2015. This award speaks to a turning point

for psoriasis patients, as Cosentyx is the first and only approved treatment targeting the IL-17 pathway, which plays a “key role in the development of plaque psoriasis. Nearly half of all psoriasis patients have not found relief from previously“ existing therapies with the condition seriously impacting their everyday lives, both physically and psychosocially. Cosentyx truly provides a better chance of achieving clear skin and improving the quality of life of psoriasis patients. Vasant Narasimhan, Global Head of Development, Novartis Pharmaceuticals

© Informa UK Ltd 2016 @scripnews scripintelligence.com March 18th 2016 13 headline news A Life Sciences Fortuitous Opportunity: NASA’s Twins Study While the goal of the yearlong mission in making more efficient and effective plans atherosclerosis related to oxidative stress, aboard the International Space Station (ISS) for these long duration plans beyond the low- inflammation and vascular function. involving US astronaut Scott Kelly and his Earth orbit,” Charles said. Another group of researchers from Russian counterpart cosmonaut Mikhail Michael Roberts, deputy chief scientist at NASA’s cardio and advanced projects labs Kornienko, who both returned to Earth on Center for the Advancement of Science in have teamed with UCSD investigators in March 2, was intended to examine the effects Space Inc. (CASIS), which manages the ISS conducting a proteomic assessment of of microgravity on the human body with the US National Laboratory, said he’d like to see fluid shifts and the association with visual aim of reducing the health risks on future an astronaut cohort be part of the Precision impairment and intracranial pressure. crewmembers, NASA serendipitously fell into Medicine Initiative, “because even though it’s Researchers from Northwestern University, a fortuitous situation to study spaceflight a small sample size, you have a segment of Rush University Medical Center and at the molecular level, potentially providing the population that goes from being perfectly the University of Illinois in Chicago are the life sciences sector a wealth of data – an healthy to manifesting some aspects of disease exploring the astronaut brothers’ dietary opportunity that may not come around again as a result of their exposure to microgravity” – differences and stressors to find out how for quite some time, if at all. an environment whose effects on physiology both affect the organisms in their guts Kelly, of course, just happens to have an can mimic the process of aging and some through a microbiome experiment involving identical twin brother, Mark, who also is an human conditions on Earth, like muscle metagenomic sequencing. astronaut – a situation never before seen at atrophy and the loss of bone mineral density. Researchers at Colorado State University NASA or any other space agency. will be working with NASA investigators The idea of studying one twin in space and to assess whether spaceflight influences the other on the ground came about more by CASIS looking to work with telomere length and telomerase activity, happenstance than a planned situation when pharma to replicate the with the hopes of providing informative Scott Kelly was selected for the ISS mission, biological indicators of aging and age-related said John Charles, chief scientist of NASA’s study and perform precision degenerative diseases, like cardiovascular Human Research Program (HRP). disease and cancer. Had anyone else been selected, “we medicine-type experiments on Investigators from Johns Hopkins wouldn’t be having this discussion” and there identical mice or flat worms University are measuring DNA methylation would be no Twins Study, Charles told Scrip. and chromatin at a genome-wide level But once the suggestion was made in 2012 Being able to include the Twins Study in biological samples obtained from the and the Kelly brothers accepted, there was data in the efforts of the Precision Medicine Kelly brothers, with the aim of integrating a “very big flurry of activities,” and Charles Initiative, which is being led by the National epigenomic data with exposure to quickly found some HRP funding and put Institutes of Health, could provide “great spaceflight conditions, looking for exposure- together a research solicitation, getting interest” for drug companies’ research and linked changes, and by comparison to the 40 responses right away, with 10 principal development, Roberts told Scrip. ground-based twin, determining whether investigators and their proposed projects He said CASIS would like to work with those are transient or long-lived effects. ultimately selected. pharmaceutical companies to replicate the They also are seeking to determine whether What surprised Charles, he said, was the fact Twins Study to perform experiments using DNA mutations arise secondarily to those that five of those 10 investigators had never models with identical mice or flat worms in epigenetic changes. before worked with NASA and previously precision medicine-type experiments with the Researchers at Stanford University are never considered how the US space agency goal of drug discovery and development. studying how long-term space travel was relevant to their genetic research. “You can perform a lot of the same tests to affects the immune system, examining “And those have now been some of the most understand how they are responding to the how parameters of the immune system enthusiastic participants,” he declared, although microgravity environment with prolonged changes at baseline and after a seasonal flu he added that most “everybody is enthusiastic exposure to that environment over time,” vaccination. They are seeking to understand when you’re on a spaceflight mission.” Roberts said. how the immune response to vaccination The twins experiment has allowed NASA He said he thought the Twins Study also differs in the twins. to connect with “a whole new community of could have implications for Obama’s and Charles noted that because the Russian investigators who can give us new insights Vice President Joe Biden’s Cancer Moon Shot Soyuz that brought Kelly back to Earth on that we need to continue the work that we’re Initiative, given the examination of Scott March 2 doesn’t have much extra room, his doing of mitigating the risks of astronauts of Kelly’s long-term radiation exposure that will blood and urine samples remained up in long-duration space flights beyond low-Earth be examined over time from his year in space, space in a freezer on the ISS and are expected orbit,” Charles said. which started on March 27, 2015. to be brought back on the return flight of the next SpaceX Dragon mission – a trip in which Precision Medicine The Experiments Eli Lilly & Co. is sending several experiments Even though it’s a very small cohort of two Among the 10 Twin Study investigations is up to the space station next month. men, the Twins Study data could wind up one being conducted by researchers from the Charles said the Kelly brothers will be playing a role in President Barack Obama’s University of California at San Diego (UCSD) and followed for at least the next nine months by Precision Medicine Initiative, he said. Dana-Farber/Harvard Cancer Center in Boston one of the groups of investigators, with most “That is one of the major reasons we in conjunction with NASA’s cardiovascular of the other researchers wrapping up their embarked on this study is to understand and nutritional biochemistry labs to examine studies in the next 60 days to six months. exactly how we can use precision medicine the metabolomic and genomic markers of [email protected]

14 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news Pharma’s Space Frontier: Come On And Take A Free Ride humans on Earth, including muscle atrophy where you looked at someone for 25-30 years,” and the loss of bone mineral density – Roberts said, noting that previously, experiments provides a unique research environment. could be done for only up to 60 days. Historically, microgravity research that went The Novartis experiment included five up on the space shuttle was essentially “one- wildtype mice and five transgenic “knock-out” Mr.Creative/shutterstock.com and-done” types of experiments, lasting only mice that lacked the MuRF1 gene, which days or weeks, he said. is believed to trigger muscle wasting by But now with the ISS, which is orbiting 240 degrading muscle protein. miles above Earth, experiments in space can The experiment was aimed at revealing last for months, Roberts said. new molecular targets for treating skeletal muscle atrophy. Merck In the follow-up RR-2 mission, Novartis Merck’s research on the ISS has focused researchers monitored the effects of the Space is waiting for you pharma. So come on primarily on protein crystal growth space environment on the musculoskeletal and take a free ride – literally. experiments of investigational monoclonal and neurological systems, with the idea Indeed, while NASA astronaut Scott Kelly, antibodies using microgravity, Roberts said. of discovering new molecular targets that who returned to Earth on March 2, was up in “Drug companies utilize the environment can facilitate the development of novel space on the International Space Station (ISS) in microgravity to grow these large crystals, therapeutics for the treatment of muscle and for the past year, with him were hundreds bring them back to Earth, take high resolution bone-related diseases. of biomedical experiments, many of which x-ray or neutron diffraction images of The mice in RR-2 also were exposed were intended to help researchers from them,” he said. “From that, they can derive to spaceflight for two to eight weeks to drug companies, the US government and information to better target their drugs so determine the progression of muscle wasting academic institutions solve the mysteries of that they have fewer side effects.” over time in the mice. human diseases. And the American taxpayers footed the bill Lilly – on average of about $7.4m per experiment Drug companies can take their Lilly has a very broad-based research approach – of getting that research from the ground science and technology into with several experiments, including some to space and back, including the costs of focusing on protein crystal growth on drug operating the ISS US National Laboratory and space and accelerate the pace formulation, expected to go up to the ISS next crew time, explained Dr. Michael Roberts, month on the SpaceX CRS-8, Roberts said. deputy chief scientist at Center for the of their discoveries “They’re actually interested in looking at the Advancement of Science in Space Inc. (CASIS). physical structure of the drugs they have in None of that $7.4m – an amount that can Roberts said CASIS also has had some development,” he said. vary – is passed along to the experiment’s discussions with Merck about model organisms Roberts said Lilly also has a rodent research investigators, whether they’re private-sector and testing of some of the experimental experiment that’s looking at a drug in the firm’s firms, universities or non-NASA government therapeutics agents in the company’s pipeline pipeline intended to prevent muscle loss. agencies, like the National Institutes of Health, for potential future missions. With Lilly’s experiments, 20 mice will be Roberts told Scrip. launched to the ISS, he said. “It’s not part of what they have to come Novartis An Opportunity To Accelerate R&D up with,” said Roberts, whose organization Novartis already has flown two drug For the most part, the experiments from was selected by NASA in 2011 to manage the research missions to the ISS, which focused drug makers involving R&D of medicines ISS US National Lab, which was created by on R&D of products to prevent muscle going up to the ISS is for diseases that affect Congress in 2005 as a way to open up and loss and combat age-related weakening of large populations, like musculoskeletal disease maximize the research opportunities of the muscles, Roberts said. and metabolic disorders, Roberts said. space environment. “Many societies are aging and there’s a He emphasized CASIS does not set the Biopharmaceutical companies, academic great interest in looking at ways to maintain research agenda. institutions or non-NASA government muscle mass and slow the weakening of “We’re simply responding to what the agencies, however, are responsible for bones,” he said. principal investigators identify as important covering the costs of getting their project Novartis’ research was included in the areas of research,” Roberts said. developed and ready for flight and the September 2014 “Rodent Research-1 (RR- What CASIS does, he said, is aid the US in supplies needed for the investigation. 1)” mission to validate the ISS Rodent ensuring the ISS US National Laboratory, which But some of those costs may be covered Research Facility, which includes modules for provides access to a wide range of hardware through CASIS challenge grants or federal transporting rodents to and from the space and R&D-enabling technologies, is” most agency funds, Roberts said. station and units to handle and house the effectively utilized as a research environment.” Companies like Merck & Co. Inc., Eli Lilly rodents, Robert said. Drug companies and others involved in & Co. and Novartis AG already have sent The Rodent Research Hardware System was biomedical R&D have an opportunity to “take experiments, or soon will, up to the ISS, he said. designed to allow rodents to spend up to six their science and technology development Roberts pointed out that microgravity months in space, he explained. up into space and accelerate the pace of their – whose effects on physiology can mimic “That’s a quarter of their natural life span,” discoveries,” Roberts declared. the process of aging and some diseases in which is the “equivalent of doing a human study [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com March 18th 2016 15 R&D bites R&D Bites spread of malignant B cells. Imbruvica was one Imbruvica Leads Sea Change All Eyes On Sun’s of the first medicines to receive FDA approval via In CLL Landscape Ophthalmology US NDA the breakthrough therapy designation pathway. Johnson & Johnson/AbbVie Inc. ‘s Imbruvica Optimism over the drug’s prospects induced (ibrutinib) has rapidly established itself as Sun Pharmaceutical Industries’ AbbVie to buy Pharmacyclics, which developed the standard of care in relapsed/refractory chronic ophthalmology NDA BromSite (0.075% medicine with J&J, for $21bn in 2015. lymphocytic leukaemia and will increasingly bromfenac), comes up for US regulatory move into the first-line setting following its recent approval next month, setting the stage for Epizyme Plans: Accelerated approval by the FDA for that use in patients with a potential push in a segment where the Tazemetostat Approval CLL, analysts say. That accolade was won after Indian firm has been prepping for a ramp A year after losing its big pharma partner, Imbruvica showed good efficacy in first-line CLL up. Bromsite, which has been assigned a epigenetic cancer therapy-focused Epizyme without the need for a chemotherapy backbone. Prescription Drug User Fee Act (PDUFA) Inc. used its quarterly earnings call on March 9 Whether the BTK inhibitor will maintain that CLL to outline a four-step strategy for becoming a action date of April 10, is the firm’s first lead is unclear, as there is a growing number commercial company, expanding the potential ophthalmology NDA coming up for approval of new drugs to treat the disease, which is the uses for lead candidate tazemetostat (EPZ-6438, aka most widespread form of adult leukemia. Still, the following the merger of Insite Vision with taz) and bringing at least three novel proprietary innovative dynamism around the condition Sun. Last year, Sun acquired Insite edging cancer candidates into clinical development by looks set to expand the CLL market enormously, out previous bidder and Canadian biotech 2020. Central to this strategy is a plan to seek largely because the orally administered drugs will QLT Inc; the acquisition was completed in expedited approval of tazemetostat based on remove reliance on chemo, and new drug classes November 2015, with InSite becoming an findings from Phase II studies in various forms will be administered more frequently than with indirect wholly owned arm of Sun. InSite is of non-Hodgkin lymphoma (NHL) and in rare previous products. seeking FDA approval for BromSite in the genetically defined solid tumors. CEO Robert treatment of inflammation and prevention Bazemore outlined a plan by which Epizyme Bass Wins Review Of Ampyra Patents of ocular pain in the post-cataract surgery will seek approval for varying indications based Shares of Acorda Therapeutics Inc. tumbled 10.7% on data from individual arms of the two Phase II setting. BromSite combines a low dose of on March 11 after word came late in the day studies. Bazemore, a lymphoma survivor, joined bromfenac with InSite’s DuraSite platform, the Patent Trial and Appeal Board (PTAB) of the the Cambridge, Massachusetts-based biotech US Patent & Trademark Office agreed to review a synthetic polymer-based formulation last September after leaving Synageva BioPharma four of the firm’s patents on its FDA-approved designed to extend the time of a drug in the Corp., where he was the chief operating officer. multiple sclerosis drug Ampyra (dalfampridine) eye relative to conventional topical therapies. The CEO said in an interview prior to Epizyme’s in response to so-called inter partes review (IPR) BromSite has a patent life extending to earnings call that tazemetostat could present petitions filed by hedge fund manager Kyle Bass August 2029, Insite said previously. Scrip a “platform-within-a-product opportunity.” The through his Coalition for Affordable Drugs. The affiliate Sagient Research’s BioMedTracker company regained almost all rights to the EZH2 stock closed the day at $32, down $2.71, or 7.8%. has placed the likelihood of BromSite’s inhibitor last year by paying Eisai Co. Ltd., its But Bass failed to win over the PTAB in seeking approval at 83%, which is 4% above the partner since 2011, $40m up front to largely a review of a US patent held by Roche AG on average probability of FDA approval for unravel the collaboration around tazemetostat. Enbrel (etanercept), a tumor necrosis factor alpha Eisai retains Japanese rights to the compound, and the specified disease group based on the marketed in the US by Amgen Inc., increasing the is responsible for 100% of development costs in odds the drug will remain patent protected well historical performance of medicines in the that market. into the late 2020s. same development phase, and expects the PDUFA date to occur on April 8 [April 10 falls Celldex Rintega Fails In Phase III Sanofi/Regeneron’s Sarilumab on a Sunday]. Bromsite’s NDA submission Celldex Therapeutics Inc.’s stock was cut by more Stiff Competition was based upon two Phase III trials that were than half to $3.79 per share after the company Regeneron/Sanofi’s IL-6 inhibitor sarilumab conducted in over 500 patients. revealed that it would discontinue the Phase has beaten AbbVie’s Humira (adalimumab) in III clinical trial known as ACT IV for the cancer a head to head trial. Top line Phase III results Imbruvica Boosts CLL Lead vaccine Rintega (rindopepimut) based on an show sarilumab more significantly improved AbbVie Inc. and Johnson & Johnson’s BTK inhibitor interim assessment of survival for glioblastoma the signs and symptoms of rheumatoid arthritis Imbruvica (ibrutinib) has reinforced its lead (GBM) patients. Hampton, New Jersey-based after 24 weeks of treatment than blockbusting position in the chronic lymphocytic leukemia Celldex closed down 53.7% on March 7 following Humira did. The data will help differentiate the market with a first-line indication from FDA. FDA the disclosure that median overall survival was drug, but competition will remain fierce in the approval of a supplemental new drug application 20.4 months in the Rintega arm of ACT IV versus RA space, say analysts. “This is the first time an (sNDA) for Imbruvica (ibrutinib) for first-line use 21.1 months in the control group for patients with IL-6 receptor blocker delivered subcutaneously in patients with chronic lymphocytic leukemia, newly diagnosed EGFRvIII-positive glioblastoma has demonstrated superiority over adalimumab announced March 4, gives the Bruton’s tyrosine and minimal residual disease. The trial’s Data monotherapy in RA,” said Janet van Adelsberg, kinase inhibitor from J&J (Janssen Biotech Inc.) Safety and Monitoring Board (DSMB) determined Regeneron’s senior director of clinical sciences, and AbbVie (Pharmacyclics Inc.) the broadest that Celldex’s lead product candidate was unlikely immunology and inflammation. Sanofi CEO Olivier label of the new generation of targeted therapies to meet the study’s primary endpoint based Brandicourt last year said that sarilumab was one for CLL. Imbruvica is already a blockbuster drug, on the interim survival data. The company said of six key products that would generate combined topping $1bn in 2015 sales following its 2014 Rintega’s performance in Phase III was consistent peak sales of up to €14bn. The drug is expected approvals, initially for CLL patients who have with past Phase II studies, but the control arm to launch by the end of the year in the US, where received at least one prior therapy and then for in ACT IV performed significantly better than it is undergoing regulatory review. Datamonitor CLL patients with a 17p genetic deletion. It is a expected. As a result, Celldex “does not anticipate Healthcare analyst Christina Vasiliou expects first-in-class, oral, once-daily therapy that inhibits incurring substantial additional costs related to that Sanofi/Regeneron will try and position the the Bruton’s tyrosine kinase protein, a key signalling Rintega at this time,” the company said, meaning drug early in the rheumatoid arthritis treatment molecule in the B-cell receptor signalling complex that it will discontinue development of the cancer pathway after patients fail on methotrexate. that plays an important role in the survival and vaccine in all indications. However, there will be a lot of competition to beat.

16 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news $1.14bn For Xtandi Royalties: How UCLA Cut Risk, Diversified Its Assets With no shortage of offers to buy its royalties Westwood board member and Los Litigation is pending between UCLA from the prostate cancer drug Xtandi Angeles-based venture capital investor Tom and Medivation to determine whether the (enzalutamide), the University of California, Unterman told Scrip that the Xtandi royalty university is getting its fair share. UCLA sued Los Angeles (UCLA) recently decided to stream is “a very visible piece of intellectual Medivation in 2014 in a dispute over the reduce its risk and diversify its holdings by property, because it’s so large compared to operating profits that the company receives selling the Xtandi revenue stream, accepting a what universities and research institutions from Astellas and whether it qualifies as bid from Royalty Pharma for $1.14bn. typically own. We have been approached sublicensing income under Medivation’s Privately-held Royalty Pharma kept in touch over the years about selling it, but this is not license agreement with the university. The with UCLA while Xtandi patent licensee something the university has done actively parties are awaiting a trial court date. Medivation Inc. and its partner Astellas before. We saw the volume of the incoming Pharma Inc. developed and commercialized calls and thought we should consider it.” UCLA’s Risk Management, the drug for later-stage and eventually front- UCLA engaged Goldman Sachs as a financial Diversification Strategy line treatment of metastatic castrate-resistant advisor to analyze whether the university Unterman said there were two key reasons prostate cancer (mCRPC). The investment should monetize the Xtandi royalty stream, why UCLA chose to sell its royalties to firm’s tenacity paid off: It beat out four other determine the asset’s value, solicit bids and Royalty Pharma: 1) risk management in bidders in a competitive process to buy the broker a transaction; five bids were received the event that a future competitor should Xtandi royalties, repeating its history of eye- in all. Legal advisors included Gibson Dunn for steal significant sales from Xtandi and 2) popping deals with nonprofit research groups. UCLA, Goodwin Procter for Royalty Pharma diversification of revenue streams that fund Royalty Pharma paid $3.3bn in November and Covington & Burling LLP for the inventors. research at the university. 2014 to acquire the Cystic Fibrosis Foundation Heyman Biotech LLC was a strategic advisor “The drug is on a strong growth trajectory, (CFF) royalty stream from sales of Kalydeco for the inventors, who include UCLA chemistry but cancer research is moving fast. Strong (ivacaftor), the ground-breaking cystic fibrosis and biochemistry professor Michael Jung and competitors could come to the market,” drug developed by Vertex Pharmaceuticals Charles Sawyers, a doctor at Memorial Sloan Unterman said. “If we could get the money Inc. with research funding from CFF. Kettering Cancer Center in New York. Sawyers now, we could assure a steady stream of Executives from the New York-based was an investigator at Howard Hughes while money for years to come.” royalty acquirer expect to negotiate more teaching medicine, urology and pharmacology UCLA will hold its $540m share of the transactions in the future with universities and at UCLA when the Xtandi-related intellectual proceeds in a broadly diversified investment patient advocacy groups as those entities get property was created. portfolio managed by the UC system’s chief more creative about financing and benefitting Sawyers and his team at Howard Hughes investment officer. The investment portfolio from their investments in new drugs. identified why patients failed to respond to is expected to generate $60m in unrestricted first-generation prostate cancer therapies and funding [annually] for UCLA through 2027. Many Offers, Great Possibilities collaborated with Jung’s lab at UCLA on the Most of the money will fund research, but the UCLA actually owns just 43.875% of the royalty discovery of the second-generation androgen university expects to set aside some cash for interest that was sold to Royalty Pharma and receptor inhibitor Xtandi. Medivation licensed scholarships and fellowships. its share of the transaction proceeds is $520m. the chemical compound’s patent, which So will UCLA via Westwood Technology The other 56.125% will be shared by the expires in 2027, in 2005. The San Francisco- Transfer cash in additional pharmaceutical Howard Hughes Medical Institute along with based biotech company allied with Astellas royalty streams to fund research and the UCLA and Howard Hughes scientists who in 2009 for global development of Xtandi and scholarships at the university? It’s possible. discovered Xtandi. The inventors get the bulk the partners won their first US approval for “We do have other therapies that have of the remaining proceeds, since the University the drug in 2012. been developed at UCLA that we, over time, of California (UC) system’s patent policy gives Xtandi is approved in the US for both pre- would consider doing similar transactions about 35% of royalty proceeds to the inventors and post-chemotherapy treatment of men for, but nothing in the next two or three – roughly $400m. with mCRPC and recent clinical trials support years or of this scale,” Unterman said, noting The Royalty Pharma deal was negotiated by the drug’s use early in the treatment of that most royalty transactions involving Westwood Technology Transfer, a nonprofit metastatic patients. Astellas reported $1.9bn research institutions total $40m to $50m. company that UCLA established in 2014 to in global Xtandi sales for 2015 and Medivation He said UCLA scientists sometimes are oversee its intellectual property portfolio and collected $695.5m of that revenue in 2015 approached by investors that want to buy maximize returns from technology invented versus $389.4m in 2014. their and the university’s royalty stream, by university researchers. UCLA has earned $2.8m in aggregate but UCLA or the UC system usually are Westwood supports the UC system’s push milestone fees under its licensing agreement approached first. to encourage entrepreneurship among with Medivation and the university earns Royalty Pharma vice president of investor its students and faculty. The UC Board of an annual maintenance fee plus 10% of all relations and public affairs Alexander von Regents approved a $250m venture capital sublicensing income from the company’s Perfall said the firm has been interested fund called UC Ventures in 2014 to invest in agreement with Astellas and a 4% royalty in the Xtandi royalties since 2010 when it companies that spin out of the university on global net sales of Xtandi. Astellas and began tracking the drug’s clinical trials and system’s 10 campuses, five medical centers, Medivation share the royalty obligation regulatory progress. three affiliated national laboratories and 20 equally for US sales, but Astellas pays royalties Read full story at: http://bit.ly/1YVWpjL technology incubators. to UCLA based on ex-US sales. [email protected]

18 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 headline news

Using Patient Biology To Shepherd Has FDA Lost Clinical Trials Its Grip? The “Pharma is throwing the term precision process.” And that is the definition of precision medicine around but it still doesn’t really medicine, he claims. Amarin Deal understand what it will take to achieve However, before that can truly become a While the FDA was insistent its settlement it,” according to the world’s first chief reality, there has to be education. Governments with Amarin Corp. plc, which a federal precision medicine officer, BERG Health’s and pharma must make a “social contract” with district judge has signed off on, only Michael Kiebish. BERG is combining artificial patients “so there is understanding that it will applies to that company, in which the intelligence and systems biology to analyze take time, it is still your data, and it will be used agency has agreed to not stand in the stacks of biological data. for the greater good.” way of the firm sharing “truthful and non- According to Kiebish, there needs to be Kiebish joined BERG in 2012 as vice misleading” information about certain a lot more collaboration: governments and president of systems medicine before being unapproved uses of its fish-oil pill Vascepa pharmaceutical companies need to open appointed to his new role. (icosapent ethyl), the deal, nonetheless, up their data repositories, there needs to be shows US regulators can be flexible, or at better infrastructure to cope with the volume Objectives least, when they’re backed into a corner. of electronic data becoming available, and we “My near term objectives are to try and evolve Indeed, to the FDA, the deal with need to develop better analytical tools, “and the bioanalytics and informatics platforms to Amarin likely was the choice of the lesser not just genomics [tools], but adaptive ‘omics’ be quicker, more economical, to engage more of two evils – settle the legal dispute and like metabolomics, proteomics, lipidomics.” in the clinical trial process. let the company have its way, although The data repositories and analytics need to be “In the mid term, I want to be establishing with input from the agency, or wind up in built up and then we have to allow people to collaborations with the big analytical/ an appeal, which had the chance of going “dig into that data.” informatics hardware companies, and hospital badly for regulators, resulting in them BERG was initially founded to develop insurance companies. losing their grip completely over off-label an oncology asset, but quickly realized that “In the long term I will be keeping my promotional activities. “the use of artificial intelligence, population eye on the prize. Developing those proof It was clear the FDA didn’t want to diversity and ‘omics’ could be used to develop points for oncology, not just for our drug, but risk the possibility of the latter situation biologics for lots of diseases.” through companion diagnostics for other happening when it agreed this past August “There were lots of pieces missing in the drugs. We want to help develop new pharma to explore a potential settlement with drug development cycle. First and foremost, economic models to overcome outcome Amarin, which a few weeks earlier had the patient,” he told Scrip. based reimbursement, the patent cliff.” been granted a preliminary injunction by BERG was founded by Silicon Valley billionaire Judge Paul Engelmayer of the U.S. District Platform Carl Berg, so doesn’t follow the model of a Court for the Southern District of New York, All of BERG’s research and clinical trials traditional venture capital backed biotech. “We who said the company could share certain employ its Interrogative Biology platform. want to evolve into a lean, adaptive, healthcare “truthful and non-misleading” information This “back to biology approach” is completely solutions company where we build diagnostics about Vascepa “without incurring liability different from the traditional pharma globally, nurture our pipeline, understand the for misbranding” – a verdict that was a approach to drug discovery through whole landscape of combination therapies for major blow to the US regulatory agency. chemical libraries and hypotheses. different diseases based on real time biology, The FDA already had walked away from BERG collects patient samples in both and collaborate heavily with big pharma and appealing its loss in an earlier decision, diseased and healthy states which are IT companies. We want to position patients to in which the US Court of Appeals for processed by high throughput mass have real time access to their health, through the Second Circuit in Manhattan had overturned the October 2008 conviction spectrometer workflow. Biological activity is connectivity via wearable devices, empowering of a New York sales representative, Alfred analyzed through adaptive ‘omics’. “We also patient knowledge.” Caronia, for conspiracy to introduce look at mitochondrial function, oxidative Kiebish says BERG has “lots of kettles a misbranded drug into interstate states and ATP production to examine how boiling” regarding collaboration discussions commerce related to discussions he had the cells are functioning.” but pharma “likes to see companies prove with doctors about unapproved uses for The process produces trillions of data themselves in stages” and hence BERG is Jazz Pharmaceuticals Inc.’s narcolepsy points from a single sample. The data is then focusing on its pipeline. drug Xyrem (sodium oxybate). combined with patient clinical information In that case, the Second Circuit ruled and analyzed by BERG’s artificial intelligence Pipeline that “truthful” off-label promotion of US machine learning analytics program. This BERG has two therapeutic products in early- approved prescription drugs is not criminal combination of systems biology and artificial stage clinical testing. activity and is protected speech under the intelligence constitutes the Interrogative BPM31510 is in Phase I/II trials as a First Amendment of the US Constitution. Biology platform. monotherapy for squamous cell carcinoma The FDA this past December also BERG builds its drugs in molecules and and as a monotherapy and a combination reached an agreement in another targets based on population diversity to “get therapy for advanced refractory solid tumors. free-speech lawsuit with Pacira into the core biological causes of disease,” BPM31543 is in Phase I trials as a topical Pharmaceuticals Inc. says Kiebish. “Patients are a part of the drug treatment for chemotherapy-related alopecia. Read full story at: http://bit.ly/1WekIHY discovery process from the beginning. Patient “2016 will be an interesting year for our [email protected] biology is shepherding the clinical trial pipeline,” says Kiebish. [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com March 18th 2016 19 business bulletin/policy & regulation briefs Business Bulletin chair, has raised SEK 437m ($51m) in a series B TiGenix Raises $26m, Fistula Therapy Patient Groups Rank financing. The transaction sees former majority Continues To Fizz ViiV Top Of Pharma shareholder Karolinska Development drop its stake The European leader in investigational allogeneic from 62% to around 19% via the conversion of SEK stem cell therapies, Belgium’s TiGenix NV, has League Table 60m of outstanding loans. The deal marks a year since turned its back for now on raising funds on The latest PatientView report on the corporate Karolinska Development’s CEO Jim Van heusden took Nasdaq, and has instead raised gross proceeds reputation of pharma from the perspective over the top job and was given the task of changing of €23.75m ($26.2m) in a private placement on its strategy in a bid to change its fortunes. He has of patient groups has been published. In a Euronext Brussels completed Mar. 10, just days after been busy spinning out portfolio companies such survey of pharma’s corporate reputation, ViiV it described the benefits of its lead product Cx601 as Pharmanest and XSpray Microparticles to sharpen at 52 weeks after administration, a longer period Healthcare retained the overall top spot, with Karolinska’s focus, and also attract outside investment than previously reported. TiGenix has been publicly AbbVie a close second. Of the 48 companies into the companies it retains. listed on Euronext Brussels since 2007 and was that patient groups commented on, the planning to raise funding in the US, but reported bottom ranked companies were Valeant and Spark Acquires Irish Mar. 9 that unfavorable capital market conditions Hospira. 2015 was a watershed year for pharma’s Ophthalmology Partner meant it had not yet launched an initial public investment in relationships with patient groups Philadelphia-based Spark Therapeutics has acquired offering of American Depository Shares (ADSs). and other patient-centric activities. This was private, Irish gene therapy company, Genable reflected in pharma’s best standing in terms Technologies, for $6m in cash and 265,000 shares Xoma Kills Gevokizumab of corporate reputation since the survey was of Spark common stock. Spark and Genable have Xoma Inc. finally stopped all development for been partners since 2014 on the development first conducted in 2011. The survey questioned gevokizumab, shifting its entire focus to endocrine of RhoNova, a drug targeting rhodopsin-linked diseases and cutting even more jobs, but the 1,075 patient groups from 72 countries on six autosomal dominant retinitis pigmentosa (RHO- company somehow expects to sell the asset to indicators of corporate reputation: patient- adRP), a form of inherited retinal disease (IRD). another party after racking up another Phase centricity; patient information; patient safety; Through the acquisition Spark will gain full III clinical trial failure. Berkeley, California-based useful products; transparency; integrity. The ownership of RhoNova, which is currently being Xoma’s share price flirted with the $1 range on report also questioned 11 pharma companies explored in preclinical studies for RHO-adRP, a March 10 as investors responded to the company’s on their activities in patient centricity and condition that leads to visual impairment and 2015 earnings report and corporate update, patient-group relations. in the most severe cases to blindness. Using an which was issued after the stock market closed on adeno-associated virus (AAV) vector developed and March 9. But Xoma ultimately ended the day just Aprea Banks $51m Series B manufactured at Spark, RhoNova, which has been shy of $1 per share – up 8.1% at $0.96 – after the Aprea AB, which is targeting the “holy grail” of granted orphan drug designations in the US and company hammered the final nail in gevokizumab’s anticancer research – the p53 tumor suppressor Europe, is designed to both suppress the expression coffin and said it would use its remaining cash to protein – and has the former head of oncology drug of a faulty gene and deliver normal copies of the advance three development programs in various discovery of Bristol-Myers Squibb as its executive RHO gene to restore normal expression. rare endocrine diseases.

Policy & Regulation Briefs No 12 Years Exclusivity In Biologics Pensions (HELP) Committee on March 9, with only Indian Court Rejects NDA-To-BLA Switch a somewhat brief debate over how the measures Whistle-Blower’s Suit Even though the Biologics Price Competition and will be funded holding up the votes for a short Innovation Act (BPCIA) – the law that permitted time. The seven bills, which were a hodge-podge India’s apex court has declined to admit the FDA to approve biosimilars – has been in place of measures that would add new responsibilities to Ranbaxy whistle-blower Dinesh Thakur’s since March 2010, it’s taken the agency six years the FDA and the National Institutes of Health (NIH), petitions that sought “urgent intervention” to figure out how to implement the so-called are intended to eventually be wrapped up into a to improve India’s drug regulatory standards “deemed to be a license” provision, which sets a package that would serve as a companion to the and challenged the constitutionality of deadline for regulators to stop approving biologics House-passed 21st Century Cures Act. certain rules under the Drugs and Cosmetics through certain pathways created under the Food, Valeant ‘Puzzled’ Over Accusations Rules 1945. Thakur had moved the Supreme Drug and Cosmetic Act (FDCA). In a new draft Valeant Pharmaceuticals International Inc. on Court against India’s health ministry, the guidance document posted online on March 11, the FDA laid out a new plan for moving protein March 10 said it was “surprised and puzzled” by the Central Drugs Standard Control Organization products, like insulin and insulin analogues, accusations from the Republican and Democratic (CDSCO) and the Drugs Consultative human growth hormone, pancreatic enzymes heads of the House Oversight and Government Committee, among others, seeking a series and follitropin, which have been approved for the Reform Committee that the firm was withholding of actions to improve the drug regulatory US market through the FDCA pathways – new documents. “We have produced more than 78,000 system in India, including “binding drug applications (NDAs), abbreviated new drug pages of documents,” said Washington lawyer guidelines” for the recall of drugs that are applications (ANDAs) or 505(b)(2) NDAs – to the Robert Kelner, a partner at Covington & Burling, not of standard quality, adulterated, spurious biologics license application (BLA) process. who is representing Valeant. Kelner said it was or misbranded. On March 11, the Supreme “standard procedure” for any company responding Round 2 ‘Innovation’ Bills Adopted to a congressional investigation and engaged Court took up Thakur’s much publicized A second set of bills intended to overhaul the US in litigation to decline to produce documents plea, but is said to have questioned the biomedical enterprise, aimed at accelerating the covered by the “attorney-client privilege,” and said whistle-blower’s locus standi and apparently discovery, development and approval processes his firm was preparing a log for the Oversight indicated that it had no time for publicity for medical products, mostly had smooth sailing Committee detailing what documents were being efforts by public activists. through the Senate Health, Education, Labor and withheld under that privilege.

20 March 18th 2016 @scripnews scripintelligence.com © Informa UK Ltd 2016 expert view Can Premium-Priced Trulicity Prickle Victoza In India? Eli Lilly’s once-weekly diabetes therapy patient population than its other traditional Mehta believes that Trulicity may also Trulicity (dulaglutide) appears to have made its insulins,” the expert told Scrip. be able to wean away some market from Indian debut priced at a premium compared Foreign firms have deployed a number of SGLT2 inhibitors like Forxiga and Jardiance with certain Western markets –an indication pricing approaches in India: Novo Nordisk’s (empagliflozin) largely on account of the that some innovator firms are less likely to once-daily basal insulin therapy Tresiba latter’s side effect profile. consider major pricing flexibilities in first-wave (insulin degludec) had some years ago made “Long term use of SGLT2 inhibitors needs markets for new products, even if these are a similar premium debut, positioning itself close monitoring. Trulicity may fetch some emerging economies. at the top end of the private market. It had a market from this class of drugs due to its once India is among the first few countries in the strong run with an estimated 6,000 patients weekly convenience of use, with weight loss/ world and the third Asian market after the prescribed Tresiba in India within just two highHbA1c reduction benefit despite being UAE and Japan where Trulicity has been rolled months of launch. an injectable. “ out and the glucagon-like peptide-1 (GLP-1) In contrast Janssen launched its selective Mehta also added that Victoza’s positive receptor agonist has been priced at INR2,499 sodium glucose co-transporter 2 (SGLT2) cardiovascular outcomes data from the (£26) for a week, translating into an annual inhibitor Invokana (canagliflozin) for type 2 LEADER trial announced recently, increases cost of around INR129,948 (£1354.5). diabetes in India at a fraction of the product’s the possibility of broader uptake of the In contrast, the annual cost in the UK US cost sticking with its “commitment” of GLP-1 class in the early armamentarium of dulaglutide 1.5mg or 0.75mg once offering India-specific pricing for its products as of treating Type 2 diabetes replacing new weekly is £1,182.35, as per details in NICE’s far as possible. Ditto for AstraZeneca’s Forxiga oral combo medications. On March 4, Novo evidence summary for the product in June (dapaglifozin) that was priced 75% lower in Nordisk announced top-line results from 2015, though an out-of-pocket market like India as compared with developed markets. the LEADER trial, indicating that Victoza India may not be strictly comparable with significantly reduces the risk of major adverse reimbursed markets like the UK. The exact Competition cardiovascular events. impact of currency fluctuations on pricing Some experts appear to give Trulicity a fair Trulicity received US FDA approval was not immediately clear. chance of making a dent in India, premium in September 2014 and EU approval in Asked about the pricing approach in India price approach notwithstanding. November that year. It comes in an easy and the premium compared with markets Ripple Mehta, senior consultant at MP to use, single-dose pen that does not like the UK, Lilly said that it believes Trulicity’s Advisors, an Indian strategic business advisory require mixing or measuring and can price reflects both the “current market and firm, told Scrip that Trulicity will be a drug of be administered at any time of the day, competitive realities” while still allowing this choice for patients uncontrolled with two or independent of meals. important class to grow as it continues to three oral antidiabetics and are obese and Lilly India’s medical director, Tarun Puri, serve more patients. need to start insulin. said that GLP-1 agonist class provides several “Every market is different in regards to “The high price makes it a treatment of benefits including a proven efficacy in pricing, access and reimbursement. Lilly choice for rich, obese diabetics,” Mehta said, controlling blood sugar levels with a lower risk offers Trulicity at a price which we believe is adding that she expects the product to take of hypoglycemia. “It might even help patients reflective of what the product offers, including market share from Novo Nordisk’s Victoza reduce a little weight,” a company statement proven efficacy, safety and patient-friendly (liraglutide), which is administered once daily. quoting Puri said. administration,” Lilly told Scrip. Victoza continues to be very successful, but The Indian diabetes market is valued at One industry expert told Scrip that Lilly’s has lost some market share to other GLP-1 around INR78.17bn ($1.16bn) and growing price point was a reflection of how the first agonists, including Trulicity, internationally. at 22.7%, as per moving annual total (MAT) wave of markets launch at “approximately the Novo Nordisk’s Victoza is available as a 6mg data for January 2016 from AIOCD AWACS, a US price,” while tiered-pricing or other such per ml solution for injection in a pre-filled pen. market research agency that tracks retail sales. flexibilities come in slightly later. One pre-filled pen contains 18mg liraglutide While Lilly did not immediately provide “India is among the first wave markets to in 3ml that costs INR4,840. details on Indian studies for Trulicity, at launch which is an acknowledgement by Novo Nordisk, however, told Scrip that the time of recommending the product Lilly of India being the diabetes capital of the based on its interactions with prescribers, for marketing authorization in late 2014, world. It’s a market that they would launch most of the patients in India are prescribed an Indian Subject Expert Committee (SEC) earlier rather than later,” the expert with a 0.6mg–1.2mg. suggested that Lilly conduct a “structured” foreign firm said. “The weekly cost of Victoza is lesser than PMS [post marketing surveillance] study. India has more than 60m people living the newly launched molecule dulaglutide “The study protocol of the same is to be with diabetes, while 77.2m Indians are seen as for most patients in India. For a 0.6mg dose, submitted to DCGI [Drugs Controller General pre-diabetic (impaired fasting glucose and/or Victoza is economical by around INR1,370 per of India] office before marketing the drug impaired glucose tolerance). week (vis-à-vis dulaglutide) and for the 1.2mg in the country,” the SEC (metabolism and The expert, though, said that India dose, Victoza is economical by INR240 per endocrinology) then said. continues to be a volume driven market and week,” Novo Nordisk told Scrip. SECs advise the Indian regulator on trial- in the absence of insurance cover and patients For all patients the starting dose is 0.6mg related permissions as part of a layered paying out of pocket, Lilly will probably not liraglutide daily; patients are expected to approval process, India currently follows see “really big volumes” unless it drops price. benefit by increasing the dose to 1.2mg a three-tier review process for clinical “However, given the nature of the product and further to 1.8mg based on the clinical trials, under which applications are initially (once weekly), Lilly’s strategy could be a ‘value response, though a daily dose higher than evaluated by specialized SECs. capture’ one too since it may target a smaller 1.8mg is not recommended. [email protected]

© Informa UK Ltd 2016 @scripnews scripintelligence.com March 18th 2016 21 stockwatch Pharmaceutical Fight Club one has much higher stakes. The patents surrounding Gilead’s multi-billion dollar HCV antiviral franchise were being challenged by Merck. Like the PCSK9 challenge, while the eventual outcome may be solved by royalties – which the analysts from Jefferies

Viktor Gladkov/shutterstock.com estimate to be worth $2.3bn to date – the real confrontation will also be between any company with a successful HCV antiviral and those who are contracted to pay for it. Developing drugs for which there is no commercial market, or downplaying the fragility of their intellectual property, may cause confrontation between companies, but they often arise from the inability of Last week was a hard week for life science There were, however, confrontations companies to confront their own issues of stocks comprising three down days in the more worth the effort last week with bigger drug development and convey them to their middle of the week that made me wonder opponents Amgen Inc. facing off in court to investors. In this respect, there is probably about early retirement followed by a strong challenge the intellectual property of partners a confrontation brewing with Circassia Plc’s enough recovery on Friday to entice me Sanofi and Regeneron Pharmaceuticals Inc. on imminent Phase III trial announcement for its back into the office on Monday. Even if we PCSK9 inhibition in the treatment of elevated lead Cat-SPIRE allergy vaccine. Circassia has a are close to a bottom if not a recovery in lipids. Whatever the outcome, at least the track record of opacity in its clinical trial failure biotechnology and pharmaceutical share lawyers will win – and if Amgen does prevail, reporting – I am recalling the time when the prices, it doesn’t help the sector ambiance the confrontation is likely to be settled by same platform that generated the Cat-SPIRE that everyone seemed to be fighting each royalties at dawn. Ironically, like the three vaccine failed to show a significant difference other last week. recently approved drugs to treat obesity, over placebo for the Phase II Ragweed-SPIRE We are in the long tail of fourth-quarter the great white hopes for PCSK9 inhibition allergy vaccine in the low bar of an exposure earnings season and by now most of the are the ongoing cardiovascular outcome chamber clinical study. reports are by loss-making companies. trials (CVOT). Expectations are perhaps Circassia may hope to divert investors’ Amongst them are all three of those that too high for a dramatic turnaround in the attention if Cat-SPIRE fails in the real-world developed the most recently approved commercial fortunes of any of these drugs, Phase III clinical study by emphasizing the medicines to treat obesity. Orexigen since – as Novartis AG has found – even in £10.2m in last-quarter sales it reported Therapeutics Inc. reported a paltry $2.6m the face of a positive CVOT the commercial last week. These sales were generated by in quarterly royalties from its partner confrontation appears to be with pharmacy spending £188m of the £191m raised in its Takeda Pharmaceutical Company Limited benefit managers, which are adverse to IPO and £275m secondary offering to buy in respect of sales of Contrave (naltrexone/ paying up for expensive drugs indicated for two companies. While some of last week’s bupropion), now in its second year on the large populations, regardless of the clinical confrontations will be resolved by careful market. Competitor Arena Pharmaceuticals outcomes in those populations. mediations, others are likely to lead to tears at Inc. reported only $3.9m in quarterly royalties In Europe last week another confrontation bedtime rather than royalties at dawn. from its partner Astellas Pharma Inc. in respect inched closer to a partial resolution with the The Magna Biopharma Income fund of sales of Belviq (lorcaserin), which, as the revocation of one of Biogen Inc.’s patents holdings include Amgen, Regeneron, Gilead analysts from JP Morgan and Piper Jaffray on the 480mg dose of Tecfidera (dimethyl and Merck. both highlighted, lost 16% in market share fumarate) for the treatment of multiple Andy Smith last quarter. sclerosis. The patent challenge had been The analysts from JP Morgan (under) stated initiated by Forward Pharma A/S, whose sole Andy Smith is chief investment officer of Mann that “overall obesity [was] not meeting growth reason for being seems to be to challenge Bioinvest. Mann Bioinvest is the investment expectations” while those from Piper Jaffray Biogen’s patents, although I had wondered adviser for the Magna BioPharma Income cut their share price target on Orexigen, if dimethyl fumarate’s long history of use in fund which has no position in the stocks noting that their estimates on its profitability inflammatory diseases in Europe may result in mentioned, unless stated above. Dr Smith gives were based on growing revenues. By the time Forward opening Pandora’s box, inside which an investment fund manager’s view on public that Vivus Inc. reported $14m in quarterly net no party ends up with European exclusivity. life science companies. He has been lead fund sales for Qsymia (phentermine/topiramate), Nevertheless, all the analyst notes I read manager for four life science– specific funds, a sales figure – like that of Belviq’s – that suggested absolutely no read-through from including International Biotechnology Trust and had declined in the last quarter, I wondered Europe to Biogen’s US patents on Tecfidera, the AXA Framlington Biotech Fund, and was if I had been the first to realize that the which was a stunning piece of analytical awarded the Technology Fund Manager of the three companies actively competing with insight bearing in mind the reasons for the year for 2007. recently launched medicines in the obesity revocation have not yet been published. indication appeared to be not so much Another patent confrontation in another For all Stockwatch articles visit in a confrontation, but a hapless series of court also commenced last week between scripintelligence.com/stockwatch misadventures. Gilead Sciences Inc. and Merck & Co. This

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 4-10 March 2016 Lead Company Partner Company Drug Indication Market Comments REGULATORY APPROVAL CSL Behring – Idelvion hemophilia B US For use in children and adults with hemophilia B. It is the first coagulation factor- (albutrepenonacog alfa) albumin fusion protein product to be approved, and the second Factor IX fusion protein product approved in the US that is modified to last longer in the blood. Vertex – Orkambi 200/125 cystic fibrosis Australia For the treatment of cystic fibrosis in patients age 12 years and older who are Pharmaceuticals (lumacaftor 200mg and homozygous for the F508del mutation in the CFTR gene. Inc. ivacaftor 125mg) Eisai Co. Ltd. Neopharm Lenvima (lenvatinib) thyroid cancer Israel Indicated for the treatment of adult patients with progressive locally advanced or metastatic, differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma refractory to radioactive iodine. SUPPLEMENTAL REGULATORY APPROVAL AbbVie Inc. Johnson & Johnson Imbruvica (ibrutinib) chronic lymphocytic US Approved as a first-line treatment for patients with chronic lymphocytic leukemia leukemia (CLL). IMBRUVICA is now approved to treat CLL patients regardless of their treatment history (treatment-naïve and previously-treated patients). REGULATORY FILING ACCEPTED Vericel Corp. – MACI (matrix applied knee cartilage defects US A BLA has been submitted for MACI, an autologous cellular product to treat characterized autologous symptomatic cartilage defects of the knee in adult patients. cultured chondrocytes) SUPPLEMENTAL REGULATORY FILING ACCEPTED Amgen Inc. – Enbrel (etanercept) pediatric psoriasis US FDA has accepted a sBLA for expanded use of Enbrel in pediatric patients with chronic severe plaque psoriasis. The sBLA, submitted on Jan. 5, 2016, is based on results from a Phase III one-year study and its five-year open-label extension study in pediatric patients with moderate to severe plaque psoriasis. Merck & Co Inc. – Keytruda (pembrolizumab) non-small cell lung cancer US FDA has accepted for review a new sBLA to include data from KEYNOTE-010, a pivotal (NSCLC) Phase II/III study comparing Keytruda to chemotherapy on the prospective measurement of PD-L1 expression in previously treated patients with advanced NSCLC. ORPHAN DRUG DESIGNATION AstraZeneca PLC – MEDI-551 neuromyelitis optica US For the treatment of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders. Currently in Phase IIb for NMO. FAST-TRACK STATUS AstraZeneca PLC – MEDI-8852 influenza A US For the treatment of patients hospitalised with Type A strain influenza. MEDI- 8852 is in a Phase Ib/IIa clinical trial as a single iv dose in combination with oseltamivir, and as a monotherapy, in adult patients. REGULATORY FILING WITHDRAWAL Otsuka Holdings – Nuedexta pseudobulbar affect EU The European Commission withdrew the marketing authorisation for Nuedexta in Co., Ltd. (dextromethorphan / the EU at the request of Jenson Pharmaceutical Services, which notified the quinidine) European Commission of its decision not to market the product in the EU for commercial reasons. REGULATORY FILING Xbiotech Inc. – Xilonix (MABp1) colorectal cancer EU For use of an anti-IL-1a MAb for the treatment of advanced colorectal cancer. Japan Tobacco Inc. Torii Pharmaceutical Co. elvitegravir, cobicistat, HIV Japan An anti-HIV single tablet regimen. Torii holds exclusive rights to market E/C/F/TAF Ltd.; Gilead Sciences Inc. emtricitabine and tenofovir in Japan, subsequent to JT obtaining manufacturing and marketing approval. (E/C/F/TAF) SUPPLEMENTAL REGULATORY FILING Novartis AG Genmab Arzerra (ofatumumab) chronic lymphocytic EU For use with fludarabine and cyclophosphamide (FC) to treat relapsed chronic leukemia lymphocytic leukemia (CLL). The application was submitted by Novartis under its ofatumumab collaboration with Genmab. PARTIAL HOLD LIFTED Medivation Inc. CureTech pidilizumab diffuse large B-cell US FDA has lifted the partial clinical hold in hematological malignancies and lymphoma confirmed the Phase II clinical trial in relapsed or refractory diffuse large B-cell lymphoma, as well as other studies that cross reference the IND, may now proceed. The partial clinical hold was not related to any safety concerns. PHASE III TRIAL INITIATION Novartis AG Genmab ofatumumab relapsing multiple – Novartis to begin Phase III studies with subcutaneous ofatumumab in patients subcutaneous sclerosis with relapsing multiple sclerosis during the second half of 2016, following the transfer of rights to ofatumumab in this disease area from GSK to Novartis at the end of 2015. The Phase III study of the subcutaneous ofatumumab in pemphigus vulgaris, which was started by GSK will be discontinued to focus on relapsing multiple sclerosis. AcelRx – ARX-04 (sufentanil) moderate to severe pain – Patient enrollment and dosing in a multicenter, open-label Phase III clinical Pharmaceuticals sublingual tablets following surgery study, known as SAP303, has been initiated. Omeros Corp. – OMS721 aHUS US A Phase III study in atypical hemolytic uremic syndrome has started in the US. Celsion – ThermoDox (heat activated hepatocellular carcinoma China The Phase III study, OPTIMA, has started to enroll patients in China with liposomal doxorubicin) hepatocellular carcinoma, as well as in other countries. Source: Sagient Research's BioMedTracker

Ameet Nathwani has been appointed to Sanofi’s executive-level positions at GlaxoSmithKline PLC. experience in working at startups and listed executive committee – effective May 1, 2016. and its predecessor, SmithKline Beecham, most companies in Germany and abroad and most Nathwani joins the company from Novartis’ taking recently as senior vice president of research and recently was CFO of Nuvisan GmbH. Prior to this the position of executive vice president, group development. he held various managerial positions at Santhera chief medical officer. From 1994 he held senior Pharmaceuticals Group. leadership roles in research and development in CRISPR Therapeutics has appointed Marc Becker Glaxo, SmithKline Beecham and GlaxoSmithKline chief financial officer (CFO); he joins the company PuretTech’s Vedanta Biosciences has appointed PLC. He joined Novartis in 2004 as senior vice from rEVO Biologics where he was CFO and senior Genzyme’s former vice president Bruce L. Roberts president and global development head of the vice president. Prior to this, he spent 10 years at as chief scientific officer. Roberts most recently was cardiovascular and metabolic franchise and held Genzyme, most recently serving as finance director head of neuro-immunology and immune-mediated various senior development and commercial for the UK and Ireland before becoming the vice disease research at Sanofi Genzyme. positions over the 11 years he was there. He was president of finance for the Genzyme’s renal and appointed global head of medical affairs Novartis endocrine business in the US. NantKwest, an immunotherapy company Pharma AG. in June 2014. focused on the immune system, has appointed Synergy Pharmaceuticals Inc. has appointed Fatih M. Uckun vice president of research and Specialist investment manager Pamplona Marino Garcia to the newly created role of clinical development. Prior to joining NantKwest, Capital Management has appointed Mark executive vice president and chief strategy officer Uckun was president of Ares Pharmaceuticals Pacala operating partner with a focus on – effective immediately. Garcia has been senior vice and he was also a professor in the department healthcare. Pacala brings over 20 years’ president corporate development and part of the of pediatrics at the Keck School of Medicine of healthcare industry experience and most leadership team since he joined Synergy in 2014. the University of Southern California and head recently was a senior advisor in the healthcare Previously he was vice president of global business of translational research in leukemia and team at Oak Hill Capital Partners. He was also development at Aptalis Pharma (acquired by lymphoma of the Children’s Center for Cancer general partner at Essex Woodlands Health Forest Labs) and vice president of US commercial and Blood Diseases. Ventures and chair and CEO of American operations and new product development at WholeHealth and Forum Group. Aspreva Pharmaceuticals (acquired by Vifor Diabetes focused Poxel has named Jonae R. Pharmaceuticals). Earlier in his career, Garcia held Barnes senior vice president, investor relations Alzheon Inc. has appointed clinical professor various US and international leadership roles in and public relations. Barnes started her career at Dennis H. Langer to its board of directors. companies like Eli Lilly & Co and Pfizer. Sepracor (now Sunovion Pharmaceuticals) where Langer is currently clinical professor in the she held various management and executive department of psychiatry at Georgetown Immunology focused biotech, Mologen AG.’s roles over a 14 year period and most recently was University School of Medicine and director of supervisory board has appointed Walter Miller senior vice president, investor relations, corporate Myriad Genetics Inc., Dicerna Pharmaceuticals member of the executive board and chief financial communications and internal communications. Inc. and Delcath Systems Inc. He previously held officer (CFO) – effective April 1, 2016. Miller has She also held senior leadership roles at Agenus.

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