R&D Advisory Committees Regulatory Update Lilly Shows Off R&D Progress Sanofi’s Shows Biomarkers Improve Odds Of With A Pain Franchise Built On Challenges Of Being Late Entrant Approval, BIO Study Finds, p. 11 New Mechanisms, p. 15 In Class, p. 7

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require assessing value but assigning differ- ent value depending on what disease the drug is used in and how beneficial it is per- ceived to be. The prospect is logical in theory, given that drugs are very often used in multiple indications with varying benefits across dis- ease states – often even within subpopula- tions in the same indication. But the pricing scheme poses many challenges, the biggest of which is arguably that in the US and many other countries, prescriptions aren’t always monitored for how they are used. “The problem becomes taking that infor- mation and linking it all the way through the

Photo credit: Jne Valokuvaus/shutterstock.com Jne credit: Photo system so that what is captured at the point of sale can be aggregated and interrogated and systematically analyzed for policies and Multi-Indication Pricing: reimbursement on a mass scale. That journey is very difficult here in the US,” Bill Dreitlein, director of pharmaceutical policy at the Insti- Big Hurdles And Actionable Options tute for Clinical and Economic Review (ICER), Jessica Merrill [email protected] said during a panel presentation at ISPOR. In the US, the drug industry has been ulti-indication pricing presents benefits and issues facing alternative pricing singularly focused on a sole price for drugs an intriguing pricing scheme for and reimbursement schemes. across indications, possibly to the detriment Mcertain drugs used for more than Outcomes-based reimbursement and of society in some cases, say if a manufac- one indication because it could better align multi-indication pricing were two key issues turer were to delay development of a drug in the cost of the medicine to value in different debated during the International Society an indication that might command a lower diseases. But the challenges to implement- For Pharmacoeconomic And Outcomes Re- price to focus on a higher-priced opportuni- ing multi-indication pricing are daunting, re- search (ISPOR) annual meeting May 21-25 in ty. Sanofi decided in 2012 to pull the chronic quiring changes across the entire health care Washington, DC, highlighting the growing lymphocytic leukemia drug Campath (alem- spectrum, from systems used by patients interest in new payment models (“United- tuzumab) from the commercial market al- and physicians to pharmacists and payers. Health Moving, Slowly, Toward More Value- together before launching the same drug However, as payers and drug manufac- Based Drug Contracts” — “The Pink Sheet” under a different brand name, Lemtrada, for turers look for new ways to better align the DAILY, May 26, 2016). multiple sclerosis in 2014. Sanofi agreed to cost of drugs to value, alternative pricing The aim of outcomes-based reimburse- offer Campath free of charge to patients on and reimbursement schemes are gaining ment is to link the cost of a drug to a mea- a compassionate use basis so that it could momentum, despite challenges. That makes sureable outcome in patients like improve- pave the way for the higher priced launch it worthwhile for industry and other stake- ment in cholesterol or reduction in hospital of Lemtrada for MS (“Sanofi/Genzyme Primed holders to take a harder look at the potential admissions. Multi-indication pricing would Continued on page 4 Maximize Your Reimbursement Potential

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exclusive online content inside: Cover Multi-Indication Pricing: Big Hurdles And Real World Superiority Data May Not Be Enough Actionable Options To Boost GSK’s Breo In COPD www.thepinksheet.com/a/00160530015 Generic Drugs Breo Ellipta is associated with a lower rate of exacerbations in real world Salford study, but some analysts question whether it’s too 23 ANDA Approval Speed-Up Leaves Sponsors With late to turn performance around in a highly competitive, highly Less Margin For Error price-conscious market. 25 FDA’s ANDA Approvals

Changing the Subject (Part 2): New Products Turning Turing Around By Offering A “National Center Of Pharmaceutical Supply” 18 FDA’s NDA And BLA Approvals www.thepinksheet.com/a/00160530010 Rather than try to “win” the drug pricing debate, the biopharma Advisory Committees sector may be better served by coming up with new ideas to change the subject. Our first proposal: a national center for off- 7 Sanofi’s Lixisenatide Shows Challenges Of Being Late patent pharmaceutical production. Entrant In Class 9 Diabetes Combos: Novo, Sanofi May Need New Treatment Paradigm To Match Products 26 Recent And Upcoming FDA Advisory Committee Meetings online only! FDA performance R&D tracker 15 Lilly Shows Off R&D Progress With A Pain Franchise Built On New Mechanisms Regularly updated information about new submissions, 19 With Baricitinib, Lilly Hopes To Succeed Where Pfizer pending applications and FDA actions, online-only Has Struggled interactive content at your fingertips 24/7 at 20 Novartis Oncology Strategy: Focus On The www.pharmamedtechbi.com/tracker Microenvironment

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thepinksheet.com May 30, 2016 | Pink Sheet | 3 R & D

Continued from cover in the Journal of the American Medical Asso- pricing & market access. Patient Community For Campath’s Removal ciation in 2014 by Peter Bach, the director of “We need to think about this area much From Commercial Distribution” — “The Pink Memorial Sloan Kettering’s Center for Health more innovatively, not just on the disease Sheet,” Aug. 27, 2012). Policy and Outcomes, that questioned why side, but also the evolution of pricing and the same drug deserves the same price reimbursement systems,” he said. “We believe Learnings From ICER’s when it offers different benefits in different that it is important to think about how we can Summit indications. The article seemed to resonate move away from a typical unit based pricing ICER – the non-profit research institute that with the public and was picked up by several approach, or per kg, to something that is a lot analyzes drug effectiveness and value – has media outlets, he added. more tied to how the drug is used.” undertaken a deep review of indication- Then, in June 2015, the pharmacy benefit The ability to implement multi-indication specific pricing, bringing together leaders manager Express Scripts Holding Co. an- pricing varies by country, Hebborn said, not- from 22 payer organizations and life science nounced it was testing an indication-based ing that following interactions with health companies at a summit on the issue in 2015. formulary for certain cancer medicines in care authorities around the world, there are ICER released a white paper outlining the 2016. The company has been keeping the some countries that have the capacity to im- findings of that meeting and analyzing the details about the pilot program close to its plement such a program. Italy, for example, challenges in March, which Dreitlein high- vest, but did confirm that the program has already has a number of drugs reimbursed in lighted at ISPOR. launched (“Payer Briefs: Express Scripts Pricing a flexible infrastructure, he said, while France The research group’s interest in evaluat- Pilot; HHS Risk Adjustment; Value Frameworks” and Spain are running pilot programs explor- ing the feasibility of indication-specific pric- — “The Pink Sheet” DAILY, April 1, 2016). ing drug utilization. Feasibility has also been ing was fueled by a couple of key events, The ESI pilot program was a reality check established for a number of cancer centers in Dreitlein said. One was an article published that led ICER to ask a lot of questions. “Is this the UK, he added. One study evaluating the something that is going to gain traction? Is feasibility of multi-indication pricing in the it a flash in the pan? What does it mean for UK was presented at ISPOR with a positive development? What does it mean for us as conclusion. payers,” Dreitlein said. “There are other countries where we face The biggest question is if indication-spe- more substantial barriers,” Hebborn said. cific pricing is a good idea at all, he noted. In “Value-based outcomes and learning are the plus column, ICER determined the ben- big themes, but how much interest is there efits are that it would align drug reimburse- beyond rhetoric,” he queried. “When it is ment closer to value and potentially save the about offering data, data sharing, working health care system money – though that’s on governance models, there is often a dis- no guarantee – and it also reflects positively play of considerable distrust or reluctance to on industry and payers that they are thinking engage.” actively and creatively about drug prices. Sean Karbowicz, director, innovation and More From ISPOR On the other hand, the administrative cost pharmacy policy for the pharmacy benefit and burden would be substantial, and indi- manager OmedaRx, offered the perspective cation-specific pricing could conflict with of a US commercial payer. His point of view Take a look at other articles existing government pricing policies. A spe- was that while a pure indication-specific produced by our editors at cific concern of drug manufacturers is that pricing system might be too challenging to ISPOR’s conference: payers might not acknowledge the added implement in the US in the near-term, there “UnitedHealth Moving, Slowly, clinical value of follow-on indications if they are actionable steps payers can take to align Toward More Value-Based Drug end up being more substantial than the ini- value to indication. Contracts” — “The Pink Sheet” DAILY, tial indication, according to Dreitlein. The fractured US health care system poses May 26, 2016 many challenges, he pointed out. “Some- A Drug Maker And A Payer times, on the prescription side, diagnoses are “FDA Orphan-Only Review Divi- Perspective not needed. The pharmacist does not need sion Could Speed Access, Gottlieb Roche is one company that is proactively to know what the drug is being used for,” he Suggests” — “The Pink Sheet” DAILY, evaluating alternative pricing models includ- pointed out. “There has to be a way to cap- May 23, 2016 ing multi-indication pricing, largely because ture that diagnoses for that patient so that “Market Access Restrictions To of its heavy involvement in cancer R&D, we could tell what it is used for. That could Entresto Are ‘Frustrating,’ ICER Of- where it is expected that high-priced combi- be a barrier. That might require prior authori- ficial Says” — “The Pink Sheet” DAILY, nation regimens will eventually be the stan- zation and additional paper work.” May 23, 2016 dard of care, according to Ansgar Hebborn, Another challenge would be making the head of global HTA & payment policy, global necessary changes to coverage contracts

4 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 R & D with members and getting the changes ap- place,” Karbowicz asked. indications that are perceived as having less proved by the insurance commission and He proposed a scenario in which a payer value. The rates would be blended together employers. And perhaps most importantly, and manufacturer would sit at the negotiat- to reach an estimated reasonable rebate to would be the value assessment required for ing table and hammer out a blended multi- be applied. each drug by indication. indication price for a particular product by “This is an example of how we may be “Can we still achieve some kind of the evaluating the cost of therapy, the number of able to leverage the work that would go into outcomes of a multi-indication pricing type people in the plan estimated to be impacted a multi-indication pricing process without of process without actually having a pure by each particular indication the drug is ap- the regulatory changes that could be need- multi-indication pricing process put into proved for, and potential rebates for those ed,” he said.

Reimbursement Changing The Subject: Stop Trying To “Win” The Drug Pricing Debate Michael McCaughan [email protected]

pollster who does some work for biopharma companies shared an insight that seems blazingly obvious when you Athink about: pharmaceutical companies can’t “win” the drug pricing debate. When it comes to prices, the interests of manufactur- ers are, in fact, diametrically opposed to those of consumers and their agents (insurers, public and private). You can justify pricing with arguments about the cost of research and development, you can tie a price to value, you can argue that the issue is really cost-sharing or transparency, but at the end of the day a simple fact remains: sellers of pharmaceuticals want their prices to be as high as possible, and buyers want them to be as low as possible. So what is his advice for the industry in the latest pricing debate? “Change the subject.” To some degree, that has always been the industry’s answer. After all, there is really nothing new about the current complaints lodged against pricing practices: they have flared and dimmed for decades. Like any hot button political issue, it has a shelf life that eventually expires. Politicians move on, eventually. The question is: how much or how little damage do they do before that happens? The current pricing debate is so intense – and the looming presi-

dential elections don’t seem likely to cool the rhetoric – that it surely Rawpixel.com/shutterstock.com credit: Photo behooves the industry to help shift the debate rather than wait for it move on of its own accord. the price (rather than the reimbursement) for specialty drugs. To some extent, that is already happening in the context of the Instead of waiting for the next idea to control prices, the industry proposed Medicare Part B payment demonstration project. With a should seize the moment and offer new ideas of its own. But what concrete policy change on the table, stakeholders across the health ideas to offer? care system have raised concerns about ripple effects on access to Over the next few weeks, we will toss out some ideas of our own care. Now, the argument is less focused on the cost of the Part B – starting now with an idea to address concerns about off-patent drugs and more on whether providers can survive de facto cuts to product costs and supplies (“Changing the Subject (Part 2): Turning their reimbursement. Turing Around By Offering A “National Center Of Pharmaceutical Sup- But that is still fundamentally a defensive battle, with the industry in ply,”” — online at thepinksheet.com). And we invite you to share your the role of fighting back against proposals intended to drive lower pric- ideas with us – what do you think the industry can or should put on es. Even if the industry wins the battle and CMS withdraws the proposal, the table as a way forward out of the drug pricing attacks? (Submit that only means moving on to a different idea that more directly attacks your ideas to [email protected].) thepinksheet.com May 30, 2016 | Pink Sheet | 5 Reimbursement

Not just any idea will do. To transform the debate, an industry pro- an “ask” of Congress and/or the Administration. Private-sector- posal needs to have most or all of the following qualities: only solutions may be the right way to do things, but that is not the point. If it doesn’t need government, government won’t •• New. This isn’t the time to dust off the standard pro-innovation talk about it – and they will keep talking about prices. agenda. Instead, this is the moment to offer new ideas – ones that •• Include some pain. The proposal has to have a clear cost to can’t just be dismissed with talking points drafted decades ago. industry, one that companies are ready to meet (provided that •• Meaningful. The goal should be to put on the table an idea that the idea itself is adopted). would have a tangible impact on the underlying issues driving •• The more stakeholders, the better. Last but not least, the the pricing debate – the overall cost and quality of care for pa- ideal proposal would (much like the Part B rule) touch on a tients in the US. broad base of stakeholders or otherwise require significant •• Simple (sounding). This is a debate driven by sound bites. The staff time for due consideration in Congress and the White idea itself may be very complex (in fact, as we point out below, it probably should be) but it needs to lend itself to a simple message House. The goal is shift the resources devoted to “pricing” in- that everyone can understand. vestigation and policy responses to something new. •• Appeal to the critics. The idea should be something that even Feeling creative? We’ll get the ball rolling with a few idea of our pharma’s harshest critics will have trouble objecting to. They aren’t own. likely to abandon their calls for price controls, but getting them to talk about something else as a positive change is the whole goal [Editor’s note: This article was first published in the RPM Report. The of the effort. Pink Sheet brings selected complementary coverage from sister •• Engage the federal government. The idea needs to include publications to our readers.]

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6 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 Advisory Committees Sanofi’s Lixisenatide Shows Challenges Of Being Late Entrant In Class Sue Sutter [email protected]

n FDA advisory committee’s views on Sanofi’s long-delayed GLP-1 ago- Anist lixisenatide could portend the market challenges the company will face with a new agent in a well-established drug class and crowded therapeutic category. At its May 25 meeting, the agency’s En- docrinologic and Metabolic Drugs Advisory Committee said there were no efficacy or safety issues that would preclude approval of single-agent lixisenatide as the sixth mem- ber of the injectable GLP-1 agonist class. They further affirmed the drug’s risk/ben- Sanofi credit: Photo efit profile when used in conjunction with nists do not. Sanofi’s response focused on ELIXA Puts To Rest CV Safety basal , voting 12-2 for approval of lixisenatide’s impact on postprandial glucose Questions … iGlarLixi, a fixed-ratio combination of Lantus levels, suggesting an avenue by which the Lixisenatide received European Union mar- () and lixisenatide, although company will attempt to differentiate its prod- keting authorization in 2013 and is currently they generally disagreed with Sanofi’s view uct once it enters the crowded US market. approved in more than 60 countries. Its entry that the combination was appropriate for Nevertheless, it’s clear that the three-year in the US market was delayed, however, after patients naïve to both types of drugs (see regulatory delay resulting from the need to Sanofi decided to withdraw the original NDA in related story, “Diabetes Combos: Novo, Sanofi complete a cardiovascular outcomes trial has September 2013 to complete the then-ongo- May Need New Treatment Paradigm To Match put Sanofi at a disadvantage when it comes ing ELIXA cardiovascular outcomes trial. Sanofi Products,” p. 9). to the single-agent product, making the fixed- said it withdrew the NDA ahead of a scheduled However, the panelists echoed FDA con- ratio combination with insulin glargine all the advisory committee meeting due to concerns cerns about risks for serious allergic reactions more important to the company’s battered that any public disclosure of the interim ELIXA and development of antidrug antibodies. They diabetes franchise (“Brandicourt’s Message To data could compromise the trial’s completion also questioned lixisenatide’s efficacy relative Sanofi Investors: Grow, Build, Explore Options” — (“FDA CV Requirements Sideline Sanofi’s Lixisena- to other agents and whether it was better “The Pink Sheet” DAILY, Nov. 10, 2015). tide” — “The Pink Sheet” DAILY, Sep. 12, 2013). suited for twice-daily dosing. The proposed Lixisenatide’s struggles to even reach the In the original NDA, an interim analysis of maintenance dose is 20 mcg once daily, which US market reinforce the maxims that firms ELIXA excluded an excess CV risk of 80% or would be a more frequent dosing schedule often rely on when developing products – more, as required by FDA’s December 2008 than three other members of the class (see box). be first in class, be unquestionably better, or guidance on CV safety evaluations of type One committee member questioned what be prepared for pitched marketing and for- 2 diabetes drugs. However, the hazard ratio lixisenatide offered that the other GLP-1 ago- mulary placement battles. point estimate for the primary endpoint was above 1.0, FDA’s briefing documents state. GLP-1 Agonists: The Current Class Of Five The NDA was resubmitted in 2015, and the user fee date is July 27. The application now Approval Date Drug Product Dosing Sponsor includes the final ELIXA data, which showed lixisenatide neither increased nor decreased 2005 Byetta () Twice daily AstraZeneca the risk of major CV events in adults with type 2010 Victoza () Once daily Novo Nordisk 2 diabetes and at high CV (“Sanofi’s Lixisenatide Gets Clean Bill Of Health On CV Safety, Heart Fail- Bydureon (exenatide 2012 Once weekly AstraZeneca ure” — “The Pink Sheet” DAILY, June 8, 2015). extended-release) Although ELIXA was the first outcomes 2014 Tanzeum () Once weekly GlaxoSmithKline trial for a GLP-1 agonist to complete, it seems unlikely the results will give lixisena- 2014 Trulicity () Once weekly Eli Lilly tide much of a commercial edge. In March, thepinksheet.com May 30, 2016 | Pink Sheet | 7 Advisory Committees

Novo Nordisk AS announced that its LEAD- Hypersensitivity Risk ER trial demonstrated a CV outcomes ben- Warrants Monitoring efit with Victoza (liraglutide), although the Although FDA did not request a vote on the full data have not yet been publicly released approvability of lixisenatide, it sought panel (“Will Novo’s LEADER Trial Move GLP-1 To The discussion on whether any safety or efficacy Front Line In High-Risk Diabetes?” — “The Pink issues precluded approval. Sheet” DAILY, March 4, 2016). “In the efficacy data that we’ve seen, my in- FDA agreed that ELIXA demonstrated no terpretation is that it has efficacy and that it is increased CV risk with lixisenatide, Further- in general comparable to other drugs within more, the drug’s safety profile was generally Sanofi credit: Photo its class,” said panel chairman Robert Smith, an similar to that of other GLP-1 agonists, with endocrinologist at Brown University. “I have gastrointestinal symptoms the most com- not seen concerning safety data for the most mon adverse reaction, the agency said. part. The cardiovascular data are quite reassur- ing from the rather large ELIXA study.” … But Allergic Reactions However, Smith said it was worth noting Are A Concern HbA1c reduction with the concern about severe allergic reactions However, FDA raised other safety issues. lixisenatide was “and (a) the possibility that they may occur in These included the risk of immunogenicity patients and (b) the perhaps not fully resolved due to a high incidence of antidrug antibod- statistically inferior possibility that there may be a greater occur- ies and the potential to adversely impact rence with this drug than from some other efficacy of lixisenatide or other drugs in the to that of exenatide members of the class, and I don’t think we class. The agency also pointed to a possible conclusively know that.” increased risk for serious hypersensitivity twice daily in an active- Smith suggested “serious consideration” reactions, including anaphylaxis, compared controlled trial. should be given to including a labeling state- with other GLP-1 agonists. ment about the need for ongoing monitoring While the overall incidence of anaphy- for severe allergic reactions, and he was among laxis in the lixisenatide clinical develop- lixisenatide was statistically inferior to that several panelists who urged FDA to require ment program was low, “it is notable that of exenatide twice daily and insulin gluli- post-marketing studies or surveillance of this the reported findings suggest an increased sine three times daily. risk (“Lantus/Lixisenatide Combo Gets FDA Panel risk for anaphylaxis with lixisenatide,” FDA’s Furthermore, twice-daily dosing with Nod, But Not Sanofi’s Device” — “The Pink Sheet” briefing document states. “While the ap- 10 mcg lixisenatide demonstrated slightly DAILY, May 25, 2016). proved GLP-1 receptor agonists are labeled greater efficacy in HbA1c reduction and Seely questioned whether the allergic re- with a Warning and Precaution for hyper- better tolerability in terms of gastrointes- action signal was real or merely an artifact of sensitivity reactions, a signal for anaphy- tinal adverse events compared to the pro- heightened scrutiny in the clinical develop- laxis is not described in the clinical trial data posed 20 mcg once-daily dose, FDA said. ment program. “The company had in place a and references to anaphylaxis are based on Committee member Ellen Seely, an endo- very, very sensitive detection system for pick- post-marketing data.” crinologist at Brigham and Women’s Hospi- ing up allergic reactions that may not have The agency noted, however, that differ- tal, questioned “what does lixisenatide give been as extensive for the previous drugs in this ences in the GLP-1 agonist development us that the other GLP agonists don’t give us class, some of which we found out had a lot of programs, “as well as the rigor of identifica- that should make us approve it?” the allergic side effects in post-marketing stud- tion, could have contributed to these differ- “The most important distinguishing factor ies,” Seely said. “I think the statement should be ences and makes across-program compari- about lixisenatide compared to other GLP that [for] all drugs of this class we need to be sons difficult.” agents is its strong effect on postprandial vigilant for allergic reactions.” With regard to efficacy, FDA said lixisena- glucose,” responded Paul Chew, Sanofi’s se- Steven Meisel, system director of patient tide demonstrated a greater reduction in nior VP-R&D. “Postprandial glucose is at least safety at Fairview Health Services in Minne- HbA1c compared to placebo across a range 50%, sometimes 70%, of the hyperglycemic apolis, said that in addition to lingering con- of clinical use scenarios. In active-controlled burden, and in fact the closer you get to goal cerns about allergic reactions he questioned studies, the difference in HbA1c reduction the more of a problem it is.” whether Sanofi’s proposed dose was the most between lixisenatide and comparators ex- Seely asked whether postprandial glucose appropriate. cluded the pre-specified non-inferiority control is similarly achievable with other GLP- “My concern is whether or not a once-daily margin of 0.4% against exenatide twice 1 agonists. “While we haven’t done compara- dose is the right dose,” he said. “That brings daily (AstraZeneca PLC’s Byetta), insulin glu- tive studies on that point, that is one aspect another concern … if it’s only once a day and lisine once daily and three that distinguishes this product from the lit- the clinicians recognize the problem, will they times daily. However, HbA1c reduction with erature that we’ve seen,” Chew said. end up prescribing it twice a day anyway?”

8 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 Advisory Committees Diabetes Combos: Novo, Sanofi May Need New Treatment Paradigm To Match Products Derrick Gingery [email protected]

ovo Nordisk AS and Sanofi continue “This hesitation which I’m feeling – how to face big hurdles for their proposed much of it is just because of the novelty of Ncombination diabetes products the two drugs we’re combining rather than even after strong “yes” votes from two FDA a data-supported concern about the side- advisory committees: The firms must con- effects of say the non-insulin component of vince a skeptical agency that the products that?” he said. have utility – and then convince patients Novo Nordisk’s product combines its Tresi- and practitioners of the same. ba () with Victoza (liraglu- Positioning the products, which offer a tide) and is referred to as IDegLira. The Sanofi fixed ratio of insulin and a -like- product combines Lantus (insulin glargine) -1 agonist in one injection, in the with lixisenatide and is known as iGlarLixi. market may need to be so fine-tuned that Both combination products are proposed they could have trouble gaining traction. as an adjunct to diet and exercise to improve

Even FDA advisory committee members glycemic control in adults with type 2 diabe- Productions/shutterstock.com Syda credit: Photo who recommended approval during their tes mellitus. The sponsors’ target populations May 24-25 review of the products had trou- are patients unable to achieve glycemic con- tes patients (“Novo’s Diabetes Combo May ble describing patient groups that may be trol with oral antidiabetic agents alone, and Find Home With General Practitioners,” p. 7). ideal. Part of the problem could be the new those not controlled on either basal insulin They also thought iGlarLixi was effective, products’ novelty and prescribers’ lack of ex- or a GLP-1 agonist. but were concerned about the proposed perience with them. Uptake of both fixed-ratio combinations dosing device (“Lantus/Lixisenatide Combo During the May 24 review of the Novo could be affected by clinicians’ visions for the Gets FDA Panel Nod, But Not Sanofi’s Device” Nordisk product, Endocrinologic and Meta- products and their existing clinical practice. — “The Pink Sheet” DAILY, May 25, 2016). bolic Drugs Advisory Committee Chairman Still, the committee gave overwhelm- Single-agent lixisenatide could en- Robert Smith, professor of endocrinology at ingly positive recommendations for both counter additional challenges in clinical Brown University, admitted he was unsure products, stating there is a place for them practice because it is arriving late to the why he was concerned about the combi- somewhere, even though it is not entirely class (see related story, “Sanofi’s Lixisenatide nation, particularly in using it with patients clear yet. Shows Challenges Of Being Late Entrant In who are not already on either of the insulin Committee members thought IDegLira Class,” p. 7). or GLP-1 agonist components. could help non-specialists treating diabe- Naïve Patients A Difficult Sell Endocrinologists on the panel seemed Advisory Committee Votes to agree that patients already on one of the combinations’ components would be iGlarLixi appropriate for the products, in part because they were hesitant to start a patient taking • Based on data in the briefing materials and presentations at today’s meeting, only oral antidiabetic medications on both do you recommend approval of the lixisenatide/glargine fixed-combination insulin and a GLP-1 at the same time. Several drug delivered using the proposed pen devices for the treatment of adult said they prefer starting naïve patients on ei- patients with type 2 diabetes mellitus? Y – 12, N – 2 ther insulin or a GLP-1 first and then adding a second drug if necessary. iDegLira Using a combination product from the • Based on data in the briefing materials and presentations at today’s meeting, beginning may require some providers to do you recommend approval of the liraglutide/degludec fixed-combination rethink their general treatment philosophy. Treatment guidelines from the Ameri- drug, delivered using the proposed device, for the treatment of adult patients can Diabetes Association suggest begin- with type 2 diabetes mellitus? Y – 16, N – 0 ning patients with metformin monothera- py, followed by dual therapy with insulin,

thepinksheet.com May 30, 2016 | Pink Sheet | 9 Advisory Committees a GLP-1 or other options, and then adding level of greater than 10% may not be able But FDA identified difficulties in compar- additional therapies if necessary. to reach control on the limited dosing level ing the combinations to current use of the During the IDegLira review, Smith said he available with both of the combination two agents individually. Agency reviewers struggled with how to apply the combina- products’ components, Burman said. said there were no clinical studies compar- tion to a naïve population. “I realize there are advantages to one in- ing the combinations to patients on insulin “I again feel confronted with the problem jection a day versus four and other issues and a GLP-1 agonist at the same time. in anticipating how to start these on the to bring up, but I think given those issues Smith said during the IDegLira meeting background of neither, which is the variabil- and the possibility of someone having re- that it appeared the committee supported ity in patient responses in terms of some- sistance if they’re obese, etc., I can’t decide giving the combination to patients already thing such as weight gain,” he said. in my mind which patients I would start” on a GLP-1 agonist. “There are patients who are very resistant injection therapy with this combination, “There may be significant patient popu- to taking insulin, either because they have Burman said. lations among individuals who are on ei- heard from various sources that weight gain Ellen Seely, an endocrinologist at Brigham ther insulin and not a GLP-1 agonist or a is a problem and it can be very difficult to and Women’s Hospital, questioned during GLP-1 agonist and not insulin in whom a convince them otherwise, or because per- the iGlarLixi meeting whether she would transition to this combination might be haps they previously had a period of insulin want to start a patient on two drugs when acceptable,” Smith said. “For patients who treatment and experienced weight gain,” “I’m not sure the second one is ever going are on insulin, there may be a significant Smith said. “So that might be a group of pa- to be needed or will be needed in the next population in which this would apply, but tients, perhaps not a very large one, where several years.” the group found this difficult to navigate in it really did make the difference in terms of Seely also said that “there’s a lot of side terms of defining that patient group.” persuading them to start insulin.” effects to drugs that are often placebo side Seely said during the iGlarLixi meeting Mitigating weight gain typically caused by effects that as clinicians we really struggle that transitioning a patient from a single insulin, was seen as an advantage for both with figuring out which drug a person is agent to two “is the ideal situation to use a combinations. One of Novo Nordisk’s trials reacting to.” combination drug.” found patients on IDegLira saw body mass “Someone’s on a single agent in your com- index actually decrease somewhat through Is Sweet Spot Transition To bination drug and you want to add a second 52 weeks, while patients on insulin alone Two Drugs? agent in your combination drug and you can saw BMI increases. Both the Novo Nordisk and Sanofi combina- do it in one delivery,” she said. Sanofi similarly reported clinical trial data tions seem destined to have a bigger place Peter Wilson, director of epidemiology showing the lixisenatide component in among diabetes patients already on one of and genomic medicine at Atlanta Veterans iGlarLixi mitigates weight gain associated the individual components. Both products Administration Medical Center, said pa- with insulin glargine. allow a once-daily injection of the insulin/ tients that are very heavy may not be ideal “Even though it is two drugs, if you’re giv- GLP-1 combination through a pen injector. for either combination because they may ing lesser of both, and it looks like hopefully However, the dosing schedule could need an insulin dose larger than the maxi- you might get them to their target and mini- require a patient already on a GLP-1 to mum recommended dose for the combina- mize any other effects, and if you mitigate move to a lower dose using the combina- tions. IDegLira has a 50-unit maximum daily the weight gain … then to me there’s a place tion than they received taking the product insulin dose, while the dose of iGlarLixi is for this drug to fit in in that category,” Marie independently. The issue is a concern for capped at 60 units. Gelato, professor of medicine at Stony Brook FDA, particularly as to whether it could While Novo Nordisk’s proposed pen in- University, said at the IDegLira meeting. cause patients to lose glycemic control jector for IDegLira was not expected to Several committee members were con- (“Novo’s Insulin, GLP-1 Combo Faces Clinical produce too many errors, the iGlarLixi pen cerned about starting patients on two drugs Practice Worries” — “The Pink Sheet” DAILY, injector caused some worries with the panel. when both may not be needed. May 20, 2016). There are two proposed iGlarLixi injectors for Kenneth Burman, director of the endocri- Burman suggested during the IDegLira marketing, representing two different dos- nology section at MedStar Washington Hos- meeting that once patients on either in- ing ranges. They would be marketed in two pital Center, said during the iGlarLixi meeting sulin or a GLP-1 agonist demonstrate they different colors, but FDA raised several con- there were advantages and disadvantages need both drugs to gain control, the com- cerns about the injector and the potential to starting two drugs in a naïve patient. A bination product could be the next step. for dosing errors associated with it (“Sanofi’s patient with an HbA1c level of 7%-9% may It would fit with the treatment philoso- iGlarLixi: Two Formulations Raise FDA Red not need both combination components, so phy of beginning a regimen with one prod- Flag On Dosing Errors” — “The Pink Sheet” “you’re spending time and money and ex- uct and then adding others as needed. DAILY, May 23, 2016). posing someone to the possible side effects Both products also would limit the num- of two agents when they really needed one.” ber of daily injections, which a number of pa- Sue Sutter ([email protected]) con- Conversely, a patient with an HbA1c tients testified was a significant advantage. tributed to this report.

10 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 Regulatory Update Biomarkers Improve Odds Of Approval, BIO Study Finds Bridget Silverman [email protected]

linical programs that used biomarkers to select patients for Quantitative Support clinical trials had a three-fold higher likelihood of approval For Efforts To Increase Cthan ones with no selection biomarkers, an analysis of 10 years Biomarker Use of clinical development programs by the Biotechnology Innovation “Advancing industry-wide understanding of Organization and Biomedtracker found. the evidentiary standards or considerations Programs that used selection biomarkers had a 25.9% likelihood governing regulatory acceptance of drug of making it from Phase I to FDA approval compared with 8.4% for development tools, including biomarkers, would increase adoption programs that did not, the study calculated. Overall, the likelihood of and use of innovative drug development tools, and serve to expedite approval from Phase I was 9.6%. Biomedtracker calculated likelihood development and review timelines and improve chances of success,” of approval (LOA) by looking at the 9,985 transitions from phase to the study concludes. phase of drug development in its database from 2006 to 2015, repre- Increasing the use of biomarkers is a priority for FDA and industry senting 7,455 clinical drug development programs. and on Capitol Hill. FDA’s Drug Development Tools guidance, issued in January 2014, sets out a qualification process for biomarkers, as “Experiencing one in four failures well as clinical outcome assessments and animal models under the Animal Rule. Qualified biomarkers can be used in clinical programs (with selection biomarkers) vs. two without the need for FDA to reconfirm the suitability of the measure. In February 2015 FDA issued a call for information to facilitate devel- in four Phase III failures (without opment and qualification of biomarkers in human drug development biomarkers) could have significant (“Biomarkers Qualification: Can FDA Get Rolling Before A Push From Congress?” — “The Pink Sheet,” Feb. 23, 2015). cost implications,” the study notes. Progress has been slow, however. Only six biomarkers have been offi- cially qualified. FDA’s most recent quarterly report, posted April 1, shows The differences in success rates “are quite convincing, quantita- two more in review and 18 in the consultation and advice stage. tively, of what many drug developers have long argued anecdot- The six qualified biomarker drug development tools include tests ally – enrichment of patient enrollment at the molecular level is a to predict drug-induced nephrotoxicity and cardiac toxicity, a patient- more successful strategy than heterogenous enrollment,” the study selection biomarker for invasive aspergillosis trials, and prognostic declares. The study was authored by BIO Senior Director of Industry biomarkers to enrich trials for chronic obstructive pulmonary disease Research and Policy Analysis David Thomas and Biomedtracker ana- and autosomal dominant polycystic kidney disease. lyst Justin Burns with colleagues from Biomedtracker and biomarker FDA has faced criticism over the pace and transparency of the bio- intelligence company Amplion. marker qualification process (“FDA Biomarker Program Needs Overhaul, The biomarker effect was most significant in later clinical stages. Genentech Says” — “The Pink Sheet,” Jul. 27, 2015). The 21st Century “Phase III transition success rates in programs utilizing selection bio- Cures Act taking shape on Capitol Hill is likely to include provisions markers in the last decade were 76.5% (n=132) compared to only 55% intended to expand use of biomarkers, although FDA is concerned (n=1,254) for non-biomarker trials,” the study states. The authors used about legislation moving ahead of the science (“FDA’s Woodcock Cau- Amplion’s Biomarker Base service to identify programs using biomark- tions Efforts To ‘Legislate A New Generation Of Biomarkers’” — “The Pink ers in the Biomedtracker database. Sheet” DAILY, Oct. 21, 2015). The analysis found the low overall rate for Phase III programs to transition to NDA/BLA filing “concerning.” The probability of successful Biomarkers Beyond Oncology transition from Phase III was 58.1% in the complete dataset. Only the Headlines have gone to breakthrough therapy approvals for molec- Phase II to Phase III transition rate was lower – 30.7% – and that find- ularly targeted therapies and immuno-oncology agents that incor- ing reflects other analyses that have identified Phase II as the primary porate companion diagnostics into the indication. Clinical trials for bottleneck in the clinical development process (“Pharma R&D Produc- such products have used what BIO’s Thomas calls “efficacy biomark- tivity Shows Signs Of Progress” — “The Pink Sheet” DAILY, Sep. 24, 2015). ers,” or measures that “are used as a readout to say if the drug was The low Phase III transition rate in the study suggests a poor return working or not.” on investment for the stage that consumes the most corporate re- The BIO study instead focused on the more mundane, and more sources – Phase III development accounts for 35% of all R&D spending widely adopted, selection biomarkers – measures used in the patient and 60% of all clinical trial costs, the authors point out. screening process for clinical trials. Even so, the study only found 512 “Experiencing one in four failures (with selection biomarkers) vs. phase transitions, or programs advancing to the next stage of de- two in four Phase III failures (without biomarkers) could have signifi- velopment, using selection biomarkers. That works out to 5% of the cant cost implications,” the study notes. 9,985 phase transitions in the 10-year data set. thepinksheet.com May 30, 2016 | Pink Sheet | 11 regulatory update

Despite the relatively low number orphan oncology products from the rare disease cohort to con- centrate on inborn genetic disorders. of biomarker phase transitions, “As many rare diseases are identified by specific genetic muta- tions, it is not surprising that success rates in rare disease indica- the difference from non-biomarker tions closely match the success rates observed in clinical trials that transitions was statistically significant utilized selection biomarkers,” the study comments. On the other hand, drug programs targeting chronic, high for all phase transitions but Phase I. prevalence diseases tend to enroll large and heterogenous patient populations in trials. The likelihood of approval in these common Despite the relatively low number of biomarker phase transitions, conditions was not only lower than for the more defined popula- the difference from non-biomarker transitions was statistically signifi- tions in biomarker selected and rare disease trials, but lower than cant for all phase transitions but Phase I. The study points out that bio- for the study dataset as a whole. The overall likelihood of approval markers are more commonly used in Phase II and III. for a Phase I product was 9.6%; for chronic high prevalence diseas- The majority of the biomarker phase transitions were in oncology, es, it was 8.7%. For both the well-defined orphan and biomarker- Thomas said in an interview with the Pink Sheet. This is not surprising, selected drug programs, about one in four Phase I programs made as genomic sequencing has had the biggest impact to date in shaping it to approval (see chart). cancer therapy by identifying specific molecular targets and popula- Biomarker-guided drug development will expand to more com- tions. Autoimmune disease and endocrinology made up the next larg- mon and chronic conditions, the authors of the BIO/Biomedtracker est groups. analysis predict. “As selection biomarkers are used more frequently Clinical trials in autoimmune and endocrine diseases like diabetes in clinical development (presently, they are only being used in a and arthritis use “biomarkers tests that capture blood proteins, circulat- small proportion of studies), phase transition success rates in high ing cytokines or other factors that are assayed in a blood sample,” Thom- prevalence diseases should improve as patient selection improves.” as explained. Blood tests are easier to incorporate into patient screening Diagnostic companies are also pursuing biomarker testing for than the biopsies often needed to identify biomarkers in oncology. personalized therapy outside of the oncology setting. Myriad Ge- The biomarker effect was most significant in late clinical stages. netics Inc. subsidiary Crescendo Bioscience Inc., for example, has “Phase III transition success rates in programs utilizing selection bio- been collecting evidence to show how its multi-biomarker blood markers in the last decade were 76.5% (n=132) compared to only 55% test, Vectra AD, which measures 12 proteins associated with rheu- (n=1,254) for non-biomarker trials,” the study states. matoid arthritis disease activity, can be useful to guide to iden- tify patients likely to respond to treatment (“Myriad Builds Case For Orphan Drug Success Rates Echo Biomarker Personalized Prescribing Of Rheumatoid Arthritis Drugs” — “The Pink Program Findings Sheet” DAILY, Nov. 10, 2015). “The impact that a targeted, well-defined patient population can have “The higher success rates for trials run with biomarker-selected was observed in the success rates for both selection biomarker us- patients suggests that the broader industry is already on the right age and rare disease studies,” the study says. The analysis removed path,” the study concludes.

The Benefit Of A Well-Defined Patient Population: Probability Of Success For Biomarker Programs, Orphan Drugs And Common Chronic Diseases Rare Diseases Programs With Chronic, High Phase Transition (non-oncology) Selection Biomarkers Prevalence Diseases

Phase I to Phase II 76% 76.7% 58.7%

Phase II to Phase III 50.6 46.7 27.7

Phase III to NDA/BLA 73.6 76.5 61.6

NDA/BLA to Approval 89.2 94.5 87.2

Likelihood of Phase I program reaching approval 25.3% 25.9% 8.7%

Source: Data from “Clinical Development Success Rates 2006-2015,” by Thomas, Burns, et al., released June 2016

12 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 Standard of Care

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Pink Sheet SScricrip Pharma intelligence | Pharma intelligence | 14 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 R & D Lilly Shows Off R&D Progress With A Pain Franchise Built On New Mechanisms Joseph Haas [email protected]

hough pain hasn’t traditionally been expected to file for approval over the suc- an area of focus for Eli Lilly & Co., the ceeding 18 months, including galcanezum- T firm’s burgeoning franchise includes ab (“Despite CETP Loss, Lilly Says Long-Term two potential first-in-class candidates near- Strategy Is Starting To Bear Fruit” — “The Pink ing regulatory filings. Coming out of a May Sheet,” Oct. 26, 2015). “We expect continued 25 R&D review, analysts are thinking the At the May 25 R&D day, Lilly execs talked pharma’s new area of specialization may be up the success of company efforts toward efforts by Lilly significantly undervalued by investors. mostly internal progress in clinical develop- to find attractive external Lilly’s R&D effort in pain is led by a pair of ment, rather than on growing through large Phase III assets in new mechanisms – galca- M&A, and outlined five priority therapeutic opportunities nezumab, a gene-related peptide areas during an investor day presentation: (CGRP) in development neurodegeneration, diabetes, oncology, im- through partnerships for cluster headaches and both chronic and munology and the emerging area of pain and licensing, as well episodic , and tanezumab, a nerve therapy, which is centered on non-opioid, growth factor (NGF) antibody partnered with first-in-class candidates that do not present as targeted small tuck-in Pfizer Inc. that seems to be past serious safety a risk of abuse/addiction. concerns earlier in the decade. Tanezumab is Analysts said Lilly’s strategy is bearing deals, but we would in Phase III to treat pain related to osteoarthri- fruit following the investor presentation in be surprised to see tis, chronic lower back pain and cancer pain. New York, with Credit Suisse analyst Vamil During recent quarterly earnings calls, Lilly Divan reiterating his “outperform” rating for Lilly pursue and larger has pointed to its increasingly productive the stock and calling the pharma’s pipeline pipeline, generated both through internal “diverse and relatively de-risked.” Lack of dis- acquisitions.” R&D and via partnering and bolt-on acqui- ruption from the aftermath of mega-deals sitions. Its business development strategy – which can affect personnel, processes and ture of a real productivity transformation” specifically has centered on early-stage as- strategic priorities – has proven to be impor- during the presentation, making its goal of sets, while later-stage assets only have been tant for Lilly in improving its R&D productiv- 20 new launches during the 10-year period targeted if they meet specific criteria, includ- ity, the analyst said, validating the pharma’s spanning 2014-2023 look realistic. He point- ing economical pricing (“Lilly Investing In Fu- stated long-term strategy. ed to tanezumab as one of three pipeline ture, But Staying Out Of The Biotech ‘Bubble’” “We expect continued efforts by Lilly candidates – along with the breast cancer — “The Pink Sheet” DAILY, July 23, 2015). Lilly to find attractive external opportunities compound abemaciclib and Alzheimer’s dis- says about one-third of its pipeline is derived through partnerships and licensing, as well ease antibody solanezumab – that offer sig- from external innovation. as targeted small tuck-in deals, but we would nificant upside to Leerink’s sales projections Last October, while trying to deflect at- be surprised to see Lilly pursue and larger ac- for the pipeline, with catalysts that should be tention from the clinical failure of its CETP quisitions,” Divan concluded. instructive over the next nine to 18 months. inhibitor evacetrapib, the Indianapolis phar- Meanwhile, Leerink Partners’ Seamus Fer- ma pointed to six new molecular entities it nandez said Lilly had “painted a strong pic- Two First-In-Class Opportunities Robert Conley, Lilly’s global development Lilly’s R&D Day Highlights leader for pain and core therapeutics, stressed at the investor day that galcanezum- “Lilly Playing Catch Up In Oncology” — “The Pink Sheet” DAILY, May 25, 2016 ab and tanezumab offer a pair of near-term candidates in pain that can address unmet “With Baricitinib, Lilly Hopes To Succeed Where Pfizer Has Struggled” — “The Pink medical needs via first-in-class mechanisms Sheet,” May 30, 2016 of action. Lilly hopes to be first to market “Lilly Diabetes Extends Feelers Into Other Diseases” — “The Pink Sheet” DAILY, with a CGRP-inhibiting antibody – galcan- May 27, 2016 ezumab is one of four Phase III candidates in the class, all being developed in migraine/ thepinksheet.com May 30, 2016 | Pink Sheet | 15 R & D headache indications, while another candi- ket. We are the only CGRP antibody in Phase CFRP levels normalize after abortive treat- date is in Phase II. The pharma estimates that III right now with replicated Phase II efficacy ment and that infusion of CGRP can induce there are roughly 8 million US migraine pa- and safety data, pointing out our innovation a migraine attack. Lilly contends that galca- tients not on preventive therapy. technique [focused on validated targets] to nezumab will offer better efficacy and toler- “For , there is a potential for try to have better molecules in Phase III.” ability than current therapies for migraine or launch for both cluster and migraine head- Lilly was able to reach Phase III relatively cluster headaches. ache prevention in 2018,” the exec noted. quickly, Conley said, by having demonstrat- In Phase III in episodic migraine, Lilly has “The cluster headache program that we ed that CGRP is a validated target for mi- been replicating Phase II findings that gal- have, we think, will not only address the sig- graine abortive therapy. It already had data canezumab provides statistically significant nificant unmet medical need but may allow showing that elevated CGRP plasma levels migraine headache day reduction at month us to be the first CGRP antibody to the mar- are seeing during migraine episodes, that three of treatment, compared to placebo. This finding has been borne out in data tracking both 50% reduction in headache days and 100% reduction in headache days. Those are key clinical endpoints of importance both to clinicians and patients, Conley said. In terms of safety, the antibody again has replicated findings from Phase II, with the only significant increase in adverse events occurring in the area of injection site pain, which is a typical finding for an injectable protein therapeutic, the executive explained. Lilly is targeting submissions in 2017 in episodic cluster headache, chronic cluster headache, episodic migraine and chronic migraine – the pivotal Phase III program comprises six trials, including an open-label Lilly’s R&D Strategy At A Glance safety study – with data in chronic cluster ex- pected before the end of 2016 and episodic Lilly is placing its R&D focus on five priority therapeutic areas in what it cluster during 2017. The company expects calls the “post-YZ” period – basically, the aftermath of its patent cliff – with in- internal readouts during 2017 from two creased early-stage research funding and an emphasis on clinical development op- episodic migraine trials and one chronic mi- timization. Through these efforts, the pharma boasts a more productive pipeline graine study during 2017, enabling regulato- that moves candidates to regulatory filing more quickly, with a higher success ry filings potentially before the end of 2017. rate in Phase III trials. With 26 approvals and 16 new starts of Phase III programs over the course of 2014- Competition Coming In CGRP 2015, Lilly is looking to continue that momentum, with 12 major submissions, 14 The pharma also has brought an oral CGRP major approvals and 7 new Phase III starts expected in 2016. Overall, it projects the antagonist into Phase I development re- launch of 20 new products over the decade spanning from 2014-2023. cently, offering the potential of a franchise complement to galcanezumab that could The pharma says its R&D strategy centers on the idea of “timely valued medicines” offer a fast-acting, daily preventive option using a patient-centric, data-driven approach to quality. This has enabled it to re- for migraine. Oral CGRP antagonists such as duce the development time from first human dose to launch from 9.8 years for its Merck & Co. Inc.’s telcagepant have been mature portfolio to 7.6 years for recent and near-term Phase III starts. studied previously but ran aground due to Features of the revised R&D strategy include: safety concerns, including liver toxicity sig- •• Advanced analytics, such as modeling and simulation, rapid data access nals (“Merck Gets A Headache: Unexpectedly and seamless multi-phase study designs. Halts Development Of Migraine Drug” — “The Pink Sheet” DAILY, Sep. 10, 2009). Lilly main- •• Patient-enrollment optimization, including patient and site input into tained that its candidate is a distinct chemi- protocols, enhanced patient outreach with the Lilly Trial Guide and cal entity that shouldn’t present the same advocacy group partnerships. safety concerns. •• Accelerated clinical drug supply and manufacturing, featuring continu- Teva Pharmaceutical Industries Ltd. and ous manufacturing and extemporaneous preparation. Allergan PLC, which are competing with Lilly in the CGRP antibody space, also have

16 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 R & D oral CGRP antagonists in development. Be- Lilly’s Novel Pipeline for Pain Indications sides galcanezumab, Teva’s TEV-48125, Am- gen Inc.’s AMG 334 and Alder BioPharma- Discovery Phase I Phase II Phase III Submission Launched ceuticals Inc.’s ALD403 are the other CGRP antibodies in Phase III, while Allergan’s ubro- Galcanezumab gepant is in Phase II. Alder advanced ALD403 (Cluster Headache) into Phase III study in episodic migraine in Galcanezumab March, with a goal of initiating a second piv- (Migrane Headache) otal study in chronic migraine following an Tanezumab* end-of-Phase II meeting with FDA (“Keeping (Osteoarthritis Pain) Up With The CGRPs: Alder Gains Momentum In A Tight Race” — “The Pink Sheet” DAILY, Tanezumab* March 28, 2016). (Chronic Lower Back Pain) BioMedTracker gives each of the Phase III Tanezumab* candidates similar, slightly above-average (Cancer Pain) chances of regulatory approval – 58% for Al- CGRP der, 56% for Teva and 55% for both Lilly and Small Molecule 2016 Amgen. is given a 17% chance *in collaboration with Pfizer of approval, which is average for a Phase II Source: Eli Lilly & Co. candidate by BioMedTracker’s formula. In a May 24 note covering Alder, Jefferies under investigation in 4,500 osteoarthritis tearthritis Trial Stopped” — “The Pink Sheet” Equity Research analyst Brian Abrahams said patients in three Phase III trials – a 16-week DAILY, June 24, 2010). The hold spread to the several of the CGRP antibodies are experi- treatment protocol (n=690), a six-month rest of the class (“Regeneron, J&J, AstraZeneca encing rapid enrollment of their trials, indica- treatment protocol (n=810) and a 3,000-pa- Pull Plug On NGF Inhibitors In Development tive of both high interest and a large market tient safety study for co-administration with For Pain Indications” — “The Pink Sheet” DAI- opportunity in migraine. Leerink’s Fernandez NSAID therapy. For chronic lower back pain, LY, Dec. 30, 2010). predicted peak sales for galcanezumab in Lilly is studying tanezumab in 1,800 patients, Conley explained that after imposing a 2026 of $800m, and is even more bullish on while a Japanese safety study will enroll 390 clinical hold, FDA conducted a retrospec- tanezumab. more. In cancer pain, a 255-patient pivotal tive analysis of data from the three anti-NGF Fernandez noted that there will be small trial is under way. Lilly expects these studies candidates then in development and deter- obstacles to reimbursement: “From a payer to complete enrollment by the end of 2016 mined that if certain risk factors were elimi- perspective, [Lilly] hopes the cluster head- or in the first quarter of 2017, enabling data nated from osteoarthritis trial populations, ache indication will give galcanezumab readouts before the end of 2017. the chances of worsened osteoarthritis lead- favorable dynamics, but fully expects step- The pharma estimates a substantial mar- ing to surgery could be reduced by 98%. It edits requiring failure of at least one generic ket of about 30 million patients who suffer then encouraged sponsors to resume study- agent (although it believes this step should from osteoarthritis or chronic lower back ing the class with revised safety protocols be relatively quick).” pain, and it thinks tanezumab will offer pa- (“Anti-NGF Trials Might Resume With Very Nar- Credit Suisse’s Divan said May 25 that he is tients better efficacy, a longer duration of row Patient Populations” — “The Pink Sheet,” more optimistic on market prospects for gal- effect and no risk of addiction compared to March 19, 2012). canezumab than tanezumab, partly because current management with opioid therapies, Conley noted that the accelerated os- he thinks the anti-CGRP class eventually will which have a long history of abuse/addic- teoarthritis was seen in less than 1% of the generate around $14bn in peak annual sales. tion issues. sample, but was of great concern because He called Alder and Teva’s Phase III antibod- The challenge will be reassuring investors of what a serious adverse event it was. FDA’s ies “potentially better assets,” but noted that and regulators about the agent’s safety af- retrospective analysis, though, determined near-term approval in cluster headache ter two separate safety concerns, including that most of the patients who suffered this could give Lilly a “small first-mover’s advan- a clinical hold that was only lifted roughly AE had more advanced osteoarthritis that al- tage” by getting galcanezumab in front of one year ago (“Pfizer/Lilly And J&J Are Ready- ready had them on the path to surgery. Most neurologists who also see patients suffering ing NGF Inhibitors For Phase III” — “The Pink of these patients also had been on longer from migraine. Sheet” DAILY, March 23, 2015). Lilly is devel- term anti-NGF therapy, 16 weeks or more, oping tanezumab in partnership with Pfizer, than was typical of the overall sample, and Overcoming Tanezumab’s which had to halt a study of the antibody in had long term co-administration of NSAID Spotty Safety History 2010 due to worsening of osteoarthritis lead- therapy. Lilly probably has a tougher story to sell ing to joint-replacement surgery (“Future Ap- “By taking those things away, by doing with tanezumab. It has the NGF antibody pears Grim For Pfizer’s Tanezumab With Os- a good screening for arthritis and incipient thepinksheet.com May 30, 2016 | Pink Sheet | 17 R & D need for surgery before you take the drug, cell size. … And also importantly, shown in marketplace for both OA and chronic low by being careful with the dose … and by the preclinical [work], in primates [was] no back pain and, importantly here, we want prescribing NSAID use to being only brief change in cardiovascular or parasympathetic to transform what people think about for and short-term … FDA felt that 98% of those function.” pain therapy,” Conley said. “That this is go- accelerated OA cases could’ve been pre- The clinical hold finally was lifted in April ing to change things by really having people vented,” Conley said. “They said, ‘okay, guys, 2015, and tanezumab resumed clinical study expect much better efficacy and tolerability do Phase III again.’ So that’s what we’re doing. that July. “We’re about halfway through [the and … that we are going to be able to pro- We have a Phase III program to show effica- Phase III program],” Conley said. “Right now, vide a therapy with no risk of addiction.” cy, but we think we are going to get efficacy. we have thousands of patients already in Despite those findings, Credit Suisse’s What we really need to do is to show safety.” study and being observed. Importantly, so far Divan is maintaining a cautious outlook on A second safety issue over concerns about our studies are all still blinded, but at this point tanezumab, given the seriousness of the pre- neuronal cell death and loss of cardiovascu- we’ve had no accelerated OA whatsoever.” vious safety issues. lar and/or parasympathetic function further The main goals of the Phase III program, “The fact that no cases of accelerated delayed the resumption of clinical testing he said, are to show the drug is safe and to osteoarthritis have been seen in the cur- of the anti-NGF class, he added (“Pfizer Plans validate subcutaneous dosing – it is being rent Phase III program is encouraging,” he To Restart Tanezumab Trials In 2014” — “The tested as an eight-week treatment. For both conceded. “Given the clear need for better Pink Sheet” DAILY, July 30, 2013). Phase III candidates, he added, Lilly’s focus is therapies to manage pain in osteoarthri- “This second hold began right when Pfizer to change thinking about pain therapy and tis, chronic low back pain and cancer pain, and [Lilly] really formed our partnership,” demonstrate that non-opioid therapy that should the safety profile remain acceptable Conley said. “And our scientists worked very does not present a risk of abuse can bring and the efficacy remain similar to what was hard together in preclinical to resolve that is- relief to unmet medical needs. seen with the drug in previous studies, this sue. We showed that there was no neuronal “For tanezumab, we feel very strongly that is an asset that could provide significant up- cell death. There is a diminution of neuronal will be the first anti-NGF antibody into the side optionality.”

New Products FDA’s NDA And BLA Approvals Below are FDA’s original approvals of NDAs and BLAs issued in the past week. Please see key below chart for a guide to frequently used abbreviations Sponsor Product INDICATION CODE Approval Date

New Drugs Braeburn/Titan Probuphine Long-acting subdermal implant formulation of buprenorphine 5/26/2016 (buprenorphine HCl) implant for maintenance treatment of opioid dependence in adults who sustained prolonged clinical stability on low-to-moderate doses of a transmucosal buprenorphine-containing product (e.g., doses of no more than 8 mg per day of Subutex or Suboxone sublingual tablet equivalent or generic equivalent) New Biologics CSL Behring Antihemophilic Factor Use in children and adults with hemophilia A (congenital Factor 5/25/2016 Recombinant (recombinant), single chain VIII deficiency) for on-demand treatment and control of bleeding Facility AG episodes, routine prophylaxis to reduce the frequency of bleeding episodes, and perioperative management of bleeding

Key to Abbreviations

Review Classifications NDA Chemical Types P: Priority review 1: New molecular entity (NME); 2: New active ingredient; 3: New dosage form; S: Standard review 4: New Combination; 5: New formulation or new manufacturer; 6: New indication; O: Orphan Drug 7: Drug already marketed without an approved NDA; 8: OTC (over-the-counter) switch; 9: New indication submitted as distinct NDA – consolidated with original NDA; 10: New indication submitted as distinct NDA – not consolidated with original NDA

18 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 R & D With Baricitinib, Lilly Hopes To Succeed Where Pfizer Has Struggled Joseph Haas [email protected]

ith regulatory filings now under review in the US, EU and “As we think about the attributes and take advice from leading Japan for baricitinib, an oral, selective JAK1/2 inhibitor, thought leaders on rheumatology, really the best place to ask for the WEli Lilly & Co. sees a chance to position the drug in the business if you will, to position the drug, is in front of biologics,” he said. competitive rheumatoid arthritis space after generic methotrexate “That doesn’t mean we won’t get broad use across the whole spec- therapy but before use of tumor necrosis factor inhibitors. trum. However, and we have data to support that, I think in the early The Indianapolis pharma outlined its strategy for baricitinib, part- days of launch in particular because of step-therapy requirements, nered with Incyte Corp., during an investor day presentation May 24 etc., we may see quite a bit of use there. Hopefully, clinicians can build in New York (see related story, “Lilly Shows Off R&D Progress With A Pain on that experience and try it earlier as well.” Franchise Built On New Mechanisms,” p. 15). Senior Medical Director Bill Macias highlighted the drug’s strong data package, derived from Strategy For Targeting Refractory TNF five Phase III trials, including data showing superiority to AbbVie Inc.’s Patients In US Humira (adalimumab) on signs and symptoms of disease as well as In a May 25 note on the R&D day, Leerink Partners analyst Seamus patient-reported outcomes. Lilly had previously presented data from Fernandez said Lilly’s strategy seems to be focused on going after pa- the RA-BEAM and RA-BEGIN studies showing superiority on PROs tients who are refractory to TNF inhibitors in the US. Internationally, (“Lilly Ready To Take Oral RA Drug Baricitinib To Finish Line” — “The Pink the company expects a more level playing field because it will be less Sheet” DAILY, Nov. 8, 2015). expensive than anti-TNF biologics, he wrote. If approved, baricitinib will be the second Janus kinase inhibitor “Despite the drug’s oral dosing and clinical profile warranting use in to reach the market in RA, following Pfizer Inc.’s Xeljanz (tofacitinib), earlier lines of therapy, Lilly urged patience regarding the initial launch which to date has been somewhat of a commercial disappointment. in the US,” Fernandez said. “Due to the structuring of rebates, early During the investor day presentation, Lilly execs extolled the drug’s adoption of baricitinib will likely occur predominantly in a TNF-refrac- advantages over Pfizer’s Xeljanz, and analysts hope they will heed the tory population. Outside of the US, it expects pre-TNF use to occur lessons available from Pfizer’s struggle in gaining acceptance of the more quickly due to a more favorable reimbursement environment.” first oral JAK inhibitor with payers and clinicians. In another May 25 note, Credit Suisse analyst Vamil Divan called Lilly started out making sure to identify a once-daily dose, which the baricitinib “a likely blockbuster” that would have greater commercial execs showed has no tolerability or safety concerns and to have struc- impact in the RA space than Xeljanz. “We sense the company has tural benefits. Xeljanz entered the market with twice-daily dosing. learned from Pfizer’s challenging launch of Xeljanz and will choose a Another hurdle baricitinib will face, however, will be overcoming lower price point for baricitinib, leading to fewer hurdles in getting pa- competition from the entrenched anti-TNF class, led by Humira. But tients on therapy and a potentially more rapid launch after regulatory analysts expect Lilly to vie for market share based on price, strong approval early next year, while also allowing them to target patients data and the convenience of a daily, oral tablet. Lilly declined to of- both before and after anti-TNF therapy.” fer specifics about its potential pricing strategy for baricitinib, but BMO Capital Markets’ Alex Arfaei concurred with this optimistic VP-Medical Affairs Dave Kendall said the company sees several ways outlook in a May 24 note, predicting that baricitinib would post peak to differentiate in RA. sales of $1.7bn by 2024. “The drug appears safe, and it’s really quite an easy treatment Although approved in 2012 for RA, Xeljanz has never built up much for physicians to use once it’s approved,” he told the audience. “We commercial momentum, leading Pfizer to scale back its overall de- are going to position this in front of biologic therapy. That will take velopment plans for the molecule (“Xeljanz Development Plans Scaled different amounts of time, depending on the reimbursement and Back By Pfizer” — “The Pink Sheet” DAILY, Oct. 27, 2015). It has aban- payer systems around the world. But we need to start with the clini- doned plans to develop the drug in Crohn’s disease, ankylosing spon- cal data … and where this drug is best used.” dylitis and possibly psoriasis, although Pfizer unveiled top-line Phase Kendall asserted that Lilly’s broad-based Phase III program for bar- III data in psoriatic arthritis earlier in 2016. Lilly has baricitinib in Phase II icitinib provided “a real world test,” including investigation against studies in atopic dermatitis and systemic lupus erythematosus. Humira as an active comparator in RA-BEAM. Over the five-study On May 3, Pfizer reported that Xeljanz posted global sales of $197m program, the drug was used in a number of patients who had taken during the first quarter, including $175m in the US, up 98% year-over- multiple biologics for RA, and while Lilly has not disclosed the spe- year for domestic sales. In February, the pharma obtained FDA ap- cific data yet, Kendall said Lilly saw “really outstanding efficacy,” in- proval of an extended-release 11 mg formulation of tofacitinib, mak- cluding separation from the competition on the American College ing it the first once-daily oral therapy for RA, potentially minimizing of Rheumatology 20 (ACR 20) score. one area of differentiation for baricitinib. thepinksheet.com May 30, 2016 | Pink Sheet | 19 R & D Novartis Oncology Strategy: Focus On The Microenvironment Lisa LaMotta [email protected]

ike some of the other companies that are behind in the immuno-oncology L space, Novartis AG is relying on combi- nation treatments to get it back in the game and is hoping that its strength in gene thera- pies will give it an advantage. The Swiss phar- ma knows it can’t recover in the near-term, but is planning to be on top in five years. Novartis has long been a leader and in- novator in the oncology space, a story best told by its blockbuster leukemia treatment Gleevec (imatinib), which not only brings in sales of over $4bn annually but its clinical trial program made a major impact on how cancer drugs could be developed in the future. Yet, with the advent of checkpoint inhibitors from competitors Merck & Co. Inc., Bristol-Myers Squibb Co. and Roche, Novartis has fallen behind in the immuno- oncology space. The company is doing everything it can to CEO Joe Jimenez said at the World Medical •• MCS110 – currently in Phase II, the im- position its oncology division for future suc- Innovation Forum on April 27. “The ability to munomodulatory agent is specific to cess (“Where Does Novartis Go From Here In impact the microenvironment is where we’re colony-stimulating factor (CSF)-1. The Oncology? A Conversation With Its Oncology, focusing. We have six agents in the clinic right drug is being tested as a single agent Gene Therapy Execs” — “The Pink Sheet,” July now, with another five set to enter. We’re quite and in combination with the chemo- 20, 2015). The big pharma announced May excited with what this will bring. It won’t be therapies carboplatin and gemcitabine. 18 that it was splitting apart its oncology as- this year, it won’t be next year, but in a three •• NIZ985 – an IL-15 agonist that is cur- sets from the rest of the pharmaceutical divi- to five year time period we are going to be rently in Phase I. sion. While this was a largely cosmetic move, strong in immuno-oncology.” •• NIR178 – a small molecule adenosine it gives Novartis Oncology a higher profile In immuno-oncology, Novartis has six receptor antagonist currently in Phase I. (“Novartis Rejiggers Pharma To Favor Oncol- compounds in the clinic: As Jimenez pointed out, the cancer immu- ogy” — “The Pink Sheet” DAILY, May 17, 2016). •• LAG525 – targets the LAG-3 pathway notherapy pipeline is all in early phases and It has chosen to focus on five areas of and is currently in Phase I/II for multiple will not be market-ready for several years. oncology: lung cancer, breast cancer, mela- solid tumors. The company also intends “This is a 15- to 20-year play. In immuno- noma, renal cancer and hematology. Novar- to test the drug in non-small cell lung oncology we are in the very early stages. tis Oncology CEO Bruno Strigini said in an cancer (NSCLC), renal cell carcinoma and The checkpoint inhibitors were first, as well interview that Novartis has chosen to build melanoma. as the CAR-T that we have been active in are “critical mass” in certain areas because of the •• PDR001 – a PD-1 inhibitor that is being both very early. We’re thinking about this as a intensifying competition in the space. tested in both Phase I and II trials for mul- very long-term horizon,” the CEO added. “On the immuno-oncology side, we were tiple solid tumors including melanoma, Strigini and other Novartis execs have talked late to the game with the first wave of check- NSCLC and triple-negative breast cancer. at length about the company’s strategy to point inhibitors, but we’re very focused on •• MBG453 – an anti-TIM3 monoclonal an- create combination therapies included IO-IO second generation immuno-oncology. If you tibody is currently being test in Phase I/ combos, as well as IO-targeted therapy match- think about the checkpoint inhibitors like PD- II trials as a monotherapy and in combi- ups. Yet, the company is keeping tight-lipped 1, they’ll work in about a third of cases, but in nation with PDR001 for advanced malig- about its specific plans regarding pairing. two-thirds of cases, the immune cell doesn’t nancies, like melanoma, NSCLC and renal Novartis has been rapidly adding to its even recognize the tumor as foreign,” Novartis cell carcinoma. IO pipeline over the last several months,

20 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 R & D part of Jimenez’s express plan to catch up (““This Isn’t The Past Novartis,” Jimenez Tells J.P. Morgan Conference” — “The Pink Sheet” NOVARTIS DAILY, Jan. 11, 2016). In October 2015, No- vartis acquired Admune Therapeutics Oncology LLC for $258m and signed licensing deals with Palobiofarma SL and Xoma Corp. The company also signed an agreement On The Verge with Surface Oncology in January, further adding preclinical IO assets. The company Novartis recently realigned its operations to set Novartis Oncology apart expects all five of the preclinical assets to from the rest of its pharmaceutical division While largely a cosmetic move enter the clinic in the next three years. the company is hoping to highlight its eort in oncology as it hopes to gain Of course, the largest driver of Novartis some ground back in the immunooncology space Oncology was the major asset swap that No- vartis conducted with GlaxoSmithKline PLC Approved Novartis in April 2014, unloading its vaccines busi- Oncology products ness and picking up GSK’s oncology assets + for $14.5bn. The deal included a portfolio of already-marketed cancer drugs with sales of approximately $2bn, and made it the pre- ferred partner for GSK’s pipeline. Products currently Progress In CAR-T  in the pipeline One area that Novartis is at the forefront is chimeric antigen receptor T-cell (CAR-T) ther- apies, where the firm has been collaborating Immuno oncology compounds in the clinic with the University of Pennsylvania since August 2012. The lead product, CTL019, has  been making headlines since the academic institution began putting it into patients in early 2012. The cell therapy targets the CD19 Hematology protein and is being tested in a number of Key Areas B-cell malignancies including relapsed/re-   New Molecular in Oncology fractory B-cell acute lymphoblastic leukemia Entity lings (ALL), diffuse large B-cell lymphoma (DLBCL) expected in  and chronic lymphocytic leukemia (CLL). “Five years ago, the company decided to take a big bet with the University of Pennsyl- Breast vania when it came to CAR-T therapies. We be- LEE Lung lieve it was the right bet,” Novartis’ Global Head of Cell & Gene Therapies Usman Azam said in an interview. “Manufacturing is a key compo- nent and the science has matured enough, Melanoma that the time felt right to make an investment.” PKC Like other first-wave products, including Kidney those from Juno Therapeutics Inc. and Kite Pharma Inc., CTL019 requires a complicated manufacturing process that includes cells being taken from patients, processed and then infused back into patients. The compa-   ny acquired a manufacturing facility in De- Oncology clinical trials Patients currently enrolled cember 2012 in Morris Plains, NJ that is now currently ongoing in clinical trials set up to handle the complicated process. Because of the need to oversee manufac- Source: Adapted from Novartis material thepinksheet.com May 30, 2016 | Pink Sheet | 21 R & D turing closely, Novartis set up the individual committee to recommend stopping the trial ASCO Highlights unit (under the oncology umbrella) to han- due to efficacy. Tafinlar (dabrafenib) and Mekinist (tra- dle the business. Azam says it’s much like a Novartis is also running the MONALEE- metinib) were the key highlight from the small biotech within a large pharma. SA-3 trial evaluating ribociclib in combina- GSK deal. The respective BRAF and MEK in- Novartis’ interest in the space helped spark tion with fulvestrant compared to fulves- hibitors were approved in combination for a flurry of interest, and newer programs are trant alone in men and women with HR+/ BRAF V600E-positive melanoma by the FDA pursuing off-the-shelf technologies that HER2- advanced breast cancer who have in May 2013; Roche entered the market with would have the jump on the complex per- received no or a maximum of one prior en- its own combination, Cotellic plus Zelboraf sonalized versions. But the pharma has led docrine therapy. in late 2015, but the targeted therapies as a the field so far and is hoping to beat Juno’s Due to the early stoppage of the MO- whole face stiff competition from the PD-1/ JCAR015 to market (“Ten Programs To Watch NALEESA-2 trial, Novartis has begun talks L1 immune checkpoint inhibitors. Novartis Out For At ASCO” — “The Pink Sheet” DAILY, with regulators and expects to file ribo- plans to give updates on the safety and ef- May 20, 2016). CTL019 will be filed with ciclib by the end of the year (or poten- ficacy of its duo at the upcoming American FDA in early 2017 in pediatric ALL patients, tially early 2017) (“ASCO Puts A Spotlight Society of Clinical Oncology conference at followed by a second filing later in 2017 in On CDK4/6 Category Ahead Of New Com- the beginning of June. DLBCL in adult patients. petition” — “The Pink Sheet” DAILY, May 19, The updates will include a genomic analy- “Here’s what is amazing – if I assume we 2016). Ribociclib has the potential to be sis and three-year data from the Phase III will gain approval of CTL019 – is that in sev- second to market behind Pfizer Inc.’s CDK COMBI-d trials that test the combination en years we have gone from clinical proof- 4/6 inhibitor Ibrance (palbociclib), but versus Tafinlar alone in melanoma patients. of-concept to approval in a therapy that Jimenez has said publicly that he believes There was also be data on the combo in seven years ago no one would have thought ribociclib would be best-in-class. the larger lung cancer market from a Phase existed. That happened because this mar- Another compound expected to go in II study, as well as Phase II data testing the riage of clinical and manufacturing hap- front of FDA this year is PKC412, also known combo in rare cancers. pened under Novartis,” touted Azam, who as midostaurin, a tyrosine kinase inhibitor Novartis will also have updates on CML noted the company is constantly optimizing meant to treat patients with acute myeloid patients who have been treated with Ta- the manufacturing process while working leukemia who are positive for an FLT-3 mu- signa (nilotinib), showing they sustained closely with FDA. tation. FDA granted the drug Breakthrough treatment-free remission. There will also Therapy Designation in February, a pathway be a five-year update on myelofibrosis pa- Ready To File that can facilitate a faster approval. The drug tients taking Jakafi (ruxolitinib) from the While CTL019 will face regulators in early gained the designation based on the Phase COMFORT-1 trial. 2017, Novartis Oncology has two new mol- III RATIFY trial, which showed a 23% improve- No major data will be presented on the ecules that will face FDA scrutiny this year, in- ment in overall survival in this dire patient closely-watched ribociclib (LEE011) and cluding LEE011, also known as ribociclib. The population, Strigini said in a recent interview. letrozole, but there is further information company announced that the cyclin-depen- The company will also file for new indi- from a Phase Ib trial testing the combination dent kinase (CDK) 4/6 inhibitor plus letrozole cations for several other already-approved in receptor-positive (ER+), HER2- showed improvement of progression-free drugs during 2016, including the combina- negative (HER2-) advanced breast cancer. survival in the Phase III MONALEESA-2 trial, tion of Tafinlar and Mekinist in patients with MONALEESA-3 will be presented as a “trial in prompting an independent data monitoring BRAF V600E-positive NSCLC. progress.”

Clinical Trial Landscape Whitepaper By Christine Blazynski

Reviewing the landscape of clinical trials that completed in 2015, the disease areas with successful outcomes, and the companies that backed them.

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22 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 Generic Drugs ANDA Approval Speed-Up Leaves Sponsors With Less Margin For Error Derrick Gingery [email protected]

eneric drug sponsors may be excited for the upcoming pos- try to submit high quality applications in order for the generic drug user sibility of gaining an ANDA approval in less than a year, but fee program to be successful, but an analysis of some fiscal year 2015 Gwith the increased speed will come a smaller window for applications found the majority received a “complete response” letter mid-review corrections. because of unresolved chemistry, manufacturing, and control (CMC) Beginning in October, the vast majority of new ANDAs will be expect- issues (“FDA To ANDA Sponsors: Don’t Forget Quality When Rushing For ed to receive a first action – an approval, tentative approval, refuse-to- 10-Month Review Goal” — “The Pink Sheet” DAILY, May 17, 2016). receive, or “complete response” letter – within 10 months (“GDUFA Perfor- mance Goals For Fiscal Years 2013-2017” — “The Pink Sheet,” Dec. 12, 2011). Most CR Deficiencies Were Minor That will limit the opportunities reviewers in FDA’s Office of Generic The smaller window for IRs may prove to be more of a burden on OPQ, Drugs and Office of Pharmaceutical Quality have to request minor at least based on data from existing applications. Still, the main areas clarifications or corrections in applications, meaning there likely will of improvement that most applications need are not major problems, be more pressure on sponsors to ensure their ANDAs have all the re- but minor deficiencies in many cases. quired elements at submission. The FDA study of ANDAs submitted in the first quarter of FY 2015 found It also could mean a boost in “complete response” and refuse-to- that those not approved during the first review cycle received a complete receive actions because there is not enough time to make a large response despite numerous IRs being sent. The agency found that 72% of number of corrections, even if they would be easy to fix. the applications had approvable bioequivalence data. The majority of the ANDAs now receive a 15-month goal for a first action. And in some problems found were CMC issues, according to Uhl’s presentation slides. cases submissions have received up to five information requests (IRs) Many of the mistakes, at least early on, also appeared minor – which from FDA during the review cycle. OGD Director Kathleen Uhl said the could prove to be a positive and a negative for industry. window for IRs under the 10-month review cycle will be much smaller. Susan Rosencrance, acting director of the OPQ Office of Lifecycle “There’s the potential for probably about two information requests Drug Products, said during a May 18 session that 67% of the complete [in the 10-month review cycle],” Uhl said May 17 during the Generic response letters issued in FY 2013 and FY 2014 were the result of issues Pharmaceutical Association’s CMC Workshop. “The ability to do five IRs that would have been included in information requests, had they been in 10 months is slim to none. … The number of information requests available. Another 32% were considered minor deficiencies. Only 1% of will obviously decrease when there’s shorter review goals.” the deficiencies in those CR letters were major. A hypothetical OGD timeline suggests one information request could be For sponsors, it means that a number of the ANDA problems FDA issued within 120 days after filing and the sponsor’s response received and is finding could be avoided and that there may not be many difficult reviewed about 2.5 months later at the latest. A second IR response could barriers to boosting the first-cycle approval rate. But it also may suggest be received and reviewed 6.5 to 8.5 months after filing, but it appears that that sponsors need to improve their quality checks prior to sending an even a second IR may be difficult for the agency, given that it would return ANDA to OGD. potentially only weeks before the 10-month review deadline. Rosencrance also reiterated that sponsors should try to ensure their FDA has been pushing for more first-cycle approvals, but the tighter applications are submitted with all the necessary components. goal date may threaten the progress towards reduced cycling. FDA re- “FDA will promise to continue to seek opportunities for enhanc- viewers also may have to adjust their review approaches because they ing the quality assessment and we ask industry to familiarize yourself will have only a limited number of chances to have their questions and with commonly seen deficiencies and strive for a right-the-first-time concerns answered. ANDA,” she said. “If we both do those things, work together, commu- Office of Pharmaceutical Quality Director Michael Kopcha said in an in- nicate well, I think we’ll see even more first-cycle approvals. FDA and terview at the workshop that his reviewers likely will have to find more ef- industry will both benefit from that.” ficient ways of conducting reviews rather that necessarily changing their During GDUFA’s first two years, median times from receipt to ap- processes. Kopcha said OPQ staff will look at the most critical areas in the proval were more than three years in part because of workload vol- portions of the ANDAs they review, which will vary based on the product. ume, but also because of problems reviewers found in applications He said reviewers will not necessarily ignore less risky items to ensure the (“FDA’s Generic Drug Workload, Productivity Beating Budget Estimates” most risky questions are addressed in the limited window for information — “The Pink Sheet,” Feb. 22, 2016). OGD also realized that it cannot requests and correspondence on easily correctable deficiencies. expect to gain control of its workload unless first-cycle approvals With additional pressure on FDA comes increased pressure on spon- increased. Through the first few years of GDUFA, two to five review sors to ensure their applications have all the necessary elements at sub- cycles were typically needed (“FDA ‘Real-Time’ Communications De- mission. OGD and other agency officials have long pleaded with indus- emphasize Phone Calls” — “The Pink Sheet” DAILY, Dec. 9, 2014). thepinksheet.com May 30, 2016 | Pink Sheet | 23 Generic Drugs

Learn From First-Cycle Approvals, Uhl Says first-cycle approvals. As of the end of March, OGD had issued full approvals to nine AN- “For the companies that are listed here, I say thank you very DAs with 15-month goals that were filed in FY 2015 (see table). much for working very closely with the agency and I say congratu- Eight of the approvals were first-cycle approvals. Another approv- lations to you for having a first-cycle approval,” she said. al was issued after the goal date, but Uhl said OGD decided to miss Those sponsors should be “doing some types of post-action re- the goal date intentionally in order to avoid another review cycle. ports and lessons learned” so they could reproduce the experience FDA approved its first clocked ANDA in August 2015 (“FDA Ap- in subsequent submissions, Uhl said. proves Its First ‘Clocked’ ANDA” — “The Pink Sheet” DAILY, Aug. 19, 2015). OGD has seen the number of ANDA approvals jump in recent OGD also issued 12 temporary approvals of applications with months as its GDUFA-enhanced review system has taken hold. review goals that were filed in FY 2015 during the same period. However, the agency likely still must improve its approval output if The first was in October 2015. Uhl added that half of the products it is to gain control of its pending workload (“ANDA Approvals Soar, were considered NCE minus 1 applications (see table). But Does FDA Need To Do More?” — “The Pink Sheet” DAILY, May 16, Uhl went out of her way to recognize the sponsors receiving the 2016).

Office of Generic Drugs Clocked ANDA Full Approvals (through March 31) Sponsor Active Ingredient Approval Date Spear Tretinoin Aug. 13, 2015 Aurobindo Loperamide* Dec. 15, 2015 Alkem Gabapentin Dec. 23, 2015 Invatech Sodium polystyrene** Feb. 18, 2016 Teligent Desoximetasone Feb. 25, 2016 Apotex Fluticasone Feb. 29, 2016 Novast Levonorgestrel March 11, 2016 Amneal Desipramine March 17, 2016 Amneal Diclofenac March 18, 2016 *Not a first-cycle approval **Approval issued after GDUFA review goal date Clocked ANDA Tentative Approvals Among FY 2015 ANDA Filings (Through March 31) Sponsor Active Ingredient Tentative Approval Date Paddock Diclofenac Oct. 14, 2015 Taro Diclofenac Jan. 14, 2016 Ajanta Sildenafil* Jan. 21, 2016 Lupin Lurasidone Jan. 25, 2016 MSN Labs Lurasidone Jan. 25, 2016 Sun Pharma Lurasidone Jan. 25, 2016 Orchid Risedronate Jan. 29, 2016 Torrent Lurasidone* Feb. 5, 2016 Emcure Lurasidone* Feb. 23, 2016 Par Aspirin + dipyridamole ER March 1, 2016 Zydus Clofarabine March 4, 2016 Cipla Efavirenz, emtricitabine, tenofovir March 22, 2016 *Not a first-cycle tentative approval

Source: FDA presentation slides

24 | Pink Sheet | May 30, 2016 © Informa UK Ltd 2016 Generic Drugs

FDA’s ANDA Approvals Sponsor Active Ingredient Dosage; Formulation Approval Date

Flamingo Metronidazole 250 mg and 500 mg; tablet 5/16/2016

Macleods Quetiapine fumarate EQ 25 mg base, EQ 50 mg base, EQ 100 mg base, EQ 200 mg base, 5/17/2016 EQ 300 mg base and EQ 400 mg base; tablet

Jubilant Sodium chloride 0.9% in plastic 9 mg/mL; injectable 5/18/2016 container

Tris Morphine sulfate 20 mg/5 mL; oral solution 5/18/2016

Taro Fluocinolone acetonide 0.01%; topical oil 5/19/2016

Kreitchman PET Sodium fluoride F-18 10-200 mCi/mL; injectable, intravenous 5/19/2016 Center

Sciegen Atorvastatin calcium EQ 10 mg base, EQ 20 mg base, EQ 40 mg base, and EQ 80 mg 5/19/2016 base; tablet

Taro Fluocinolone acetonide 0.01%; topical oil 5/19/2016

Accord Bendamustine HCl 25 mg/vial and 100 mg/vial; powder for IV infusion 5/19/2016

Hospira Bendamustine HCl 25 mg/vial and 100 mg/vial; powder for IV infusion 5/20/2016

Ajanta 2.5 mg and 5 mg; tablet 5/20/2016

Amneal Temazepam 7.5 mg, 15 mg, 22.5 mg and 30 mg; capsule 5/23/2016

Lupin Atlantis Mibelas 24 FE (ethinyl /nor- 0.02mg/1 mg; chewable tablet 5/24/2016 ethindrone acetate)

Appco Voriconazole 50 mg and 200 mg; tablet 5/24/2016

Tentative Approvals

Alkem Rosuvastatin calcium 5 mg, 10 mg, 20 mg, 40 mg; tablet 5/19/2016

Anchen Desvenlafaxine 50 mg and 100 mg; extended-release tablet 5/20/2016

Macleods Olmesartan medoxomil 5 mg, 20 mg and 40 mg; tablet 5/24/2016

Strides Efavirenz 600 mg; tablet 5/24/2016

Xellia Voriconazole 200 mg; injectable 524/2016

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2014 HIS ISSue Taking Wing With ALSO IN T Biotech Angel Investorsre supplying more early stage 12 past the Series A stage.gly And like In the life sciences, rich individuals a capital than ever, occasionally well enon fly? 1 Valuation Watch some are banding together into groups that look increasin Device Firms See No Correlation traditional venture capital. How far will this phenom Between Series A And Exit By Paul Bonanos Start-up is the first and best resource for the hottest new rounD 3 Venture ’ Declaration Of Independence: Toward Spectacle-Free Perlstein Lab Goes Solo Against Cataract Surgerymes that dominated cataract Rare Diseases 18 dtech start-ups that presented Precision and accuracy are the the Spine Tingling After LDR surgery in 2013, according to the me Holdings’ IPO technologies, start-ups and finance strategies today. at this year’s Ophthalmology Innovation Summit. tuart Juno Launches With Competing By Mary s Immunotherapy Programs 10 c apital Matters The Conundrum Of With $100M Fund, NYC Wants Alzheimer’s Disease R&Dng disease- isk associated with developiotechs are A Bite Of The Biotech Apple proFilesnce is in disarray and the r field. But venturesome bi But don’t take our word for it — get your FREE issuE now! | 26 Alzheimer’s disease scieiven many players from theorward. | 29 science Matters modifying agents has drort efforts to look for a way f nts. n. | 31 45 finding backers to supp for genetically at-risk patie rly Alzheimer’s detectio | 32 UCSF Start-Up Shows Off Its Alzheon develops AD treatments king technology promises ea isorders. noninvasive eye-trac ents for treating cognitive d 34 Approach To K-Ras Inhibition Neurotrack’s ression. | develops epigenetic ag Rodin Therapeutics o treat memory loss and dep Ve caps PDE4 enzymes t 46 o n the Mo Tetra Discovery Who’s Going Where In Biopharma | 36 Across Health Care t monitoring. And Medtech Start-Ups Start-UpS for quantified self and patien creates knitted textiles | 38 | 39 Ve suMMaries Footfalls & Heartbeats artments, slowly. ting cancer. e xecuti roton accelerator for trea 54 GrayBug delivers drugs to eye comp | 41 develops ultra-compact p aroscopy. HIL Applied Medical re following abdominal lap aims to simplify closu | 44 neoSurgical nd Pulmocide Biomedical, NightSense, a F | Dual Therapeutics, Gecko www.PharmaMedTechBI.com/SU/FREE 48 Deals eMergings in Brie Recent Start-Up Financings and Tech Transfers

thepinksheet.com May 30, 2016 | Pink Sheet | 25 Advisory Committees

Recent And Upcoming FDA Advisory Committee Meetings Topic Advisory Committee Date Novo Nordisk’s insulin degludec/ liraglutide injection as adjunct treatment to diet and exercise to Endocrinologic and May 24 improve glycemic control in adults with type 2 diabetes mellitus Metabolic Drugs Sanofi’s insulin glargine/lixisenatide injection fixed-ratio drug product and lixisenatide injection for Endocrinologic and May 25 treatment of adults with type 2 diabetes mellitus Metabolic Drugs Teva Branded Pharmaceutical Products R&D Inc.’s hydrocodone extended-release tablets, formulated with Anesthetic and Analgesic purported abuse-deterrent properties, for management of pain severe enough to require daily, around- Drug Products; Drug Safety June 7 the-clock, long-term opioid treatment and for which alternative treatment options are inadequate and Risk Management Pfizer’s oxycodone/naltrexone extended-release capsules, formulated with purported abuse- Anesthetic and Analgesic deterrent properties, for management of pain severe enough to require daily, around-the-clock, Drug Products; Drug Safety June 8 long-term opioid treatment and for which alternative treatment options are inadequate and Risk Management Merck Sharpe & Dohme’s bezlotoxumab (MK-6072) for prevention of Clostridium Antimicrobial Drugs June 9 difficile infection recurrence Research programs in the Laboratory of Plasma Derivatives in CBER’s Division of Hematology June 20 Research and Review, Office of Blood Research and Review (open session); intramural research Blood Products (teleconference) programs site visit report and personnel staffing recommendations (closed session) Boehringer Ingelheim’s Jardiance (empagliflozin) and Synjardy (empagliflozin/metformin) for adults Endocrinologic and with type 2 diabetes mellitus and high cardiovascular risk to reduce the risk of all-cause mortality by June 28 Metabolic Drugs reducing the incidence of CV death and to reduce the risk of CV death or hospitalization for heart failure Anesthetic and Analgesic Development plans for establishing the safety and efficacy of prescription opioid analgesics for Drug Products; Drug Safety Sept. 15-16 pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation and Risk Management; Pediatric

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