Sarepta, FDA and the Dangers of Strong Early Results

Regulatory Update Business & Finance Manufacturing EMA, FDA Get Together On Drugs Lundbeck Takes A Singular View FDA Making A Generic Case For Eligible For PRIME And Breakthrough Toward Tackling Challenging CNS Continuous Manufacturing, p. 23 Designation, p. 19 Disorders, p. 5

Pharma intelligence Pinkwww.ThePinkSheet.com SheetVol. 78 / No. 18 May 2, 2016 informa

tinue to work with FDA as it completes the Sarepta, FDA And The Dangers eteplirsen review and that it remains committed to gaining approval for a Duchenne treatment. Of Strong Early Results Debra Miller, CEO and founder of the advocacy group CureDuchenne, said in an Derrick Gingery [email protected] interview with “The Pink Sheet” that she wants to make sure Duchenne patients and arepta Therapeutics Inc.’s proposed advocates remain focused on dealing with Duchenne muscular dystrophy treat- the agency’s concerns. Sment eteplirsen may have been “We just work as hard as we can to help doomed by the optimism created from its Sarepta and make sure this doesn’t happen early study results, which it turned out could again and design trials that FDA will like,” not be replicated. she said. And now the company finds itself in a pre- The committee’s decision was made diffi- carious situation as it looks for a way to gen- cult by the emotional and admittedly com- erate additional scientific data that match pelling testimony from dozens of patients, the overwhelmingly positive anecdotal evi- parents and advocates (“Patients Can’t Res- dence of efficacy. cue Sarepta’s Eteplirsen” — “The Pink Sheet” FDA made no secret of the fact that it had DAILY, April 25, 2016). serious concerns about the external control Patient groups dominated the audi- trial that Sarepta used to show the efficacy of ence at the meeting and testified about eteplirsen, which is proposed for Duchenne eteplirsen’s effect on Duchenne. One group patients that have a gene mutation amenable Sarepta credit: Photo also was able to contribute its own data as to exon 51 skipping (“Sarepta’s Additional Data Sarepta CEO Ed Kaye part of Sarepta’s presentation, a first for an Doesn’t Sway FDA On Eteplirsen” — “The Pink FDA advisory committee meeting (see re- Sheet” DAILY, April 21, 2016). the Icahn School of Medicine at Mt. Sinai in lated story, “Duchenne Group’s Presentation Is Agency officials said during an April 25 Pe- New York, worried that the result creates Milestone For Patient Involvement,” online at ripheral and Central Nervous System Drugs too much uncertainty about eteplirsen’s thepinksheet.com). Advisory Committee meeting on the product path forward. that they advised the company on several oc- “I don’t believe an external control is cus- Accelerated Approval Still casions, as early as June 2011, that its efficacy tomary in a study like this at all and so I can’t Possible? evidence would be difficult to interpret and say I’m in favor of that, but I’m very fearful With questions about the study results, a that a placebo-controlled trial was preferable. that we’ll leave here with some sort of stale- placebo-controlled trial may be required to Committee members agreed that the tri- mate between the FDA and [Sarepta],” said determine whether the anecdotal evidence al did not create enough evidence for an ac- Green, who supported accelerated approv- of effectiveness is accurate. celerated or full approval. The vote against al and abstained on the full approval vote. That may leave accelerated approval, accelerated approval was close, 7-6, and the Sarepta did not indicate it was consider- which Sarepta has requested, off the table. rejection of full approval included three ab- ing walking away from the drug after the Agency officials said during the meeting stentions (see box, p. 4). meeting. Interim CEO Edward Kaye said that if the product becomes available to all But Mark Green, a neurology professor at in a statement that the company will con- Continued on page 4 DRUGS I BIOLOGICS I DEVICES There are 6,912 known languages in the world…

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Duchenne Group’s Presentation Is Milestone For Regulatory Update Patient Involvement www.thepinksheet.com/a/ 00160502008 19 EMA, FDA Get Together On Drugs Eligible For PRIME And Breakthrough Designation Advocacy group gets portion of Sarepta’s formal presentation period to present eteplirsen patient experience data, believed 21 Putting the Patient in Labeling (And Drug Approval to be a first for an advisory committee meeting. Will it become Decisions) in ODE1 commonplace?

Advisory Committees 26 Recent And Upcoming FDA Advisory Committee Meetings

Business & Finance The US Trade Representative reports on which 5 Lundbeck Takes A Singular View Toward Tackling companies are on Watch Lists for providing Challenging CNS Disorders Data inadequate protection of IP rights. See an 10 Venture Funding Trends For Biotech Largely Improved In 2015 interactive map identifying those countries at 13 Deal Watch: AbbVie, arGEN-X To Explore www.thepinksheet.com/a/ 00160502012 Immuno-Oncology According To GARP

International 17 India’s Patent Policy Needs More Stakeholder Input, US Trade Office Urges  join the conversation People In The News We are tweeting, liking and sharing the latest industry 7 New CEOs Helm Melinta, Apollo news and insights from our global team of editors and 8 Perrigo’s Papa: Bridge Over Valeant’s Troubled Waters analysts — join us! Or Shark Bait?

@thepinksheet1 Manufacturing 23 FDA Making A Generic Case For Continuous Manufacturing

thepinksheet.com May 2, 2016 | Pink Sheet | 3 Advisory Committees

ing that the agency was open to using accel- Why No Placebo-Control erated approval for eteplirsen. She said more Trial Before? uncertainty will be tolerated and “sometimes Committee members seemed perplexed we will collectively get it wrong,” suggesting that a placebo-controlled trial was not com- the agency would be willing to put it on the pleted, stating that based on patient testi- Continued from cover market and pull it later if efficacy could not be mony an approval may have been much patients through accelerated approval, a con- confirmed. easier to endorse with such a study. firmatory study might be difficult to conduct. FDA has usually been fairly flexible with the “Reading the data from Sarepta, every “Any kind of product that’s approved under single secondary clinical endpoint seemed accelerated approval or any kind of approval, evidence it requires for approval of new treatments for rare diseases where there is an un- to be so positive and listening to the testi- the question of whether you can then do a trial monials and the experiences of the boys met need (“FDA Orphan Approval Flexibility Re- that’s placebo-controlled becomes very chal- and the families it just seems to me that had mains Steady As Pressure Increases” — “The Pink lenging, particularly in serious or life-threaten- there been a true placebo group that the Sheet,” Oct. 27, 2014). ing diseases where patients may not be want- differences would have been so striking and But the case for accelerated approval ap- ing to be on placebo,” said Office of New Drugs that the study may have even been stopped pears much tougher to make now and may Director John Jenkins. sooner,” said Nicole Gonzales, an associate mean Sarepta has to pursue a full approval. Sarepta has committed to conduct two con- professor in the University of Texas-Houston Woodcock’s flexibility argument also didn’t firmatory studies. PROMOVI, an open-label trial Medical School neurology department. comparing eteplirsen to untreated non-exon appear to play among the committee mem- “I’m trying to understand why there wasn’t 51 skipping patients, is expected to produce bers. After her comments, the committee an adequately powered placebo group.” data in two to three years. voted 7-3 against full approval with three ab- Sarepta officials argued during the meet- ESSENCE, a double-blind, placebo controlled stentions. ing that once its early data showed substan- study in Duchenne patients skipping exons 45 Of the three votes in favor of full approval, tial increases in dystrophin production and a and 53 that is testing another product with the two came from the committee’s patient rep- clinical response among eteplirsen patients, same mechanism of action as eteplirsen, is ex- resentatives, which may have been expected. a placebo-controlled trial would be extreme- pected to begin enrollment soon. While their voices were important additions ly difficult or impossible to enroll. Parents Center for Drug Evaluation and Research Di- to the committee, there was only one vote in would not be willing to risk not receiving rector Janet Woodcock said during the meet- favor from a non-Duchenne patient or parent. eteplirsen if they joined the study. Kaye, who also is the company’s chief medical officer, said the company at that Advisory Committee Votes time had limited manufacturing capabilities, which prevented a placebo control study. • Has the applicant provided substantial evidence from adequate and well-controlled “When we had initially done the Phase II studies that eteplirsen induces production of dystrophin to a level that is reason- study, there wasn’t enough drug at that time. ably likely to predict clinical benefit? 7-6 against (original vote was 8-5 against, but We didn’t have the ability to manufacture one committee member said he pushed the wrong button) until almost two years later,” he said. “When we had enough drug to do a placebo-con- • Were discussions to administer the six-minute walk test (vs. conclusions that the trol trial, because of the response to the fact patient could no longer walk) sufficiently objective and free of bias and subjective that this drug produces dystrophin and also decision-making by patients, their caregivers, and/or health care professionals to the clinical response, there really wasn’t a allow for a valid comparison between patients in Study 201/202 and an external possibility at that time to be able to do a for- control group? 7-5 against with one abstention mal placebo-controlled trial. • What is the impact of the North Star Ambulatory Assessment results on the “We had to make a decision at that time persuasiveness of the findings in Study 201/202? Strengthen: 1 (originally 2, but a what was in the best interest of the patients committee member pressed the wrong button), Weaken: 5, No effect: 7 (originally and we decided to do the external control, 6, but changed after wrong button pressed) which is the next best thing.” Although unmentioned, the desire to rush • What is the impact of the other tests of physical performance, such as rise time and to market in the face of a potentially com- the 10-meter run/walk, on the persuasiveness of the findings in Study 201/202? peting product presumably played a role in Strengthen: 1, Weaken: 2, No effect: 10 how Sarepta structured its clinical program. • Do the clinical results of the single historically-controlled study provide substantial Another Duchenne candidate, BioMarin evidence that eteplirsen is effective for the treatment of Duchenne muscular dys- Pharmaceutical Inc.’s drisapersen (proposed trophy? 7-3 against with three abstentions trade name Kyndrisa) got an advisory committee review last fall.

4 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 Advisory Committees

But FDA had efficacy concerns with dris- Eric Bastings, deputy director of the Divi- FDA was open to Sarepta showing effi- apersen as well and ultimately issued a “com- sion of Neurology Products within FDA’s Of- cacy through the external control trial, but plete response” letter following a negative fice of New Drugs, said it was an unfortunate it had to be strong enough to be interpre- advisory committee vote on the product situation and that the early phase results table. “Really what I feel like I’m trying to do (“BioMarin’s Drisapersen ‘Compete Response’ may have led to the situation. is set the record straight and try to explain Shows FDA Flexibility Still Limited” — “The “As Duchenne muscular dystrophy is an to people the way that we see the data Pink Sheet” DAILY, Jan. 14, 2016). orphan disease, an important issue to con- and some of the things that we’re not real Sarepta’s Phase IIb data for eteplirsen was sider is whether it could have been possible happy about, the way that the data itself positive when released in 2014, but inves- for the applicant to conduct an adequate was presented and some of the things that tors still were nervous (“Sarepta Continues and well-controlled study,” Bastings said. “The we’re not really able to say,” Farkas said. To Show Results In DMD, But Is It Enough?” — answer clearly is yes.” Questions over how best to assess prod- “The Pink Sheet” DAILY, July 10, 2014). ucts continue even after FDA released Unfortunately for Sarepta, the pivotal ex- FDA Has To Manage PR As Well a draft guidance on the topic based on ternal control trial showed far less promis- Ronald Farkas, clinical team leader in the Divi- a proposal submitted by the Duchenne ing results: instead of the expected 25% to sion of Neurology Products, also said there was community (“Duchenne Muscular Dystro- 50% of dystrophin, the result after a biopsy a lot of information about eteplirsen not publi- phy: FDA Supports Broader Outcome Mea- at week 180 was 0.9%, which raised more cally available until recently. “For many years we sures, Biomarkers” — “The Pink Sheet” DAILY, questions at FDA. haven’t heard the whole story,” he said. June. 10, 2015).

Business & Finance Lundbeck Takes A Singular View Toward Tackling Challenging CNS Disorders Jessica Merrill [email protected]

. Lundbeck AS is 100% invested in The restructuring included the developing drugs for central nervous loss of some 1,000 jobs, mainly Hsystem disorders, and its singular in Europe. focus and long-term view toward tackling At the same time, Schultz has challenging diseases is what sets it apart been focused on executing on from the competition, according to Exec VP- new launches and narrowing Lundbeck Research, USA Stevin Zorn. the company’s already special- “We have a singularity of focus,” Zorn ized therapeutic areas of focus said in an interview. “That’s why I think we to four specialties: depression, can succeed. [CNS] is where we are going schizophrenia, Parkinson’s dis- to live or die.” ease and Alzheimer’s disease.

The Danish drug company, 70% owned by Lundbeck is doubling down Lundbeck credit: Photo The Lundbeck Foundation, has gone through in the challenging area of re- some resetting in the last year. search at a time when many other drug mak- tunity,” Zorn said. While Lundbeck has a New CEO Kare Schultz is approaching ers have gotten out of CNS because of sci- long heritage working in CNS disorders, the his one-year anniversary at the helm, after entific hurdles, regulatory challenges around company used to be more opportunistic joining from Novo Nordisk AS in May 2015 defining clinical endpoints and the high com- about working across the entire therapeu- (“Kare Schultz Becomes Lundbeck’s CEO As New mercial bar for launching new drugs in highly tic area, he added. Launches Gather Pace” — “The Pink Sheet” genericized markets. Despite the challenges, “But the brain is so complicated and this DAILY, May 6, 2015). Schultz implemented a the unmet need in many CNS categories re- is such a difficult area to make progress in restructuring aimed at seeing the company mains extraordinarily high. The field is poised that if we continue to be diffuse, if we con- through the loss of its top-selling product Cip- for a comeback (“Neuroscience Could Play A tinue to cover the entire landscape of neu- ralex to generic competition in 2015, with the Major Role In FDA’s 2016 Approvals Story” — roscience, our ability to create something goal of returning the company to profitability “The Pink Sheet,” Feb. 29, 2016). that’s going to be meaningful … is going to in 2016 and cutting DKK 3bn in costs by 2017. “We see those challenges as our oppor- be difficult,” Zorn said.

thepinksheet.com May 2, 2016 | Pink Sheet | 5 Business & Finance

A Growing US Presence ing Rexulti as a treatment for agitation as- Lundbeck generated sales of DKK14.59bn sociated with Alzheimer’s disease. The drug’s ($2.22bn) in 2015, representing growth of mechanism of action is not entirely under- 8%, helped by currency fluctuations. Rev- stood but it is believed to work as a partial enue was flat in local currencies because In Alzheimer’s, the agonist of serotonin 5-HT1A and dopamine of significant generic erosion on Cipralex in D2 receptors and as an antagonist of sero- Europe and Canada, but partly offset by key arrival of disease- tonin 5-HT2A receptors. newer drugs, including the once-monthly Among nursing home patients with Al- injectable schizophrenia therapy Abilify modifying drugs that zheimer’s disease, 50% have significant agi- Maintena (aripiprazole), the antidepressant give patients more tation that is troubling to the patients and Brintelix (vortioxetine) and the atypical anti- their caregivers, Zorn said. psychotic Rexulti (brexpiprazole), approved time will increase the “Based on what we know about Rexulti in 2015 (“Keeping Track: Rexulti, Iressa Ap- and its effect on mood disorders and other proved; Takeda Submits Oral Myeloma Drug need for symptomatic conditions, we thought it would be worth Ixazomib” — “The Pink Sheet,” July 20, 2015). therapy, Zorn notes. trying in Phase III in agitation in Alzheimer’s The company is partnered with Otsuka disease,” he said. Pharmaceutical Co. Ltd. on Abilify Maintena The company has initiated two Phase III and Rexulti and with Takeda Pharmaceuti- Zorn said the company is in discussions studies, with the primary outcome measure cal Co. Ltd. on Brintelix. now with FDA about next steps for adding being the change in the Cohen-Mansfield Lundbeck’s strength in the US is grow- the information to labeling, with one of the Agitation Inventory (CMAI) total score. ing. The company generated DKK 6.35bn challenges being how best to measure the ef- Idalopirdine, a 5-HT6 receptor antagonist, ($965.2m) in the US in 2015, growth of 43% fect on cognition in patients with depression. is the other candidate Lundbeck is studying in local currencies. Revenue in the US ac- “What we are encouraged about and in Phase III as a treatment to improve cog- counted for 44% of the company’s total rev- what we’re happy about is that the FDA nition in Alzheimer’s disease patients. The enue last year compared to 28% in 2014. actually worked with us,” Zorn said. “They company has initiated three Phase III studies now recognize that cognition is a signifi- with data expected in 2017 and a potential ‘Encouraged’ By Discussions cant area of depression and that is encour- regulatory approval targeted for 2018. With FDA On Brintelix aging to us.” In Phase II testing, idalopirdine improved Complete Response cognitive function in patients with moder- The company’s focus in late-stage R&D is Phase III Trials Underway ate Alzheimer’s disease already taking the on expanding labeling for Rexulti and Brin- For Rexulti, Idalopirdine currently marketed cholinesterase inhibitor telix and on two Phase III programs for Al- For Alzheimer’s donepezil (Pfizer Inc.’s Aricept and generics). zheimer’s disease. In Alzheimer’s disease, Lundbeck has moved “What we saw in Phase II was almost an Lundbeck and Otsuka filed a sNDA with Rexulti and another compound, idalopirdine, equivalent amount of improvement on top FDA to extend the use of Rexulti to mainte- into large Phase III trials, not as potential dis- of a cholinesterase inhibitor. That is exciting,” nance treatment of adults with schizophre- ease-modifying treatments but as new op- Zorn said. nia. The drug was approved by FDA in July tions for addressing some of the symptoms The company is testing an immune-based 2015 for the treatment of schizophrenia and of the debilitating disease. therapy in Phase I, a vaccine that targets vari- as an adjunctive treatment for adults with Several drug makers are making sub- ous fragments of beta-amyloid. The vaccine major depressive disorder. Action on the ex- stantial investments in potential disease- is designed to stimulate the immune system panded labeling is expected in September. modifying drugs and Lundbeck is working in to build antibodies against the body’s own At the same time, the company recently earlier stages in the disease-modifying arena amyloid. “It may be a way that we can vac- received disappointing news from FDA, as well, but the company sees a near-term cinate patients against a-beta early in the when the agency rejected its application opportunity for symptomatic treatments. course of the illness either to prevent the ill- to add new data to the clinical studies “What some of the original [disease- ness or slow it down,” Zorn said. section of labeling for Brintelix related to modifying therapies] are doing is they are Succeeding in Alzheimer’s and other CNS improvement in cognitive function. The modifying the course of the illness to a cer- disorders will require perseverance, but agency issued a “complete response” let- tain extent where they are giving patients a that’s something Zorn insists Lundbeck has ter to Lundbeck and Takeda March 29, de- little more time, where symptomatic issues in spades, at least in part because it is major- spite the fact that FDA’s advisory commit- continue to be a significant problem,” Zorn ity owned by a foundation and thus buffered tee supported the additional claim (“FDA’s said. “Until we actually figure out how to alter by the whims of the stock market. Thinking On New Psychiatric Endpoints: or stop the course of the illness, focusing on “We have a solid investor, the foundation, What Does Brintellix CRL Portend For Nupla- symptomatic research is important.” and we set our strategy and we just go after zid?” — “The Pink Sheet,” April 4, 2016). In the first instance, Lundbeck is study- it,” he said.

6 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 People In The News / Tracking the latest personnel moves in the pharmaceutical industry. New CEOs Helm Melinta, Apollo

CEOs And Presidents Altimmune taps Sybil Tasker as senior VP, clinical research and de- Investment fund Apollo Therapeutics brings on Pfizer Inc. veteran velopment, joining from Genocea Biosciences. Takeda Pharmaceuti- Richard Butt as CEO, effective May 23. Apollo is a collaboration of cal Co. Ltd.’s Efe Egharevba joins the company as head of clinical proj- AstraZeneca PLC, GlaxoSmithKline and Johnson & Johnson and the ect management … Esai Inc. selects Avinash Desai as VP, Americas technology transfer offices of Imperial College London, UCL and the oncology medical affairs for the Oncology Business Group. He moves University of Cambridge. to the US subsidiary of Eisai Co., Ltd. from Janssen Pharmaceuticals Acting Melinta Therapeutics Inc. CEO Eugene Sun takes the helm of- Inc., where he was global medical affairs leader, oncology. ficially and also joins the company’s board of directors. He’s served in Conatus Pharmaceuticals Inc. selects Edward Smith as senior VP, an acting basis since September 2015 and previously held various posi- regulatory affairs and quality assurance. For the past several years he tions at Abbott Laboratories. was VP, regulatory affairs and drug safety at Zogenix, Inc., and has held a variety of regulatory affairs and R&D posts at other companies. Daniel Cohen moves to KemPharm Inc. as executive VP, government and public relations. He had been head of North American Government Relations for Grünenthal USA. Also joining KemPharm is Rene Braeckman as VP, clinical development. Braeckman earlier was Amarin Pharma, Inc.’s VP of clinical development. Astellas continues to build its leadership team in the Americas. Bob Chib, who led the company’s Strategic Business Accounts Richard Butt Eugene Sun Unit, becomes executive director, corporate strategy, planning and More Executive Changes initiative management and delivery, a part of the corporate devel- AMAG Pharmaceuticals Inc. selects Edward Myles as chief financial opment organization. Cassie Hogenkamp continues in her post as officer and senior VP. He had been CFO and chief operating officer at executive director, commercial strategy and innovation, but now Ocata Therapeutics Inc. … PhaseBio Pharmaceuticals Inc. expands also joins the corporate development. its executive line-up, with former Quintiles VP and Global Head, Car- Also at Astellas, Rodrigo Fernandez is the new executive direc- diovascular Center of Excellence John Lee becoming chief medical tor, international business, with responsibility to oversee business officer and HUYA Bioscience International CFO John Sharp taking in Latin America outside of Brazil. He had headed AstraZeneca’s the same post at his new company … Catalyst Biosciences Inc. adds Central America operations … In addition, Joseph Fleishaker be- two to its executive ranks. Threshold Pharmaceuticals’ Jeffrey Lan- comes VP, clinical pharmacology and exploratory development. dau becomes Catalyst’s VP of business development. Howard Levy, Most recently at the company, he was VP and and global therapeu- who has held posts at a number of companies and been an industry tic head of neuroscience. consultant, is the new CMO. Nektar Therapeutics Inc. Senior Director of Preclinical Pharmacology Rekha Hemrajani is FLX Bio, Inc.’s new COO. She had been CFO Kathleen Gogas moves to Symic to be VP of preclinical development. and senior VP of business and financial operations at 3-V Biosciences. CASI Pharmaceuticals Inc. taps James Goldschmidt as VP of busi- Nivalis Therapeutics Inc.’s new CMO and executive VP of discov- ness development. His 25-plus years in the industry include stints ery is David Rodman, most recently CMO and exec VP R&D at mi- at Macrophage Therapeutics, Johnson & Johnson, Wyeth Pharma- Ragen Therapeutics and earlier VP and head of respiratory clinical ceuticals and SmithKlineBeecham. development at Vertex Pharmaceuticals Inc … Luiz Belardinelli will split his time between his new position as CMO at privately held Trade Associations And Professional InCarda Therapeutics Inc. and senior advisor for the cardiovascular Societies therapeutic area at Gilead Sciences Inc. … BeiGene Ltd. announces The Infectious Diseases Society of America’s new CEO Christopher that clinical advisor Eric Hendrick will serve as interim CMO, replac- Busky takes the helm in July, joining from the Heart Rhythm Society ing RuiRong Yuan who is departing the company. Before joining where he was COO and exec VP. He succeeds Mark Leasure, who has BeiGene in June 2015, Hendrick was CMS at Epizyme Inc. been with IDSA for nearly two decades. Gritstone Oncology brings on Karin Jooss as chief scientific of- The International Society for Pharmacoeconomics and Outcomes ficer. She had headed cancer immunotherapies and immunophar- Research (ISPOR) selects Richard Willke as its first CSO. He had been macology at Pfizer … Lumos Pharma Inc. taps two execs from aTyr Pfizer VP, and cluster lead for the outcomes and evidence and the Pharma Inc.: John McKew as CSO and David Weiner as CMO. McKew global health and value divisions. had been aTyr’s VP of research and held earlier posts at the National Center for Advancing Translational Sciences. Weiner had been CMO Consultants there … AnaptysBio Inc.’s new CSO is Matthew Moyle, formerly VP Cynthia Schnedar, until recently director of FDA’s Center for Drug Evalu- of biotherapeutics at Boehringer Ingelheim. ation and Research Office of Compliance, joins Greenleaf Health as -ex thepinksheet.com May 2, 2016 | Pink Sheet | 7 People In The News ecutive VP, regulatory compliance. Other additions at Greenleaf include ate chief counsel for enforcement in the Office of Chief Counsel at Jones Day attorney Laurie Clarke, who will serve as executive VP, medi- the FDA. Peeples-Dyer joined several months earlier, having been ex- cal devices and combination products and Liz Stevulak, as associatw VP, ecutive director, legal and head of corporate compliance at Acorda regulatory compliance. She joins from the Food and Drug Law Institute. Therapeutics Inc.

Law Firms [Editor’s Note: On the first Monday of each month, “The Pink Sheet” McDermott Will & Emery announces two new co-leaders of its FDA chronicles employment changes, professional awards and other news practice: Vernessa Pollard and Veleka Peeples-Dyer. Pollard has just about people in the pharmaceutical industry. Submit announcements joined from law firm Arnold and Porter and had earlier been associ- to [email protected]]

Business & Finance Perrigo’s Papa: Bridge Over Valeant’s Troubled Waters Or Shark Bait? Mandy Jackson [email protected]

aleant Pharmaceuticals International Inc. hired Perrigo Co. PLC’s Chairman and Chief Executive Joseph Papa to replace CEO V Michael Pearson, but will Papa bridge the gaps between Valeant and its shareholders, debtors and the politicians who are demanding information about the company’s drug pricing policies? Or, like Pearson, will he be bitten by the sharks in Valeant’s troubled waters? Pearson was unable to stay afloat as controversy after controversy led to his eventual firing a month ago and the soon-to-be-former CEO landed in more hot water with a US Senate committee as well as Vale- ant’s board of directors, who demanded his appearance at a public hearing on drug pricing issues. But Papa also is no stranger to controversy, since Perrigo’s stock price plummeted in the months after the company rebuffed a buyout offer from Mylan NV.

Perrigo closed at $121.35 per share with a market cap of $16.1bn Gonzalez/Shutterstock.com Leonardo credit: Photo on April 22 – the last business day before Papa’s move to Valeant was announced – trading well below the $26bn value of Mylan’s last offer Prior to Cardinal, however, Papa was president and chief operating to buy the company. The news that Papa was floating over to Vale- officer at Watson Pharma Inc., the predecessor of one of Valeant’s big- ant along with a preview of Perrigo’s first quarter financial results sank gest rivals – Allergan PLC, which was Watson before the acquisition the company’s stock further on April 25, and the share price plunged of Actavis when Watson took on the Actavis name and Irish corporate 18.1% to $99.40, dragging the market cap down to $14.2bn. domicile. That all happened prior to Actavis’s $66bn acquisition of Al- Meanwhile Valeant, which is trading 86.6% below its one-year high lergan Inc. in 2014, which led to the company’s name change to Al- of $262.52 on Aug. 5, fell just 2.3% to close at $35.16 on April 25 fol- lergan PLC in 2015. lowing the announcement that Papa would take over Pearson’s CEO After a thorough CEO search, Valeant Chairman Robert Ingram said role in early May. in a statement from the company that the board of directors “believes that Joe is the ideal leader for Valeant at this time,” since he remained in Pharma Experience To Be Applied At Valeant good stead with shareholders after getting other companies through While Papa comes from a company that’s largely focused on over-the- tough times. counter and generic medicines, he has more than 35 years of experi- Papa said he looks forward to his new role at Valeant, which has ence with health care and pharma businesses. He’s led Perrigo, which “an opportunity to move forward with a renewed focus on operating has $5bn in annual sales, since 2006, but before that he was chairman with integrity.” and CEO of the Pharmaceutical and Technologies Services segment The company has a lot of shareholder and debtor trust to regain af- of Cardinal Health Inc. Papa’s other pharma experience includes ter restating earnings and defaulting on loans in the wake of a special- stints with DuPont Pharmaceuticals Co., Pharmacia Corp., G.D. Searle ty pharma scandal that had Valeant cutting ties with outside pharma- & Co. and Novartis AG. cies with which the company may have had fraudulent relationships.

8 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 Business & Finance

However, Hendrickson apparently has not been a prominent player in Perrigo said that its president, Perrigo’s successes and failures – at least not one that investors have had a lot of contact with – but he’ll be pushed into the spotlight in short order. John Hendrickson, who has been “Mr. Papa’s planned successor, John Hendrickson, is a Perrigo insider with a long track record working in senior management operational with the company since 1989, roles. To date, we have not met or spoken with the new CEO and will take over as CEO. according to investor relations, he’s generally operated behind the scenes,” Gerberry noted.

Papa Reassures Valeant Investors As Perrigo Moving Forward With Renewed Perrigo’s Stock Slides Focus, Discipline Papa’s reassurances about “integrity” in Valeant’s April 25 announce- However, Hendrickson said in Perrigo’s leadership and financial up- ment probably helped keep the company’s stock from falling further date that “we are aware that we need to execute against our goals than it did, but Perrigo’s notice that earnings per share (EPS) would be with a renewed sense of focus and operational discipline,” noting that 15% lower than previously expected is the most likely reason for that more details about the company’s financial status will be revealed company’s double-digit stock slump, since there were several days of along with its first quarter earnings report, which the new Perrigo CEO speculation that Valeant was recruiting the executive before his move will lead on May 12. to the company was officially announced. At that time, the company also will have a better understanding of Perrigo said that its president John Hendrickson, who has been how much its $4.5bn purchase of Omega Pharma NV in March 2015 with the company since 1989, will take over as CEO. That should give will hurt its 2016 earnings. Perrigo’s earnings may be hurt by a valua- some comfort to investors that there will be a smooth transition as tion write-down for the Omega business. Papa departs, despite the revelation that adjusted EPS for 2016 is ex- “Expectations for [Omega] have now been revised downward twice pected in the range of $8.20 to $8.60 versus the company’s estimate since the acquisition, first because of 2015 [foreign exchange] head- in February that EPS for the year would come in between $9.50 and winds and some unfavorable channel dynamics in prior quarters, then $9.80 versus $7.59 in 2015. today on ‘weaker than expected operating results,’ although details “Perrigo’s 2016 guidance revision was mainly attributed to com- have not been provided,” Gerberry wrote on April 25. petitive price pressure to its [prescription] business, which typically Deutsche Bank analyst Gregg Gilbert said in a same-day note that included products playing in limited competition markets with favor- he still had some confidence in Perrigo’s consumer health care busi- able pricing and gross margins (60% to 61% historically versus peers ness, but noted that it will take time to reconcile the expectations for in the mid-to-high 50% range). The company isn’t calling out any spe- slower sales growth among the company’s branded consumer (the cific products, but noted that [Novartis’s] Sandoz Inc. and other play- Omega assets) and generic pharma businesses. ers in the extended topical category have been increasing volume “Recurrent challenges, especially associated with the recently ac- growth by getting more aggressive on price leading to category price quired Omega business, are especially disappointing in light of Perri- deterioration versus the original management forecast,” Leerink ana- go’s decision (led by then-Chairman/CEO Joe Papa) to fend off Mylan’s lyst Jason Gerberry wrote in a note to investors. attempt to acquire Perrigo,” Gilbert wrote.

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ast year was a tumultuous one for the biopharma industry in the public capi- L tal markets, but on the private investment side, most of the indicators of investor interest and confidence in the biotech sector improved. There were both more deals and larger deals, on average, for biotech last year, Christian Plaza, a partner in Cooley LLP, pointed out at the BioHealth Capital Region Forum on April 19. Cooley both invests in and tracks private investment in the life sciences sector, including biotechnology, medtech and health services. And 2015 was a record-setting year for venture capital investment in the life sciences, Plaza told a session on financing trends for private and public health care companies

held at MedImmune LLC’s corporate head- Crockett/Shutterstock.com David credit: Photo quarters in Gaithersburg, Md. Biotech attracted between $7.2bn and $7.3bn of private investment last year, ac- “Capital seems be syncing up with the regulatory counting for 60% of the VC deals in life sciences and between 73%-74% of the dollars pathway, so visibility into how you get products invested, Plaza said. Overall, life sciences approved is certainly helping investors put dollars deals increased 12% from 2014, according to Cooley’s data, and deals were 15% larger on to work,” Plaza said. average. In terms of therapeutic sectors, oncology attracted the most venture investment once proved is certainly helping investors put dol- better but there are still significant disease again, the exec said. Cancer-related deals lars to work,” Plaza said. areas where there is huge unmet need that accounted for between 25%-30% of the VC Reginald Seeto, MedImmune’s VP and still needs to be addressed. That’s why there’s investment in biotech in 2015, compared head of partnering and strategy, told “The such huge interest in oncology.” to infectious disease and central nervous Pink Sheet” that the potential for cures and Asked what companies focused on other system disorders, both of which pulled in for addressing unmet medical needs is driv- therapeutic areas can do to draw similar lev- between 12%-15% of aggregate investment. ing the heady investor interest in oncology. els of capital, Seeto said it still comes down Those spaces were followed by cardiovascu- “I think the field of oncology is going to innovation and “good science.” lar, metabolic and endocrinology disorders, through unprecedented change, particu- “Good science and innovation will always which each accounted for about 5%-7% of larly with the paradigm potentially leading trump,” he said. “So if you have leading inno- VC investment. to cures, specifically combination therapies vation, it doesn’t have to be in oncology. If This presents an interesting finding when with immuno-oncology,” he said. “This con- you have technology or a therapeutic which overlaid against FDA’s 48 new drug approv- tinual evolution of paradigm change con- will be game-changing, then I think that will als in 2015, Plaza pointed out, as oncology tinues to pique the interest of investors [for draw a lot of attention. With orphan diseases, had the most approvals last year, followed therapeutic spaces] where there is still huge there certainly was a lot of attraction for in- by metabolic and endocrinologic diseases. unmet need. For example, if you talk about vestors and, in that case, you have a situation “It’s clearly a sense that the capital seems treating hypertension, there are good anti- where there’s a defined patient class and be syncing up with the regulatory pathway, hypertensive treatments out there today. If good treatment options where previously so visibility into how you get products ap- you talk about treating cancer, we’re doing there weren’t.”

10 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 Business & Finance

The forum was a second annual meeting convened by MedImmune and other Another general positive is that of the funding stakeholders in Maryland, Virginia and Washington, DC, aimed at encouraging the rounds last year, 76% were “up rounds,” development of a biotech cluster in the region that might compete with those found according to Cooley, compared to 60% in 2014. in and around Boston and San Francisco. Seeto said this is important because suc- “That’s really good to see, that investors both in the case of a sale or liquidation of cess breeds success and the Capitol region at least are coming back to some of the ear- the company. Cooley also more “participat- does not pull down its proportional share ly-stage markets and helping companies to ing preferred” deals – those in which the of VC investment dollars, especially when be built, and that’s an area that had been VCs take a pro rata share of whatever cash compared to the talent and brain power underserved for a while,” Plaza said. “There’s is left after all the investors have been reim- consolidated in the area. probably a ways to go.” bursed following a sale or liquidation. Another general positive is that of the Roughly 45% of VC fundings were Early-Stage Investment Up funding rounds last year, 76% were “up tranched in 2015, Plaza said, including ap- Substantially rounds,” according to Cooley, compared to proximately half of Series A rounds, up sig- On a macroeconomic level, Plaza noted 60% in 2014. “So, new investment capital is nificantly from about 30% in 2014. “What that investment in early stage compa- coming in and it’s coming in as higher valu- we’re seeing is larger Series A deals, more nies increased significantly in 2015. There ation,” Plaza noted. complicated Series A deals, more investors were about 450 early-stage venture deals Not all the indicators were bullish, how- are making bets, but they’re also spread- in the life sciences totaling about $5.9bn, ever, as there were signs that investors ing that bet over a longer period of time he said, up 27% from 2014 and reversing a continue to hedge their bets. Cooley saw and making sure that there is de-risking [of trend that had been seen in recent years. an uptick in both tranched financings, in those investments],” he explained. Of that, about $2bn went into first-time which VC funds spread out their investment In 2015, about 45% of the deals Cooley funding, to companies that had not taken over time contingent on milestones being reviewed had “participating preferred” institutional investment previously, which met, and in rounds in which the VCs took positions, up slightly from 2014, and “a was a 67% increase compared with 2014, preferred positions, those in which the VC pretty significant percentage,” according he added. investors got their money back off the top to Plaza.

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Our print content is great, but… #1 INDUSTRY RESOURCE INCLUDES: Our online content is even better! ■ Superior Coverage ■ • The latest industry insight In-depth features • Searchable archived articles ■ Timely, thought provoking commentary • Access to key documents ■ Unsurpassed insight • Links to related articles ■ Cutting-edge intelligence • Animations and streaming video FOR A FREE NO-RISK TRIAL OR TO SUBSCRIBE VISIT: www.PharmaMedtechBI.com Or Call +1-888-670-8900 FOLLOW US ON: (outside the USA: +1-908-547-2200) Subscription options include single-user, multiple-user, and firm-wide pricing. 12 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 deal watch / A look at some of the most noteworthy recent biopharma transactions. AbbVie, arGEN-X To Explore Immuno-Oncology According To GARP “The Pink Sheet” regularly covers business development and deal-mak- AbbVie/arGEN-X ing in the biopharmaceutical industry. Below is a roundup of some of AbbVie announced a collaboration with arGEN-X BV on April 21 the most noteworthy transactions that occurred between April 16-29. to develop and commercialize ARGX-115, a preclinical human an- Deal Watch is supported by deal intelligence provided by Strategic tibody program targeting the novel immuno-oncology target GARP Transactions. (glycoprotein-A repetitions predominant protein), which is believed to contribute to immunosuppressive effects of T-cells. Sanofi/Medivation (No Deal, Yet) It was one of a string of recent deals AbbVie has made to shore up Following weeks of speculation, Sanofiwent public with its hos- its oncology portfolio. As part of its strategy to offset the coming Hu- tile offer for Medivation Inc. Analysts largely agreed that the deal mira patent cliff, AbbVie is looking to oncology as a “significant pillar would make “strategic sense” for Sanofi, but it’s likely other suitors of growth” going forward. The Chicago-area pharma’s only marketed will throw their hats into the ring. Medivation only increased the oncology drug at the time it split from Abbott Laboratories Inc. speculation by publicly rejecting Sanofi’s bid on April 29. was Lupron (leuprolide), a gonadotropin-releasing hormone agonist The offer for Medivation followed CEO Olivier Brandicourt’s re- (GnRH agonist). But AbbVie launched its late entrance into hematol- organization of Sanofi, under which oncology is one of the busi- ogy and immuno-oncology with the $21bn purchase of Pharma- nesses in which he plans to build a competitive position. cyclics Inc. in March 2015. That purchase gave AbbVie a share in Sanofi said it made a non-binding proposal to acquire San Fran- the blockbuster Bruton’s tyrosine kinase (BTK) inhibitor Imbruvica cisco-based Medivation for $52.50 per share, an all-cash transac- (ibrutinib), which has been approved to treat four hematological tion valued at $9.3bn, almost two weeks ago (“Sanofi Goes Public malignancies. With Hostile Medivation Bid” — “The Pink Sheet” DAILY, April 28, 2016). The company now has two oncology compounds in Phase III and It proposes that Medivation would sit within its successful Gen- four in Phase II, according to BioMedTracker, including the hemato- zyme Corp. specialty unit. logical cancer drug candidate venetoclax that is being developed In a public follow-up letter dated April 28 and addressed to Me- in partnership with Roche. Branded Venclexta, the drug earned its divation’s CEO David Hung, Brandicourt said he first called Hung first approval, in a high-risk segment of the chronic lymphocytic leu- about a potential combination of the companies on March 25 kemia population, on April 11 (“Venclexta Out Of The Starting Gate but “you said you were unwilling to meet.” The offer was then sent With Approval In High-Risk CLL Subset” — “The Pink Sheet” DAILY, April on April 15. “We have not heard anything from you in almost two 11, 2016). weeks… We do not understand the delay in responding,” com- In addition to the arGEN-X deal, AbbVie has announced oncol- plained Brandicourt. ogy-related deals with Stemcentryx, CytomX and the University of The $52.50 per share proposed purchase price represents a pre- Chicago this month (see p. 14). mium of over 50% to Medivation’s two-month volume weighted arGEN-X will be responsible for IND-enabling studies of the can- average price (VWAP) prior to there being takeover rumors – but didate, with AbbVie holding an option to acquire the program and just 1% to the closing price on April 27. take over all development. Medivation has one marketed drug, the prostate cancer therapy Tim van Hauwermeiren, CEO of arGEN-X, says the candidate offers Xtandi (enzalutamide), and two additional oncology assets in late- the potential to advance immuno-oncology by selectively targeting stage clinical development. tumor immune escape pathways. Goldman Sachs analysts have forecast Medivation sales of The Dutch biotech will receive an upfront payment of $40m from $1.15bn in 2017, rising to $1.71bn in 2020. They believe the deal AbbVie for the exclusive option to license ARGX-115 and can earn makes “strategic sense” as it strengthens Sanofi’s position in the key near-term preclinical milestones of $20m. The biotech is eligible to US oncology market, and would immediately enhance earnings. receive additional development, regulatory and commercial pay- “Sanofi are likely to need to pay a higher premium if they wish to ments up to $625m upon achievement of predetermined mile- acquire this company,” Exane BNP Paribas analysts suggested. “We stones as well as tiered, up to double-digit royalties on net sales believe other suitors may now step in. Medivation’s partner on lead upon commercialization. drug Xtandi, Astellas Pharma Inc. would be an obvious candidate.” In addition, arGEN-X gets the right to co-promote ARGX- Goldman Sachs analysts note that Astellas had a “standstill” 115-based products in the EU and Swiss Economic Area and com- agreement restricting it from acquiring Medivation, “but according bine the product with its own future immuno-oncology programs. to Astellas this can be broken if there is an unsolicited bid,” which If AbbVie elects not to exercise its option on ARGX-115, arGEN-X now seems to have occurred. AstraZeneca PLC and AbbVie Inc. retains the right to pursue development of the compound alone. also are thought to be in the running as potential bidders. Upon reaching a predetermined preclinical stage milestone, thepinksheet.com May 2, 2016 | Pink Sheet | 13 deal watch

AbbVie will fund further GARP-related research by arGEN-X for an successfully engineering and manufacturing antibodies and anti- initial period of two years. AbbVie will have the right to license addi- body-drug conjugates for those targets.” tional therapeutic programs emerging from this research, for which arGEN-X could receive associated milestone and royalty payments. AbbVie/University of Chicago In a same-day note, WedBush Equity Research analyst David Nie- It’s been a busy couple weeks for AbbVie, which on April 20 an- rengartner called the deal attractive, given the preclinical status of nounced a five-year collaboration with the University of Chicago to ARGX-115, but “representative of clinical potential.” improve the pace of discovery and advance medical research in on- GARP is a transmembrane protein expressed on regulatory T- cology both at the university and at the Chicago-area pharma. cells (Tregs) that regulates the activation of the cytokine active That same day, AbbVie and CytomX Therapeutics Inc. unveiled a transforming growth factor–b1 (TGF-beta1) and can inhibit T-cell partnership to co-develop and co-commercialize Probody drug con- responses, which the analyst sees as “a compelling target for cancer jugates against CD71, also known as transferrin receptor 1 (TfR1). treatment to improve the efficiency of immunotherapy approaches. The research agreement between AbbVie and the University of Chi- Direct targeting of Tregs remains a challenge, however, due to the cago is designed to encourage and strengthen collaboration among lack of specific cell surface antigens,” he added. researchers. Initially, both organizations will work together to advance research in several areas of oncology, which could include, among AbbVie/Stemcentryx others, breast, lung, prostate, colorectal and hematological cancers. AbbVie’s move into oncology will benefit greatly from both the pipeline AbbVie also gains an option for an exclusive license to certain Univer- candidates and the solid tumor R&D engine it will obtain in the $5.8bn sity of Chicago discoveries made under the agreement. purchase of Stemcentrx Inc. announced April 28, CEO Richard Gonza- As part of the agreement, AbbVie will provide funding for the col- lez told investors (“AbbVie Gains Lung Cancer ADC, Solid Tumor Platform laboration that may be used for purposes including preclinical re- With Stemcentrx Buyout” — “The Pink Sheet” DAILY, April 28, 2016). search, clinical trials and possible future programs at the university The firm agreed to pay $2bn in cash and $3.8bn in stock for Stem- resulting from this partnership. centrx, making it one of the highest valuations ever for a venture- backed biotech takeout, along with up to $4bn in regulatory and AbbVie/CytomX clinical development milestones to Stemcentrx shareholders. In Antibody-drug conjugates have taken a back seat to immune check- tandem with the purchase, the pharma announced that it plans to point inhibitors as the hot modality in oncology of late, but AbbVie execute an accelerated share buyback of up to $4bn in AbbVie stock and CytomX are partnering to develop an ADC targeting CD71 that after the sale closes. the latter company is calling a further validation of its Probody tech- Central to the deal is Rova-T (rovalpitizumab tesirine), an antibody- nology platform (“AbbVie Partnership On CD71 Gives CytomX Big Up- drug conjugate being studied in small cell lung cancer that targets front, Co-Promotion Potential” — “The Pink Sheet” DAILY, April 22, 2016). the stem cell protein DLL3 (delta-like protein 3). It is being studied AbbVie is paying $30m up front to co-develop and potentially co- in third-line SCLC, for which there is no approved therapy, and a reg- commercialize a Probody-drug conjugate against CD71, also known istrational trial is expected to complete enrollment by year’s end, as transferrin receptor 1 and highly expressed in a number of solid Gonzalez noted. and hematologic cancers. Longer-term, AbbVie believes Rova-T can earn approval as first- Unlike prior deals around the Probody platform with Pfizer and line therapy in SCLC and might demonstrate utility in a range of Bristol-Myers Squibb Co., CytomX will have greater involvement cancers, including metastatic melanoma, glioblastoma multiforme in this partnership, being responsible for development of the lead and prostate, pancreatic and colorectal cancers. In Phase II data for candidate through the end of Phase I and having the right to either third-line SCLC presented last year at the European Society of Medi- co-commercialize in the US or share US profits (“Bristol Signs Two cal Oncology meeting, the candidate demonstrated an overall re- Cancer Immunotherapy Partners With Eye On Combos” — “The Pink sponse rate of 44% in patients expressing DLL3 who had failed at Sheet” DAILY, May 27, 2014). least one previous therapy, Gonzalez said. DLL3 is expressed in more AbbVie and CytomX are not disclosing the payload under consid- than 80% of SCLC tumors, but not in healthy tissue. eration for the anti-CD71 candidate, which currently is in preclini- In addition to Rova-T, the deal brings AbbVie four additional solid- cal development. The South San Francisco, Calif.-based biotech can tumor candidates in early-stage clinical development as well as a earn up to $470m in development, regulatory and commercial mile- portfolio of preclinical assets, which will help the company build stones under the pact, as well as tiered, double-digit royalties on upon its R&D productivity in hematologic cancer. Pfizer Inc. holds sales occurring outside the US. rights to two of Stemcentrx’s preclinical assets under a prior deal, The pharma also gets the right to select two additional targets on but the biotech’s pipeline is otherwise unencumbered and Pfizer which it can use the Probody platform. During an April 21 investor has no rights to any of the clinical assets, including Rova-T. call, CytomX CEO Sean McCarthy said the $30m upfront payment “Stemcentrx’s proprietary solid-tumor platform leverages cancer also covers the second target, while his firm can earn a further un- stem cell biology to identify and validate novel therapeutic targets,” disclosed sum if AbbVie selects a third target for collaborative work. Gonzalez noted. “The company has demonstrated a track record of In an April 21 note, Jefferies analyst Biren Amin called the deal

14 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 deal watch

“additional evidence of platform validation” for CytomX. He pointed liver cancer and liver failure. It may affect up to approximately 15 mil- out that the company’s preclinical data at AACR showed efficacy in lion-20 million people worldwide and is reported to be present in ap- shrinking tumor volume in mice in several types of cancer, including proximately 4.3% to 5.7% of chronic HBV carriers. lung, pancreatic and endometrial cancers as well as non-Hodgkin lymphoma. Vertex/Enterome “CD71 was also shown to be highly expressed in many types of Vertex Pharmaceuticals Inc. licensed Enterome Bioscience SA ex- metastatic cancers,” Amin wrote. “The highest expressors were rectal, clusive worldwide rights on April 16 to develop and commercialize cadia, cervical and skin cancers. A comparison of side effects was small-molecule FimH antagonists for treating inflammatory bowel done in cynomolgus monkeys and demonstrated that a CD71 PDC diseases (IBD) including Crohn’s. No financial terms of the deal were was well-tolerated and had less toxicity than a CD71 ADC, which disclosed. caused life-threatening hematological toxicity.” Paris-based Enterome plans to move the lead FimH antagonist, McCarthy also said AbbVie was an ideal partner because of its EB8018, into the clinic sometime this year, in additional to develop- experience in the ADC space. Its predecessor Abbott Laboratories ing a companion diagnostic (IBD210) to determine populations that Inc. partnered with ADC pioneer Seattle Genetics Inc. in 2011, a would benefit from EB8018’s use. deal that has been expanded three times since to add targets and Through its metagenomics research, Enterome has discovered that technological modalities. adherent-invasive Escherichia coli (AIEC) can trigger inflammation in AbbVie’s pipeline lists currently includes five ADC candidates in IBD by adhering to gut epithelial cells using FimH adhesion proteins on clinical development, led by ABT-414, which is in Phase II for malig- the cell surface. Therefore, inhibiting FimH blocks AIEC from adhering nant brain tumors and Phase I/II for solid tumors. Other ADCs under and proliferating in the gut, offering potential as a treatment for IBD. development, in Phase I, include ABBV-399 for solid tumors, ABBV- 085 for advanced solid tumors, ABBV-838 for multiple myeloma, and Ironwood/AstraZeneca ABBV-221, which the company says is being developed for several Ironwood Pharmaceuticals Inc. has been looking to acquire an types of solid tumors. on-market or market-ready product to pair commercially with its gastrointestinal drug Linzess, and it thinks it hit that target at very Bristol-Myers Squibb/Eiger reasonable terms in acquiring the unlaunched gout drug Zurampic Eiger BioPharmaceuticals Inc. in-licensed the pegylated interferon (lesinurad) from AstraZeneca. lambda-1a April 20 for study as an investigational therapy for hepa- In a deal announced April 26, the Cambridge, Mass.-based com- titis delta virus (HDV) infection, from Bristol. The transaction involved pany said Zurampic, approved by FDA Dec. 22 but not yet launched, an undisclosed upfront payment and the issuance of Eiger common offers the chance to target many of the same primary care physi- stock to Bristol and includes development and regulatory milestones cians now being contacted for Linzess (linaclotide) and will leverage through first commercial sale in the US, EU and Japan as well as mile- its existing commercial operation without great additional expense stone payments based on commercial sales achievement and tiered (“Ironwood Buys AstraZeneca’s Zurampic As Ideal Linzess Complement” annual net sales royalties. — “The Pink Sheet” DAILY, April 26, 2016). AstraZeneca had held off on The candidate, a novel, well-characterized, first-in-class type III in- launching the drug, which doesn’t fit into its core areas and doesn’t terferon, has been administered in clinical trials involving over 3,000 have the ideal profile, as it considered prospects for “externalization” subjects. Eiger plans to evaluate Lambda as a potential monotherapy (“AstraZeneca’s Hudson Optimistic On Return To Growth In 2017” — and combination treatment for chronic HDV infection, the most ag- “The Pink Sheet,” Jan. 25, 2016). gressive and deadly form of human viral hepatitis. Ironwood plans to launch Zurampic, the first inhibitor of uric acid Eiger CEO David Cory said Lambda, along with Sarasar (lonafarnib), transporter URAT1 approved for gout, around the midpoint of the an oral farnesyl transferase inhibitor in Phase II for the treatment of second half of this year, CEO Peter Hecht said during a same-day in- HDV, gives his company “a strategic position” in the space. The Palo vestor call, and looks forward to the anticipated late 2016 filing and Alto, CA-based firm plans to test Lambda as both a solo therapy and 2018 approval of a fixed-dose combination of lesinurad and another in combination with other agents. gout drug, allopurinol, that will be transferred over by AstraZeneca While most human cells express the receptor for interferon alfa, a under the agreement. type I interferon, the company notes, receptors for type III interferon The deal divests AstraZeneca of the key asset from its 2012 are expressed on liver cells, an ideal location for treating viral hepatitis. $1.26bn buyout of Ardea Biosciences Inc., although the pharma Lambda could yield a “promising and potentially better tolerated in- retains rights to other pipeline assets it acquired in that transaction terferon therapy for HDV,” Eiger Senior VP-Liver and Infectious Diseases (“AstraZeneca’s Ardea Acquisition: A Rich Deal Spurred By Phase III Gout Eduardo Martins said. Candidate” — “The Pink Sheet” DAILY, April 23, 2012). Ironwood, how- HDV is considered one of the most severe forms of viral hepatitis ever, does get an option on a follow-on gout compound discovered in humans and occurs only as a co-infection in individuals harboring by Ardea, RDEA3170, in Phase II. hepatitis B virus (HBV), Eiger said. HDV leads to more severe liver dis- Ironwood will pay $100m up front for US rights to all products ease than HBV alone and is associated with accelerated liver fibrosis, containing lesinurad, along with up to $165m in milestones, which thepinksheet.com May 2, 2016 | Pink Sheet | 15 deal watch

Hecht said are largely contingent upon commercial success. Astra- very strongly. They’ve been quite public about it toward immuno- Zeneca will also get single-digit sales royalties on product sales un- oncology and their three core strategic areas. And primary care isn’t der the deal. The pharma will manufacture and supply Zurampic to one, [so] this is an outside of the core area.” Ironwood, provide undisclosed product support services and retain Ironwood cited market estimates that about 4 million Americans responsibility for a postmarketing study of the drug for renal and are being treated for gout with xanthine oxidase inhibitors, and that cardiovascular safety that is due by 2025. roughly half of those have uncontrolled disease. This leaves a market Asked on the call why AstraZeneca would divest a recently ap- opportunity for Zurampic of about 2 million patients who are highly proved asset for which it paid a premium price just four years ago, motivated to alter their treatment to reduce suffering and doctors Hecht asserted the pharma’s decision was more about strategic who are very open to the potential added benefits of Zurampic’s focus on immuno-oncology than on getting rid of a drug with a mechanism of action. Zurampic is indicated for second-line, com- questionable safety profile (“AstraZeneca’s Gout Drug Zurampic Clears bination therapy with an XOI agent (generic allopurinol or Takeda FDA; Renal, CV Safety Trial Required” — “The Pink Sheet,” Jan. 4, 2016). Pharmaceutical Co. Ltd.’s Uloric (febuxostat) in patients with hyper- “The development program was very strong,” he told the call. “The uricemia associated with uncontrolled gout who have not achieved regulatory package was very strong. They did a fabulous job negoti- target serum uric acid levels with XOI monotherapy. ating what I think is really a quite good label that effectively captures the benefit and the risk in the product well. And ... they prepared a Joseph Haas [email protected] terrific launch package in every level, from marketing materials to Lisa LaMotta [email protected] medical affairs. I think at the strategic level, AstraZeneca is moving Sukaina Virji [email protected]

DRUGS I BIOLOGICS I DEVICES

16 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 International India’s Patent Policy Needs More Stakeholder Input, US Trade Office Urges Brenda Sandburg [email protected]

he rift between India and US drug issues – the use of compulsory licenses which does not result in the enhancement makers deepened as the United to override patents. The US-India Business of the known efficacy of that substance” is T States Trade Representative once Council submitted a statement to the USTR not an invention. In 2013, India’s Supreme again rebuked India for patent policies that suggesting that the Indian government had Court denied Novartis AG’s efforts to ob- make it difficult for biopharmaceutical com- “privately reassured” western drug industry tain patent protection for an updated ver- panies to obtain and enforce patents in the officials that it would not award licenses to sion of its cancer drug Gleevec (imatinib) country. USTR urged the government to al- local generic companies to make cheaper on the grounds it did not satisfy the test of low “interested parties” to provide more in- copies of patented drugs (“Public Commit- novelty or inventiveness. put on its forthcoming National IPR Policy. ment, Not Reassurances, Needed On Indian IP: The USTR notes that government experts The USTR detailed its criticisms of India in Industry” — PharmAsia News, March 11, 2016). released the first draft of India’s National IPR its 2016 Special 301 Report, released on April But the Indian government denied that it policy for public comment in December 27. The annual report places US trading part- had provided such assurances (“India Compul- 2014 and that the official version is near- ners deemed to provide inadequate protec- sory Licensing: What USTR Hearing Transcripts ing release. It says the US is continuing to tion of IP rights, or to deny fair and equitable Say” — PharmAsia News, April 27, 2016). urge India to allow stakeholders “to review market access, on a “Priority Watch List” or The Pharmaceutical Research and Manu- and provide comments that would help “Watch List.” India was among 11 countries facturers of America praised the USTR’s deci- strengthen the document and provide clar- placed on the priority list, which includes sion to keep India on the Priority Watch List. ity to assist the implementing authorities trading partners that are considered to pres- “While biopharmaceutical innovators saw to effect substantive changes in India’s IPR ent the most significant concerns and will be potentially positive signs from the Indian regime.” the subject of particularly intense bilateral government in 2015, translating these posi- Médecins Sans Frontières/Doctors With- engagement in the next year. There are 23 tive statements into concrete progress has out Borders objected to India’s continued countries on the Watch List (see map, p.18). remained a challenge,” the association said in inclusion on the Priority Watch List. It said The report marks a sharp divide between a statement. India’s policies promote generic competition foreign countries and non-governmental and limit abusive pharmaceutical industry organizations who contend that the report Rejected Patents, Localized practices, including patent “evergreening.” process is dictated by US industries and im- Manufacturing “India’s policies save lives and are fully pedes access to affordable medicines, and Most of the countries on the lists held the consistent with global trade rules,” Judit Rius industry groups who claim policies in over- same status in previous reports. With regard Sanjuan, MSF’s US Manger and Legal Policy seas markets are undermining their IP rights to market access for pharmaceutical com- Adviser, said in a statement. “The US govern- and harming innovation. panies, the report reiterates concerns about: ment should support countries, rather than In an April 25 statement, India’s Ministry taxes or tariffs imposed on imported medi- penalize them, for not bowing to the per- of Commerce & Industry said the Special cines; delays in obtaining regulatory approv- sistent efforts of the multinational pharma- 301 Report “is a unilateral measure to create al; non-transparent pricing and reimburse- ceutical industry to severely restrict generic pressure on countries to enhance IPR protec- ment policies; and disclosure of test data. competition in India and worldwide.” tion” beyond the World Trade Organization’s The USTR devotes nine pages of its 69- The USTR highlights practices in other Trade-Related Aspects of Intellectual Prop- page report to India. It says India’s proposed countries, which it says are affecting market erty Rights, a treaty that provides minimum Patent Rule Amendments would provide access for biopharmaceutical companies: levels of protection that each government new incentives to pressure patent applicants • China’s Work Plan for the Reform of Chemi- has to give to other WTO members. to localize manufacturing in India and re- cal Drug Registration Categories, which “The government is committed to fully uti- quire the submission of sensitive business in- went into effect on March 4, limits the lizing all the flexibilities provided under the formation to India’s Patent Office. It says that definition of “new drugs” to those for which TRIPS agreement to protect [the] domestic India has rejected many patents that were marketing approval is first sought in China; pharmaceutical sector from pressure exerted granted in many other jurisdictions, includ- • Indonesia requires foreign companies to by the foreign countries,” the Ministry said. ing the United States. transfer technology to Indonesian enti- Before the report was released it seemed The report also criticizes India’s Patents ties or to partially manufacturer pharma- that the Indian government had shifted its Act, which specifies that “the mere discov- ceuticals in Indonesia as a condition for position on one of the most contentious ery of a new form of a known substance obtaining marketing approval; thepinksheet.com May 2, 2016 | Pink Sheet | 17 International

• Algeria bans importation of more than PhRMA has advocated moving Canada In 2013, Eli Lilly & Co. filed a complaint 350 pharmaceutical products and medi- to the priority list (“U.S. Patent Protection against the Canadian government claiming cal devices in favor of local products; and Watch List Doesn’t Match PhRMA’s Wish List” this policy is a breach of IP protection provided • Turkey’s pharmaceutical manufacturing — “The Pink Sheet” DAILY, April 30, 2014). It under the North American Free Trade Agree- inspection process is criticized for lack of said the Canadian judiciary has invalidated ment. It is seeking $500m for lost revenue efficiency, transparency and fairness. patents on 25 medicines and “upended a from Canadian court rulings that invalidated practical and proven process used to bring its Zyprexa (olanzapine) and Straterra (atomox- PhRMA Criticizes Canada new medicines to market in countries etine) patents on the grounds that the drugs And Columbia around the world.” are not useful (“O Canada! Lilly Claims Country’s It its release on the report, PhRMA specifi- The report expresses concern about the Invalidation Of Its Patents Violates NAFTA” — cally criticizes the IP policies of Canada and availability of rights of appeal in Canada’s “The Pink Sheet” DAILY, Sep. 19, 2013). Columbia, both of which remain on the administrative process for reviewing drug As for Columbia, PhRMA said it has con- Watch List. The USTR also put Columbia on approvals and the breadth of the Minister sistently failed to fully implement its IP com- an “Out-of-Cycle Review,” which indicates of Health’s discretion in disclosing confiden- mitments under the U.S.-Columbia Free the agency is seeking to remedy issues tial business information. It also cites the Trade Agreement. And it says a new National through heightened engagement with the heightened utility requirements for patents Development Plan is delaying review of bio- country and stakeholders. imposed by Canadian courts. pharmaceutical patents.

Countries On USTR Watch Lists The United States Trade Representative’s 2016 Special 301 Report places 11 countries on its “Priority Watch List” and 23 countries on its “Watch List” for providing inadequate protection of intellectual property rights to US trading partners. Trading partners on the Priority Watch List are deemed to present the most signi cant concerns and will be the subject of particularly intense bilateral engagement in the next year.

I Watch List I Priority Watch List

Watch List Priority Barbados Watch List Bolivia Jamaica Algeria Brazil Lebanon Argentina Bulgaria Mexico Chile Canada Pakistan China Colombia Peru India Costa Rica Romania Indonesia Dominican Republic Switzerland Kuwait Ecuador Turkey Russia Egypt Turkmenistan Thailand Greece Uzbekistan Ukraine Guatemala Vietnam Venezuela

Source: USTR’s Special 301 Report

18 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 Regulatory Update EMA, FDA Get Together On Drugs Eligible For PRIME And Breakthrough Designation Vibha Sharma [email protected]

he European Medicines Agency and PRIME is a relatively new scheme and is which includes national drug regulatory au- the US Food and Drug Administra- one of several topics that will be discussed thorities from the EU member states – “have Ttion are looking at ways to exchange at a conference on “Accelerated Develop- enough resources” to manage the scheme. notes on drugs that become eligible for their ment and Access to Innovative Medicines In fact, EFPIA wants the EMA to further respective schemes on speeding access for Patients” being jointly organized by the expand the scope of PRIME by allowing to new innovative medicines, that is, Prior- UK’s BioIndustry Association (BIA) and the all companies – independent of their ity Medicines (PRIME) in the EU and break- UK’s Medicines and Healthcare products size – to apply for PRIME eligibility at the through therapy designation in the US. Regulatory Agency (MHRA) on May 4 in proof-of-principle stage, just before ex- The exercise involves considering how to London. Jordi Llinares García, the EMA offi- ploratory trials. At present, only SMEs and facilitate parallel discussion on medicines cial who heads the department responsible academics can apply for PRIME eligibility admitted under PRIME and those that re- for developing PRIME, will give conference at proof-of-principle stage, whereas larg- ceive breakthrough therapy designation to attendees more details about how the er companies have to wait until the proof- support the development of specific prod- scheme is faring. of-concept stage (“PRIME Time: Smaller ucts, an EMA spokesperson said. Within the first month of PRIME’s launch, Companies In Focus As EMA Launches Prior- The initiative is being conducted within the EMA had received 18 applications ity Medicines Scheme” — “The Pink Sheet” the remit of existing confidentiality agree- under the scheme and this number is ex- DAILY, March 7, 2016). ments between the two agencies. pected to grow with each passing month By contrast, BIA – whose members in- However, as no details are available as (“EMA’s New PRIME Scheme Gets 18 Applica- clude start-up, emerging and more estab- to how this information exchange will take tions In First Month” — “The Pink Sheet” DAILY, lished bioscience companies, pharmaceuti- place between EMA and the FDA, the Eu- April 7, 2016). EFPIA believes that “PRIME has cal companies as well as academic, research ropean Federation of Pharmaceutical In- got off to an excellent start”, while BIA said and philanthropic organizations – seems dustries and Associations (EFPIA) said: “It is the high number of submissions vindicates content with PRIME’s early entry advantage difficult for us to express any opinion at this the industry’s need for such a scheme. for SMEs and academics. stage as to whether, or to what extent, it BIA added that it had seen a “real interest” By applying for PRIME at the proof-of- would benefit companies.” among its member companies, who are ea- principle stage, “SMEs would be able to While the EU and the US schemes have ger to engage with the scheme. benefit from earlier scientific and regula- a different legal basis, they both share the Given the significant interest from com- tory advice and better plan their medicine same objective of ensuring timely patient panies to participate in PRIME, it remains to development programme and generate access to innovative medicines. Hence, it be seen whether the EMA has enough re- good quality data in support of marketing is expected that most medicines that are sources to efficiently manage the scheme in authorisation applications,” BIA said. eligible for PRIME should also be eligible the long run. In the US, the popularity of the For academics, BIA said it supports mea- for breakthrough therapy designation and breakthrough therapy designation program sures that would encourage them to form vice-versa, the EMA and EFPIA explained. is already straining FDA employees and re- businesses. “Thinking through business The EMA said it could not share details sources (“Breakthrough Pace Shows No Signs planning for innovative science should en- of whether any drug application has been Of Slowing” — “The Pink Sheet,” Feb. 22, 2016). courage greater translation of the science submitted for both PRIME and break- At the BIA-MHRA conference, Amgen base into products for patients,” it said. through therapy designation. It said it Inc.’s Rhian Thomas will discuss industry’s In addition, EFPIA believes that drug would publish a list of all active substanc- experience with the US scheme through a sponsors could further benefit from PRIME es that are accepted for PRIME after each case study involving the FDA’s approval of if the EMA were to: open the scheme for meeting of its human medicines evaluation Blincyto (blinatumomab) to treat a rare form new indications, formulations, etc; increase committee (CHMP), starting May 2016. Fair- of acute lymphoblastic leukemia. The drug the level of flexibility in scientific advice; and ly detailed information on drugs approved was granted breakthrough designation in generate a stronger link between PRIME under the breakthrough therapy designa- July 2014 – as well as priority review and and the involvement of health technology tion program, instituted in 2012, is available orphan product designation – and was ap- assessment bodies. (see the ‘Breakthrough Therapy’ Designations proved by FDA in December 2014. In addition to the EU and the US, Japa- interactive table on Pink Sheet’s online FDA With respect to PRIME, EFPIA believes nese regulatory agency PMDA has also Performance Tracker). that the EMA and its scientific network – launched its version of a scheme to im- thepinksheet.com May 2, 2016 | Pink Sheet | 19 Regulatory Update prove patient access to innovative drugs, National Health Service. The BIA hopes that cine (PIM) designation and an EAMS called Sakigake (“INSIGHT: Understanding there will be effective recommendations for scientific opinion, from April 1. Japan’s New ‘Sakigake’ Process” — PharmAsia EAMS-type schemes in the wider context of • Aligned with other EU regulatory initia- News, April 20, 2015). The table below com- the AAR. tives such as PRIME. pares the three schemes. For EAMS-type schemes to have maxi- • Developed into a “gold standard” for the mum beneficial effect, the BIA said they rest of Europe with various UK organiza- Accelerated Development need to be globally competitive and capable tions – such as the MHRA, NICE and the In UK of bettering alternative offerings available NHS – helping to effectively drive and set The BIA-MHRA conference will also provide to life science companies, such as schemes standards for data collection. an update on the UK’s Early Access to Medi- in France, Germany and in other markets. At the conference, MSD’s executive di- cines Scheme (EAMS), which was launched To that end, the BIA said it has argued that rector for regulatory affairs, Joanna Mait- in April 2014 with the aim of giving patients EAMS should be: land Smith, will share industry’s experience access to promising new drugs that are not • Reimbursed, particularly to support with EAMS through a case study involving yet licensed. The BIA welcomed the fact SMEs to cover the costs of supplying Keytruda (pembrolizumab) for advanced that a number of medicines have now been drugs during an extended EAMS period. melanoma, which was the first medicine to made available to patients under the EAMS. The BIA is currently awaiting recommen- be made available to patients through the Also, updates will be provided on the UK dations from the AAR to see whether scheme. government’s accelerated access review its demand for reimbursement is taken (AAR) project that is expected soon to issue a up by concerned authorities. Earlier, the [Editor’s note: This story is also published range of recommendations to support faster BIA had welcomed fee reductions intro- in Scrip Regulatory Affairs. “The Pink Sheet” development of, and access to, new drugs duced by the MHRA, including for appli- brings selected complementary coverage and medical devices for patients under the cations for promising innovative medi- from sister publications to our subscribers.]

Comparison of EU, US And Japanese Initiatives For Speedier Review Of Innovative Medicines Breakthrough therapy PRIME (EU) designation (US) Sakigake (Japan) Qualifying criteria Demonstrate potential to address to Treat a serious or life-threatening Products that are innovative treatments, and eligibility significant extent unmet medical need disease or condition and provide have prominent effectiveness in treat- for maintaining and improving health; preliminary clinical evidence indicating ing the targeted disease, applicant is potential to bring a major therapeutic a potential for substantial improvement willing to carry out early development advantage to patients through a mean- over existing therapies on one or more and submit the authorization appli- ingful improvement of efficacy clinically significant endpoints cation in Japan and target a serious disease with a significant effect on life Engagement with Intensive guidance, including early Increased communication and guidance Prioritizing consultation with shortened regulators and ongoing scientific advice on the from the FDA during development waiting times for clinical trial consulta- development plan, with involvement of and review; cross-disciplinary project tion; substantial pre-application consul- multiple stakeholders; early appoint- lead assigned to the FDA review team; tation; assignment of a PMDA manager ment of CHMP/CAT rapporteur; initial increased involvement of senior manag- as a concierge kick-off meeting ers and experienced review staff Submission efficiencies Scientific advice on key decision points/ Submission of portions of an applica- Likely prioritized review issues for the preparation of marketing tion (rolling review) authorization application Regulatory response 40 days from the start of procedure Within 60 calendar days of receiving Application period time to request request Review timeline If confirmation of eligibility for acceler- Could be eligible for priority review (i.e., Six months from submission to ap- implications ated assessment, then 150 days eight months) if supported by clinical proval (versus the 12-month target for data at the time of submission. To standard product reviews) date, all approvals with breakthrough therapy designation have received priority review Source: EFPIA

20 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 Regulatory Update Putting the Patient in Labeling (And Drug Approval Decisions) in ODE 1 Cole Werble [email protected]

ne of the signs that FDA’s recent “patient-focused” initiative may be having a long-term impact on the agency’s drug re- Oview operations is the extent to which the leadership of the drug review operations accepts and applies the principle that patient input should be a key factor in approval decisions. From that perspective, recent comments from Office of Drug Evalu- ation 1 Director Ellis Unger at a meeting of the Psychopharmacologic Drugs Advisory Committee are illuminating as a marker of progress. The March 29 meeting of that committee was called to review Aca- dia Pharmaceuticals Inc.’s Nuplazid (pimavanserin) for treatment of psychosis related to Parkinson’s Disease. The session went well for the sponsor (three strong votes for approval) and provided an opportunity for public discussion of long-term safety concerns regarding use of the product by the primary FDA reviewer on the application (“Nuplazid’s Dean Andy Photography/Shutterstock.com credit: Photo Black Box: Warning May Depend On Antipsychotic Classification” — “The Two of the temporary advisory committee members, John Duda, Pink Sheet,” April 4, 2016). The product was approved a month later (see University of Pennsylvania, and Stanley Fahn, Columbia University, Keeping Track, online at ThePinkSheet.com) responded to Unger by noting that other antipsychotics (both men- After a short and non-contentious pre-vote discussion, the commit- tioned quetiapine) are typically titrated carefully and can be reduced tee rapidly endorsed the drug for efficacy, safety and risk-benefit. The or discontinued if they are not working. relative lack of discussion by the committee led Unger to take the mi- Helpful perspective, but not exactly what Unger seemed to be crophone to try to elicit further comments on ways to incorporate the seeking. He wanted to know whether there was some way that patient experience into the assessment of the drug. making sure that the patient’s reaction to taking the drug could be “One of the places that I had hoped someone would go” during the built into the planned use for the product (in this case its labeling) committee discussion, Unger said, “is whether the individual patient can and how that might change the premarket risk-benefit assessment. figure out whether they are deriving benefit from the drug they are taking.” That’s a striking attempt to build future patient response into the He noted that there are drugs where the patient has to take the phy- premarket review for the product. sician’s word that there is a benefit: “sometimes you put a stent in some- It is all the more striking because ODE 1 is not one of the FDA body’s coronary artery and you say ‘take this anti-platelet drug for the review areas that would seem immediately oriented toward patient rest of your life, good luck.’ The patient just takes it and is subjected to responses. Center for Drug Evaluation & Research Deputy Director whatever the risk is.” For the anti-psychosis indication, however, Unger for Clinical Science Bob Temple has been the driving intellectual seemed very interested in the patient’s ability to assess the success of force within ODE 1 (if not all of the drug review divisions) for more the drug in cutting hallucinations and illusions. than four decades. The ODE I director wanted to know “whether an individual patient Temple has been skeptical of the value of patient assessments for who has psychosis associated with Parkinson’s can take the drug and many of the review decisions faced in ODE 1. He has asked, for ex- figure out if they are feeling better; that they are having fewer hallucina- ample, how patient responses could help balance the risks from QT tions, less problems, and continue the drug. Whereas the person who prolongation to the benefits against angina from use of a calcium is not really feeling any better would know … that they could stop the channel blocker. His point has been that a patient’s assessment of drug. That really enhances the benefit-risk relationship of the drug.” his/her response in that case does not add much to the decision Unger noted that being able to advise about when to continue and FDA has to make. when to stop a drug in labeling is one way to address safety concerns. Unger’s March 29 comments may indicate that skepticism is begin- “That is something that we sometimes put in the label: reassess how ning to change. The Nuplazid approval decision is coming up soon -- well you think the patient is doing and reassess the need for the drug. by the beginning of May. A small detail in how the label treats patient Maybe that could help mitigate some of the concerns around the room self-assessment may mark a big step by ODE 1. about the safety.” Unger suggested that ongoing reassessment for this drug could [Editor’s note: This article also is published in The RPM Report. “The Pink rest directly on the patient’s own experience – supplemented by Sheet” brings selected complementary coverage from affiliated publica- caregivers and treating physicians. tions to our subscribers.] thepinksheet.com May 2, 2016 | Pink Sheet | 21 regulatory Pink Sheet update & Scrip Marketing SolutionS

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Pink Sheet SScricrip Pharma intelligence | Pharma intelligence | 22 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 Manufacturing FDA Making A Generic Case For Continuous Manufacturing

Derrick Gingery [email protected]

DA is hoping a standardized continu- fice of Pharmaceutical Quality, said in an could be more easily changed to make dif- ous manufacturing platform will entice interview with “The Pink Sheet” that FDA ferent drugs. Fthe generic industry to embrace the is hoping the continuous manufacturing “If this happens in 10 or 20 years, that new technology. process becomes standardized in the com- whole industry will truly be revolutionized,” Brand companies now are becoming in- ing years, which should help remove the Yu said. “Generic firms actually benefit tre- terested in the process that aims to replace cost barrier for generic companies. mendously more than the innovator be- the conventional batch manufacturing “In the future if we have a battery of plat- cause they have so many products.” system. A continuous manufacturing op- form technology in place and the generic Continuous manufacturing moved to eration does not have scale-up issues like industry probably just adopts one and the forefront of conversation again in April batch processing and can be more efficient takes it and uses it for their own benefit,” he when the agency announced that it had ap- and reliable. said. “If this happens, the cost will be signifi- proved its second application for a continu- But it also requires a significant up-front cantly lower.” ous manufacturing operation. And while investment to retool a manufacturing Yu said a platform system would allow Janssen Products LP’s HIV-1 treatment operation, which may be out of reach of continuous manufacturing systems to Prezista (darunavir) doesn’t get the distinc- many generic operations that have narrow work similar to automobile manufacturing. tion of the first product ever produced un- profit margins. He said it could function “like a plug-and- der continuous manufacturing, it is the first Lawrence Yu, deputy director of the Cen- play instead of from scratch.” Rather than time FDA had approved a change from a ter for Drug Evaluation and Research’s Of- starting over for each product run, parts batch process to a continuous process – in many ways a more important milestone as the agency encourages industry to transi- Batch Manufacturing tion to the new approach. FDA’s first-ever approval for a continuous manufacturing operation came in July 2015, Raw Material when the agency approved Vertex Phar- maceuticals Inc.’s cystic fibrosis product Orkambi (lumicaftor/ivacaftor) (“Vertex’s Ork- ambi Approved With Broad Label For Cystic Fi- brosis” — “The Pink Sheet” DAILY, July 2, 2015). A number of brand companies now are interested in continuous processes, includ- Product ing Pfizer Inc., Merck & Co. Inc., Eli Lilly & t = 0 t = 2 hours t = 4 hours Co. and others. And thanks to research and development efforts, the technology is be- Continuous Manufacturing ginning to mature. But several officials have said the indus- Raw Material Raw Material Raw Material try has not rushed to embrace the process, despite the potential savings in time and money that it promises (“Industry Proponents Make the Case for Continuous Manufactur- ing” — “The Gold Sheet,” April 2015).

Early Stages Of Generic Product Product Product Adoption t = 0 t = 2 hours t = 4 hours Generic companies may have a much tougher time justifying the investment, but A simple depiction of two types of manufacturing. Batch manufacturing: the material(s) is charged before continuous manufacturing could answer a the start of processing and the product is discharged at the end of processing. Continuous manufacturing: number of quality questions the generic in- material(s) and the product are simultaneously charged and discharged from the process, respectively dustry has been asked in recent years. Source: FDA FDA officials have consistently demanded

thepinksheet.com May 2, 2016 | Pink Sheet | 23 Manufacturing the generic industry improve its manufactur- that the trade association supports the on- needs of the pharmaceutical sector.” ing operations and increased facility inspec- going dialogue on “potential new technolo- Yu’s vision for broad platform develop- tions, particularly those outside the US, as gies in the pharmaceutical manufacturing ment likely will not be realized until many part of the generic drug user fee program industries,” but added that their value for the more brand companies successfully under- (“FDA Inspections Ombudsman Could Help industry requires more discussion. stand and refine the technology. Foreign Manufacturers” — “The Pink Sheet,” “The risk-benefit of implementation of Indeed, FDA is hoping that its break- March 14, 2016). these technologies, net value to product through therapies program, which included The agency has met with the Generic Phar- quality and other considerations will merit Orkambi, can push more companies to in- maceutical Association about continuous ongoing stakeholder discussions,” Gaugh stall continuous manufacturing operations. manufacturing on a couple occasions, but as said. “We fully support looking for technolog- Breakthrough designees have to consider of now the idea remains in its early stages. ical advances that will help assure the quality the risk-benefit analysis related to manufac- GPhA Senior VP for Sciences and Regulato- of pharmaceuticals and determining those turing rather than consider meeting a set of ry Affairs David Gaugh told “The Pink Sheet” technologies that can be adopted to fit the minimum standards. Sponsors also have to

Example Of Traditional Tablet Manufacturing Process

Blending Wet Granulation Drying Milling Blending Compression Coating

• Product collected after each unit operation • Finished product is tested at o -line laboratories, after processing is complete Finished • Actual processing time = days to weeks Product

Conceptual Example Of Continuous Manufacturing Receiving Continuous Compression Continuous Blending Film Coating

Continuous Blending Continuous Granulation Finished • Product ows between each unit operation • Process is adjusted based upon in-process measurements Product • Product is monitored during processing • Actual processing time = minutes to hours

Source: FDA

24 | Pink Sheet | May 2, 2016 © Informa UK Ltd 2016 Manufacturing make manufacturing decisions much earlier are applied consistently in development than when using the tra- and transparently when FDA’s Emerging Technology Team ditional approval pathway (“Breakthrough such an application has been leading the charge to Designation Can Be ‘Lever’ For Manufactur- comes to the agency. ing Evolution, FDA Says” — “The Pink Sheet” The team is led by help sponsors embrace continuous DAILY, April 12, 2016). Sau Lee, the Office of Pharmaceutical Qual- manufacturing and help agency Agency Still Learning As It ity’s associate director staff regulate it. Advices for science, who told FDA also is learning about continuous man- “The Pink Sheet” that More Research Projects ufacturing processes, even as it pushes for its the group can look at a number of similar ap- Coming adoption. plications for the same technology to ensure Research into continuous manufacturing Yu said there is an internal policy in place for consistency in policy application. also continues in the hopes of bringing the evaluation and approval of continuous manu- FDA officials also encourage sponsor process into commercial production. facturing operations. Guidance also is expect- questions before a continuous manufactur- FDA has been working with NIH, the ed to be released very soon, he said. ing application arrives. Yu said in many cases Biomedical Advanced Research and De- Yu said that because moving to the new those advance meetings help prevent “com- velopment Authority on research projects, process is “a huge paradigm shift” FDA also plete responses” because FDA can commu- and awarded continuous manufacturing needed new regulatory standards. nicate its expectations to the sponsor as the research contracts to several universities in Continuous operations no longer have firm is still developing its systems. 2015 (“FDA Contracts in Brief” — “The Gold batches to release, which means no more ex- Yu also said agency officials also could Sheet,” November 2015). tended waiting periods before product can be take a site visit to a continuous manufactur- BARDA is working with FDA on using shipped. Quality results in a continuous manu- ing facility to “have a good understanding continuous manufacturing potentially to facturing operation can be gained in seconds. when the application is submitted,” he said. produce medical countermeasures (“FDA Yu said FDA had to determine how to adjust, FDA uses a similar tactic with biosimilar Procurements in Brief: Funding for Continu- including determining how to measure batch- sponsors. The biosimilar product develop- ous Manufacturing, Quality Metrics, ICH and es when product is being produced constantly. ment system was created to allow sponsors More” — “The Gold Sheet,” June 2015). “We cannot continue to use the practice ap- the opportunity to communicate with FDA The House-passed 21st Century Cures plied for batch processing equally applied to before sending their marketing application. legislation also included funding for con- continuous manufacturing process,” he said. A series of meetings is allowed so FDA can tinuous manufacturing research (“Exclusiv- FDA’s Emerging Technology Team has help biosimilar sponsors keep product de- ity Incentives In Cures Bill Not Overwhelmingly been leading the charge to help sponsors velopment on track and answer questions Costly, CBO Says” — “The Pink Sheet” DAILY, embrace continuous manufacturing and (“How To Get A Meeting With FDA: Guidance June 23, 2015). help agency staff regulate it. Yu said the Describes Formal Meetings For Biosimilars” — team makes sure that regulatory standards “The Pink Sheet” DAILY, March 29, 2013).

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thepinksheet.com May 2, 2016 | Pink Sheet | 25 Advisory Committees Recent And Upcoming FDA Advisory Committee Meetings Topic Advisory Committee Date Drug Safety and Risk Manage- Results from assessments of the extended-release and long-acting (ER/LA) Opioid ment; Anesthetic and Analgesic May 3-4 Analgesics REMS Drug Products Anesthetic and Analgesic Drug KemPharm’s benzhydrocodone/acetaminophen oral tablets, formulated with purported abuse- Products; Drug Safety and Risk May 5 deterrent properties, for short-term (up to 14 days) management of acute pain Management Updates of the research program in the Laboratory of Bacterial Polysaccharides in CBER’s Divi- Vaccines and Related Biological May 11 sion of Bacterial, Parasitic and Allergenic Products; closed session to discuss intramural research Products (teleconference) program report and make recommendations regarding personnel staffing decisions Novo Nordisk’s insulin degludec/ liraglutide injection as adjunct treatment to diet and exercise Endocrinologic and Metabolic May 24 to improve glycemic control in adults with type 2 diabetes mellitus Drugs Sanofi’s insulin glargine/lixisenatide injection fixed-ratio drug product and lixisenatide injection Endocrinologic and Metabolic May 25 for treatment of adults with type 2 diabetes mellitus Drugs Teva Branded Pharmaceutical Products R&D Inc.’s hydrocodone extended-release tablets, Anesthetic and Analgesic Drug formulated with purported abuse-deterrent properties, for management of pain severe enough Products; Drug Safety and Risk June 7 to require daily, around-the-clock, long-term opioid treatment and for which alternative treat- Management ment options are inadequate Pfizer’s oxycodone/naltrexone extended-release capsules, formulated with purported abuse- Anesthetic and Analgesic Drug deterrent properties, for management of pain severe enough to require daily, around-the-clock, Products; Drug Safety and Risk June 8 long-term opioid treatment and for which alternative treatment options are inadequate Management Merck Sharpe & Dohme’s bezlotoxumab (MK-6072) for prevention of Clostridium difficile infec- Antimicrobial Drugs June 9 tion recurrence Anesthetic and Analgesic Drug Development plans for establishing the safety and efficacy of prescription opioid analgesics for Products; Drug Safety and Risk Sept. 15-16 pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation Management; Pediatric

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