FDA Biologic Transition Plan Creates

Pharma intelligence Pinkwww.ThePinkSheet.com SheetVol. 78 / No. 21 May 23, 2016 informa

vator trade groups, individual insulin manu- FDA Biologic Transition facturers and legal experts call for a more balanced approach, suggesting that unex- pired marketing protections should carry Plan Creates ‘Dead Zone’ For over after products transition to BLA licenses or that such products should have the bene- Applications, Sponsors Fear fit of 12-year biologic exclusivity dating from original NDA approval. Sue Sutter [email protected] These same commenters suggest FDA’s proposed approach on exclusivity would DA’s interpretation of the Biologics represent a constitutional “taking” under Price Competition and Innovation Act’s the Fifth Amendment, thereby laying the F“transition provisions” for certain protein groundwork for a legal challenge if the agen- products would create a “dead zone” or “black- cy sticks to its original plan. out” period for new applications that could last several years, industry stakeholders say. Protests Over Pending In comments responding to an FDA draft FDA’s approach on Applications guidance on the BPCIA’s “deemed to be a li- FDA’s draft guidance, released in March, cense” provisions, representatives from inno- exclusivity violates the marked its first public explanation for how it vator, generic and biosimilar industries say planned to implement the BPCIA’s transition the agency should allow pending NDAs and Fifth Amendment’s provisions (“BLAs More Appealing As ‘Transi- ANDAs for affected products to be reviewed Takings Clause and tion’ NDAs, ANDAs Set To Lose Exclusivity” — and approved after March 23, 2020. That is “The Pink Sheet,” March 21, 2016). the date when insulin, human growth hor- free trade agreements, The agency said it would not approve any mone and other products that traditionally application under Sec. 505 for a biological have been approved under the Food, Drug innovators said. product subject to the transition provisions and Cosmetic (FD&C) Act will be deemed that is pending or tentatively approved on to be licensed as biological products un- March 23, 2020. Such applications may be der Section 351 of the Public Health Service “This proposal, if implemented, will have a withdrawn and resubmitted under 351(a), (PHS) Act. devastating effect on current development the traditional BLA pathway, or as a bio- FDA proposes transition products that programs for many important protein prod- similar under 351(k). In addition, FDA said it have not received final approval by March ucts, including insulin, thereby impairing would remove affected biological products 23, 2020, would not be approved under the competition for lower-cost biological medi- from the “Orange Book” on the transition FD&C Act and must be resubmitted as BLAs. cines, increasing health care costs in the US date because these products would no lon- However, this approach would disrupt ongo- and, most importantly, limiting patient ger be “listed drugs.” ing reviews, significantly impact develop- access to affordable biological products,” FDA acknowledged that its interpreta- ment programs and dissuade companies Mylan NV’s comments state. tion could have a significant impact on from submitting applications under the FDA’s proposal that transition products development programs for products in af- FD&C Act long before the transition date, in- should lose marketing exclusivity also drew fected classes. It advised sponsors to evaluate dustry representatives said. fire from some industry stakeholders. Inno- Continued on page 4

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exclusive online content inside: Cover FDA Biologic Transition Plan Creates ‘Dead Zone’ For Applications, Sponsors Fear Will Fortune Favor The Brave? Biosimilar Sponsors Need High Tolerance For Uncertainty www.thepinksheet.com/a/00160523015 Regulatory Update Regulatory framework for biosimilars is still a work in progress, 7 Aegerion Juxtapid Settlement Shows REMS Have Teeth: especially on the analytical and labeling issues that featured in Alternate Route To Enforce Off-Label? the Pink Sheet’s Drug Review Profile of Zarxio. 11 European Notebook: Bayer Bids For Monsanto; Biosimilar Uptake Still Sluggish; EMA Enters Drug Pricing Debate Expanded Access Programs Need FDA Policy Changes To Really Expand www.thepinksheet.com/a/00160523011 Biosimilars Agency should issue statement that deaths occurring during 5 Insulin Makers To FDA: Clarify ‘Transition’ Impact On compassionate use will not automatically penalize a drug’s Drug/Biologic Combos development, ethicists from NYU Langone Medical Center say. Generic Drugs 21 FDA’s ANDA Approvals online only! New Products FDA performance 25 FDA’s NDA And BLA Approvals tracker Advisory Committees Regularly updated information about new submissions, 26 Recent And Upcoming FDA Advisory Committee Meetings pending applications and FDA actions, online-only interactive content at your fingertips 24/7 at R&D www.pharmamedtechbi.com/tracker 15 FLAME Shoots LABA/LAMA Combos Up To First Choice In COPD 17 Can Checkpoint Inhibitors Jump-Start Glioblastoma Drug Development?  join the conversation 20 What To Look Out For In Glioblastoma At ASCO Reimbursement We are tweeting, liking and sharing the latest industry news and insights from our global team of editors and 9 Part B Demo Comments Overwhelmingly Negative, analysts —­ join us! Uniform In Content

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thepinksheet.com May 23, 2016 | Pink Sheet | 3 Biosimilars

Continued from cover FDA’s proposal “creates a in a product’s development in the face of whether planned submissions under Sec. 505 longer than expected FDA reviews, requests would allow adequate time for approval by regulatory ‘dead zone’ of a for major amendments or multiple review the transition date and suggested they may cycles,” the firm’s comments state. want to consider submitting an application as year or more between the a standalone or biosimilar BLA instead. Wanted: Compromise On Most of the public comments disagreed time no rational sponsor Exclusivity with FDA’s proposed handling of applica- would submit a 505(b)(2) In the draft guidance, FDA concluded that tions pending at the time of the transition any remaining non-orphan exclusivities – date. This approach is contrary to the BPCIA’s application or ANDA … and five-year new chemical entity, three-year clear language, which allows sponsors to Hatch-Waxman, or pediatric – associated submit applications under Sec. 505 until the the first date a biosimilar with an approved NDA subject to the tran- transition date, the comments said. sition provisions would cease to have any “FDA’s proposed policy will force spon- application could be effect on March 23, 2020. Furthermore, noth- sors who are ready to submit applications for submitted” – GPhA and ing in the BPCIA suggests Congress intended lower-cost biologics prior to March 23, 2020, to grant transition products a new 12-year to delay their submissions until after March the Biosimilars Council period of exclusivity available to biologics li- 23, 2020, thereby significantly delaying the censed as standalone BLAs, the agency said. review, approval and availability of biologi- FDA’s hardline interpretation on exclusiv- cal products that compete with expensive ity surprised some industry observers, who brand name biologics,” the Generic Pharma- pending at the transition date, commenters thought the agency would have tried to take ceutical Association (GPhA) and the Biosimi- said. “We caution that FDA’s proposal as it more of a middle-of-the-road approach. lars Council’s joint comments state. relates to sNDA submissions would slow While the GPhA, Biosimilars Council and “For example, if a sponsor is ready to down the approval of changes that may of- Mylan supported the agency’s view, innova- submit a 505(b)(2) application or ANDA for fer significant benefit to the public health tor groups said terminating existing exclu- a transitional biologic in June 2019, FDA’s (e.g., new indication, dosage form, or other sivity would be inconsistent with the BPCIA, proposed policy would provide a strong in- change that enhances patient compliance harm innovation incentives and disrupt on- centive for the sponsor to forgo any submis- or safety),” the Biotechnology Innovation Or- going patent litigation. sion at that time because of the meaningful ganization’s comments state. “The draft guidance also raises constitu- possibility that the application would not be “While manufacturers that are considering tional issues concerning a taking of private approved prior to March 23, 2020,” GPhA and an NDA for a new product may have more property without just compensation in viola- the council said. flexibility to choose a BLA over an NDA from tion of the Fifth Amendment and threatens However, it also would be impossible for the start, a manufacturer pursuing a supple- the nation’s compliance with its free trade a sponsor to submit a biosimilar application ment is forced to work with the regulatory agreements,” PhRMA said. prior to March 23, 2020, because, until that status of the currently approved product PhRMA and BIO suggest that any exclu- date, there would be no reference product and thus would have to choose, essentially, sivities in effect at the transition date should licensed under Sec. 351 upon which an ap- between waiting until March 23, 2020, to carry over until they would have expired un- plicant could rely. submit its supplement or otherwise go der the FD&C Act. “FDA’s proposed policy thus creates a ahead and submit as an sNDA only to then “More broadly, until expiry of every Orange regulatory ‘dead zone’ of a year or more be- have to resubmit as an sBLA after March 23, Book-listed patent, including any pediatric tween the time no rational sponsor would 2020,” BIO said. exclusivity extension, for a given listed drug, submit a 505(b)(2) application or ANDA (be- Commenters suggest that NDAs and FDA should continue to treat the application cause of the likelihood it would not get ap- supplements pending at the transition date for that drug, as well as the follow-on applica- proved in time) and the first date a biosimilar could be deemed BLAs during review, or tions that cite it, as Sec. 505 applications for application could be submitted (i.e., March they could retain their status until approval, at exclusivity and patent purposes,” PhRMA said, 23, 2020),” GPhA and the council said. which time they would be licensed as BLAs. asserting that this approach would be less Similarly, the Pharmaceutical Research The law firm Hyman, Phelps and McNa- disruptive to sponsors of transition products and Manufacturers of America’s comments mara suggests an approach that would engaged in Hatch-Waxman patent litigation. say FDA’s proposal “would create a blackout recognize “a narrowly tailored cohort” of ap- period during which applicants would be plications submitted by the transition date Novo, Sanofi Eye Different unable to submit either NDAs or BLAs for that would continue to be reviewed after Fixes their proposed medicines.” the listed drugs they reference are deemed Insulin makers are expected to be among FDA’s approach also would have a det- to have a license under Sec. 351. “This would the biopharma companies most impacted rimental impact on supplemental NDAs serve to protect the substantial investment by the transition provisions (“Insulin Exclusiv-

4 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 Biosimilars ity: How Big Will The Fight Be?” — “The Pink prevents conflict with the Takings Clause, interchangeable competition ‘until the year Sheet,” March 21, 2016). but also avoids upsetting and creating 2032,’” Sanofi’s comments state, quoting Novo Nordisk AS’ Tresiba (insulin de- greater uncertainty around any ongoing from the draft guidance. “It is merely con- gludec), approved in September, would court litigation between sponsors,” Novo sistent treatment of all biological products, lose several months of new chemical exclu- Nordisk’s comments state. as Congress intended when it directed that sivity under FDA’s draft guidance. The com- However, Lantus insulin maker Sanofi all biological products should be unified pany’s Xultophy, a combination of Tresiba takes a different approach, saying that tran- under one regulatory scheme.” and the GLP-1 agonist Victoza (liraglutide), sition products should be eligible for the Sanofi said its investigational product is under FDA review. balance of 12-year reference product ex- combining Lantus (insulin glargine) and the Novo said the exclusivity rights granted clusivity for biologics dating back to their GLP-1 agonist lixisenatide would be directly under a sponsor’s chosen regulatory ap- original NDA approval. affected by the transition provisions, and it proval pathway should continue to apply “This does not, as FDA asserts, provide urged FDA to issue guidance that specifi- after the transition date until they naturally windfall exclusivity to products approved cally addresses the impact on drug/biolog- expire. “Such an interpretation … not only ‘decades ago,’ nor does it stifle biosimilar or ic combinations (see related story below).

Insulin Makers To FDA: Clarify ‘Transition’ Impact On Drug/Biologic Combos Sue Sutter [email protected]

lthough the biopharma industry may glargine) and the GLP-1 agonist lixisena- transition date,” Sanofi said of its combina- not have liked much of what it saw in tide is undergoing a priority review at FDA, tion product. “We also are anticipating that AFDA’s initial guidance on the Biologics thanks to the firm’s redemption of a prior- the lixisenatide component will be granted Price Competition and Innovation Act’s “transi- ity review voucher (“Keeping Track: Exelixis, five-year NCE exclusivity, that a balance of tion provisions,” it remains in search of clarity on Sanofi Submit NDAs While AstraZeneca, Ac- this exclusivity will be unexpired on March a host of issues untouched in the March docu- telion Collect Approvals” — “The Pink Sheet,” 23, 2020, and that one or more patents ment, including the impact on combination Jan. 4, 2016). An advisory committee review claiming, among other things, the drug sub- products and therapeutic equivalence ratings. is scheduled for May 25. stance will be listed in the ‘Orange Book.’” FDA’s draft guidance on the “deemed to Insulin is one of several types of protein The BPCIA transition provisions do not be a license” provisions should be revised to products that will transition from regulation give FDA authority to deny the drug com- address the impact on drug/biologic combi- under Section 505 of the Food, Drug and ponent of a combination product rights nation products, Sanofi said. Cosmetic Act to Section 351 of the Pub- that flow from approval under the FD&C “For drug/biologic combination products lic Health Service Act on March 23, 2020. Act, Sanofi said, adding, “FDA must address that are approved or will be approved under Under FDA’s draft guidance, such transi- this issue in its implementation of the tran- NDAs during the transition period, it is possi- tion products will lose any remaining non- sition statute.” ble that – if FDA considers the primary mode orphan exclusivities on that date and be FDA should consider administratively of action for such a product to be attributed removed from the “Orange Book” (“Insulin separating the NDA for the drug/biologic to the transition biologic component – the Exclusivity: How Big Will The Fight Be?” — “The combination into an NDA for the drug com- approved NDA for the combination product Pink Sheet,” March 21, 2016). ponent (with its corresponding exclusivity may in its entirety be ‘deemed to be a license’ Innovators have challenged FDA’s ap- and patent listings) and a BLA for the bio- as of March 23, 2020,” Sanofi’s comments state. proach on exclusivity as contrary to the logic component, Sanofi said. “We recognize If that were the case, under the draft guid- statute and potentially unconstitutional. this is a particularly complex issue and we ance all Hatch-Waxman protections would be The agency’s proposed treatment of NDAs anticipate that FDA may need to address it extinguished and such products would be re- and ANDAs pending on the transition date through further proposals and elicitation of moved from the “Orange Book,” Sanofi notes. also has drawn strenuous objections from comments from affected stakeholders.” “For Sanofi, this issue is not theoretical,” the industry (see related story, “FDA Biologic Tran- Sanofi’s insulin market rival Novo Nord- company said. sition Plan Creates ‘Dead Zone’ For Applica- isk AS also has a drug/biologic combina- Sanofi’s 505(b)(1) application for a tions, Sponsors Fear,” cover). tion under FDA review. Xultophy, which fixed-dose combination of Lantus (insulin “We expect to obtain approval before the combines Tresiba (insulin degludec) with thepinksheet.com May 23, 2016 | Pink Sheet | 5 Biosimilars the GLP-1 agonist Victoza (liraglutide), will What Will ‘Deemed’ So that stakeholders have adequate time be the focus of a May 24 advisory commit- Products Look Like? to plan and prepare for these matters be- tee meeting. In their comments on the guidance, innova- fore the transition date, FDA should provide In contrast to Sanofi’s lixisenatide, which tor trade organizations identify several other guidance on this issue promptly.” has not yet been approved in the US, Novo’s areas in need of agency clarity, including Innovators also seek clarity as to how liraglutide has been on the market for six whether applications approved under Sec. approved NDAs with an “A” therapeutic years. The drug is protected by three-year 505 will be deemed standalone BLAs under equivalence rating will be treated under the Hatch-Waxman exclusivity until April 2019, Sec. 351(a) or biosimilars under 351(k). transition with regard to biosimilarity or in- 11 months ahead of the transition date. As FDA acknowledged in its draft guid- terchangeability determinations. However, Tresiba, which was approved in ance, 505(b)(2) applications do not com- “Given the two distinct statutory stan- September, stands to lose several months pletely align with the requirements of either dards – one for therapeutic equivalence of new chemical entity exclusivity under Section 351(a) or 351(k), the Pharmaceutical under the FDCA and the other inter- FDA’s draft guidance. Research and Manufacturers of America’s changeability under the PHSA – we urge In comments, Novo Nordisk also calls on comments state. “It is unclear how FDA in- that FDA consider a previously A-rated FDA to clarify the handling of fixed-combi- tends to reconcile these discrepancies when protein product that transitions to the nation products in which one component these applications transition to BLAs.” PHSA as biosimilar but not interchange- remains in the FD&C Act pathway and the “What is clear, however, is that FDA’s ap- able absent the sponsor providing sup- other transitions to the BLA pathway. proach could have significant implications plemental data to demonstrate that the “FDA must address which constituent for transition biological product sponsors,” transitioned product satisfies the BPCIA party they believe has the ‘single primary PhRMA said. “For instance, whether an appli- standards for interchangeability relative mode of action’ or at least indicate how cation is deemed licensed under Sec. 351(a) to its transitioned reference product,” the they plan to work with the sponsor to de- or 351(k) of the PHSA may affect whether Biotechnology Innovation Organization’s termine such criteria, since this determina- interchangeability provisions of the PHSA comments state. tion will affect whether the product transi- apply to the application, as well as the appli- “In any case,” BIO said, “clarity to stakehold- tions or not,” the company said. cable patent dispute resolution framework. ers on this issue is needed.”

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6 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 Regulatory Update Aegerion Juxtapid Settlement Shows REMS Have Teeth: Alternate Route To Enforce Off-Label? Cole Werble [email protected] Michael McCaughan [email protected]

egerion Pharmaceuticals Inc.’s pro- CEO, Marc Beer, for statements about the use two alternatives to a traditional “off- posed settlement with the Depart- product soon after approval on CNBC’s Fast label” claims: (1) using SEC disclosure laws Ament of Justice over its marketing of Money which FDA alleged went beyond rather than FD&C Act advertising and pro- the homozygous familial hypercholesterolemia approved labeling. motion laws; and (2) focusing on violations therapy Juxtapid includes one count related to That letter was cited by critics of FDA’s off- of the REMS agreement rather than tying violation of the FDA-mandated Risk Evaluation label enforcement policy as an example of claims directly to labeling. (DoJ did also & Mitigation Strategy for the product. overreach in the context of the broader (and pursue a misbranding claim based on inad- The company’s May 12 announcement of a increasingly successful) effort to expand First equate directions for use which is presum- preliminary settlement with DoJ and the Se- Amendment protections for communica- ably more like a traditional “off-label” case.) curities & Exchange Commission does not get tions by industry (“FDA’s Strategic Retreat In There are plenty of pieces of the Juxtapid deeply into the specifics of the violations. This Off-Label Case: Concedes Broader Use of Ex- REMS from which violations could arise is just the press release pre-alert in advance of parel, Gets Firm To File sNDA” — The RPM Re- either from failure to undertake all of the the formal settlement agreement; both DoJ port, December 2015). pieces or assure the effectiveness of train- and SEC have to finalize the terms, and then it FDA formally closed out the warning letter ing and patient selection. There is a training will be subject to acceptance in federal court. in 2014 – but DoJ subpoenas followed (“Ae- requirement, for example, for prescribers The specific reference to a REMS violation gerion Resolves FDA Warning About Juxtapid tied to correct patient choice and under- is significant, as it appears to be the first time Promotion But DOJ Probe Continues” — “The standing of hepatotoxicity risks. There is a REMS violation has been part of a broader Pink Sheet” DAILY, Aug. 27, 2014). also a separate prescription authorization DoJ marketing settlement. It may also point form for each patient to receive a prescrip- to an alternate enforcement mechanism to Two Alternatives To tion that says that patients have a clinical or punish off-label promotion without raising “Off-Label” laboratory diagnosis of HoFH and have had First Amendment defenses. With the settlement disclosure it now ap- pre-treatment liver-related lab tests. The press release announcing the settle- pears clear that prosecutors were able to The press release suggests that Aegerion ment describes the REMS violation tersely. also withheld information from investiga- One of the two counts of the FD&C violation, tors related to the REMS. The press release the release says “would involve an alleged notes that part of the proposed settlement is failure to comply with a requirement of the a five-year deferred prosecution agreement Juxtapid Risk Evaluation and Mitigation Strat- tied to Aegerion engaging “in obstruction of egies (“REMS”) program (21 U.S.C. §§ 352(y)).” The investigation justice relating to the REMS program.” The other count is for “marketing of Juxtapid The action is also noteworthy as a market- with inadequate directions for use.” Both are also dispels any sense ing crack-down on an orphan drug com- misdemeanor misbranding violations. pany. The investigation dispels any sense Aegerion is separately settling allegations that orphan product that orphan product companies have spe- brought by SEC related to the performance of companies have special cial protection from government marketing Juxtapid. Altogether, the company says it ex- charges because of the heightened public pects to pay $40 million to resolve the claims. protection from service of addressing a small underserved Juxtapid (lomitapide) was approved for patient market. homozygous familial hypercholesterolemia government marketing Aegerion was more vulnerable than most (HoFH) at the end of 2012. That approval charges because of orphan companies to a government action was explicitly based on the medical need in for two reasons: (1) there are other HoFH al- the very limited and seriously affected HoFH the heightened public ternatives and (2) the company created an population; lomitapide was not considered on-the-edge marketing push for Juxtapid safe for any other uses despite its significant service of addressing almost from the time of approval. efficacy in lowering LDL. a small underserved Aegerion has pushed the limits on the The company also got into early trouble tight manufacturer/patient relationship in with FDA for statements by the former patient market. the orphan field since the approval. Ae- thepinksheet.com May 23, 2016 | Pink Sheet | 7 Regulatory Update gerion went as far as to recruit current LDL lowering activity and a non-orphan Outstanding amounts would accrue inter- patients as “ambassadors” to talk to pro- price point. est from the date of the final agreements in spective patients. That program does not principle at a rate of 1.75% per annum, com- appear to be one of the direct causes for Impact Larger Than Dollar pounded quarterly.” The payments would the settlement but is indicative of an ap- Value of Settlement be accelerated if Aegerion is purchased or proach that pushed the boundaries for A $40 million settlement is relatively small in an if the company sells either of its two prod- patient support and patient recruitment. era of billion-dollar plus False Claims Act cases, ucts, Juxtapid or Myalept (metreleptin). While the FD&C Act violations are mis- but it is significant relative to Aegerion’s size. The timing of the settlement announce- demeanors with relatively small penalties The company says it will report first quarter ment from the company’s perspective is clear: directly attached, they provide significant sales of about $36 million. So the settlement to address the issue before new management leverage for prosecutors since they open is about 10% more than a quarter’s revenue. presents the first quarter results. (Mary Szela up the potential for criminal cases against Moreover, Aegerion is not a profitable was recruited to be CEO in early January.) individual executives and the potential company and the payment terms noted in From the government’s perspective, an for exclusion from federal programs un- the press release strongly suggest that the announcement a week earlier might have der the False Claims Act. final settlement amount was carefully cali- been more newsworthy as an event for the Juxtapid may be a relatively rare exam- brated to the company’s ability to pay. annual convening of the food and drug bar ple of an orphan drug where exclusion The press release describes a five-year at the FDLI annual meeting – where a set- could at least be considered as a credible schedule for payments: “approximately $3 tlement with an orphan drug company and threat, given the increasing pool of alter- million upon finalization of the settlement one that enforced REMS might have drawn natives available for patients. The drug with the DOJ and the SEC, approximately even more attention. was approved essentially simultaneously $3.7 million per year, payable quarterly, with another HoFH therapy, Genzyme for three years following finalization of the [Editor’s note: This article first appeared the Corp.’s mipomersen. More recently, the settlement, and approximately $13 million RPM Report. The Pink Sheet brings selected new PCSK9 cholesterol lowering class per year, payable quarterly, in years four and complementary coverage from affiliated pub- has entered the market with significant five following finalization of the settlement. lications to our readers.]

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8 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 Reimbursement Part B Demo Comments Overwhelmingly Negative, Uniform In Content Cathy Kelly [email protected]

takeholders on both sides of the proposed payment demon- The agency’s next steps will be to review the comments, potentially stration for Medicare Part B drugs appear to have made efforts modifying the proposal in response to them, and then to finalize the Sto organize comments to the Centers for Medicare and Medic- regulation. But the sheer volume of comments, combined with con- aid Services, with opponents constituting the overwhelming majority gressional concerns about the proposal – which already resulted in a of the stakeholder submissions. House hearing May 17 – and the limited runway CMS officials have About 92% of the approximately 1,300 comments posted online at until the end of the Obama administration, suggest the reg is unlikely regulations.gov as of May 18 were negative, based on an analysis by “The to get off the ground anytime soon. Pink Sheet.” That doesn’t bode well for the future of the demonstration, Patients, particularly those with cancer or inflammatory disease, which has faced strong opposition since it was announced in March. and individual commenters made up the largest group ( 53%) object- The proposal would test an alternative approach to paying physicians ing to the demonstration in terms of sheer numbers of comments for Part B drugs by reducing the amount of reimbursement that is tied to (see chart). a drug’s average sales price (ASP), thereby diminishing incentives for phy- Most of the patient comments focus on the ASP payment part of sicians to prescribe higher cost drugs (“CMS Unveils Bold Approach To Man- the demonstration. They express alarm over the prospect that a reduc- aging Medicare Part B Drug Costs” — “The Pink Sheet” DAILY, March 8, 2016). tion in Medicare payments will force their doctor to stop treatments, The demonstration would also test different approaches to paying requiring them to seek care elsewhere, such as in a hospital, which for drugs based on value, including reference-based pricing (“Medi- they argue would be less convenient and more expensive. Patients care Value-Pricing Options Vary Widely In Part B Payment Experiment” also take issue with the prospect of being forced into an experiment. — “The Pink Sheet,” March 14, 2016). Part B drugs are generally infused Many mention the drug they are taking by name; Janssen Pharma- or injected treatments administered in a physician’s office, infusion ceutical Cos.’ Remicade (infliximab) is cited frequently. And patients center or hospital outpatient center. often indicate their comment had been prompted by their health A Tough Sell, Any Way You Slice It

Opposed I Patients ⁄ patient groups ⁄ individuals % I Oncologists % Doctors or health care I Rheumatologists % providers I Ophthalmologists ⁄ retina specialists % 34% I Other health care providers ⁄ hospitals % I Drug manufacturers ⁄ other industry ⁄ policy experts %

In Favor I Doctors ⁄ medical students ⁄ individuals % I Advocacy groups ⁄ policy experts % 8% stakeholders I Payers ⁄ unions % in favor

Stakeholders broke into their expected camps in expressing opinions about the proposed Part B payment demonstration project. Physicians were somewhat divided, but as a group their comments were still overwhelmingly opposed.

Source: Pink Sheet analysis of comments posted by CMS

thepinksheet.com May 23, 2016 | Pink Sheet | 9 Reimbursement

Patients often indicate their comment increasing numbers of patients being sent to hospitals for treatment. Physician Craig Hildreth, of Missouri, says: “Because the new pay- had been prompted by their health care ment model reimburses us LESS than the acquisition cost of these new agents, and no professional business can survive being paid less provider, noting they received a letter than the cost of goods, our patients will be forced into hospitals for treatment, which will insure HIGHER costs to Medicare, restricted ac- from their physician’s office saying they cess to vital treatments including long waiting periods for treatment may have to go elsewhere for treatment similar to our VA system, and a complete deterioration in the overall health of our citizens living with cancer.” because of the demonstration. Organizations like the Community Oncology Alliance made similar arguments in their comments (“Medicare Payment Demo Would Put care provider, noting they received a letter from their physician’s of- Often-Prescribed Cancer Drugs ‘Underwater’” — “The Pink Sheet,” May fice saying they may have to go elsewhere for treatment because of 16, 2016). the demonstration. One typical comment, which is signed by Anthony Scalzo of New Off-Label Avastin Could Be Hurt York, states: Several ophthalmologists argue the proposal would not encourage “This new payment system is an experiment in which the test sub- physicians to choose the lowest-cost effective option, Roche’s Avastin jects (patients) have no protection. It is NOT a model. There has been (bevacizumab) off label. Instead, the change in payment would en- no forethought regarding the damaging ramifications of this draco- courage the choice of higher-cost options, such as Roche’s Lucentis nian proposal which will adversely affect thousands of patients and (ranibizumab) and Regeneron Pharmaceuticals Inc.’s Eylea (afliber- force the closure of many oncology practices severely limiting the cept) in order to cover costs and reduce losses, they say. public’s access to lifesaving treatments. Shame on you!!” The ophthalmologists also point out their supply of Avastin is al- ready being threatened by an FDA draft guidance regarding com- ICER’s Multiple Myeloma Review Called Out pounded biologics. The guidance includes a “beyond use date” of Although most patient comments appeared to focus on the revised five days for agents such as Avastin that is considered “unreasonably ASP payment part of the test, one subset of that group takes specific short,” according to ophthalmologists. issue with the prospect of CMS relying on the technology assessment Avastin is compounded into micro-doses suitable for treating con- conducted by the Institute for Clinical and Economic Review (ICER) to ditions such as age-related macular degeneration off label. The FDA develop a value-based approach to reimbursing drugs for multiple draft guidance was issued in February 2015 and it is not clear when myeloma. the final version will be released (“FDA Compounding Guidances Might For example, Inez Lensch of Iowa states: “ICER’s inherently flawed Cull Outsourcing List” — “The Pink Sheet” DAILY, Feb. 13, 2015). approach in measuring cost-effectiveness fails to take many things Several drug manufacturers commented on the proposal, all list- into account, and the results cannot accurately conclude the true ing numerous objections to the payment revision, the scope of the cost-effectiveness of myeloma drugs. Myeloma patients are already demonstration, timing and other issues. Manufacturers also took issue limited in their treatment options and treatment decisions should re- with the agency’s plan to launch value-based payment approaches flect a conversation between doctors and patients, not what CMS will beginning in 2017, maintaining there are many legal and regulatory cover as a result of ICERs research.” obstacles in the way. In the Part B proposal, CMS cites ICER as an independent organiza- tion whose value assessments could help facilitate new approaches The Favoring Few to reimbursement, though it does not specifically mention the group’s The relatively small number of commenters who generally support review of drugs for multiple myeloma. the demonstration included doctors and medical students, advocacy A draft version of the ICER report was released in early April (“ICER and policy organizations and some payers. Questions Cost Effectiveness Of Empliciti, Kyprolis, Ninlaro” — “The Pink Many of the comments by doctors and medical students were simi- Sheet” DAILY, April 8, 2016). It will be considered at an expert panel larly worded. They state: meeting convened by ICER May 26. “As a physician advocating on behalf of the patients I see every day, Physicians and healthcare providers comprise the second largest I support the proposal by the CMS to test a sensible set of models group in opposition to the demonstration (roughly 34%). They in- aimed at changing how CMS pays for medications under Medicare clude significant numbers of oncology, rheumatology and ophthal- Part B. High drug prices affect all types of patients... It is only through mology specialists, who would be hardest hit by the change because this testing of pilot reforms that we will be able to choose the best they prescribe the drugs that make up the largest categories of Part option for our health care system and our patients moving forward.” B expenditures. Advocacy organizations supporting the demonstration include Many of the health care providers identify themselves as commu- AARP, the Center for Medicare Advocacy, Families USA and the Medi- nity practices or infusion centers that would be unable to absorb a care Rights Center. Payers commenting in favor of the experiment in- decrease in reimbursement under the demonstration, resulting in clude Aetna Inc., Blue Shield of California and Kaiser Permanente.

10 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 european notebook / Recent developments and perspectives, reported by our European bureau Bayer Bids For Monsanto; Biosimilar Uptake Still Sluggish; EMA Enters Drug Pricing Debate John Davis [email protected]

fter a series of new CEO appointments over the past several months, Europe’s big pharma companies have moved on and are Anow looking to strengthen or reorganize parts of their businesses. Confirmation by Germany’s Bayer AG on May 19 that it was in preliminary talks to acquire Monsanto Co. is the latest example of an emerging trend among European pharmaceutical companies to pursue M&A. Monsanto said May 18 it had received an unsolicited, non-bind- ing acquisition proposal from Bayer, a judicious move that would strengthen Bayer’s agriculture business, one of three prongs to its life sciences business that consists of pharmaceuticals, consumer health and crop science. The proposal comes just weeks after Werner Baumann stepped up from Chief Strategy Officer to become CEO of Bayer, suggesting a desire to get on with putting some of his previous planning into effect (“European Notebook: All Change In The C-Suites; Maschek/shutterstock.com Victor credit: Photo EMA PRIME Starts; French Experts Recommend Phase I Changes” — “The Pink Sheet,” March 28, 2016). Slowly Growing Biosimilars Market Swiss multinational Novartis AG also announced plans May 17 to M&A activity is partly driven by the pressure big pharma will come reorganize its business, with the formation of two business units both under over the next few years from the marketing of biosimilar ver- reporting to CEO Joe Jimenez – Novartis Pharmaceuticals and Novar- sions of some of their leading products. But although there are more tis Oncology – that will form the Innovative Medicines division of the biosimilars approved in Europe than in the US, their slow uptake by company (“Novartis Rejiggers Pharma To Favor Oncology” — “The Pink physicians is still a cause for concern for biosimilar developers. That Sheet” DAILY, May 17, 2016). Meanwhile, France’s Sanofi has offered just was the view of several speakers at the Medicines for Europe’s (for- over $9bn for the US company Medivation Inc., a move that would merly the European Generics Association) annual biosimilars meeting, add weight to the Paris-headquartered big pharma’s cancer portfo- held in London at the end of April. lio (“Sanofi Earnings Emphasize Need For Medivation Buy” — “The Pink The uptake of biosimilar infliximab has been fairly slow in the five Sheet” DAILY, April 29, 2016). major EU countries, but has been higher in smaller European coun- tries, according to meeting presentations. For example in Denmark a more from europe proactive approach to using biosimilars has been adopted centrally by the health service, while in Norway, patients being treated with Other European developments covered over infliximab have been switched from one biosimilar, Celltrion Inc.’s the past month include: Remsima, to another, Hospira Inc.’s Inflectra, without any problems. Samsung Bioepis Co. Ltd./Biogen’s etanercept biosimilar, Benepal- CLICK “Comparing EU Vs. US Accelerated Pathway is, has also taken 20% of the market in Norway in the month after its Approval Times Makes Senior UK Regulator launch (“European Roll Out For Samsung Bioepis’s Etanercept Biosimi- ‘Slightly Defensive’” — “The Pink Sheet” DAILY, lar” — PharmAsia News, Jan. 19, 2016). But the use of Benapalis has May 17, 2016 not taken off in countries with decentralized purchasing, such as the “Biosimilars In EU Seeing Reduced Clinical UK. Some European countries are however dropping their opposition Data Requirements” — “The Pink Sheet” DAILY, to biosimilar switching. In France, the interchangeability of biosimilars May 10, 2016 is no longer proscribed, although patients who are switched must still be closely monitored, the regulatory agency ANSM said in a position “France Relaxes Stance On Biosimilar statement released May 3. Switching” — “The Pink Sheet” DAILY, May 6, 2016 Alleviating Budget Pain “EMA Seeks More Doctor Input Into Officials at Europe’s top regulator, the European Medicines Agency, Regulatory Decision-Making” — “The Pink have come out in favor of approving “me-too” products at a reason- Sheet” DAILY, May 4, 2016 able speed as one of a series of actions that could be adopted to help address the “budgetary pain” of high-priced new pharmaceuticals. thepinksheet.com May 23, 2016 | Pink Sheet | 11 european notebook

EMA Executive Director Guido Rasi and Senior Medical Officer lier, without relaxing the need to determine risk/benefit profiles, the Hans-Georg Eichler point out in the May 12 issue of the New England European regulators said (“Regulators Have Ways To Address Drug Af- Journal of Medicine that regulators are being “drawn into the acrimo- fordability, EMA Officials Say” — “The Pink Sheet” DAILY, May 12, 2016). nious debate over the cost of medicine,” and they suggest a series Other authors of the article included the head of the Netherlands reg- of measures that could be adopted to ensure a competitive market- ulator, Hugo Hurts, and the president of the German Federal Institute place, including the rapid approval of generics and biosimilars, the for Drugs and Medical Devices, Karl Broich. speedy approval of me-toos, and encouraging clinical studies that measure value. Regulators And Brexit They concede that drug regulations act to increase R&D costs, but The EMA is located in London, and is doubtless viewing the fast-ap- they are not the only factor, or even the most important one lead- proaching referendum on whether the UK should leave or remain in ing to high prices. Not only that, relaxing regulations are not likely to the EU with some trepidation, as a leave vote would mean finding a lead to lower prices, because companies tend to charge whatever new location. A raft of UK pharma CEOs have highlighted the risks to the market will bear. But regulators could facilitate the generation of UK jobs and life science research of leaving the EU, including Glaxo- patient outcome data in mandated post-approval studies, that could SmithKline PLC’s Andrew Witty, AstraZeneca PLC’s Pascal Soriot and then be used by payers, the regulators suggest. Pfizer Inc.’s Richard Blackburn. Additional food for thought was provided by Rasi and colleagues, Close election results are increasingly common in Europe; an incon- who were giving their personal views and not those of the EMA, in- clusive general election last December in Spain has meant a govern- cluded modifying the current development pathway for drugs. This ment could not be formed, and Spain’s voters go to the polls again on is economically inefficient, and a more flexible approach, such as the June 26, when increasing government spending on health is again adaptive approvals pathway that the agency is currently exploring, likely to be an important issue for candidates. might allow companies to stagger costs and generate revenues ear- Pricing Debated In Germany, Portugal In Germany, talks between the pharmaceutical industry and the gov- Risks Of Inhaled Steroids, ernment in the long-running Pharma Dialog process have come up New Generation Factor VIII with the possibility of updating the AMNOG legislation, including a cap or discount on spending on drugs in the first year after launch, when The risk of pneumonia associated with the use of companies are free to set their own prices. The health ministry is assess- inhaled corticosteroids to treat chronic obstructive ing whether it should draw up revisions for later this year on AMNOG, pulmonary disease (COPD) is well known and common, the law on pharma sector restructuring that emphasizes price controls. but their benefits continue to outweigh their risks, EMA In Portugal, the regulator Autoridade National do Medicamento e Produtos de Saude (Infarmed) has said it will reassess the reimburse- said April 29 after the completion of a review; there is no ment of 115 high-priced medicines, with the aim of saving around conclusive evidence of a difference in this risk between €35m ($39m) annually on the government’s drug spending. There are different products, EMA added. lower-priced therapeutic alternatives on the market, and companies are being encouraged to lower the prices of the high-priced medi- At the latest meeting of the Europe’s pharmacovigi- cines that include antibiotics, antidepressants and cardiovasculars. In lance risk assessment committee (PRAC) on May 10-13, Switzerland, a consultation will take place this year on the proposed the committee also concluded there was no evidence introduction of a reference pricing system. currently to suggest that patients treated with second- generation full-length recombinant Factor VIII products Pricing And Trade Deals are at a greater risk of developing inhibitors (antibodies) The European industry is deflecting criticism about high prices by than those treated with older products. pointing to treatments that have actually fallen in cost. Denmark’s pharmaceutical trade association, Lægemiddelindustriforeningen Published studies involving Bayer’s second-generation (LIF), noted May 18 the launch of generics for Alzheimer’s therapies agents, Kogenate and Helixate NexGen (both octocog has led to an 85% reduction in the amount Denmark spends on drugs alfa), should be monitored by the company to keep data for the condition. The annual cost of treating a patient with dementia up-to-date about the potential adverse event, the PRAC has declined from DKK 10,000 ($1,500) in 2012 to DKK 1,500 ($227) in added. Other PRAC reviews, including those involving 2015, LIF noted. Between 2007 and 2015, the number of dementia sufferers in Denmark has increased 57%, to around 164,000. Johnson & Johnson’s Invokana (canagliflozin), Gilead Denmark is one European country that could benefit from the Sciences Inc.’s Zydelig (idelalisib), direct-acting hepatitis signing of the Transatlantic Trade and Investment Partnership (TTIP) C agents and gadolinium-containing contrast agents, between the EU and the US. Pharmaceuticals account for 13.5% of are continuing. all Denmark’s exports, and the number of Danes working in the sec- tor has doubled since 2000. TTIP could further increase jobs and ex-

12 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 european notebook ports in the country, argues a LIF legal advisor. This increase would zerland, to another US company, Wilmington, Delaware-based IIncyte come about by mutual recognition of GMP inspections, harmonis- Corp., that includes medical, sales and marketing operations. ing requirements for pediatric studies, and the continuation of IP Going the other way, UK biotech Scancell Holdings PLC has opened protection and enforcement for pharmaceuticals. an office in San Diego, California. The company has a novel immuno- While all eyes are on the TTIP, the free trade bloc consisting of Ar- therapeutic approach to cancer in Phase I/II studies. And Germany’s gentina, Brazil, Paraguay, Uruguay and Venezuela, known as Merco- Merck KGAA, that operates as EMD Serono Inc. in the US, announced sur, and the EU, are again taking tentative steps to forge a free trade May 4 an expansion of its facilities in Carlsbad, California, to manufac- agreement, a process that has been on and off for decades. The cur- ture viral and gene therapies. rent program restarted in 2010, and numerous talks have been held since then. On May 11 negotiating offers were exchanged that will Last Word: Salmon Fishing now be discussed in detail by both sides. Mercosur is the 6th largest And finally, any researcher feeling disappointed by the slow develop- export market for EU pharmaceuticals. ment of human DNA vaccines, particularly against cancer, might be heartened by the first recommendation from Europe’s Committee Investing in Europe for Veterinary Medical Products at the end of April to approve a DNA Novartis announced it would invest €68m in its cell culture manu- vaccine. Although the recommendation was to protect salmon from facturing facilities in Marburg, Germany, that will produce biologics salmon pancreas disease caused by a particular virus, the approach and provide 50 new jobs. Previously, the sale of Novartis flu vaccine was judged to be sound, with antigenic proteins being synthesised business had cast doubt on the company continuing operations at within the fish, and with no environmental risk from the product, that the site. Troubled Ariad Pharmaceuticals Inc. has stepped back from was degraded during passage through the fish gastrointestinal tract. Europe by selling its European operations, based in Lausanne, Swit- Vaccinated fish were also safe to eat, the CVMP ruled.

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Pink Sheet SScricrip Pharma intelligence | Pharma intelligence | 14 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 R & D FLAME Shoots LABA/LAMA Combos Up To First Choice In COPD Emily Hayes [email protected]

AN FRANCISCO – New data from Call For Guideline Change daily product marketed in the US is the same. Novartis AG’s head-to-head FLAME Novartis’ global head of development for the “Exhaustive studies were performed to see Sstudy support wider use of LABA/ respiratory franchise Mark Levick stressed that how a half dose twice a day works, and the LAMA combinations in at-risk patients for the results don’t have specific ramifications for good news is that it is almost identical to the preventing exacerbations in COPD – in the US market, as Ultibro is not available there. once-daily dose,” she said. preference to a combination of a LABA with Tosh Butt, the head of the respiratory business A study has not been done comparing an inhaled corticosteroid – and could trig- at competitor AstraZeneca PLC, was reluctant the twice-daily dose to Advair/Seretide, but ger a change in global guidelines for treat- to speculate on the impact on the US mar- Wedziga said that she expects the results ment, researchers say. ket due to dosing differences but noted that would be “identical” to FLAME. The FLAME study found that Novartis’s there’s a place for both combinations: “ICS/ Wedziga also said that she expects that oth- once-daily Ultibro Breezehaler, which com- LABA for a certain patient type, LAMA/LABA er LABA/LAMA combinations would also have bines the long-acting beta agonist (LABA) for another patient type.” similar results, though studies are not available. indacaterol with the long-acting muscarinic However, experts think that the FLAME Three others are on the market in the US. antagonist (LAMA) glycopyrronium, was study broadly supports a class effect for the GlaxoSmithKline’s AnoroEllipta (umeclidinium/ superior to GlaxoSmithKline PLC’s aging LAMA/LABA combinations and therefore has vilanterol), which is dosed once daily, became blockbuster Advair/Seretide, which com- broad implications globally. the first LABA/LAMA combination with an ap- bines the LABA salmeterol with the inhaled Guidelines will need to be rewritten to posi- proval in 2013 (“FDA Approves GSK’s Anoro El- glucocorticoid fluticasone, in terms of fewer tion LABA/LAMA as the preferred regimen for lipta, The First LABA/LAMA Combination” — “The disease flare-ups. FLAME included 3,362 pa- treating COPD patients at risk for exacerbations, Pink Sheet” DAILY, Dec. 18, 2013). Boehringer tients who had an exacerbation within the Wedziga said during an ATS press briefing. Ingelheim GMBH’s once-daily Stiolto Respimat last year. The annual rate of exacerbations, The Global Initiative for Chronic Obstruc- (tiotropium/olodaterol) received FDA approv- the primary endpoint, was 11% lower for tive Lung Disease (GOLD) guidelines advise al in 2015. And most recently, AstraZeneca’s patients taking Ultibro versus Seretide and using a long-acting muscarinic antagonist as BevespiAerosphere (glycopyrolate/formoterol) the dual bronchodilator approach was also monotherapy or a LABA/ICS combination for was cleared for the US in April (“Keeping Track: superior on secondary endpoints (see box). first-line treatment in this setting. Approvals For Nuplazid, Cabometyx, Bevespi And The message from the study is that the During the press briefing, Wedziga said she More; Digital Aripiprazole Tablet Needs More treatment with dual bronchodilators is the prefers once-daily treatment because she Study” — “The Pink Sheet,” May 2, 2016). “combination of first choice in COPD,” lead thinks it improves overall compliance, but that The GOLD guidelines are revised on a yearly investigator Jadwiga Wedzicha said during she expects that in terms of efficacy, the twice- basis. Claus Vogelmeier, who chairs the GOLD a May 15 briefing at the American Thoracic Society annual meeting in San Francisco. Wedziga, of the Imperial College London, FLAME Facts And Figures and colleagues published their results in the New England Journal of Medicine the • Tested: Novartis’ Ultibro (LAMA/LABA) vs. GSK’s Advair/Seretide (LABA/ICS) for same day. Novartis had issued a top-line re- reducing exacerbations in noninferiority study of 3,362 patients in 43 countries. lease last November. The Ultibro Breezehaler is available in 80 • Primary endpoint: Ultibro proved non-inferiority then superiority in terms countries, including EU members, but not of lower annual rate of exacerbations, in patients with a range of disease in the US. In the US, the company got a severity and eosinophil counts (3.59% vs. 4.03%). twice-daily product approved in October 2015 and markets it as Utibron Neohaler. No- • Secondary endpoints: Ultibro superior for secondary endpoints related to vartis reported strong growth for Ultibro/ the time to first exacerbation of any kind, time to first severe exacerbation, lung Utibron in the first quarter, with sales up by function as measured by forced expiratory volume, and effect on quality of life. 58% to $78m. For its COPD products alto- • Safety findings: Similar adverse event rates, but significantly higher rate of gether, the company reported first quarter sales of $146m, up by 15% from the same pneumonia for Advair/Seretide (4.8% vs. 3.2%). No difference in mortality. period in 2015.

thepinksheet.com May 23, 2016 | Pink Sheet | 15 R & D

The FLAME study is the first large study comparing a Farmaceutici SPA’s CHF 5993 and AstraZen- eca’s PT010, Datamonitor analyst Christina LAMA/LABA combination against the LABA/ICS standard Vasiliou noted in an April 8 report. of care, and the results are being viewed as enough to “While pulmonologists and primary care prompt practice changes. physicians are excited about the potential of triple therapies to simplify the management science committee, attended the FLAME press guidelines, but in this case the “data are ex- of COPD for highly symptomatic patients, pay- conference and after the briefing he told the tremely persuasive,” to support a change in ers hold a more reserved outlook as they are Pink Sheet that he believes that a guideline treatment algorithms, adding that it would be unconvinced about the long-term efficacy of change toward a preference for LAMA/LABA good to see similar studies in different patient such therapies, and are concerned about their over LABA/ICS or a single bronchodilator in at populations. potential overuse,” she said. risk patients will “quite likely” be considered in Peter Calverley, professor of pulmonary and FLAME investigator Wedziga suggested that the “near future,” with change possible this year rehabilitation medicine at the University of there should still be a role for steroids for at-risk or the beginning of next year. Liverpool, expects it’s a class effect and noted patients who still have exacerbations while on However, the process is complicated and a that past studies showing the value of two LAMA/LABA therapy. lot of people are involved, so the outcome is bronchodilators over one complement the Researchers presented a post-hoc analysis difficult to predict, said Vogelmeier, who is di- FLAME data. “FLAME fills in another part of the of the effects on exacerbation of withdrawing rector of pulmonary medicine at the Marburg story,” he said in an interview. inhaled glucocorticoids from dual LABA LAMA University Hospital in Germany. The clinician added that there probably is therapy in Boehringer’s WISDOM study at the Typically, the guidelines do not make rec- “enough momentum” now for that to happen,” ATS meeting on May 17. ommendations for specific doses or particu- with respect to dual bronchodilators as a first- The study looked at Boehringer’s LAMA lar products, he said. So if there is a change, line therapy for people with a history of exac- Spiriva (tiotropium), GSK’s LABA Serevent (sal- it likely would be broadly for the LAMA/LABA erbations and who are symptomatic. meterol) and ICS Flonase (fluticasone) in 2,296 combinations. COPD patients with a history of exacerbations. Payers Focus On Generics The rate of exacerbations after ICS withdrawal LABA/LAMA Migration In terms of changing practice, a lot depends corresponded to the counts of eosinophils, a The FLAME study is the first large study com- on whether payers feel comfortable with go- type of white blood cells at various thresholds. paring a LAMA/LABA combination against ing to a dual bronchodilator approach from And in those at higher count thresholds, this the LABA/ICS standard of care, and the results the beginning and ultimately that may be a was a significant finding. Boehringer reports are being viewed as enough to prompt prac- financial decision. Calverley doesn’t see a sci- that based on the results, only 20% of the tice changes. entific basis for staged therapy, starting with study population benefited from having a Novartis’ Levick said that the LABA/LAMA a single bronchodilator and adding on. steroid on top of the LABA and LAMA. Eosino- regimen offers the chance for patients to have The COPD market is very competitive and phils are already being used as a biomarker in an effective treatment, but without the ste- has been confronting generic erosion in recent asthma, though FDA has not fully endorsed its roids and side effects that come with steroids. years (“COPD Market Snapshot: New Products, use (“Birth Of A Biomarker? FDA Doesn’t Define “From a medical practice point of view it is Limited Differentiation” — “The Pink Sheet,” May 6, Eosinophilic Asthma, Defers To Docs On Nucala” significant because it offers an alternative for 2013). Two ANDAs for generic versions of Advair — “The Pink Sheet,” March 21, 2016). prescribers now,” he said in an interview. are pending at FDA, with action dates in 2017. The data raise the question of whether you In a May 15 NEJM editorial accompanying “US payers plan to use step therapy require- might be able to know “from the get go” who FLAME results, the University of North Caroli- ments and co-pay differentials as tools to drive should be on what treatment – prescribing na’s James Donohue said that the study does uptake of generic inhaled corticosteroid/long- could be much more rational in the future, said appear to be enough to support the use of acting beta 2 agonist (ICS/LABA) inhalers in an Calverley, who was an author on the publication LABA/LAMA regimen over the a LABA-in- effort to contain costs,” Datamonitor analyst of the WISDOM study in the Lancet on April 7. haled glucocorticoid regimen, though more Astrid Kurniawan said in a May 12 report. The eosinophil count looks like a reason- trials are needed to be sure that “FLAME has There has been no clear LAMA/LABA win- able biomarker for identifying those who can cast a new light on prevention of COPD ex- ner with payers so far, and success may come benefit from inhaled corticosteroids, he said. acerbations.” down to pricing, she concluded. However, prospective datasets that random- “The FLAME trial shows that a LABA-LAMA ize patients by eosinophil counts are needed regimen appears to be safe and efficacious Role For Triple Therapy? to support use in clinical practice, he said. with respect to a wide variety of outcomes, The FLAME data also raise questions about In his NEJM editorial on FLAME, Donohue including exacerbation rate, lung function and the role of triple LAMA/LABA/ICS therapy. concluded: “I think the final word on the use health status,” Donohue concluded. The late-stage pipeline for COPD has a of blood eosinophil count as a predictor of Wedziga said at the briefing that normally strong focus on these triple combos, with response to inhaled glucocorticoids is not one study might not be enough to change three in Phase III – GSK’s FF/UMEC/VI, Chiesi yet established.”

16 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 R & D Can Checkpoint Inhibitors Jump-Start Glioblastoma Drug Development? Emily Hayes [email protected]

t’s early days yet, but checkpoint immunotherapies have the po- tential to jump-start the high-risk, high reward glioblastoma drug Idevelopment space, which has been prone to many a setback, the latest casualty being Celldex Therapeutics Inc.’s Rintega vaccine. Checkpoint inhibitors, namely Bristol-Myers Squibb Co.’s Yervoy and Opdivo, Merck & Co. Inc.’s Keytruda and Roche’s newly approved Tecentriq (atezolizumab), have dramatically shaken up the oncology landscape. Among many other studies of its checkpoint inhibitors in various tu- www.primalpictures.com credit: Photo mor types to be presented at the American Society of Clinical Oncology GBM tumors usually develop in the cerebrum. annual meeting in June, Bristol will be presenting updated data for GBM patients enrolled in a Phase I cohort of the Phase III CheckMate 143 trial PD-L1 inhibitor durvalumab (MEDI4736) are ongoing, and Roche pre- (see sidebar, p. 20). sented preliminary safety results from a GBM cohort of atezolizumab It’s unclear how far the checkpoint inhibitors will go in terms of in a Phase I study in 2015, but the data are very early and in a small breadth of indications, and whether they can score another break- group of patients. through in treating glioblastoma multiforme patients, who have a ter- Bristol got an early start with Opdivo (nivolumab) in glioblastoma, ribly poor prognosis. The research literature suggests a median survival having initiated the Phase III cohort of the CheckMate 143 study of of one year for GBM and a five-year survival rate of less than 10%. Opdivo with or without the CTLA-4 inhibitor Yervoy (ipilimumab) Datamonitor Healthcare estimates that the number of GBM cases diag- against Avastin for recurrent disease back in 2014. That study is event- nosed in the US, Japan and five major EU markets will rise from 27,230 in driven and results could be available later this year. 2013 to 35,420 in 2033, based on demographic trends and other factors. A second Phase III study – CheckMate 498 – tests Opdivo against Merck’s alkylating chemotherapy agent Temodar (temozolomide), Merck’s standard-of care alkylating agent Temodar, both on top of ra- now generic, is commonly used with radiation therapy for first-line pa- diation therapy in newly diagnosed GBM with unmethylated MGMT. tients and may also be used as a monotherapy in the second-line setting. Methylation of the MGMT gene is associated with better response to Roche’s Avastin (bevacizumab) is an option for recurrent GBM. The chemo and a better prognosis, whereas those with unmethylated drug received accelerated approval for this indication in 2009 from MGMT have a poorer prognosis and limited treatment options. FDA, but was not approved in Europe. Two Phase III studies in newly With that study, Bristol “strategically positioned Opdivo head-to- diagnosed GBM yielded mixed results – AVAglio showed an improved head with Temodar,” in MGMT unmethylated type GBM, Datamonitor quality of life but an RTOG study showed the opposite, and neither analyst Brandon Goode wrote in a recent report on the GBM pipeline. study showed a benefit for an improvement in overall survival (“Avas- “Positive data from this study would propel Opdivo into the mar- tin QoL Data In First-Line Glioblastoma Muddy Expansion Plans” — ket as the only therapy dedicated specifically to the treatment of this “The Pink Sheet,” March 3, 2014). subtype of disease that affects a large share of patients,” Goode noted. Still, many clinicians still find value in using Avastin in relieving The primary completion date on CheckMate 498 is March 2019. symptoms, such as edema, and minimizing the need for steroids, and would like to see it retain labeling for glioblastoma, Patrick Wen, direc- Tough Nut To Crack tor of the Dana Farber’s Center for Neuro-Oncology, commented in There are many challenges in developing a drug for glioblastoma, an interview. including difficulty getting over the blood-brain barrier, tumor resis- As with other cancer types, interest in using checkpoint inhibitors tance mechanisms, heterogeneity of disease and the fact that micro- has been rising in brain cancer. However, as Johns Hopkins specialist scopic disease is invisible on imaging studies, Mark Gilbert, senior in- Michael Lim and colleagues pointed out in an August 11, 2015 article vestigator and chief of the National Cancer Institute’s neuro-oncology in Nature Reviews Neurology, they are relying on data extrapolated branch at the National Cancer Institute, said in an interview. from other tumor types, and “at present, the exact involvement of That has made it tough to get through Phase III and approval (“R&D checkpoint pathways in brain tumor pathogenesis is unknown.” Realities Disturb Dreams About Orphan Brain Cancer Blockbusters” — Pharmaceutical Approvals Monthly, October 2010). Bristol’s Early Start EMD Serono Inc.’s cilengitide and AstraZeneca PLC’s Recentin Of the leading four sponsors of PD-1/L1 checkpoint inhibitors, Bristol (cediranib) are among the drugs that failed in the past. Exelixis Inc. is by far the most invested in GBM. Early-stage, investigator-sponsored was bullish on taking its multikinase inhibitor XL184, now marketed studies of Merck’s Keytruda (pembrolizumab) and AstraZeneca PLC’s as Cometriq (cabozantinib), into Phase III, but the indication dropped

thepinksheet.com May 23, 2016 | Pink Sheet | 17 R & D from its pipeline in 2011 (“Full Steam Ahead For Exelixis’ Phase III Glio- study of recurrent GBM, but Avastin is not a terribly effective drug and blastoma Trial” — Pharmaceutical Approvals Monthly, October 2010). that wasn’t the target population for the pivotal trial, Goode added. Celldex’s Rintega (rindopepimut), a cancer vaccine designed to in- The Rintega failure emphasizes the need for more randomized duce immunity against EGFRvIII, a permanently activated mutation mid-stage work, because the use of single arm studies with historical on tumor cells, is the latest failure. The drug had breakthrough therapy controls can be misleading, Lim, who is director of brain tumor im- status with FDA for EGFRvIII-positive glioblastoma, which accounts for munotherapy at Johns Hopkins, told the Pink Sheet. about 30% of GBM cases. NCI’s Gilbert suggested that the optimal study might be an integrat- ed randomized Phase II/Phase III study, where efficacy is examined early Rintega: Lessons Learned and researchers move quickly to a fully powered Phase III study if they The company announced the failure of the Phase III ACT IV study in EG- see a signal. Gilbert is the principal investigator on a multi-arm study of FRvIII+ newly diagnosed GBM in March. The trial was terminated early checkpoint inhibitors and Temodar that the NCI is running with such when it became clear the drug was unlikely to improve overall survival, a design (NCT02311920). The first cohort has enrolled and once the but it was shown to be safe (“Celldex At A Loss To Explain Why Brain Cancer safety evaluation of the patients is complete, the next one will open. Vaccine Rintega Failed Phase III” — “The Pink Sheet” DAILY, March 7, 2016). Gilbert commented that the EGFRvIII target was interesting, with some promising earlier stage results, and that following the failure, Johns Hopkins’ Lim sees a silver lining “we need to always, always remember that there are other cancers that were in the same boat we are in, like melanoma, which now is a in the Rintega trial failure. The study phenomenally successful area.” has hopefully established that Rintega Bristol Undeterred is safe and the door is still open to BioMedTracker analyst Edny Inui acknowledges the Rintega failure research of well-tolerated vaccines as was disappointing but does not expect it will keep pharmas from part of combinations, including with the space, which offers a large market share for those who can make even a small impact. PD-1 and IDO inhibitors. Inui does expect, however, that interest will shift to more targeted immunotherapy as opposed to global immunotherapy. The company said that it was at a loss to explain the outcome be- No vaccine has succeeded in 50 years of ongoing effort, but that cause performance in mid-stage single arm studies of newly diagnosed “will not detract enthusiasm for immuno-oncology approaches for patients had looked promising in comparison with historical controls glioblastoma,” Bristol’s Jean Viallet, global clinical research lead in on- with Temodar. But in the pivotal trial, performance of the comparator cology, asserted in an interview. Temodar was far better than expected, according to the company. Johns Hopkins’ Lim sees a silver lining in the Rintega trial failure. The Overall survival in an interim analysis was 20.4 months for Rintega study has hopefully established that Rintega is safe and the door is still vs. 21.1 months for the comparator Temodar (both drugs were given open to research of well-tolerated vaccines as part of combinations, on top of radiation). including with PD-1 and IDO inhibitors, he said. Researchers interviewed for this article said that they would need to In January, a Duke University investigator started a study see the full results to understand what happened in the study. (NCT02529072) of a dendritic cell vaccine developed in-house in Some question whether the right historical controls were used for combination with Opdivo in 66 patients. comparison in the mid-stage studies. Celldex noted that the OS for temozolomide ranged from 12 months to 18 months across trials. What’s In The Pipeline But there are other historical studies that show similar results for te- The industry-sponsored pipeline is diverse and includes PD-1 inhibi- mozolomide as the Rintega pivotal trial specifically in EGFRvIII+ newly tors, gene therapies and cancer vaccines, Goode noted in his GBM diagnosed patients with stable disease, Datamonitor’s Goode pointed pipeline report. out. In a trial published by Nicola Montano and colleagues in the journal According to the BioMedTracker database, for brain cancers overall, Neoplasia in December 2011, the OS for EGFRvIII+ patients treated with including malignant gliomas, anaplastic astrocytomas and GBM, there Temodar was 19.3 months, which is close to ACT IV results, he noted. are now nine drugs in Phase III, 39 in Phase II and 24 in Phase I. There H.C. Wainwright analyst Swayampakula Ramakanth also highlight- are also 73 suspended programs in the pipeline. ed the same study in a March 8 note, observing that “the majority of Six drugs are in late-stage development for GBM. In addition to the patients in the Montano study had received gross total resection Opdivo, they include two cellular therapies – Northwest Biothera- (59 out of 73 patients) and received standard-of-care treatment con- peutics Inc.’s DCVax-L vaccine and ImmunoCellular Therapeutics sisting of radiotherapy and temozolomide, similar to the patients in Ltd.’s ICT-107 autologous dendritic vaccine ICT-107 – and VBL Thera- the control arm of the ACT IV study.” peutics’ gene therapy VBL-111, which is being developed in combi- The Montano data suggest EGFRvIII expression was a positive, not a nation with Avastin (see chart). negative prognostic factor in the pivotal study of Rintega, Ramakanth said. In their Nature Reviews Neurology paper, Lim and colleagues noted Rindopepimut did show a survival benefit over Avastin in a Phase II that “the traditional assumption has been that immune responses in

18 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 R & D the CNS were limited,” because of the blood-brain barrier, among oth- Inui noted that along with increased interest in exploring checkpoint er reasons, but “this view has recently been challenged, as it has be- inhibitors will come a rise in development work to tackle the challenge come clear the CNS [central nervous system] actively communicates of how to sequence and use immunotherapies together and with stan- with the immune system.” dard-of-care treatments. A range of checkpoint inhibitors and other Regarding checkpoint inhibitors, the authors were enthusiastic, types of immunotherapies could potentially play a role in treatment. while cautioning of challenges in glioblastoma studies, including the “That’s something you will see more of as immunotherapy fever lack of assays for immune response, the need for different measures of takes over in the glioblastoma space,” Inui said. response for checkpoint inhibitors, and management of immune-re- Glioblastoma tumors are highly immunosuppressive, which sug- lated CNS adverse events, they noted. gests a combination approach is needed, and more research is also Bristol’s Viallet said that the field is clearly focusing on reversing needed to develop biomarkers to help predict response, Lim said. mechanisms of immunosuppression in the tumor microenvironment as the most promising way to bring immuno-oncology to patients Personalized Approaches with glioblastoma. The trend in recent years has been for therapies to be personalized, The rate of PD-L1 expression is very high in GBM at 88% of first-line based on mutation and MGMT methylation status, the Datamonitor tumors and 72.2% in recurrent disease, and PD-1 therapy improved report notes. overall survival in preclinical studies, Goode noted in his report. Fur- Immunocellular Therapeutics’ ICT-107 autologous dendritic cell thermore, there are some clinical data; results for 10 patients in a vaccine targets the human leukocyte antigen A2 (HLA-A2), which is safety cohort of one study suggested biologic activity of checkpoint present in about half of patients. This candidate targets six different inhibition in GBM. antigens associated with GBM and by “targeting multiple biomarkers, Goode cautioned in his pipeline report that excitement aside, the ICT-107 overcomes the tumor escape mechanisms commonly associ- supporting clinical data are lacking for checkpoint inhibitors. ated with single antigen targeting,” Goode noted.

Glioblastoma: Late-stage Pipeline Sponsor Drug Target+ Drug Type Pros Cons Northwest DCVax-L Immune Dendritic cell Could be first brain cancer vaccine Personalized and complex Biotherapeutics system vaccine to market. Compassionate use in manufacturing. Expected to be Germany lends credibility. Early data expensive. Limited trial data for suggest long-term survival benefit. small number of patients, not peer Safe, infrequent dosing after initial reviewed. infusions. Immunocellular ICT-107 AIM-2, gp100, Dendritic cell Targets multiple biomarkers to Limited to HLA-A2 positive disease. Therapeutics HER-2, Il- vaccine overcome tumor escape. Safe, Likely to be expensive. Personalized 13ra2, MAGE- infrequent dosing. Works in un- and complex, Likely to reach market 1, TRP-2 methyated and methylated GBM. long after competing DCVax-L. Bristol-Myers Opdivo PD-1 Monoclonal Bristol’s brand-success in Lack of GBM-specific data. Squibb antibody numerous cancers. Well-tolerated. Expensive when used with Yervoy. Tested in high unmet need subtype: Biweekly dosing is more frequent unmethylated GBM. than vaccines. Vbl VB-111, TNF-alfa Gene therapy Novel mechanism involving gene Use with Avastin means more Therapeutics developed in biologic therapy. Avoids problems with treat- expensive and more side effects than combination ment resistance by targeting tumor other pipeline drugs. May not enter with Roche’s vasculature. Less costly to make than EU as Avastin not approved there. Avastin dendritic vaccines.

Tocagen Toca-511 and DNA Gene therapy Novel mechanism of action involving Limited to patients undergoing Toca Fc biologic gene therapy elicits antitumor planned surgery. Limited to recurrent and small autoimmune response and kills GBM. Company lacks experience in molecule cancers directly. Less costly to make market. combination than dendritic vaccines. +AIM-2 = absent in melanoma 2; gp100 = glycoprotein 100; HER-2 = human epidermal growth factor receptor 2; IL-13Ra2 = interleukin-13 receptor alpha 2; MAGE-1 = melanoma antigen-encoding gene 1; PD-1 = programmed cell death protein 1; TNF-alpha = tumor necrosis factor-alpha; TRP-2 = tyrosinase-related protein 2 Sources: Datamonitor Healthcare, BioMedTracker. Examples of strengths and weaknesses based on Datamonitor assessments. thepinksheet.com May 23, 2016 | Pink Sheet | 19 R & D

“Additionally, the therapy targets biomarkers found on cancer stem were not peer-reviewed, Goode noted in his report. cells, which are believed to be a key contributor to the proliferation Interim Phase III results were expected in 2015 but never material- and recurrence of tumors,” the analyst added. ized. A partial clinical hold was placed on the trial in December, stop- However, while ICT-107 improved progression-free survival signifi- ping enrollment of new patients. In a May 2 statement, the company cantly in a Phase II study, it failed to improve OS, he noted. said it has enrolled over 300 out of 348 patients in the pivotal trial and A pivotal study will stratify outcomes based on MGMT methylation sta- hopes for a resolution soon. tus, which could enhance positioning with payers, in Datamonitor’s view. The company also said it was in talks to run three different Phase On the other hand, ICT-107 development trails behind NorthWest II studies of its vaccine in three different combinations. It did not dis- Biotherapeutics’ DCVax-L, which Datamonitor points out has a shot close the tumor types or trial partners, aside from saying the deals at being the first brain cancer vaccine on the market, with approval involved “leading participants in the immunotherapy field.” possible as early as the second quarter in 2017 in the US (versus a The partial hold is unlikely to have a big effect on the study consid- third-quarter 2020 US entry for ICT-107). ering 300 were already enrolled and continued, Inui commented, but DCVax-L still needs to prove itself clinically, however. Early stage the hold is not a good sign for development generally if robust results data looked promising but were derived from very small trials that aren’t observed in GBM.

What To Look Out For In Glioblastoma At ASCO Highlights of abstracts at the upcoming Opdivo alone was also better toler- bevacizumab-naive patients could be American Society of Clinical Oncology ated than the combination, “consistent even greater as endoglin upregulation meeting include early studies in recur- with observations in other tumor types,” is hypothesized to be a VEGF inhibitor rent glioblastoma from Bristol-Myers analysts noted. escape pathway,” the report adds. Squibb Co., Tracon Pharmaceuticals Bristol said it will be presenting ad- The combination is in Phase II for Inc. and Ziopharm Oncology Inc., ditional, updated data at the meeting. Avastin-naïve GBM. according to a meeting preview from BioMedTracker analysts also dubbed Ziopharm’s updated Phase I results BioMedTracker. Tracon as one of six companies to watch for its adenovector-based technology- Glioblastoma multiforme is a high- at the meeting, based on Phase II recurrent based candidate Ad-RTS-hiL-12 in risk space, considering all of the past GBM data for TRC105 (Abstract #2035). combination with oral veledimex (IXN- trial failures, but it also offers rewards The candidate is a first-in-class human 1001), an activator ligand, in heavily for sponsors that succeed in even chimeric monoclonal antibody that binds pretreated, recurrent glioma, including marginal improvements and research- to CD105 (endoglin), a receptor over- GBM, at ASCO are also noteworthy. ers are hopeful about the potential of expressed on proliferating endothelium One injection of Ad-RTS-hIL-12 checkpoint inhibitors (see related story, that is required for angiogenesis. The drug was administered into patients’ brain “Can Checkpoint Inhibitors Jump-Start Glio- has shown efficacy in kidney cancer in the tumors and veledimex was given orally blastoma Drug Development?” — “The Pink past and with its novel mechanism could to activate production of IL-12, an Sheet,” p. 17). play a role for multiple cancers treated anti-cancer cytokine, and an immune Bristol is presenting updated data with Roche’s Avastin (bevacizumab), the response at the tumor site, the abstract from the first cohort of the CheckMate analysts noted. notes (#2052). 143 study at the ASCO meeting, which The study tested TRC1-5 with Avastin “Even at its lowest dose, the presence will be held June 3-7 in Chicago. in Avastin-refractory patients. Median of IL-12 in the bloodstream could be de- One ASCO abstract (#2014) includes overall survival for 15 patients in the tected, demonstrating that veledimex is data for 20 patients with recurrent GBM study taking the combination was 5.75 bioavailable and crosses the blood-brain who took the PD-1 inhibitor Opdivo months, “which is higher than the 4 barrier at sufficient levels,” the investiga- (nivolumab) alone versus two different month OS historical control data for tors reported. doses of a combination with CTLA-4 [bevacizumab]-refractory GBM, but a With follow-up of 6.2 months, 10 of inhibitor Yervoy (ipilimumab). larger controlled study is necessary to 11 patients were alive. According to the study abstract, the determine the actual clinical benefit,” BioMedTracker analysts said that the 12-month overall survival rate was 40% the report notes. The combination was “results confirm the ability to trigger for Opdivo alone versus 30% or 25% also well-tolerated. an immune response in brain tumor for the combination of Yervoy/Opdivo, ‘While these are early results in only cells via an oral agent and are encourag- depending on the dose – figures that Bi- 15 patients, we believe that the ben- ing for the further development of this oMedTracker described as “encouraging.” efit of the combination of TRC105 in adenoviral vector-based technology.”

20 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 Generic Drugs FDA’s ANDA Approvals Sponsor Active Ingredient Dosage; Formulation Approval Date North Creek Dapsone 25 mg and 100 mg; tablet 5/10/2016 Zydus Glyburide 1.25 mg, 2.5 mg and 5 mg; tablet 5/10/2016 Novel Labs Desoximetasone 0.25%; topical ointment 5/10/2016 Orion Propafenone HCl 150 mg, 225 mg and 300 mg; tablet 5/11/2016 Qilu Oxaliplatin 50 mg/vial and 100 mg/vial; injectable, IV infusion 5/11/2016 Fougera Acyclovir 5%; topical ointment 5/11/2016 Aurobindo Zolmitriptan 2.5 mg and 5 mg; tablet 5/11/2016 0.025 mg/0.18 mg, 0.025 mg/0.215 mg, 0.025 mg/0.25 mg; Haupt Ethinyl estradiol/ norgestimate 5/12/2016 oral-28 tablet Teligent Triamcinolone acetonide 0.1%; topical ointment 5/13/20106 Aurolife Hydromorphone HCl 2 mg, 4 mg and 8 mg; tablet 5/13/2016 Aurobindo Bupivacaine HCl 0.25% and 0.5%; injection 5/13/2016 Roxane Rufinamide 200 mg and 400 mg; tablet 5/16/2016 Glenmark Rufinamide 200 mg and 400 mg; tablet 5/16/2016 Mylan Rufinamide 200 mg and 400 mg; tablet 5/16/2016 Tentative Approvals Puracap Pioglitazone HCl 15 mg, 30 mg and 45 mg; tablet 5/12/2016 Teva Ranolazine 500 mg and 1000 mg; extended-release tablet 5/12/2016 Mylan Febuxostat 40 mg and 80 mg; tablet 5/13/2016 MacLeods Vardenafil HCl 10 mg; orally disintegrating tablet 5/13/2016 Aurobindo Dalfampridine 10 mg; extended-release tablet 5/13/2016 Olmesartan medoxomil/ hydrochloro- Prinston 20 mg/12.5 mg, 40 mg/12.5 mg and 40 mg/25 mg; tablet 5/13/2016 thiazide 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg and Macleods Pregabalin 5/18/2016 300 mg; capsule

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22 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 deal watch / A look at some of the most noteworthy recent biopharma transactions. Anacor Purchase Marks Pfizer’s Post-Allergan Bolt-On Strategy

“The Pink Sheet” regularly covers business development and deal-mak- sales,” he wrote. ing in the biopharmaceutical industry. Below is a roundup of some of “We would expect Pfizer the most noteworthy transactions that occurred between May 14-20. to remain active on the Deal Watch is supported by deal intelligence provided by Strategic business development front Transactions. and believe it has plenty of flexibility to do so while re- Pfizer/Anacor turning cash to sharehold- Pfizer Inc. has made its first M&A move since the planned mega-deal ers,” Gilbert added. Pfizer with Allergan PLC collapsed. The big pharma announced May 16 that reportedly has thrown itself pio3/shutterstock.com credit: Photo it will buy Anacor Pharmaceuticals Inc. for $99.25 per share in cash, into the bidding process to buy cancer company Medivation Inc. as or approximately $5.2bn. it looks to strengthen its budding oncology business (“Pfizer Oncol- The deal is a bolt-on acquisition by Pfizer’s standards, nothing like ogy Strategy: Keeping Pace In The Doublet/Triplet IO Race” — “The Pink the $160bn merger Pfizer had been planning with Allergan that was Sheet,” May 9, 2016). thwarted in April by the US treasury (“With The End Of Pfizergan, Pfizer Anacor also holds rights to Kerydin, a topical treatment for onycho- Has To Grow It Alone” — “The Pink Sheet” DAILY, April 6, 2016). But it is mycosis, a toenail fungus, that is commercialized in the US by Novar- in line with the way management has been guiding investors to think tis AG’s Sandoz unit and competes with Valeant Pharmaceuticals about Pfizer’s M&A strategy, mainly that the company is interested in International Inc.’s Jublia (efinaconazole). on-market or late-stage assets that will help drive growth in the in- novative side of the business. Celgene/Agios Anacor owns a non-steroidal topical phosphodiesterase-4 (PDE-4 Agios Pharmaceuticals Inc. will get $200m to kick off a new part- inhibitor), crisaborole, that is currently under review by FDA for the nership with longtime collaborator Celgene Corp. under a complex treatment of mild-to-moderate atopic dermatitis, commonly known agreement to develop therapies that alter the metabolic state of im- as eczema (“Pfizer Buys Anacor With Blockbuster Ambitions For Crisab- mune cells to enhance the immune response to cancer. orole” — “The Pink Sheet” DAILY, May 16, 2016). The drug, which has an The companies did not disclose any specific immuno-oncology FDA action date of Jan. 7, 2017, could become an important first-line drug targets, but Agios Chief Scientific Officer Scott Biller said during treatment in a therapeutic area where there are few safe topical op- a May 17 conference call with analysts that the collaboration will seek tions, according to Pfizer. There have been no new molecular entities to validate Agios-discovered targets “that are not on the radar screen approved for atopic dermatitis in 15 years, the company noted. The of other researchers.” pharma projects crisaborole could achieve peak annual sales exceed- Yet, while the company granted Celgene a major stake in its early- ing $2bn. stage, metabolic immuno-oncology program, Agios also regained Crisaborole fits neatly in Pfizer’s inflammation and immunology global rights to AG-120, which Celgene previously licensed outside of portfolio, which includes the JAK inhibitor Xeljanz (tofacitinib), ap- the US under a 2010 agreement tied to the smaller company’s cancer proved for rheumatoid arthritis, and prior experience marketing En- metabolism research platform. brel (etanercept). While Celgene returned its ex-US rights to AG-120 to Agios, the big “We believe we are well positioned to maximize crisaborole’s com- biotech remains committed to other programs under the companies’ mercial potential through our strong relationships with pediatricians first agreement. Celgene CSO Rob Hershberg said in a statement and primary care physicians,” Albert Bourla, group president of Pfizer’s that the collaborators’ new deal “builds upon the extremely produc- Global Innovative Pharma and Global Vaccines, Oncology and Con- tive partnership and working relationship that exist between our two sumer Healthcare Businesses, said in a statement. companies.” Datamonitor Healthcare analyst Christina Vasiliou noted that “the The rights to two cancer metabolism programs discovered under extent of crisaborole’s uptake will be primarily determined by its cost, the existing relationship between Agios and Celgene, including one as it will be in direct competition with well-established and low-cost focused on methylthioadenosine phosphorylase (MTAP) deleted corticosteroids.” cancers, will now fall under the companies’ new metabolic immuno- Pfizer will need to drive blockbuster sales of the drug to get a re- oncology agreement. Any other cancer metabolism programs discov- turn on its investment, Deutsche Bank analyst Gregg Gilbert said in a ered at Agios will remain wholly owned by the company, since the same-day note. “Achieving accretion to non-GAAP EPS in 2018 should discovery phase of its 2010 deal with Celgene expired on April 14. not be difficult (as per Pfizer’s press release), but achieving a good The terms of the new agreement are similar to the companies’ 2010 financial return on the deal would likely require very significant peak deal. Agios will receive $200m up front to lock in the initial four-year thepinksheet.com May 23, 2016 | Pink Sheet | 23 deal watch research term, but Celgene can pay an undisclosed option fee to ex- tend up to two years. Agios will lead all early research, discovery, pre- clinical and Phase I clinical trials. Celgene may decide which programs it wants to collaborate on when drug candidates reach the preclinical stage and the company has until the end of Phase I dose escalation studies to pay a fee of at least $30m to exercise its option to license an asset. Celgene and Agios will split worldwide development and commer- cialization costs and profits for each licensed metabolic immuno-on- cology program on a 50-50 basis, and Agios may earn up to $169m in clinical and regulatory milestone fees for each program. The compa- nies will alternate leadership of US development and commercializa- tion for each asset with Agios leading the first program, but Celgene f11photo/shutterstock.com credit: Photo will lead ex-US development and sales. In addition, Celgene may pay Agios up to $209m in milestone fees Biogen’s deal with UPenn will tap in exchange for a 65% share of costs and profits for one program un- der the agreement. For this program, Celgene will lead worldwide de- into work by James Wilson, head velopment and commercialization. of the university’s gene therapy Other flexibility pre-written into the deal gives Celgene an option to license exclusive worldwide rights to any inflammation and auto- program, and Jean Bennett, director immune programs discovered under the companies’ new agreement. Agios will earn milestone fees up to $386m for each inflammation or of Penn’s Center for Advanced Retinal autoimmune program plus double-digit royalties on net sales. Jefferies analyst Brian Abrahams said in a May 17 research note and Ocular Therapeutics. about Celgene that its new deal with Agios “is unlikely to have mate- rial impact to Celgene in the near/medium term, though we believe LLC in 2014 as head of its gene therapy unit – previously Danos had it does reflect Celgene’s continued flexibility leveraging evolving sci- been director of the Gene Therapy Consortium at University College ence and partnership learnings to pivot into more strategic areas. We London (“Spotlight Returns To Biogen R&D To Sustain Success” — “The continue to view Celgene’s growth prospects, pipeline breadth and Pink Sheet,” Feb. 2, 2015). R&D strategy as best-in-class and underappreciated.” In 2014, the biotech signed a deal with Sangamo BioSciences Inc. to develop and commercialize therapies for sickle cell disease and Biogen/Regenxbio/University of Pennsylvania beta thalassemia. That was followed in 2015 by an agreement with Adding to a deal signed not quite a year ago with Applied Genetic Italy’s San Raffaele Telethon Institute for Gene Therapy to develop Technologies Corp. to move into ophthalmic gene therapy, Biogen gene therapies for hemophilia A and B. Inc. inked a pair of agreements May 16 that will bring it adeno-as- Under the new deal, Biogen will pay Penn $20m up front and up to sociated virus (AAV) technology and research assistance to advance $62.5m in funding over the next three to five years to fund R&D efforts programs for a pair of undisclosed rare genetic vision disorders into under seven distinct preclinical target areas through the labs of Wil- clinical development (“Biogen Expands Gene Therapy Efforts Via Deals son and Bennett. The collaboration will focus on both gene therapy With Regenxbio, Penn” — “The Pink Sheet” DAILY, May 16, 2016). and gene-editing technologies, Biogen said, and could result in Penn The big biotech announced a three-to-five year R&D pact with the earning up to $2bn through R&D funding, options and milestones. University of Pennsylvania, through which it will work with research- Various milestones specified under the agreement could trigger pay- ers James Wilson, head of the university’s gene therapy program, ments ranging between $77.5m and $137.5m per potential product. and Jean Bennett, director of Penn’s Center for Advanced Retinal and The collaboration will address multiple objectives – beyond the Ocular Therapeutics. In an interrelated move, Biogen also agreed to eye, the partners will focus on skeletal muscle and central nervous license AAV technology from REGENXBIO Inc., including an exclusive system (CNS) therapies. They also will attempt to validate next-gener- worldwide license to Regenx’s proprietary NAV (novel adeno-associ- ation gene transfer technology using AAV gene-delivery vectors and ated virus) AAV8 and AAV9 vectors, with rights to sublicense. explore the expanded use of genome-editing technology as a poten- “Bennett is really the world expert in genetic vision disorders using tial therapeutic platform. AAV technology, so we’ve had a relationship with Penn for years, in- Mills said the agreement between Biogen and his company is a cluding with both Bennett and with Jim Wilson, our scientific founder, straight licensing arrangement, but as the Penn/Biogen collabora- across a number of indication areas,” Regenx CEO Kenneth Mills ex- tion develops, opportunities for Regenx to take on a greater role in plained in an interview. the work may emerge. He described the deal as facilitating the Penn/ Biogen has been ramping up its gene therapy R&D efforts in recent Biogen work in the two undisclosed indications. Biogen will select a years, as signified by its hiring away Olivier Danos from Kadmon Corp. single vector for each indication.

24 | Pink Sheet | May 23, 2016 © Informa UK Ltd 2016 deal watch

Specific financial terms were not disclosed, but Regenx will get an clinical T-cell redirecting compound MGD015, plus up to $665m in upfront fee, ongoing fees and can earn milestones and royalties on re- milestone fees and double-digit royalties on global net sales. sulting products. Mills said Regenx will disclose in an SEC filing during Leerink Partners analyst Michael Schmidt wrote in a May 18 report the second quarter the receipt of “low single-digit” millions of dollars that “bispecific antibodies are poised to play a more important role in from the deal with Biogen. cancer immunotherapy and MacroGenics has the broadest bispecific The additional investment Biogen is taking should help it move pipeline in clinical development, with multiple shots on goal.” more quickly into clinical development. Most of the firm’s gene thera- The company entered into a clinical trial collaboration with Merck py programs remain in preclinical development – Biogen’s lone clini- & Co. Inc. in October to test its Phase III HER2-targeting monoclonal cal gene therapy candidate at present is called XRLS Gene Therapy, antibody margetuximab in combination with Merck’s PD-1 inhibitor now in Phase II in X-linked retinoschisis (XRLS). Keytruda (pembrolizumab) in a Phase Ib/II trial enrolling patients with That candidate had been advanced to Phase I by AGTC before the advanced gastric cancer. 2015 deal with Biogen, which also transferred a preclinical candidate MacroGenics also initiated a Phase III trial in August to test mar- for X-related retinitis pigmentosa, plus two other preclinical ophthal- getuximab versus Roche’s Herceptin (trastuzumab) – both in com- mology candidates and a third non-ophthalmic candidate, to the big bination with chemotherapy – in the third-line treatment of HER2- biotech. Biogen paid AGTC $94m up front, made a $30m equity in- positive breast cancer. All of the DART antibodies in the MacroGenics vestment and could pay out up to $472.5m in milestones on the two pipeline are in Phase I or earlier stages of development, but preclini- most advanced candidates under the agreement. cal data to date have led to some lucrative and flexible collaboration agreements with big pharma and others. Janssen/MacroGenics As with the Phase I asset MGD011, the first bispecific antibody li- Janssen Biotech Inc. apparently likes what it’s seen so far from the first censed by Janssen, the J&J biotech business group will lead global bispecific antibody that it licensed from MacroGenics Inc., because clinical development and commercialization for MGD015. However, the Johnson & Johnson subsidiary obtained rights to a second asset MacroGenics may contribute funding to help cover MGD015 clinical from the Rockville, Md.-based firm’s Dual Affinity Re-Targeting (DART) development costs in exchange for a share of profits from US and Ca- platform. nadian sales. The biotech company may also opt in to co-promote MacroGenics has entered into collaborations with seven different MGD015 in the US. partners for the development of DART compounds yielding a slew of upfront and milestone fees to support its wholly-owned and part- Joseph Haas [email protected] nered programs. The company will get $75m up front from Janssen Jessica Merrill [email protected] under the companies’ second agreement, which pertains to the pre- Mandy Jackson [email protected]

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 Roche Tecentriq Use of the PD-L1 inhibitor to treat locally advanced or metastatic 1 5/18/2016 (Genentech) (atezolizumab) urothelial carcinoma in patients with disease progression during or following platinum-containing chemotherapy, disease pro- gression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy 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

thepinksheet.com May 23, 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 Endocrinologic and May 24 to 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 Endocrinologic and May 25 for treatment of adults with type 2 diabetes mellitus Metabolic Drugs Teva Branded Pharmaceutical Products R&D Inc.’s hydrocodone extended-release tablets, Anesthetic and Analgesic formulated with purported abuse-deterrent properties, for management of pain severe enough to Drug Products; Drug Safety June 7 require daily, around-the-clock, long-term opioid treatment and for which alternative treatment and Risk Management options are inadequate 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 difficile Antimicrobial Drugs June 9 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 with type 2 diabetes mellitus and high cardiovascular risk to reduce the risk of all-cause Endocrinologic and June 28 mortality by reducing the incidence of CV death and to reduce the risk of CV death or Metabolic Drugs hospitalization for heart failure Anesthetic and Analgesic Drug Development plans for establishing the safety and efficacy of prescription opioid analgesics for Products; Drug Safety and Risk Sept. 15-16 pediatric patients, including obtaining pharmacokinetic data and the use of extrapolation Management; Pediatric

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