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November 20th 2015 No 3778 scripintelligence.com

Brandicourt’s ‘Big Reveal’ Falls Flat For Sanofi Seven months into the job and the shine is wearing off Sanofi’s new CEO Olivier Brandicourt. His first “Meet the Management” investor day on Nov. 6 left analysts underwhelmed and shares slipping. Previous CEO Christopher Viehbacher’s ignominious departure last year was blamed on the poor performance of its US diabetes franchise, weak oversight of local management and poor communication with Sanofi’s board of directors. Brandicourt may feel he has made strides to tackle management Bplanet/shutterstock.com and communication issues, but the diabetes franchise continues to be problematic. “Sanofi provided a 2020 growth outlook with a disappointing near-term earnings MISSING THE TARGET: Sanofi CEO lays out plans as further diabetes trajectory – flat EPS growth to 2017 versus franchise decline looms consensus expectations of 3-5% growth,” noted Goldman Sachs. Building on a reorganization of Sanofi that Brandicourt outlined four strategic priorities 2. To deliver “outstanding” launches with a he announced in July, Brandicourt delivered for Sanofi: particular focus on six major products: a set of ambitious priorities for the French 1. To reshape its portfolio around the Toujeo (insulin glargine injection), Praluent pharma major. “The company will remain core businesses where it can sustain a (alirocumab), Dengvaxia (dengue fever diversified but with a portfolio focused on leadership position or build a competitive vaccine), sarilumab, LixiLan (lixisenatide and areas where we can win,” he said. position. Turn to page 6 Beyond Tax: Portfolio Opportunities In Pfizer-Allergan Deal Pfizer Inc. and Allergan plc continue to be in they have in common, Allergan could add and established Alzheimer’s franchise (see closed-door discussions regarding a potential marketed drugs and investigational therapies separate article here), its growing antibiotics merger that could significantly cut Pfizer’s tax for indications that Pfizer lacks – and vice business and a large women’s health focus. rate due to Allergan’s Irish corporate base, but versa, since it’s possible that Allergan could Pfizer also could tap into categories like Allergan also has several commercial products buy Pfizer to prevent the larger company from dermatology and aesthetics – where it doesn’t and research-stage assets that could fill gaps moving its tax base overseas in a controversial have any products – and ophthalmology, in Pfizer’s portfolio. tax inversion following the merger. which are big businesses for Allergan. Allergan The companies have some overlapping Some portfolio opportunities for Pfizer CEO Brent Saunders told Scrip in an interview programs, but within therapeutic areas that include Allergan’s diverse neurology portfolio Turn to page 8

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Eleanor Malone, Editor, 4 Scrip Intelligence

The trend of increasing co-operation between 1 Brandicourt’s ‘Big Reveal’ 14 Policy & Regulation Briefs Falls Flat For Sanofi industry and the regulators has its critics, but 16 Interview: Lilly’s Carroll: Let’s Debate by and large most would probably agree that 1 Beyond Tax: Portfolio Opportunities Pricing But Don’t Lump Us With Turing the net effect is a benefit to patients. In Pfizer-Allergan Deal 18 R&D Bites Closer dialog between regulatory agencies and manufacturers has sped up 3 The Culture Of Change: Pfizer’s The Perfect Storm For 20 Expert View: and to some extent reduced unnecessary Workforce Challenge M&A Shows No Signs Of Abating uncertainties in the process whereby better 4 FDA Pazdur’s Opdivo Love Affair 21 Stockwatch: Bulls, Bears And White medicines become available to the public. And Other Adventures Elephants There is a desire on both sides to continue 6 Citron Tweet Whacks Mallinckrodt 22 US Capitol Capsule: Don’t Make to evolve through dialog. True, in some cases accusations have been levelled quite Cellectis Success With Off-The-Shelf Assumptions On Biosimilars Actions, 7 FDA Official Warns vociferously at a regulator for apparently CAR-T Threatens Kite, Juno, Novartis bending to external pressures (the FDA’s 23 Pipeline Watch 10 Business Bulletin approval of Sprout Pharmaceuticals’ female 24 Appointments sexual dysfunction pill Addyi springs to 11 More Drug Pricing Probes: Merck, Lilly Targeted mind). Nevertheless, medicines agencies listening to companies in order to adapt 11 Cost Could Drag regulatory pathways to accommodate On Lilly’s Baricitinib Outlook new types of therapy, or giving companies 12 Horizon Infected By Valeant Scandal earlier guidance on their products’ route to approval, are signs that the relationship 12 Bayer’s Wolters Explains Downside between industry and regulation has usefully Of Success matured from one of head-on confrontation. 13 Cell Therapy Developers Debate But even in the context of regulators and Hurdles, Big Pharma Drags Its Feet industry holding each other in higher regard than they once did, comments by the FDA’s Valeant Looks For Forgiveness 13 head of hematology and oncology Richard Pazdur reveal a surprisingly pro-active attitude towards getting drugs to market. Scrip By his account the FDA practically dragged Editor: [email protected] Opdivo onto the lung cancer market while its Managing Editor: [email protected] maker, Bristol-Myers Squibb, kicked its heels News Editor: [email protected] waiting for a conference to report its data. For South Asia Editor: [email protected] Washington Editor: [email protected] more on Pazdur’s remarkably frank discussion US West Coast Editor: [email protected] of the backroom workings of the US agency Features Editor: [email protected] – and for an insight into how he might be Senior Reporter: [email protected] Principal Analysts: [email protected]; injecting some oomph into proceedings [email protected]; [email protected] We would love to hear your comments about there – see Donna Young’s report on p4. Reporter: [email protected] Scrip’s coverage. Feel free to tweet us or post Innovative therapies are one thing, [email protected] Reporter: a discussion on our LinkedIn group, for your Creative Content Reporter: [email protected] biosimilars quite another. While breakthrough chance to interact with editor Editorial Assistant: [email protected] Eleanor Malone medicines are seemingly being ushered and the rest of the Scrip Intelligence team. Production: [email protected] through the FDA on red carpets, the rate of Pharma Data Editor: [email protected] Global Content Director: [email protected] Follow us at: @scripnews action on biosimilars is far slower (see p22). All stock images in this publication courtesy of Some of this will be to do with deficiencies in www.shutterstock.com unless otherwise stated. Join us at: linkd.in/scripintelligence the drugs or in manufacturing facilities, but Customer Services that’s not the whole story. The agency also Tel: +44 (0)20 7017 5540 or (US) Toll Free: 1 800 997 3892 Email: [email protected] grossly under-estimated the number of drugs To subscribe, visit scripintelligence.com that would be put through its new biosimilar To advertise, contact [email protected] pathway and has not had the necessary Scrip is published by Informa UK Limited. resources to deal with its workload. The ©Informa UK Ltd 2015: All rights reserved. ISSN 0143 7690. pathway was a long time coming and it looks like we’re now at the start of another long road to effective implementation.

2 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 headline news The Culture Of Change: Pfizer’s Workforce Challenge Pharmaceutical firms boast a wealth of experience in M&A thanks in no small part to a boom in activity over the past year, but the struggle to prevent value leaking from a deal remains a major challenge. The huge scale of the potential deal between Pfizer Inc. and Allergan PLC dramatically raises the stakes. At this stage, it would be easy for those at the top to focus on the terms of a merger, but it’s also vital that they do not forget to start thinking in practical terms about how to Lightspring/shutterstock.com make it work. So where should they start?

People As Assets Workforce stability is often talked about REALISING POTENTIAL: Any company being as the greatest business challenge after acquired has value locked in its people a merger or acquisition. It’s a problem that extends far beyond retention, to performance, engagement, and ultimately, Fear Of The Unknown speed is of the utmost importance, but productivity. Yet, even though the majority Fear of loss is often one of the predominant speed alone is not enough. of executives recognize the importance of individual concerns. This can mean loss of To execute the new narrative successfully getting this aspect of a deal right, in reality, money, colleagues, privileges, the job itself, and consistently across the whole business integrating systems and processes effectively or more generally the loss of a comfortable requires a detailed strategy, but individuals almost always comes before the cultural status quo. While this fear is an inevitable also need to be involved, for instance being aspect of integration. feature of change, it is something that leaders given responsibility as a team to implement Placing the workforce towards the and managers can mitigate against early top-level changes. If staff feel they’ve bottom of a long list of priorities is perhaps in the process, if it’s a problem that they’re individually had a hand in authoring change a particular risk for pharmaceutical firms, focused on solving. then it immediately ceases to be something which can easily get caught up in the value alien and threatening. of their intellectual property, and lose track To make the change genuinely resonate of what makes the company tick. After all, Alongside the loss of identity, the throughout the entire company, it must be the very thing that raised Allergan to its change will mean adapting to supported at every level. Creating a cohort prominent market status was the ingenuity of respected and trusted leaders from both and scientific acumen of its research teams, new supervisors and co-workers, old and new companies that can be inspired the skill of its marketers and the vision of by the company’s new narrative gives rise its leadership. What, then, should firms do different systems and processes, to powerful ambassadors for change. These to ensure that the people the company is and maybe a new location leaders can then be enabled to take that built upon are not lost or alienated along knowledge to the next level of the business the way? On a practical and rational level, employees recreating the same process at each level To employees on the ground, the need to understand that the business will until everyone understands and supports the pressure of being acquired can feel like a continue to support them, and that they will changes that have taken place and can drive loss of identity. The acquiring business is have a role to play which is both important forwards together. asking them to abandon the emotional and tangible. This requires placing staff within Any company being acquired has value attachment to their old company – one of a new narrative, which extends well beyond locked in its people. By not fully embracing the most powerful sources of motivation the current project. This narrative will be the fears, ambitions and expectations of those and loyalty – and instead immerse neither that of the old company, nor the new. employees, the dominant firm will be eroding themselves in an entirely new culture. Worse It will be a story which lays out a vision of the value of the investment before the deal still, for most, the new culture will be that their combined future. is even complete. Framing the merger or of a former competitor, and therefore one acquisition in the context of the long-term which the firm will have, in the past, viewed Practical Steps journey the company is on puts a human face as alien and opposing. Even the best-intentioned companies often on the change. The overall story is broken up Alongside the loss of identity, the change communicate the dynamics of change too into a multitude of smaller, personal stories. It will also mean adapting to a new group of late, without enough detail and through becomes one of individual heroes, diligently supervisors and co-workers, a new set of purely corporate channels. Employees will advancing the company, rather than victims systems and processes and maybe even a often be aware of changes right from the left behind in the confusion. new location. However, there is plenty that start – whether by accident or design – and Marcus Hayes companies can do to remove uncertainty insufficient communication leaves them to and fear, and so improve engagement and invent their own stories, something which Marcus Hayes is Co-founder and Director of empowerment. can be very dangerous. For this reason, culture change consultancy The Storytellers

© Informa UK Ltd 2015 @scripnews scripintelligence.com November 20th 2015 3 CODE: PXL-15-6A PUB/POST: Life Science Leader: Convert to PRODUCTION: Michael Eibner LIVE: 196.85 mm x 263 mm DESCRIPTION: How to Keep Your Journey/Consulting WORKORDER #: 007734 TRIM: 208 mm x 273 mm Hogarth & Ogilvy FILE: 11A-007734-11B-PXL-15-6A.indd SAP #: PXL.PXLBRD.15018.K.011 BLEED: 215.9 mm x 282.57 mm 212.237.7000

headline news FDA Pazdur’s Opdivo Love Affair And Other Adventures staff from academic medicine – noting that when he came to the FDA 16 years ago, he recognized it needed to “change from a regulatory agency to a more academic platform.” Working at the FDA, he argued, “is as interesting as academic medicine.” “We do more academic work here than most academic places,” Pazdur declared, adding he wasn’t talking about “grants or

focal point/shutterstock.com publishing papers up the wazoo.” “I’m talking about sitting down and really analyzing a problem” together with statisticians, clinical pharmacologists, toxicologists and drug safety officers, NO COMMITMENTS: Director said FDA should not be considered a partner of drug companies weighing the pros and cons of a drug, he said. Pazdur said one thing that has helped change the culture at the FDA’s oncology HOW TO KEEP This year’s Biopharma Congress conference say, ‘Yeah, this is important, what are we divisions is the breakthrough therapy in Washington had something for everyone going to do?’” Pazdur said. designation – a status created under the YOUR JOURNEY FROM – debates on the current drug pricing When the FDA reached out to BMS, Food and Drug Administration Safety and atmosphere, discussions about what’s missing however, the firm actually told Pazdur it was Innovation Act intended to expedite the R&D in the House-passed 21st Century Cures Act considering waiting a couple of months until and regulatory processes. BECOMING AN ODYSSEY. that may be included in the Senate’s version the annual meeting of the American Society Firms whose products win the of the legislation and an update about the of Clinical Oncology (ASCO) to report the breakthrough status have more opportunities Anticipating all possibilities for a safe passage. status of those pending FDA biosimilars Opdivo NSCLC data. to engage with the FDA, he noted. “It isn’t that guidances, which was essentially to confirm But Pazdur, shaking his head, said he told the oncology divisions were not interacting A successful journey is a well-planned journey. they’re still pending. the company the agency was going to work with the sponsors, but it really kind of That is why at PAREXEL, our clinical, regulatory But by far the high point of the conference, to approve Opdivo in lung cancer before the highlighted the urgency to have that iterative and commercial experts work in concert to hosted by the analysis firm Prevision Policy May 29-June 2 ASCO meeting anyway. And discussion, not just waiting for these end-of- understand and deﬁ ne your development goals. and patient advocacy group Friends of the FDA did – giving its blessing on March 4 Phase II meetings, end of this meeting, end of Moreover, our holistic, collaborative approach Cancer Research, was when FDA’s Richard to BMS to market Opdivo as a treatment for that meeting,” Pazdur said. and best-in-class know-how simplify the journey Pazdur, director of the Office of Hematology patients with advanced squamous NSCLC The breakthrough status, he said, is “really and Oncology Products, described the thrill after prior therapy. getting the staff more involved” with drug to attain product approval and maximize patient he got when seeing the lung cancer data That decision came only days after BMS makers – something he said he’s been access. Take a deeper look at our integrated for the first time from Bristol-Myers Squibb had revealed it won a priority review – pushing his reviewers to make more of an approach at proof.PAREXEL.com/consulting Co.’s programmed death-1 (PD-1) immune actually winning the FDA’s nod more than effort to do. “I keep telling the review staff, checkpoint inhibitor Opdivo (nivolumab). three months ahead of Opdivo’s Prescription ‘If you have a question, just call up the A few days before Christmas last year, Drug User Fee Act action date in the NSCLC damn company,’” Pazdur said. “I have no Pazdur said he sat down at his desk at home indication, which had Evercore ISI analyst compunction about picking up the phone late in the afternoon after receiving an email Mark Schoenebaum declaring it was the and calling somebody rather than waiting for from Patricia Keegan, director of the FDA’s fastest approval he’d ever seen. some meeting and discussing this and what Division of Oncology Products-2, telling him The drug previously was cleared for the should we do about this,” he said. he could access the survival curve data for market in melanoma, which also came Pazdur said that while FDA should not Opdivo in patients with advanced squamous three months early, and has since gained be considered a partner of drug companies non-small cell lung cancer (NSCLC). broader use in that disease and lung cancer – because, after all, “we are a regulatory Pazdur said he put in his password, the file – demonstrating further Pazdur’s love affair agency” – regulators are “somebody who opened, “and I said, ‘Holy [expletive]! This is great.’” with Opdivo, which competes with Merck could facilitate a potentially very important What it showed was a median overall & Co.’s PD-1 immune checkpoint inhibitor drug to patients.” survival of 9.2 months in the Opdivo patients, Keytruda (pembrolizumab). “I want the pharmaceutical companies to versus six months in the docetaxel group know what we’re looking for for approval – the first time a PD-1 had demonstrated It’s Academic endpoints, what we would be flexible on,” an overall survival in previously treated But Pazdur acknowledged not everyone at he said. metastatic squamous NSCLC. the FDA is as enthusiastic as he is – bluntly For instance, Pazdur said, “if our traditional The FDA oncology chief said he pointing out there are those who like to just stance had been to accept overall survival immediately called Keegan and others at “sit in their office” and check things off the lists on a disease, if you have a huge effect on the agency and told them “We really need and “not interact with anyone else.” response rates, well, that might be good to get on this.” “You have to have people in the divisions enough for us.” “You have to have that energy when you who want to do this,” he said. Pazdur said he “So let’s start talking about this,” he declared. see something to motivate people and to likes to recruit scientists for his oncology [email protected]

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HOW TO KEEP YOUR JOURNEY FROM BECOMING AN ODYSSEY.

Anticipating all possibilities for a safe passage. A successful journey is a well-planned journey. That is why at PAREXEL, our clinical, regulatory and commercial experts work in concert to understand and deﬁ ne your development goals. Moreover, our holistic, collaborative approach and best-in-class know-how simplify the journey to attain product approval and maximize patient access. Take a deeper look at our integrated approach at proof.PAREXEL.com/consulting

Art: PXL15006A_001C_SWOP3.tif (CMYK; 300 ppi; Up to Date), PXL- PAREXEL wTag Gray-4C.ai (Up to Date) headline news Citron Tweet Whacks Mallinckrodt The same short-seller that smacked Valeant Mallinckrodt is known for buying older drugs Citron questioned whether Valeant Pharmaceuticals International Inc. last and raising their prices, as it did with HP was the pharmaceutical version of Enron month with a report exposing the firm’s Acthar Gel (repository corticotropin injection), Corp. – the scandal-ridden company that relationship with specialty pharmacies used which it obtained when it acquired Questcor became emblematic of corporate fraud only a tweet on Nov. 9 to whack its next Pharmaceuticals Inc. in August 2014. and corruption and was what triggered the victim, hedge-fund favorite Mallinckrodt Acthar, an adrenocorticotropic hormone financial reforms under the Sarbanes-Oxley PLC, whose shares plummeted 26%, before analogue, was initially approved in the US in Act of 2002. closing at $58.01, down $11.88, or 17% – 1952. The drug is indicated as monotherapy The Citron report triggered BMO Nesbitt demonstrating again the power of social to treat infantile spasms in infants and Burns Inc. analyst Alex Arfaei to ask “What media on stock prices. children under 2 years and for exacerbations else is out there that we don’t know” about In its Nov. 9 tweet, Citron Research, run of multiple sclerosis in adults. Acthar also is Valeant, which further panicked investors, by Andrew Left, called Mallinckrodt a “far approved for other disorders and diseases, who drove shares of the company down worse offender” of the reimbursement such as rheumatic, collagen, dermatologic, another 20% on Oct. 22. system than Valeant. allergic states, ophthalmic, respiratory and After days of providing few answers to Citron pointed to Mallinckrodt’s prices edematous state, according to the drug’s a lot of unanswered questions, Valeant on – insisting the firm has significantly more labeling. But it was Questcor that had initially Oct. 26 finally explained the details about its downside than Valeant, which it said “can’t live in raised the wholesale acquisition cost of Acthar relationship with Philidor Rx Services, which it a vacuum.” significantly long before Mallinckrodt was even has since broken ties with. It’s unclear what dirt, if any, Citron may in the picture – spiking it in 2007 from about Valeant is already being investigated for have on Mallinckrodt, but it said there was $2,000 per vial to about $23,000. The drug its price increases by federal prosecutors “more to follow,” although it didn’t say when. reportedly now costs about $35,000 per vial. in Massachusetts and New York and by A spokesperson for Mallinckrodt told Scrip While Citron has yet to reveal what it may lawmakers on Capitol Hill – Sen. Bernie the company “generally does not respond to have uncovered about Mallinckrodt that Sanders (I-VT) and Rep. Elijah Cummings in market speculation.” sparked the Nov. 9 tweet, its Oct. 21 report, one probe and Sens. Susan Collins (R-ME) and “That said, we are fully confident in our in which it accused Valeant of conspiring Claire McCaskill (D-MO) in another. business model and remain focused on with specialty pharmacies to create “phantom But Valeant is not alone. Most recently, executing on our long-term growth strategy,” accounts, sent shares of the drug company Merck & Co. and Eli Lilly & Co. revealed they, the spokesperson said. spiraling down 40%, with other firms in the too, are under investigation for their pricing Like Valeant and other specialty pharmas, sector, like Allergan PLC and Horizon Pharma practices, as is Turing. such as Turing Pharmaceuticals AG, PLC, also feeling the pain that day. [email protected]

Brandicourt’s ‘Big Reveal’ Falls Flat For Sanofi (Continued from page 1)

insulin glargine) and dupilumab. Sanofi position. “We are fifth in consumer healthcare outcomes. In Google, Sanofi has a world-class expects to generate peak sales of €12bn to and MS, 11th in oncology, and we have no partner for connecting the dots in diabetes €14bn for these products. on market position as yet in immunology.” But care. We are working to integrate devices, 3. Continue “innovation in R&D.” As its late Sanofi believes these are “attractive businesses services, data analytics, and drugs to improve stage development pipeline launches, where we have or can acquire the assets to patient outcomes.” “we need to replenish it,” acknowledged build competitive positions.” These first two In cardiovascular, Sanofi believes it has the Brandicourt. “We expect to increase our R&D business groups will be the growth drivers for opportunity to transform the management of investment up to €6bn annually. This is in Sanofi, said Brandicourt. However, the animal hypercholesterolemia through Praluent. “It has part to create headroom to pursue more health and generics businesses in Europe will multi-blockbuster potential,” said Brandicourt. external innovation.” see Sanofi exploring divestment opportunities. 4. Simplify its organization and generate Consumer Health €1.5bn in cost savings by 2018 (to “partly Diabetes Headwinds Sanofi is aiming “to achieve leadership” in offset lower diabetes sales expectation.”) “We have come through a patent cliff consumer health. “Today we are the number and still face a patent hill as Lantus loses five player globally with 3% market share.” Reshaping Its Portfolio exclusivity,” noted Brandicourt. The outlook Brandicourt listed three reasons why he wants Brandicourt is reshaping Sanofi’s business for its diabetes business is “challenging,” to stay in the consumer health space business. by categorizing the portfolio into businesses and Sanofi expects global diabetes sales “First, consumer healthcare is a highly where Sanofi intends to remain in a to decline at an average annualized rate fragmented market right for consolidation. “leadership position” (in a top three position), of between 4% to 8% over the next three Second, it offers consistent growth businesses where Sanofi plans to “build a years. However, Brandicourt outlined three with different dynamics to the branded competitive position,” and businesses where it priorities to return the diabetes business to prescription market. Third, it’s a good portfolio intends to “explore strategic options.” growth beginning in 2019. fit where we can capture real synergies.” Sanofi is “already a leader in diabetes, rare “First, we are developing the insulin Sanofi will “maximize the value of existing diseases, vaccines and emerging markets,” franchise with Lantus, Toujeo, and soon LixiLan. brands, shape new categories and build scale said Brandicourt. In the second set of Second, we will strengthen our pipeline. Third, through bolt-on acquisitions.” businesses, Sanofi does not have a leadership lead the market shift to managing diabetes [email protected]

6 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 headline news Cellectis Success With Off-The-Shelf CAR-T Threatens Kite, Juno, Novartis An unexpected breakthrough announced Table: Major allogeneic and autologous CAR-T development candidates by Cellectis for its experimental off-the-shelf CAR-T therapy has raised the possibility that Lead Company Technology Name Autologous/Allogeneic Indication Phase much-hyped therapies using a patient’s Novartis CTL019 Autologous Chronic lymphocytic leukemia II own cells, under development at Kite, Juno (CLL)/small cell lymphocytic and Novartis, may become commercially lymphoma obsolete before they even reach the market. Novartis CTL019 Autologous Acute lymphoblastic leukemia II Cellectis announced on Nov. 5, 2015 Novartis CTL019 Autologous Diffuse large B-cell lymphoma II that an 11-month-old baby girl was put Novartis CTL019 Autologous Multiple myeloma I into remission using UCART19, its off- the-shelf experimental CAR-T therapy. Kite KTE-C19 Autologous CLL/Small-CLL I/II While these preliminary results are based Kite KTE-C19 Autologous Diffuse large B-cell lymphoma I/II on a limited single-patient application, Kite KTE-C19 Autologous Indolent Non-Hodgkin’s I/II UCART19’s universal administration could lymphoma pose a significant threat to CAR-Ts being Kite KTE-C19 Autologous Acute lymphoblastic leukemia I developed by Kite, Juno, and Novartis, as their personalized therapies have high costs of Kite KTE-C19 Autologous Mantle cell lymphoma I production and logistical challenges likely to Kite EGFRvIIICAR Autologous Brain cancer I/II limit market access. Juno JCAR014 Autologous Hematological Cancer I/II In this case, the child, who suffered from Juno JCAR015 Autologous Acute lymphoblastic leukemia II progressive acute lymphoblastic leukemia (ALL), had exhausted all other treatment Juno JCAR015 Autologous Non-Hodgkin’s lymphoma I options. Unable to generate personalized Juno JCAR015 Autologous Diffuse large B-cell lymphoma I CAR-T cells from the patient, doctors Juno JCAR017 Autologous Acute lymphoblastic leukemia I/II administered the off-the-shelf UCART19 under an emergency compassionate-use protocol. Juno JCAR017 Autologous Non-Hodgkin’s lymphoma I/II Two months after treatment with the Juno JCAR018 Autologous Acute lymphoblastic leukemia I experimental therapy, the child has apparently Juno JCAR018 Autologous Non-Hodgkin’s lymphoma I been cleared of cancer. Juno JCAR020 Autologous Ovarian cancer I If Cellectis’ approach is more widely validated, there could be significant fall-out Juno JCAR021 Autologous Non-Hodgkin’s lymphoma I for companies that are developing ways of Juno JCAR023 Autologous Neuroendocrine tumors I using a patient’s own cells to create CAR-T Juno CD19 Armored CAR Autologous Hematologic cancers I immunotherapies. This is because of the Juno ROR-1 CAR-T Autologous Solid tumors Preclinical difference in the complexity and cost of the autologous (i.e. personalized) approach National Institute Anti-mesothelin CAR Allogenic Solid tumors I/II compared with the allogeneic (ie. off the shelf, of Health (NIH) donor cell-based) approach. NIH Anti-GD2 CAR Allogenic Solid tumors I Despite the impressive clinical efficacy Cellectis UCART123 Allogeneic Acute myelogenous leukemia Preclinical for autologous CAR-T therapies highlighted Cellectis UCART19 Allogeneic Acute lymphoblastic leukemia Preclinical by trials thus far, their administration will likely be limited to specialized Cellectis UCART22 Allogeneic Hematologic cancer Preclinical transplantation centers immediately post- Cellectis UCART38 Allogeneic Acute lymphoblastic leukemia Preclinical approval, where physicians and scientists Cellectis UCART38 Allogeneic Multiple myeloma Preclinical will be able to extract T-lymphocytes from Cellectis UCARTCS1 Allogeneic Multiple myeloma Preclinical patients for transformation and reinfusion. In addition, current production processes require between one to two weeks in order significantly impact wide-scale distribution isolation. Such development platforms also to genetically engineer the patient’s T-cells and severely limit commercial uptake. allow for streamlined production, quality to express the appropriate chimeric antigen Cellectis’ off-the-shelf therapies, by control, and ease of distribution. This would receptor (CAR). The large investments in contrast, will use T-lymphocytes derived result in a significantly lower cost. The CAR-Ts time and resources required for production from healthy third-party donors, and will would then be frozen after manufacturing, will certainly translate to higher prices for be manufactured to scale using contract and shipped anywhere in the world for patients. As a result, the major challenge manufacturing organizations. In theory, immediate use. for manufacturers of autologous CAR-T allogeneic CAR-T approaches could supply [email protected] therapies will be the shift to large scale thousands of treatments from a single production because of the costs associated T-lymphocyte since healthy donor cells can Dustin Phan is an analyst with Datamonitor with such personalized therapies. This could be grown into larger populations following Healthcare.

Beyond Tax: Portfolio Opportunities In Pfizer-Allergan Deal (Continued from page 1) following the company’s R&D Day on Nov. that the company can focus on higher margin (progesterone) for preterm labor, and WC3011 4 that pharma largely has backed away brand-name products. for vaginal atrophy. Phase II testing also is from Allergan’s seven key therapeutic areas: under way for the contraceptive pill Estelle, ophthalmology, neurology, dermatology and Diversity In Women’s Health and Colvir is in Phase I development for aesthetics, gastrointestinal, women’s health, Like Allergan’s neurology platform, which cervical dysplasia. urology and anti-infectives. includes four out of the nine blockbusters Allergan highlighted Esmya during its “We are typically the largest player in the highlighted during the R&D Day R&D Day, noting that the company expects space,” Saunders said. presentations, the company’s women’s health to submit an NDA for the Phase III drug While Allergan does not have a significant portfolio is quite diverse. candidate in 2017 with FDA approval presence in oncology, which is a major Allergan has been building its women’s expected in 2018. There is a need for an research and development focus for Pfizer, health business since before January 2013 effective treatment, since 11m women Datamonitor Healthcare noted recently when the company – still known as generics- between the ages of 25 and 49 have been that some of the companies’ overlapping focused Watson Pharmaceuticals Inc. – bought diagnosed with the condition. Esmya has categories provide opportunities for growth Uteron Pharma. At the time, Watson noted that been shown in mid-stage studies to reduce as revenue from certain Pfizer blockbusters there was little competition in women’s health tumor size, relieve pain and bleeding, and dwindles over a decade. as big pharma competitors were leaving the help patients delay the need for surgery. For instance, annual sales of the space, including Pfizer’s Wyeth. In May during “Women’s health is a $1bn business for neuropathic pain drug Lyrica (pregabalin) the same year, after Watson became Actavis, Allergan in the US. This product can double are expected to decline by $3.9bn between the company boosted its women’s health the business,” William Meury, executive vice 2014 and 2024, while Datamonitor notes portfolio when it bought Warner Chilcott PLC. president and president of branded pharma, that Pfizer’s rheumatoid arthritis drug Xeljanz Allergan has Atelvia (risedronate sodium or said during the company’s R&D Day. (tofacitinib) will bring in just $958m in new delayed-released Actonel) for osteoporosis; Allergan projects that Esmya could sales in that time. Cervidil (dinoprostone) for labor induction, generate $1bn in annual US sales based on Growth from some of Allergan’s products Crenone (progesterone) for amenorrhea; the drug’s use in Canada, where it is approved could help fill the revenue gap: $376m Proquin SR (ciprofloxacin) and Metronidazole and marketed as Fibristal. from the low estrogen birth control pill Lo 1.3% vaginal gel for urinary tract and Pfizer’s small women’s health portfolio Loestrin Fe, $177m from Canasa (mesalamine) reproductive tract infections; Thyrolar (liotrix) includes the hormone replacement for ulcerative proctitis, $160m from the for hypothyroidism; and the contraceptives therapies Duavee (bazedoxifene and beta blocker Bystolic/Valsartan (nebivolol) Ella, Generess Fe, Liletta, Lo Loestrin Fe, Lo estrogens), Premarin (conjugated estrogens) for hypertension, and $127m from Estrace Minastrin Fe, and Ovcon-50. and Prempro (conjugated estrogens and (estradiol) for vulvar and vaginal atrophy. A new drug application (NDA) has been medroxyprogesterone acetate). The company The Datamonitor assessment included submitted to the US FDA for a progestin-only has an NDA pending with the FDA for Viviant Allergan’s approved products, but didn’t contraceptive patch while Phase III clinical (bazedoxifene) to treat osteoporosis and it is take into account programs in the research programs are under way for Esmya (ulipristal) investigating rhBMP-2/CPM (dibotermin alfa) and development pipeline with blockbuster in uterine fibroids, nestorone and ethinyl in a Phase II osteoporosis study in partnership potential, according to the company: estradiol contraceptive vaginal ring, Prochieve with Bioventus LLC. ➤ abicipar pegol (formerly known as DARPin) for age-related macular degeneration (AMD), Future Blockbuster And Other Key Pipeline Opportunities rapastinel for depression, Viberzi (eravacycline) Product Indication Launch Projected Peak Sales for irritable bowel syndrome (IBS), Esmya for uterine fibroids, Kybella (deoxycholic acid) for Abicipar pegol AMD 2020 $1bn to $2bn+ double chin and at least four others. Rapastinel Depression 2020 $1bn to $2bn+ Allergan presented details for several of Botox (onabotulinumtoxinA) Various new indications Now through 2020 $1bn to $2bn+ its 70-plus pipeline programs during the pipeline company’s R&D Day, which took place at its Oral CGRP antagonist Migraine 2019 $1bn to $2bn research campus in Irvine, California, and Viberzi (eravacycline) IBS w/diarrhea (IBS-D) 2015 $750m to $1bn shared a slide that highlighted 13 assets with at least $250m and as much as $2bn – or Esmya Uterine fibroids 2017 $500m to $1bn more – in projected annual sales. Relamorelin Diabetic gastroparesis 2018 $500m to $1bn With an eye on currently marketed brand- Vraylar (cariprazine) Schizophrenia and bipolar 2015 $500m to $1bn name drugs and the companies’ pipeline disorder potential, Credit Suisse analysts said in a Kybella (deoxycholic acid) Double chin 2015 $500m to $1bn recent report that Pfizer is on track for a 3.5% compound annual growth rate (CAGR) for the Bimatoprost sustained-release Glaucoma 2018 $500m to $750m (SR) next 10 years, while Allergan is expected to experience an 8% CAGR for the next decade. XEN45 Glaucoma 2016 $500m to $750m The investment bank’s analysis included Tavilermide Dry eye 2019 $500m to $750m revenue from Allergan’s lower margin Sarecycline Severe acne 2017 $250m to $300m generics business, which is being sold to Teva Pharmaceutical Industries Ltd. for $40.5bn so Source: Allergan plc

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With no contraceptives or treatments for submitted an application for FDA approval specific conditions like uterine fibroids and of a multi-use, preservative-free, single-bottle amenorrhea in Pfizer’s portfolio, there is formulation of Restasis, which has a Prescription little overlap with Allergan’s women’s health Drug User Fee Act (PDUFA) date in March. business with the exception of hormone pinkomelet/shutterstock.com The long-delayed abicipar pegol program replacement therapies. Combined, the recently entered Phase III with data from two companies could cover a wide swath of clinical trials expected in mid to late 2017 women’s health, handing over Allergan’s with commercialization of the long-acting market-leading position to Pfizer in a market VEGF inhibitor targeted for 2020, Nicholson FILLING THE GAPS: Allergan with few players – pharma or otherwise. products will boost Pfizer’s portfolio told Scrip. Pfizer has just two commercial More Antibiotics For ID Portfolio ophthalmology products and three Allergan’s infectious disease portfolio mainly treat wrinkles around the eyes. If Pfizer buys in development, including Besivance consists of antibiotics: Avycaz (ceftazidime- Allergan, the blockbuster wrinkle-reducer (besifloxacin 0.6%) for bacterial conjunctivitis avibactam), Dalvance (dalbavancin), Pylera and migraine treatment with roughly $2bn and Macugen (pegaptinib sodium) for wet (bismuth subcitrate potassium, metronidazole in annual sales would be the larger pharma AMD, which are partnered with Allergan rival and tetracycline) and Teflaro (ceftaroline company’s first aesthetic drug product. And Valeant Pharmaceutical International’s Bausch fosamil). The company has ongoing Phase III the aesthetic market, Allergan noted during & Lomb subsidiary. clinical trials for Avycaz in hospital-acquired its R&D Day, is expected to double by 2020. Allergan noted at its R&D Day that it has pneumonia, Dalvance in community-acquired a 57% share of the ophthalmology pharma pneumonia, and Teflaro-avibactam for skin market, while Novartis AG has 35%, Valeant infections. Allergan also is developing the ‘The goal for Kybella is to has 4% and Pfizer has 2%. The company antifungal agent albaconazole. very much build it like Botox has five out of six ophthalmology segments Pfizer’s infectious disease platform, on covered, except for the retina, which would the other hand is quite diverse, led by the was built’ turning the single change with approval of abicipar. Prevnar vaccines, which generated $1.6bn in 3) Allergan’s gastrointestinal (GI) portfolio worldwide third quarter sales – up 44% from product into a pipeline of is led by Linzess (linaclotide) for IBS with $1.1bn a year earlier. fat-reducing treatments constipation (IBS-C), but the company The big pharma’s other commercial expects Viberzi for IBS with diarrhea (IBS- infectious disease products include the Latisse (bimatoprost ophthalmic solution D) – purchased via the acquisition of Furiex HIV/AIDS drugs Epzicom (abacavir and 0.03%) for eyelash growth is another Pharmaceuticals for up to $1.46bn – to be lamivudine), Lexiva (fosamprenavir), Rescriptor legacy Allergan aesthetic product, and a fast-rising star. The drug was approved in (delavirdine), Selzentry (maraviroc), Tivicay the new Allergan bought the double chin the US in May and its commercial launch is (dolutegravir), Triumeq (abacavir; dolutegravir; treatment Kybella (deoxycholic acid) via expected in late 2015 following controlled lamivudine), Trizivir (abacavir, lamivudine and the recent $2.1bn acquisition of Kythera substance scheduling by the US Drug zidovudine) and Viracept (nelfinavir mesylate), Biopharmaceuticals Inc. in July. Enforcement Administration (DEA). all of which are marketed by ViiV Healthcare, “The goal for Kybella is to very much build it With blockbuster expectations for Viberzi, Pfizer’s six-year-old partnership in which like Botox was built,” Saunders told Scrip, with Allergan is preparing a massive launch later GlaxoSmithKline holds an 85% share. multiple indications turning the single product this year, including direct-to-consumer Other Pfizer infectious disease drugs into a pipeline of fat-reducing treatments. advertising, so that “promotionally, this will be include the antifungal Eraxis (anidulafungin); Allergan is targeting fat under and behind the the largest launch ever in the GI space,” Meury the antibiotics Synercid (quinupristin and arm, around the knee and on the hips (love said during the company’s R&D Day. dalfopristin), Tygacil (tigecycline), Zmax handles) for aesthetic purposes, with therapeutic Allergan’s pipeline GI programs include new (azithromycin) and Zyvox (linezolid); the indications that may include lipoma, HIV indications and formulations for Linzess and FluMist seasonal influenza vaccine (as a lipodystrophy buffalo hump, obstructive sleep the Phase IIb drug candidate relamorelin for partner with AstraZeneca plc); and the apnea and familial lipomatosis. diabetic gastroparesis, which hasn’t had a new meningococcal vaccine Trumenba. 2) The blockbuster dry eye therapy Restasis treatment for 30 years. The company has high (cyclosporine) leads Allergan’s ophthalmology hopes for relamorelin, a ghrelin agonist, given Other Major Areas Of Growth portfolio, which includes 13 approved the unmet need and Phase IIa results that Allergan also claims to hold the top spot in products and 17 pipeline programs. Other show a 60% improvement versus placebo in terms of global sales in dermatology and top-sellers are the glaucoma treatments vomiting symptoms. Allergan paid $40m up aesthetics with $2.1bn in 2015 revenue Alphagan (brimonidine tartrate 0.1% or front for rights to the drug and has an option through the third quarter of this year, as 0.15%), Combigan (brimonidine tartrate/ to acquire its developer, Rhythm Health. well as a number two spot in eye care timolol maleate 0.2% or 0.5%) and Lumigan Pfizer has no approved brand-name GI with $3bn in sales, and a number 3 spot (bimatoprost 0.01%). drugs, but the company has four Phase I and II in gastrointestinal diseases with $1.2bn in The ophthalmology pipeline includes the candidates in development for Crohn’s disease. sales. The three categories are characterized Phase III assets abicipar pegol for wet age- In total, Deutsche Bank analysts project by several marketed therapies and pipeline related macular degeneration (AMD) and $23.6bn in total revenue for Allergan in 2020, candidates, including: bimatoprost sustained release for glaucoma which would boost Pfizer’s revenue by 50% 1) Before and after its $66bn acquisition by as well as the Phase II Restasis X program – a based on the investment bank’s forecast of Actavis, Allergan probably was best known product candidate in development to protect $57.6bn in sales by 2020. for Botox cosmetic, which is used primarily to Allergan’s dry eye franchise. The company [email protected]

© Informa UK Ltd 2015 @scripnews scripintelligence.com November 20th 2015 9 business bulletin Business Bulletin that could be worth $25bn by 2020, according to colleagues,” a Roche spokesperson told Scrip in an Allergan Assets a roadmap released Nov. 10 by Innovate UK, the email. “If there is no divestment option, production government agency that identifies, plans and invests will be ceased in a phased approach, currently Diversify Pfizer’s in emerging technologies that have the potential to estimated to be completed between 2018 and 2021. Neurology Portfolio drive future economic growth. It has long been held We will approach only reputable companies, and If Pfizer Inc. were to buy Allergan plc – or vice that animal studies and models are not particularly will have more clarity about divestment options by good models for what happens in patients, but it is the end of the second quarter next year,” she said. versa – the merged companies would have only in recent years that cell culture techniques and To manufacture new generations of specialized a large and actually quite diverse portfolio computer-based analytics have proven themselves medicines based on small molecules, Roche said it of drugs for central nervous system (CNS) as alternatives. With such technology advances, the will also invest CHF300m into a dedicated facility diseases and conditions. Both pharmaceutical global market for cell-based assays used in drug in Kaiseraugst, Switzerland, to support future firms disclosed in late October that they’re discovery, safety and toxicology is now expected to technology requirements. “This investment will in friendly negotiations about a transaction reach $21.6bn by 2018, and the global market for strengthen the company’s development and launch between the companies, though Allergan nor induced pluripotent stem cells is expected to reach capabilities,” the company said. Pfizer made it clear which one would buy the $2.9bn in 2018, the roadmap says. Leo CEO: Global Ambitions And other. A merger of the two would result in a Bertarelli-Backed Allergy Leader Astellas Buy lower tax rate for Pfizer’s operations, because Targets M&A The acquisition of Astellas’s dermatology business for of Allergan’s corporate domicile in Ireland, and The CEO of the newly merged Stallergenes Greer €675m ($725m) by Denmark’s skin disease specialist a combination of the companies would create PLC says he is looking for business development Leo Pharma, announced Nov. 11, is as much about one big CNS portfolio – one of Allergan’s opportunities, and certain actions should be satisfying the company’s desire to reach critical mass seven therapeutic areas – ranging from pain expected “this year and, if not, in 2016.” Stallergenes in certain markets as it is about reviving an aging medications to Alzheimer’s drugs. Greer now accounts for 32% of the $1bn global portfolio of products. Over the past six years, Leo allergy immunotherapy (AIT) market, the largest has been re-inventing itself as a global specialty Astellas Buys US Cell Therapy Firm of any company, and it expects to bring the “next company rather than a Europe-focused mid-pharma, Astellas Pharma Inc. has entered into a generation of allergy products and technologies and the Astellas dermatology acquisition is its largest definitive agreement to buy the US clinical- to the market, driven by R&D and business so far. Through the acquisition, Leo obtains a “strong stage regenerative cell therapy venture Ocata development,” said chairman and CEO Fereydoun foothold in markets such as China and Russia, and Therapeutics Inc., in a move that will give the Firouz in a Nov. 5 analysts’ briefing. adds critical mass in many other markets. It’s a great Japanese firm a new presence and pipeline in strategic fit for the company,” said Leo’s president ophthalmology and boost its research efforts in NightstaRx Raises $35m and CEO Gitte Aabo. Leo believes it can revive a field being strongly supported by the Japanese Spun out from the University of Oxford, new born the Japanese company’s dermatology products, government. The move is aimed at “establishing NightstarRx is finding its feet in the biopharma that include the immunosuppressive Protopic a leading position in cell therapy” by acquiring field and has closed a $35m series B funding, (tacrolimus) ointment for eczema, and products for Ocata’s “world-class” researchers and pipeline with which it will boost its inherited retinal the treatment of acne and skin infection including programs, which will be combined with Astellas’s disease pipeline. Founded in 2014 and funded Locoid (hydrocortisone butyrate) and Locobase existing regulatory and commercial know- by a £12m investment from Syncona Partners, cream for skin care and Zineryt (erythromycin plus how, the firms said. Astellas in Tokyo told Scrip’s NightstaRx is a company focused on therapies zinc acetate) solution for acne. sister publication PharmAsia News that strategy for retinal dystrophies. The company is set to relating to the main geographic targets for the begin its Phase III pivotal trial next year into Will Genentech’s Cotellic Survive commercialization of Ocata’s pipeline had yet to be treatment for choroideremia, an inherited X-linked Alternative Pricing Demands? decided, given the still early stage of the deal. recessive disease that eventually causes blindness. Genentech Inc.’s and Exelixis Inc.’s Cotellic NightstaRx’s gene therapy technology consists of a (cobimetinib), a MEK inhibitor, made it across the Hanmi Hits Jackpot Again viral vector adeno-associated virus (AAV). FDA’s finish line on Nov. 10, but now the firms must Hanmi Pharmaceutical Co. Ltd. has inked confront the ultimate test of the drug’s success a licensing out agreement with Janssen Roche’s Modernization Drives – selling it, which is increasingly becoming more Pharmaceutical Co. for the development and Site Closures difficult in a climate where payers are becoming commercialization of its diabetes and obesity Roche Holding AG will cease manufacturing at more and more demanding about using alternative therapy HM12525A, a long-acting GLP/GCG analog. four sites in Europe and the US in a modernizing pricing arrangements. Cotellic’s approval gave shares Following a string of major licensing out deals move that could see up to 1,200 jobs lost as a result of Exelixis a 5.2% boost on Nov. 10, before closing at with multinationals this year, the agreement will of changes in the cancer specialist’s portfolio of $6.33, up 23 cents, or 3.8%. But investors in Roche bring further international recognition of Hanmi’s therapies. The decision follows a review of Roche’s Holding AG, the parent company of Genentech, were new diabetes therapies and once again prove global manufacturing network for small molecules unimpressed, with the stock down throughout the the firm’s potential as a leading South Korean and an assessment of future drug innovation day, falling 1.35%, or 45 cents, before closing at $33.09, innovator. Under the agreement, Janssen will have patterns. The new generation of specialized a loss of 21 cents. The FDA OK’d Cotellic, which was the exclusive worldwide rights to the therapy, medicines, many based on large-molecule biologics, discovered by Exelixis, in combination with Zelboraf excluding in South Korea and China. Hanmi will are made in smaller amounts than medicines have (vemurafenib), a kinase inhibitor, to treat patients with receive an upfront payment of $105m and a total hitherto been, and they demand different innovative unresectable or metastatic melanoma with a BRAF of up to $810m in milestone payments, plus manufacturing technologies. As Roche’s portfolio V600E or V600K mutation. Zelboraf was co-developed double-digit sales royalties after commercialization. mix has changed, its network of manufacturing under a 2006 license and collaboration agreement plants has become increasingly underutilized. It between Roche and Plexxikon Inc., which is now part Replacing Animals: therefore plans to exit four manufacturing sites in of Daiichi Sankyo Co. Ltd. Zelboraf, which gained the Multi-Billion Dollar Industry? Clarecastle, Ireland; Leganes, Spain; Segrate, Italy; and FDA’s approval in August 2011, is indicated as a single Using new and emerging “non-animal technologies Florence, South Carolina in the US. “For all exits, we agent to treat patients with unresectable or metastatic (NATs)” in the testing of the safety and efficacy of are looking into divestment options as the best way melanoma with BRAF V600E mutation as detected by new pharmaceuticals is a growing industrial sector to ensure long-term sustainable workplaces for our the cobas 4800 BRAF V600 mutation test.

10 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 headline news

More Drug Pricing Probes: Cost Could Drag Merck, Lilly Targeted On Lilly’s Baricitinib Merck & Co. and Eli Lilly and Co. are the for Medicare and Medicaid Services and at latest drug makers to reveal their pricing the company’s patient assistance programs. Outlook practices have caught the attention of Valeant said most of the materials requested by Eli Lilly & Co. and partner Incyte Corp. federal prosecutors – both disclosing in the subpoenas are related to documents with have added to the growing dataset for recent Securities and Exchange Commission its patient assistance programs and financial their once-daily oral JAK1/JAK2 inhibitor (SEC) filings the US Attorney’s Office for the support for patients. baricitinib ahead of their planned filing by Eastern District of Pennsylvania has got the Turing also is under investigation by New year-end, with detailed results from the companies in its sights. York’s attorney general for possible antitrust pivotal Phase III RA-BEAM which showed Merck disclosed late on Nov. 5 it had violations related to the nearly 5,500% the investigational therapy had superior received a civil investigative demand from increase of the company’s toxoplasmosis patient-reported outcomes compared federal prosecutors in Pennsylvania, who medicine Daraprim (pyrimethamine). Valeant with AbbVie’s market-leading injectable requested information about the firm’s and Turing have been at the heart of the anti-TNF antibody, Humira (adalimumab), contracting and pricing of its asthma drug criticism coming from patient advocacy along with better response claims and Dulera (mometasone furoate/formoterol groups, physicians and lawmakers over rising structural improvements for patients. fumarate dihydrate) inhalation aerosol with drug prices – especially for older medicines. Detailed baricitinib data was also certain pharmacy benefit managers and Recently, a group of Democrats formed a released at the joint meeting of the Medicare Part D plans. new task force focused on combating the American College of Rheumatology “skyrocketing” costs of medicines and Sens. and the Association of Rheumatology Susan Collins (R-ME), chair of the Senate Health Professionals, held Nov. 6-11 Merck, Lilly disclosures came Special Committee on Aging, and Claire in San Francisco from the Phase III in the midst of the firestorm McCaskill (D-MO), the ranking member, trial RA-BEGIN, a non-inferiority study opened a bipartisan investigation into testing it against methotrexate in early over pricing practices of Valeant, Turing, Retrophin Inc. and Rodelis rheumatoid arthritis, showing baricitinib Valeant and Turing Therapeutics Inc. – who all had significantly alone and in combination were superior increased the prices of certain medicines in to methotrexate monotherapy in helping recent months – and revealed plans for a rheumatoid arthritis patients achieve Merck said it was cooperating with the hearing on the matter in December. clinical remission. investigation. The Pharmaceutical Research and Lilly aims to submit baricitinib for FDA Tucked inside Lilly’s most recent 10-Q filing Manufacturers of America (PhRMA) and the regulatory approval for the treatment of with the SEC was the revelation the company Biotechnology Industry Organization (BIO) rheumatoid arthritis by the end of the had been advised by the same Justice have distanced themselves from Valeant and year. If approved, the drug will represent a Department office in Pennsylvania about Turing and have insisted that any conversations new therapeutic category for Lilly. how the firm handled certain distribution about cost needs to focus on value. But, Rep. But competition in the rheumatoid service agreements with wholesalers Elijah Cummings, who is leading the Affordable arthritis market is intense. Injectable when calculating and reporting average Drug Pricing Task Force, told Scrip last week anti-TNFs dominate the market following manufacturer prices in connection with the that neither PhRMA nor BIO had approached treatment with older disease-modifying Medicaid drug rebate program. him about having discussions with lawmakers anti-rheumatic drugs like methotrexate. Lilly said it was voluntarily responding to about cost versus value. Nevertheless, Lilly sees an opportunity prosecutors’ request. Meanwhile, Health and Human Services for an effective oral drug with a solid Merck’s and Lilly’s disclosures came in Secretary Sylvia Mathews Burwell is safety profile. the midst of the firestorm over the pricing convening a Nov. 20 invitation-only forum Baricitinib’s clinical performance to practices of Valeant Pharmaceuticals to hash out the challenges and complexities date has been promising. As an oral International Inc. and Turing Pharmaceuticals involved in reducing the costs of medicines small molecule, baricitinib has the AG, who also are under investigation. and ensuring access, while driving innovation, potential to be positioned early in Valeant disclosed late on Oct. 14 it had strengthening incentives and promoting the RA treatment paradigm. However, received subpoenas from the US attorney competition of new drugs. Burwell also Datamonitor Healthcare believes that offices in Boston and New York seeking wants to hear about innovative strategies for its uptake will be largely driven by its incorporating value- and outcomes-based information about the firm’s pricing decisions. cost, should the drug receive approval The federal investigators are examining models into purchasing programs in the in RA. This assumption is based on the the sharp increases in the prices of drugs public and private sectors. case of Xeljanz (Pfizer Inc.’s JAK inhibitor like Nitropress (sodium nitroprusside), which Rising drug prices also has become a tofacitinib) in the US and Japan, where jumped from $257.80 to $805.61, or 212.5%, bipartisan prop for politicians vying for the the oral small molecule was approved for and Isuprel (isoprenaline), which rocketed White House – with two of those candidates, use after conventional disease-modifying from $215.46 to $1,346.62, or about 525%, former Secretary of State Hillary Clinton and antirheumatic drugs but has been after the company purshed them from Sen. Bernie Sanders (I-VT) declaring they relegated to later lines of therapy due to Marathon Pharmaceuticals Inc. in February. were proud to count the biopharmaceutical its high cost. Prosecutors also are taking a look at industry among their greatest enemies. [email protected] information Valeant provided to the Centers [email protected]

© Informa UK Ltd 2015 @scripnews scripintelligence.com November 20th 2015 11 headline news Horizon Infected By Valeant Scandal Horizon Pharma is the newest victim of companies are distributing their products Horizon responded with accusations that Valeant International’s woes as the biopharma’s to patients. While the use of specialty analysts called unfounded and “nothing scandal begins to seep into other areas of the pharmacies is a common practice that can new,” accusing Express Scripts of profiteering industry. Valeant’s bad behavior has prompted offer customers a cheaper, faster way to get and trying to control competition due to its pharmacy benefit giant Express Scripts to cut certain drugs, exclusive agreements with ownership of a mail order pharmacy. ties with a specialty pharmacy associated with these businesses are frowned upon. Express “This competitive role, in our view, creates Horizon, putting 5% of its revenues in jeopardy. Scripts is using the term ‘captive pharmacies” a clear conflict of interest, as Express Scripts The PBM revealed Nov. 10 that it is to describe these businesses that are deriving stands as both a pharmacy’s overseer and removing Linden Care Pharmacy from its the bulk of their revenues from schilling the competitor. Based on its Accredo ownership, formulary because the specialty pharmacy products of one company. it’s not surprising that Express Scripts would almost exclusively sells Horizon products in “We are also evaluating several other target small, competitive independent violation of a contractual agreement Express pharmacies that appear to be predominantly specialty pharmacies in order to force those Scripts has with Horizon. dispensing Horizon prescription drugs. In pharmacies from its network, attempt to The decision comes on the heels of a addition, we are reviewing and evaluating all dominate the US specialty pharmacy medicine recent scandal with Valeant that has caused similar captive pharmacy arrangements that distribution channel and further boost its own the company’s stock to lose almost 70% of its we know of and will work to identify others,” profits at the expense of patients,” said Horizon value since August. It recently came to light said Express Scripts in a statement on Nov. 11. chair and CEO Tim Walbert. that a specialty pharmacy dubbed Philidor, “We routinely monitor our network and Walbert added that Horizon does a large which had an exclusive relationship with take action when we see pharmacies trying chunk of its business with Accredo and is Valeant, may not have been acting ethically to circumvent solutions, like formulary currently reevaluating that relationship. He or legally. The pharmacy was accused of management, that protect payers and patients went on to call Express Scripts reckless in its misconduct related to filling prescriptions and from wasteful drug spend,” the statement added. labeling of Linden Care and reiterated that auto-refill options for patients. Beyond severing ties with Linden Care, Horizon does not own a stake in Linden Care. It’s still unclear whether Philidor’s actions Express Scripts has also filed a complaint Horizon is currently conducting a tender are illegal and how much Valeant will be against Horizon to seek $140m Express offer to acquire Depomed through a hostile held accountable, but an ad hoc committee Scripts says it is owed due to breach of takeover. The issue with Express Scripts is established by the company is investigating contract. “Because of Horizon’s continued likely to have an impact on this offer that the matter. The scandal, which broke several non-compliance with the agreement, Express has already been adamantly rejecte by the weeks ago, has prompted payers and insurers Scripts is taking this action to recover money Depomed board of directors. to take a closer look at how pharmaceutical rightfully due its clients,” said the statement. [email protected] Bayer’s Wolters Explains Downside Of Success Bayer Healthcare’s key therapy areas of focus out there and so many research groups.” early stage, where clearly there are more are oncology, cardiology, ophthalmology However, recently Bayer did sign a significant opportunities available, the tricky part is and women’s health, according to vice- academic partnership with the Wilmer Eye finding the best one. Once this is identified president and head of early licensing Dr. Mark Institute, at Johns Hopkins. though “we are not alone,” Wolters said. “We Wolters; but while the company is investing Bayer is bulking out its ophthalmology have our competitors who identify the same in programs in these areas at all stages of development pipeline following the strong opportunities as the best ones and we have development, it has to keep its lasers focused success of Eylea (aflibercept). “Our entry to manage that situation.” and can’t step into unapproved zones. into ophthalmology is a brilliant example of Geographically, opportunities are “There are a few areas where we are not thinking across the borders and leaving the everywhere, he added. “We are a global active, like pain treatment for instance, also corporate mainstream,” Wolters said. “We had company and all regions are important. Alzheimer’s disease and the whole area of an offer from Regeneron about 10 years ago From a licensing perspective I do not care CNS, these are not areas where we have early when we were not active in ophthalmology. where the opportunity comes from. If it is stage research. This is because we have been But we have since recognized the the best opportunity, it doesn’t matter if it so successful in recent years that we have commercial opportunity and medical need, comes from China, the US or Australia or had to focus our activities,” Wolters told Scrip, so we were able to realize this opportunity somewhere else.” on the sidelines of BIO-Europe conference in with Regeneron.” As for in-licensing new technology as Munich, Germany. Eylea turned out to be a big success story: opposed to in-house research, Wolters said, “The downside of success is that you have sales of the drug are expected to reach $4.1bn “It’s complementary. We have a significant to invest a lot of money in large, late stage worldwide by 2017, according to forecasts number of researchers doing high quality studies and marketing activities. So we have from Sagient Research’s BioMedTracker. science, but you can never have all the to be focused.” “When you have such a successful front innovation in-house, especially looking into He said Bayer is working together with runner, it is wise to then move up the recent developments in science where very biotech companies “which we very often pipeline; so this is what we are doing and we often it is early days, so high risk. Everyone meet at conferences like BIO-Europe,” but that have some early stage projects in this area,” realizes it would not make sense to internalize “identifying academic partners is a little more Wolter’s said. every scientific finding. “ difficult as there are just so many universities He added that when investing at an [email protected]

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Cell Therapy Developers Debate Valeant Looks For Hurdles, Big Pharma Drags Its Feet Forgiveness Companies developing ‘advanced’ treatments for it is quite another,” said TiGenix’s Bravo. Valeant CEO Mike Pearson finally checked such as cell therapies face many of the The problem, as Bravo sees it, comes back to his ego at the door and started handling same challenges in getting their innovative data again. Because of the small number of the company’s scandal with a little finesse. products to market, yet the attitudes of patients in the trials, the resulting volume of While the effort may be too little, too late management towards the various hurdles data “is not enough to convince payers.” for many investors, it sparked some hope differs quite significantly, Scrip found at Aberman of Pluristem looks at it differently. for analysts that the company can begin Alliance for Regenerative Medicine’s third “We need to aim for significant improvement. putting the ordeal behind it by the middle annual European Advanced Therapies Investor If the improvement is significant, people will of next year. Day on Nov. 12. want to pay for it,” he believes. “Even if it’s with “The past few weeks have been a Zami Aberman is chair and CEO of only 20 patients, a large improvement will painful learning experience for me Pluristem Therapeutics, an Israeli company give you the p value [you need].” personally and I know it has been painful developing an ‘off-the-shelf’ therapy made Kelliher from Avita reminded everyone for many of you as well,” said Pearson on a from expanded placental cells. He feels the to get an agreement from regulators on Nov. 10 business update call. “One of the biggest hurdle is “persuading the [pharma] endpoints early on in the clinical design consequences of such rapid growth is that industry and regulators of the consistency of process “to avoid a grenade in the lap” at a you don’t always take the time to listen allogeneic products, which could be derived later stage. to what the world outside your company from many different donors.” Here, Aberman said the EU’s adaptive is saying. This has been a mistake on our Eduardo Bravo is CEO of TiGenix, a Belgian pathways approach works well. “You are asked part as a company and on my part as its cell therapy developer. He believes the to work alongside the [regulator’s] people leader. We’re going to fix that.” root of all the difficulties in the space is the from the beginning,” he noted. This helps to The beleaguered multi-national hosted scarcity of large-scale data. “We don’t as yet avoid nasty surprises. “The adaptive pathway is the conference call to help further clarify have large amounts of compelling data and looking for clear data on efficacy,” and will work its situation with the specialty pharmacy this is our major problem,” he told attendees with companies to help them achieve that. Philidor and how the termination of of the Investor Day. However, according to TiGenix’s Bravo, cell this relationship will impact its business Avita Medical is a medical technology therapies are never going to be cheap “so we going forward. company with regenerative products on the have to target indications where patient need Valeant put a temporary plan into place market to treat wounds, scars and other skin allows us to charge a higher price.” to minimize distribution disruptions while conditions. CEO Adam Kelliher said his most Pluristem’s Aberman disagrees. “We it looks for a way to replace Philidor, which significant obstacle is “medical orthodoxy.” need only to be confident of a significant is expected to be completely unwound Physicians have a “set way of doing things and improvement strategy. We shouldn’t make by January 2016 at the latest. That plan it’s difficult to persuade them to do it differently.” excuses for that.” He acknowledges that includes distributing the prescriptions Avita gets around this by positioning its reimbursement agencies “only care about from its specialty pharmacy unit for free products as an “adjunct” to existing ones. money” but by demonstrating significant for commercially-insure patients or a improvement it would leave them with “little payment of $35 for cash-pay patients. Manufacturing choice” but to pay for the product. Pearson noted that there will be an Unsurprisingly Alexander Vos, CEO of cell impact on several of Valeant’s business therapy-focused contract manufacturer Pharma Investment units, including dermatology and PharmaCell, highlights other concerns. He The speakers all bemoaned the relative lack neurology – particularly in the fourth believes it is the scaling up of manufacturing of investment by big pharma in the cell quarter. While Valeant has yet to see an processes where many companies trip up. therapy space. impact on prescribing volumes so far, it is “Companies are desperate to get to the next “Big pharma coming in will help us in two very likely to happen, and the company stage, the next clinical trial, to show their ways,” explained Bravo. “One, they will invest in is losing money by giving its drugs out potential partners. But they need to be able to enabling technologies. Two, they will have the for free. demonstrate scalability of their manufacturing money and long-term commitment to do the “In the very short-term, disruption processes, and this isn’t always easy.” large clinical trials that will bring the data.” in our dermatology business will be Vos also warns that a contract manufacturer Pharma’s delay in entering the space is significant,” said Pearson. “Until we is “no substitute for in-depth scientific because of a “herd mentality,” he claimed. “If implement a new Valeant access program, knowledge of your production process. You you think about the early days of monoclonal many doctors will likely change their need to understand it thoroughly [on a small antibodies, no pharma wanted to take part. prescribing [habits].” scale] before you can consider scaling it up.” Hence the big biotechs – Amgen, Biogen – Valeant will not be on the acquisition And when a company is ready for scale-up, became big. Roche bought Genentech and path any longer and instead will use its “we can step in and help.” look how well that turned out.” cash in the near-term to pay down debt “When we talk to pharma companies we – something that should finally begin to Pricing have to demonstrate that we have solved all please investors. The company has $23m The panel of speakers also differed in their the problems,” concluded Aberman. “We have in debt due in the fourth quarter, as well attitudes towards the pricing of their cell to show all the solutions, and then pharma as $832m due in 2016. therapies. “Getting approval is one thing, will enter the cell therapy space.” [email protected] getting reimbursement authorities to pay [email protected]

© Informa UK Ltd 2015 @scripnews scripintelligence.com November 20th 2015 13 policy & regulation briefs Policy & Regulation Briefs sessions like what White House seeker Hillary What Law Applies Tashatuvango/shutterstock.com Clinton endured last month answering questions at the House “Benghazi” hearing. Even though In The Unified Patent most have expected Califf’s confirmation is all but Court? assured, he’s likely to be grilled more at his Senate When the pan-European Unified Patent Court HELP Committee hearing than Obama’s first FDA commissioner, Margaret Hamburg, who faced few comes fully into force, it will have divisions tough questions in May 2009 – addressing mostly in a number of EU member states. But given inquiries about improving food safety and tackling its geographical scope, what is the law that the burden of tobacco in the US, although she did will apply to disputes in the court? In the of Zantac (ranitidine), a drug used to treat and acknowledge she was hoping to gain authority latest in his series of columns on the UPC, prevent gastrointestinal ulcers, which indicated at the agency to approve biosimilars, which, of Paul England explains the law applicable to non-sterile manufacturing and packaging. course, regulators did obtain the next spring under the Affordable Care Act. The job of approving infringement, validity and “objects of property.” O’Neill On The UK AMR Review biosimilars is expected to get more difficult as The substantive law on acts of infringement Lord Jim O’Neill – ex-chair of Goldman Sachs Asset and their exceptions that will apply in the biologics become more complex – something that Management and the man appointed by UK Prime will now be Califf’s responsibility to figure out, if UPC are found in Articles 25 to 27 of the UPC Minister David Cameron to launch and chair a he’s confirmed. Agreement, while the rules on provisional review into the crisis of antibiotic resistance – spoke measures, including preliminary injunctions, to Scrip at the recent BioInfect conference about WTO IP Exemptions Give Bangladesh, are included in the Rules of Procedure. These what will happen when the Review of Antimicrobial Indian Firms Competitive Leg-Up provisions apply to unitary patents and Resistance (AMR) reaches its conclusion in summer The WTO Council’s recent decision permitting European patents litigated in the new court. 2016, pharma’s reaction to the review so far, and least-developed country (LDC) members a 17-year However, there is no single model approach how China is joining the game. BioInfect, an exemption from implementing intellectual property event focused solely on the issue of antimicrobial to how these provisions should be applied in (IP) provisions, such as patents, on medicines is resistance held at AstraZeneca PLC’s old Alderley expected to give Bangladesh’s up-and-coming detail in any particular case, and the national Park site in Cheshire, UK, saw O’Neill explain that if laws of infringement, which can provide pharm industry valuable buffer time to catch the pharmaceutical industry banded together to up with and possibly take on some peers in the guidance, differ. Instead, the UPC judges must produce the 10-12 new antibiotic drugs he believes region. The extension for LDCs, some experts say, develop their own approach in their own case are needed globally, the cost would reach between could also potentially serve as a useful window law, over time. $16bn and $37bn. A huge amount of money for of opportunity for Indian generic firms if stymied the average person to consider, however, O’Neill by newer treaties such as the recent Trans-Pacific Violations Uncovered At GSK, noted that the mid amount of $25bn is equal to Partnership (TPP). Dr Shawkat Haider, general Pfizer Chinese Plants just one quarter of 1% of global annual GDP and manager (business development) at Bangladesh’s Two recently released inspection results by one quarter of what the top three pharmaceutical Beximco Pharmaceuticals Ltd, said that although western pharmaceutical regulatory authorities companies spent buying back their own shares over the Bangladesh industry has been producing some have put GlaxoSmithKline PLC and Pfizer Inc. the last few years. The UK’s AMR Review has already of the old and conventional active pharmaceutical in the spotlight after both multinationals ran released three papers of the six it has planned ingredients (APIs) on a commercial scale, it is “far into manufacturing problems in China. The UK’s looking at key topics involved in the global issue from” synthesizing new and patented drugs, and Medicines and Healthcare products Regulatory of antibiotic resistance. It is preparing to release meeting growing demand. Agency (MHRA) released an inspection report a fourth paper, looking solely at agricultural use on the EudraGMDP database operated by the of antibiotics in December, and will follow up Cancer Drug Fund Clarity Coming Soon European Medicines Agency (EMA), which found with a paper on alternative options for antibiotics, Companies should learn more about what is likely to a GSK manufacturing plant in Tianjin, China including vaccines, in the first quarter of 2016. A come next after England’s current Cancer Drugs Fund was non-compliant with Good Manufacturing final report summarizing the infectious disease ends in April 2016. After delaying the consultation for Practices (GMPs). The non-compliant operations landscape in general will be issued next summer. some time, NHS England has told Scrip that it should involved non-sterile products, packaging and finally come out the week starting 9 November. NHS quality control testing. “We confirm the UK ‘Benghazi’-Like Hearing Unlikely England declined to say why the consultation was MHRA has made the decision to withdraw any For Califf late, nor if the delay would impact on whether what previously issued GMP certificates and issue Robert Califf, President Barack Obama’s nominee follows will be ready for implementation on 1 April. a statement of non-compliance with EU GMP to lead the FDA, is expected to have a fairly easy According to an “emerging proposal” released earlier for our GSK’s site in Tianjin, China,” Susan Song, time of it when he goes before a Senate panel at this year, a “managed access fund” will finance drugs GSK China Communications, told Scrip’s sister a confirmation hearing on Nov. 17 – so much so that get a conditional nod from HTA body NICE. publication PharmAsia News in an email response. that he’s still planning to speak later that day at The delay has been criticized by the pharmaceutical “The decision relates to an inspection by the the annual Conference on Clinical Cancer Research industry which is still in the dark, not only about MHRA in June 2015 and, specifically, the Tianjin hosted by the Friends of Cancer Research (FOCR) how new cancer medicines will be assessed, but also site’s internal processes of investigation and and the Brookings Institution. FOCR spokesperson about what will happen to the drugs delisted from reporting to relevant authorities,” Song added. Ryan Hohman told Scrip Califf would simply be the fund. The ABPI said it was disappointed by the According to the report, from the knowledge speaking at a later time in the afternoon rather lack of progress and called on the government to gained during inspection of this manufacturer, than as the lunchtime keynoter – switching publish its proposals. The consultation’s publication the latest of which was conducted on 25 June, his plans after getting word his confirmation will come the week after another round of drugs were 2015, a critical deficiency was cited with regards to hearing was set for Nov. 17 with the Senate axed from the list following a review in September. system failures to ensure that the manufacture of Health, Education, Labor and Pensions (HELP) The fund was only meant to run from 2010 to 2014, medicinal products were fit for their intended use. Committee, which has jurisdiction over the FDA. but value-based pricing, which was supposed to Also, the UK-based company didn’t take actions So the FDA commissioner contender apparently ensure better access to high cost drugs, never to address identified tablet stability problems doesn’t anticipate one of those 11-hour marathon materialized and the fund was extended to 2016.

14 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 FINALIST PREVIEW

HUYA BIOSCIENCE’S BEST NEW MANAGEMENT TEAM OF THE YEAR DRUG AWARD Sponsored by Covance

This Award recognizes excellence in pharmaceutical Scrip’s Management Team of the Year Award will honor development. Launching innovative new products is the achievements of management teams whether they the most important function of the industry, and a are from the top tier of management at a pharma or successful new drug launch marks the culmination of biotech company or a team responsible for specific years of risky and expensive R&D. The shortlist is: operations or projects within a company. The shortlist is:

Bristol-Myers Squibb’s Opdivo (nivolumab) Clinigen’s Management Team Opdivo became the first PD-1 immune checkpoint inhibitor to This is a rapidly growing specialty global pharmaceutical receive regulatory approval anywhere in the world when it company with a unique business model of four got the go-ahead in Japan for unresectable melanoma. The US complementary divisions. In four years the management team FDA melanoma approval came later in 2014, and was swiftly has driven a six-fold increase in revenues and 17-fold growth followed by a second approval for metastatic squamous non- in profits, leading Clinigen from its IPO on AIM in 2012, to small cell lung cancer with progression on or after platinum- the £225m acquisition of Idis in April 2015 - a deal which based chemotherapy. doubled its size overnight and created a global market leader in the ethical unlicensed supply of medicines. Merck & Co’s Keytruda (pembrolizumab) Keytruda is a humanized monoclonal antibody that blocks the Horizon Discovery’s Management Team interaction between PD-1 and its ligands, PD-L1 and PD-L2, This team has led the company through a transformational releasing the PD-1 pathway-mediated inhibition of the immune year post its IPO in March 2014 to firmly establish it as a response, including the anti-tumor immune response. It was the world-leading translational genomics company. The firm first anti-PD-1 therapy approved in the US and received the FDA’s has transitioned from a newly listed AIM company with 80 Breakthrough Therapy designation for advanced melanoma. employees located in a single facility in Cambridge, to an international life science group employing approaching Novartis’s Cosentyx (secukinumab) 250 employees in the UK, US, and Austria, and grown its This human monoclonal antibody is the first and only customer base and revenues. approved IL-17A inhibitor for plaque psoriasis, offering an important new treatment option, and a better chance of Marathon Pharmaceuticals’ Management Team achieving clear skin. IL-17A plays an important role in the vicious cycle of psoriasis, signalling skin cells to grow at a This team, formed more than a decade ago at Ovation faster rate and build up on the skin’s surface, and at the same Pharmaceuticals, launched Marathon to continue working to time, triggering itching and redness. bring new rare-disease treatments to patients after Ovation was acquired by Lundbeck. Adding to its achievements Otsuka’s Jinarc (tolvaptan) developing or keeping on the market drugs for a range of Jinarc is the first and only disease-modifying treatment proven orphan drugs, it has successfully advanced its development to slow the progression of autosomal dominant polycystic pipeline and earned Fast-Track status for deflazacort as a kidney disease (ADPKD). It is a potent vasopressin receptor potential treatment for Duchenne muscular dystrophy. antagonist that reduces the growth rate of renal cysts through V2 receptor antagonism so that the increase in kidney size Sunovion Pharmaceuticals’ Global Clinical Development typically observed in ADPKD is slowed, helping to decrease Management Team the rate of kidney function decline. Taking “Together as One” as its mantra, this matrix-model team of R&D professionals from Sunovion in the US, Canada, PTC Therapeutics’ Translarna (ataluren) and Europe along with colleagues from parent company In August 2014, PTC Therapeutics’ Translarna became the Sumitomo Dainippon Pharma has realized its vision of world’s first approved drug to treat an underlying cause globalized clinical development. The team has followed of Duchenne muscular dystrophy, a rare and fatal genetic strategic and cultural initiatives recognized internally for disease. The orally bioavailable small molecule is designed to driving global collaboration in trials conducted in multiple enable the formation of a functioning protein in patients with countries, using coordinated plans and strategies, and genetic disorders caused by a nonsense mutation. harmonized processes across geographies.

SPONSORED BY SPONSORED BY SPONSORED BY SPONSOREDSOCIAL MEDIA BY SOCIALSOCIAL MEDIA MEDIA SOCIAL MEDIA SPONSOR SPONSOR SPONSOR interview Lilly’s Carroll: Let’s Debate Pricing But Don’t Lump Us With Turing any, R&D. So we should ask the question, ‘Are those companies really like the innovation- base pharma sector?’ I think the answer to that is probably, ‘Not very much.’ We play very different roles in the eco-system. [Editor’s note: The first company to come under scrutiny in the current US drug pricing probe was Turing Pharmaceuticals AG for possible antitrust violations related to the nearly 5,500% increase of the company’s toxoplasmosis medicine Daraprim (pyrimethamine).]

LE: How do these sometimes scandalous stories about certain companies affect the wider pharma industry? DC: We get paid by society to take big risks and to try to solve, or provide so kind of solution for, major unmet medical needs. Those activities span decades of work and you can’t let a passing debate deter you from Darren Carroll those goals. It hasn’t changed anything in how we invest in medicines, we still focus on At the recent BIO-Europe meeting, held copays patients pay for non-pharmaceutical the biggest unmet medical needs and game in Munich, Germany, Eli Lilly & Co’s senior therapies. A patient might have a very low changing medicines, and we aim to present vice president of corporate business copay for an expensive hospitalization but a quality data packages that people can rely development Darren Carroll, in an exclusive high copay for a drug that might have been on to pick a medicine. There can be any interview with Scrip, highlighted his able to prevent that situation. So our view number of issues that come up in broader expectations for 2016 and concerns for at Lilly is that we should have this debate society from time to time, because these can innovative pharmaceutical companies now as free and open societies, and have a be twenty-year-long activities. We don’t get being tarred with the same brush as current conversation about what patients are actually deterred because we think society wants us businesses which are under the spotlight for paying. If patients are currently paying far to focus on innovation. Are these important unfounded soaring drug prices in the US. more out-of-pocket for a medicine that is issues? Sure they are. But we would rather Carroll spoke to Lucie Ellis about what actually the more cost-effective option then have a wider conversation about innovation debates are really needed to address that’s a discussion that needs to happen. and value, and talk about the price a patient drug pricing arguments, as well as how Pricing is just one of many elements in this pays for all the things that go into their care. big pharma needs to balance in-house situation. Also the actual price some of the That would be an interesting conversation innovation with partnered and acquired payers are paying for new medicines is very to have. assets and what technology firms have to different to the cost that is listed in some offer in the healthcare space. public domains. LE: What is Lilly’s strategy moving into I’d also say that some of the more recent 2016 and what key products would you Lucie Ellis: In light of the drug pricing pricing debates in the US are focused on highlight? debate heating up in the US, what are companies that I almost don’t recognize. What DC: Earlier this year we announced that Lilly’s concerns? we do at Lilly is invest heavily in R&D, we Lilly is narrowing its focus to a smaller number Darren Carroll: I start at the proposition invest about 20% maybe slightly more of our of therapeutic areas, so moving forward into that to develop a medicine you have to have total revenues into R&D. And we have been next year we will be concentrating on three a belief that the medicine is going to be a investing like that now for decades and the core areas and two emerging fields. In the cost-effective therapy compared to all other medicines we bring to market are the result core areas we have of course diabetes, which therapies that are available – and before Lilly of that investment and decades of taking risk. we have been involved in for many decades; invests, we have to convince ourselves of This is a very risky business. oncology, which we have been involved in for that. We know across most of the healthcare As you just saw recently we had another a very long time, but recently have had a lot spectrum that an investment hypothesis has late stage failure despite a string of successes. more molecules coming forward in this area; to start with that belief. That’s the industry we are in. Projects fail, and the third area is CNS [central nervous We also know that what is critical for late and early. It’s very expensive to do this system], in this we have made a pivot away patients is that they get access to new work at the level we are doing it. But some from the neuro-psychiatric therapies that we medicines. One of the things I see around the of the companies that have gotten the most are well known for – we developed Prozac world is that copays for what patients pay notoriety for some of their pricing behaviors among other well-established treatments for medicines can be very different from the have been companies that do very little, if – towards neurodegenerative disorders. We

16 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 interview have made some significant investments in Europe is an important market place hormone-receptor-positive (HR+) advanced or Alzheimer’s disease, an area we have been for us but the pricing and reimbursement metastatic breast cancer; our Alzheimer’s drug investing in for more than 25 years. Here we issues are frankly calling into question how solanezumab; and necitumumab, a non-small have a lead monoclonal antibody molecule, much some of the payers there actually cell lung cancer (NSCLC) drug, which came solanezumab, but we also have a partnered value innovation. When you keep seeing from an acquisition initially but we have had it molecule with AstraZeneca, a beta secretase instances across the industry where some now for a long time in our hands. cleaving enzyme (BACE) inhibitor known brand new, innovative medicines – that A number of the other products are in as AZD3293. We also have a long pipeline in other market places are becoming the partnered relationships. Our expectation following these products. new gold standards of therapy – in some though is that our lab will continue to Those are the core areas but there are European markets are being equated with produce close to two thirds of what we need two emerging areas we are focusing on: generic medicines that have been available long-term. And when you look back over one is immunology and here we have one for years before, it’s very hard to know how the long arch of history, 30-40 years, you’ll molecule already under regulatory review, that market place is going to evolve. Europe find periods where that amount flexes and ixekizumab, an interleukin 17 (IL-17) cytokine will still be a strong market place for us but wanes but over time our lab has produced inhibitor. We also have in this therapy it is less exciting than it once was. about two thirds of what we need. However, area baricitinib, an oral JAK1 and JAK2 On the growth side, China seems to be a we have had some great successes with inhibitor, for which we recently reported very important market place for us. We have externally sourced innovation as well. They some very interesting data on the head- invested heavily in China; outside of the US both succeed, they both fail sometimes, and to-head comparison of this drug against the largest place of employment for Lilly is they are very much like each other in that world leading therapy Humira (AbbVie’s China. We have the second largest number of way. You have earlier failures and late failures; adalimumab). Furthermore, earlier this year employees in a single country unit in China. obviously you want early failures if you can we announced a large partnership with The other growth area we are interested but we get them in both areas. Korean company Hanmi Pharmaceutical for in is Latin America, as our products line up its BTK inhibitor, HM71224, for immunology really well there. We sell our products in well LE: There are currently a lot of technology disorders. Immunology is an area of over 100 markets all over the world, but companies getting involved more in significant new investment for us. We haven’t some regions are more important to us than healthcare in various ways, how do you yet commercialized anything in this area but others. Some of our products are just more view this movement? we very much like the molecules we have at suited to various markets. For example, with DC: Actually, this can only be positive. We the late-stage end of our pipeline, so we will the exception of China and very few other are seeing some fascinating convergence in be making more investment here. markets, we are no longer involved in the areas of technology that could impact a lot The fifth and final key area for Lilly, which anti-infectives areas. So in some emerging of aspects of healthcare. Anything that could is also one we consider an emerging filed for markets where anti-infectives are still a critical help a patient stay compliant is a very positive us, is pain treatment. We announced about part of how you take to the market, that’s less thing for the patient and the industry. When a year and a half ago a deal with Pfizer for of an opportunity for us. But those markets we conduct years and years of research we its product tanezumab and earlier this year are evolving and maturing, and chronic do so with the goal that if the medicine gets the FDA lifted a clinical hold on this drug, diseases are becoming more of a concern as approved we can convince patients to stay so we are now heavily working together populations in those markets get wealthier, compliant with the medicine because that is with Pfizer on a Phase III development plan as people are able to reach middle-age. This how it works best. We are seeing, for example, for that molecule. Then we also have a is where we have a lot more focus in terms of lots of small apps becoming available to Lilly-sourced molecule in this area, a CGRP our own initiative. help patients with this compliance issue. We inhibitor, LY2951742, for migraine which we are seeing larger investment by some of the had deprioritized previously. It was developed LE: What is your opinion on in-house bigger companies in delivery systems and in a partnership with Arteaus Therapeutics innovation vs. acquisitions for new the like and this is very positive. Anything you LLC, then we bought that company and technologies? can do to enhance the patient experience with the company all the rights to that drug. DC: My view is you have to have both. and help them to understand how to take LY2951742 is now in Phase III, so we have two The notion that any company with a really the medicine can only be a positive thing. We Phase III compounds in our pain portfolio but ambitious R&D agenda could actually invent welcome new companies getting involved we are looking to add more to that, primarily everything they need would be without in drug development but it’s a hard business. through our own lab but also through precedent. By the same token though I A lot of technical understanding is required external innovation. believe the idea that you can sustainably to run an investigational compound through acquire or in-license everything you need its paces, to get it all the way through Phase LE: Are there any countries where you are is very difficult to pull off. There needs to I, II, III clinical trials and eventually to market. targeting more activity or regions where be some balance; you need to be able to I would suggest that this is probably not a you are pulling back investment? invent some of your own medicines if only great place for on the job training. That being DC: Geographically the US is clearly Lilly’s to be able to actually identify what is good said there can be great ways for a company most important market and will remain so. on the outside. If you take a look at our like Lilly to partner with some of these tech Japan though in many respects is our second late-stage pipeline right now we have eight companies where the two areas converge. most important market, because it is a very molecules that are in or could be in regulatory [Editor’s note: Following this interview, pro-innovation market place and the key processes in the next 12-18 months. Three Lilly was also linked to US drug pricing probes issues around pricing, reimbursement and of these came directly from our pipeline: (see P11). The company said it was voluntarily market access in Japan we believe are still abemaciclib, a cyclin-dependent kinase (CDK) responding to prosecutors’ request.] competitive on a global scale. 4 and 6 inhibitor, for patients with refractory [email protected]

© Informa UK Ltd 2015 @scripnews scripintelligence.com November 20th 2015 17 R&D bites R&D Bites “THe Pink sHeeT” & scriP inTelligence still on hold. While this should be positive news, organizational priority.” Clearly we are not happy AZ’s Anifrolumab the incremental nature of the announcement with the fact that we could not resolve the Form Marketing SolutionS is still incredibly limiting to the company. The 483 observations to the agency’s satisfaction. Impresses In Phase II Massachusetts biotech revealed Nov. 11 that the We have always taken quality and compliance A Phase II trial of AstraZeneca’s regulatory agency has lifted its partial clinical matters seriously and we will continue to remain investigational monoclonal antibody, hold on a Phase II trial of encenicline for cognitive focused on the remedial measures,” Prasad said anifrolumab, in patients with moderate-to- impairment in schizophrenia (CIS). The hold in an investor call on Nov. 9. A Form 483 is a severe systemic lupus erythematosus (SLE) applied to a 26-week extension study in CIS, as notice of the FDA’s inspectional observations that met its primary and secondary endpoints. well as the entire Alzheimer’s disease (AD) program lists deficiencies in the quality system. Prasad The data were presented at the American the company had been undertaking. A Phase said that the warning letter cites GMP violations College of Rheumatology 2015 Scientific III extension study of the current trial, as well as primarily relating to documentation practices and two other Phase III trials in CIS, will be used as the control, laboratory testing procedure, incident Meeting in San Francisco this week. Only foundation for a new drug application to FDA. The investigation practices and some standard How long will it take your sales team one new drug - GlaxoSmithKline’s Benlysta AD program will remain on clinical hold and Forum operating procedures (SOPs). (belimumab) - has been introduced for intends to discuss the program with FDA further the treatment of lupus in the past 60 in 2016. Fast AZ Tagrisso Approval to reach 42,000 senior decision makers years, highlighting the difficulties in new Prescription Drug User Fee Act (PDUFA) action drug development for this condition. Derma Sciences Exits Drug dates have become meaningless at the FDA’s AstraZeneca decided to back anifrolumab Development Office of Hematology and Oncology Products, in pharma companies globally? over sifalimumab earlier this year and a Wound care specialist Derma Sciences knows which has almost consistently for the past year or Phase III trial with anifrolumab was initiated when to throw in the towel and has decided to two leaped ahead of those timelines and approved stick with what it knows.The Princeton, NJ-based cancer medicines well ahead of schedule – the in July. The study met its primary endpoint company announced Nov. 12 that it is terminating most recent being AstraZeneca PLC’s lung cancer of showing a significant difference in the its entire development program for the drug drug Tagrisso (osimertinib). The FDA wasn’t due to percentage of responders compared to aclerastide after a data monitoring committee act on the Tagrisso application until Feb. 6, 2016, Let us demonstrate how we can placebo as measured by the SLS Responder determined that its Phase III clinical trial in patients but gave its nod to the drug on Nov. 13, granting Index 4 (SRI4) at day 169, along with a with diabetic foot ulcers would be unable to hit its an accelerated approval of the once-daily oral sustained reduction of oral corticosteroid primary efficacy endpoints.While aclerastide had tablet, which previously was known as AZD9291, as do this and show you ROI now! (OCS) use between day 85 and 169. 34.4% no safety issues, Derma Sciences decided to cut the a treatment for patients with metastatic epidermal of patients receiving anifrolumab 300 mg program completely – it will not pursue any other growth factor receptor (EGFR) T790M mutation- IV for four weeks achieved a response while indications for the product. The trial had already positive non-small cell lung cancer (NSCLC) who enrolled about 600 patients and was expected to have progressed on or after EGFR tyrosine kinase 28.8% who received anifrolumab 1,000 mg enroll a total of 1,055 patients. Enrollment will end inhibitor (TKI) therapy. Indeed, Tagrisso had IV for four weeks responded. Both beat the and it will cost the company about $2m to wind gone from entering clinical trials to crossing the placebo response rate of 17.6%. down the program by the end of the year. Work regulatory finish line in just over two and a half will also stop in the scare reduction and radiation years. Fredrickson noted that to help speed things Cytokinetics Awaits Amgen’s Plan dermatitis programs. along, the FDA had granted Tagrisso’s application Next steps in the development of heart failure fast-track status and breakthrough therapy drug omecamtiv mecarbil are unclear following Avanex Lays On The Hype designation – both intended to expedite the R&D the successful conclusion of a Phase II clinical trial While positive trial results are never a bad thing, and regulatory processes. while Cytokinetics Inc. waits to determine with they can be overblown – a surefire way to partner Amgen Inc. whether the mid-stage data upset your investors. Avanex did just that this Merck Survives Futility Exam are sufficient to justify investment in a Phase III weekend when the biotech overhyped some Merck & Co. Inc. has been fairly tight-lipped program. Omecamtiv mecarbil, a cardiac myosin positive results from a small mid-stage study. The about its cholesteryl ester transfer protein (CETP) activator, met the primary pharmacokinetic biotech announced data from a Phase IIa study inhibitor anacetrapib for hypercholesterolemia objective and showed statistically significant of AVANEX 2-73 at the Clinical Trials in Alzheimer’s while the 30,000-patient Phase III REVEAL clinical improvements in all secondary measures of cardiac Disease 2015 conference in Barcelona, Spain. The trial is ongoing, but the company said on Nov. function in the Phase II trial known as COSMIC-HF. drug, which targets the sigma-1 and muscarinic 13 that the drug passed a recent futility test. Though the data presented in a Nov. 8 late-breaker receptors, is meant to prevent or reduce the The REVEAL data monitoring committee (DMC) session at the American Heart Association (AHA) number of misfolding proteins like beta-amyloid conducted a planned review of unblinded Scientific Sessions in Orlando, Florida were seen and tau – both suspected to be involved in safety and efficacy data and said the trial should as positive, a Cytokinetics spokesperson told Scrip causing Alzheimer’s Disease. So far, the 2-73 has continue with no changes. But whether CETP that “the company believes the data are supportive shown in preclinical and early-stage studies that inhibition safely increases good HDL cholesterol of potential progression to Phase III, and Amgen is has potential to help slow down symptoms and lowers bad LDL cholesterol, producing BRANDING I THOUGHT LEADERSHIP I LEAD GENERATION and Cytokinetics will make a joint decision in the of cognitive decline. The Phase IIa study wasn’t important cardiovascular benefits, is a question coming months.” Amgen executive vice president any different – it showed that 2-73 had statically that will remain unanswered for at least another of research and development Sean Harper said significant improvement in cognitive decline, year and a half, since no other safety or efficacy Matt Dias • HeaD of aDvertising as much during the big biotech company’s third according to a number of different regularly used analyses are planned for REVEAL before the study’s quarter earnings conference call at the end of AD measurements. conclusion in early 2017. Merck is forging ahead Phone: +44 (0) 20 701 74188 October after Amgen and Cytokinetics reported through a field littered with failures, including Eli top-line COSMIC-HF results. Dr Reddy’s Set For Quality Revamp Lilly & Co.’s recently concluded Phase III program Email: [email protected] Days after investors battered the company’s for evacetrapib. The Merck and Lilly drugs were A Step Forward For Forum, But Not In AD stock following a surprise three-plant FDA the last two Phase III candidates in development Forum Pharmaceuticals Inc. has gotten a slight warning letter, Dr Reddy’s Laboratories’ CEO, GV to broadly treat high LDL cholesterol when Lilly’s reprieve from FDA regarding its schizophrenia Prasad, has emphasised that a “revamp” of the ACCELERATE clinical trial was stopped for futility program, but the Alzheimer’s disease program is firm’s quality systems and processes is a top in October. “The Pink Sheet” 18 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 “THe Pink sHeeT” & scriP inTelligence Marketing SolutionS

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Matt Dias • HeaD of aDvertising Phone: +44 (0) 20 701 74188 Email: [email protected] “The Pink Sheet” expert view The Perfect Storm For M&A Shows No Signs Of Abating AstraZeneca plc’s deal to buy ZS Pharma is the latest in a record wave of deal making and consolidation in the pharmaceutical sector that has lasted more than 18 months, with the value of mergers and acquisitions since the start of last year running into the hundreds of billions of pounds. From household names and global giants right through to up-and- coming young companies, the wave has swept every part of the sector and – even as some investors are beginning to portray signs of skepticism – shows no sign of abating just yet. This is because the sector is in the middle of a “perfect storm” for deal making – a rare combination of four key factors that photoff/shutterstock.com make acquisitions attractive for a range of businesses in the sector. This combination is not going away. First and foremost, borrowing costs remain at historically low levels. Near-zero interest rates mean lower capital costs, ensuring that the return on investment from buying assets executive Ian Read has said publicly, on more senior skillsets that the company does not is much higher than has previously been the than one occasion, that tax is a competitive currently have. They also require lots of case. Equally importantly, there is a growing challenge for his company in the US, and only hard work and investment to achieve small awareness that the cost of debt will not be as last year his firm tried to use a merger – in percentages here and there. low as it is currently for very much longer, and that case with UK-based AstraZeneca – to Even in this sector, where M&A activity therefore the opportunities that exist now create a tax inversion. has become almost commonplace, striking should be grasped while they can be. Its latest interest in Ireland-based Allergan an exciting new deal still catches the eye There is more to low cost of capital than has been seen by some in a similar light and, of investors, who are more than happy to low interest rates, however. There is expertise despite repeated claims by governments that give boards the time, space and funding at play as well. During the financial downturn, they want to crack down on tax inversions, tax to prioritize them. The result is that there a large number of M&A bankers moved out arbitrage has never been more of a prominent are businesses out there that still have a of finance and into industry – including motivation to acquire than it is now. Part of quagmire of management structures, or a into pharmaceutical companies. As a result, that is due to the fact that inversion deals plethora of different sites duplicating work the sector has more in-house acquisitions are difficult to carry out, often so much in numerous locations. These weaknesses expertise than ever before, analyzing deals so that the protracted process can often may prevent those firms from achieving and securing the best possible funding outweigh any potential benefit. The difficulty their full potential, and will at some point options to support them. has undoubtedly increased in recent years need addressing. But for as long as the Neither of these factors, however, is unique following the Obama administration’s moves other three factors mentioned above to pharmaceuticals. So why is this sector last year to tighten five different pieces of the mean that there are opportunities to be seeing more activity than others? US tax code to make inversions less profitable. had, those businesses will continue to be The ongoing consolidation of the pharma Ultimately, while difficult to execute, on the acquisition trail, making hay while customer base, coupled with the increased inversion deals are equally tough to prevent the sun shines. scrutiny on public healthcare spending entirely. For as long as they allow shareholders Not all four factors are at play in each and and an ever lower number of blockbuster to receive higher earnings per share, the every deal, of course. For as long as all four products based on small molecular entities, motivation will be there to pursue them. conditions remain as they do at the moment, is leading to a disruption in the traditional Finally, and perhaps most interestingly, however, the current wave of deals will generics industry. As a result, generics firms acquisitions can be a useful distraction for continue. Investors hungry for transactions have used acquisitions to move towards financial markets that are attracted to big, will continue to ask boards what their M&A providing higher-value, branded products, exciting moves like mergers – and by contrast, strategy is, and management teams will in while the large drug makers whose are not enthused by less glamorous moves turn keep pursuing them. patents have expired in large numbers such as becoming incrementally more Only when liquidity is withdrawn, or when have sidestepped years of research and profitable by addressing weaknesses in other the pool of targets reduces to such a size as development investment by buying young areas. For a senior management team, it can to make even an inversion deal unaffordably biotech specialists. Just as interest rates won’t be hard to get shareholders to buy into a expensive, will the feeding frenzy stop. So far, stay low forever, there won’t always be a pool programme of addressing a shortcoming in that point still seems a long way away. of available companies with proven new operations, for example, almost regardless of Philipp Gutzwiller drugs, or established branded drugs, to buy. how badly needed that is. The third factor in the perfect storm is tax. Tackling traditional problem areas is often Philipp Gutzwiller is the global head of The most obvious example is Pfizer. Chief also much harder to achieve and may require healthcare for Lloyds Bank Global Corporates

20 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 stockwatch Bulls, Bears And White Elephants at companies as potential investments, we now think about target product profiles that include the phrase “large patient populations that are motivated and able to change and resolve their disease.” This is why we do not have significant exposure to companies developing or selling drugs to treat alcohol or drug dependency, or even type 2 diabetes. One product to treat type 2 diabetes that is rapidly turning into an archetypal white elephant is Afrezza (inhaled human insulin),

Vjom/shutterstock.com from MannKind Corp. and partner Sanofi. Afrezza ‘s sales in the third-quarter were $2.2m, which the analysts from JP Morgan described as ‘disappointing’, having not grown from the previous three months. Many have suggested that it is now only a matter of time before Sanofi returns the rights to MannKind. In a Investors classify each other as bulls or bears. has not yet been accepted by its management. cynical attempt to persuade Israeli investors Bulls are greedy for rising markets whereas BTG’s wholly-owned and internally developed that Afrezza was a raging bull rather than bears fear falling markets. After another great white hope – Varithena (polydocanol a rogue white elephant, MannKind tried to down-week for the NASDAQ Biotech Index foam), for the treatment of varicose veins – raise $50m by parlaying its US $1bn market that included a savage selloff on Thursday, had dismal sales in BTG’s first six months of capitalization into a significant weighting I suspect the weight of money is bearishly £0.4m. This was compounded by the refusal in Israeli index funds after completing a moving away from the sector, and some of the Centers for Medicare and Medicaid secondary listing on the Tel Aviv stock market. of this flight away from riskier life science Services to recognize the value of Varithena In the end, the intervention by the Israeli investments may be due to the focus on quite and grant a J-Code. Varithena is currently (or, regulator outweighed the enthusiasm for the a different stock market animal. more accurately, barely) reimbursed under a offering and continued ‘Buy’ recommendation I have been writing for years about temporary code that provides strong support for from the analysts at Jefferies, and the offering the white elephant approach to drug its classification as a white elephant. raised $35m, although all that means is that development where smaller companies Whilst the defining characteristics of the there will be 35 million white elephant hunters embark on the development of drugs that mammalian variety of white elephants are at some point in the future. clearly will never recoup the money invested, that they are big and white, those of the life The animal and life science product types let alone lead to a profit for the developing science variety may be a little less obvious. of white elephant have some characteristics in or licensing partners. With so many white Before their approval, a common characteristic common. The latter has a big impact on the elephants rearing their ugly heads during of white elephant products is that they will viability of a small company and in many cases the tail end of earnings season last week, also be big, or “blockbuster” in the forward- can lead to its demise. Both types can therefore other investors may be getting the idea that looking parlance of company management make a big mess, but while a skilled tracker this is an inevitability for many life science and its analysts. The target product profiles can find the white elephant animal from many companies with smaller capitalizations. of the past would have included the phrases miles away, the skill that many investors seem Since we don’t run a hedge fund, I do not “a large patient population” and “an unmet to lack is to spot a white elephant product gain financially nor take any pleasure from clinical need” in order to have justified the before it has trampled all over their assets. the misfortunes of others. My only reward for development of drugs to treat obesity. Those Andy Smith predicting white elephants is the satisfaction drugs from Orexigen Therapeutics, Inc., Arena that I actually learned and retained something Pharmaceuticals, Inc. and Vivus, Inc., recently Andy Smith is chief investment officer of Mann whilst working in pharmaceutical companies reported third-quarter sales of $12.8m, $12.6m Bioinvest. Mann Bioinvest is the investment and avoided losing my investors’ money. Thus and $13.8m, respectively. There is probably adviser for the Magna BioPharma Income I only felt vindicated when BTG Plc’s first-half no hope for these companies with their fund which has no position in the stocks results were critiqued by the analysts from white elephant products dragging them into mentioned, unless stated above. Dr Smith gives JP Morgan as being “mixed.” Although both the arms of the liquidators but at least other an investment fund manager’s view on public JP Morgan and Jefferies maintain their buy companies can learn from their demise. Many life science companies. He has been lead fund recommendations on BTG, both sets of analysts cancers, certainly in second- and third-line manager for four life science– specific funds, highlighted the low quality of BTG’s earnings settings, have both large patient populations including International Biotechnology Trust and that were flattered by one-off backdated and unmet clinical needs. However, unlike the AXA Framlington Biotech Fund, and was royalties from Johnson & Johnson for its product many morbidly obese patients, most cancer awarded the Technology Fund Manager of the Zytiga (abiraterone acetate), and a temporary patients are able to or want to eliminate the year for 2007. lower tax rate. Before the end of the week, BTG cause of their disease. Obese patients probably admitted a financial accounting error which only want a drug that allows them to continue For all Stockwatch articles visit cut its already flattered underlying earnings by to eat as much as they have always done scripintelligence.com/stockwatch a staggering 21%. However, the bigger error without putting on weight. Thus when we look

© Informa UK Ltd 2015 @scripnews scripintelligence.com November 20th 2015 21 US capitol capsule Don’t Make Assumptions On Biosimilars Actions, FDA Official Warns While FDA action dates may have come and Celltrion Inc.’s 351(k) application for its But Christl also noted that biosimilars has gone on some biosimilar applications, known infliximab biosimilar of Johnson & Johnson been an “under-resourced program” at the FDA. as 351(k)s, it would be wrong to make an Inc. unit Janssen Biotech Inc.’s Remicade, but Indeed, earlier in the day at the Nov. 12 assumption regulators had issued a complete the agency postponed the meeting “due Biopharma Congress meeting, Janet Woodcock, response letter (CRL) due to the lack of to information requests pending with the director of the FDA’s Center for Drug Evaluation biosimilarity, warned Leah Christl, associate sponsor. Celltrion later attributed the meeting and Research, pointed to biosimilars as one director for therapeutic biologics. delay to the FDA’s request for details of the of the “many, many” congressional mandates “As a general matter, for any application, firm’s statistical analysis data. lawmakers have left underfunded. there’s a number of things that could create a Also eagerly awaited is the news on the fate “We have a user fee program, but the bump in the road,” she explained. of Apotex Inc.’s application for its version of investment exceeds the revenue we are going Issues that may arise may have nothing to pegfilgrastim, which is referenced on Amgen’s to get,” Woodcock declared. do with biosimilarity, but could be related to Neulasta, a long-acting form of Neupogen. And, Christl added, even when the user fees the facility where the product is being made The application was accepted by the FDA are paid, “the resources don’t just appear the or a current good manufacturing concern, this past December, meaning the firm should next day” – meaning it takes time for the FDA Christl said last week at the 2015 Biopharma have heard last month. to hire more people to review applications Congress conference in Washington, hosted by In court documents filed last month in an and provide other services under BsUFA. the analysis firm Prevision Policy and patient ongoing legal dispute between US biotech Even though having the authority to approve advocacy group Friends of Cancer Research. giant Amgen and Canadian firm Apotex, the biosimilars has been “really great,” Woodcock There also could have been a major companies said the FDA’s decision on the complained “it’s a huge amount of work.” amendment submitted during the course pegfilgrastim 351(k) “could be issued at any time.” While reviewing applications has expanded of the review, so the FDA may have needed But so far, privately held Apotex has the FDA biosimilars role well beyond the more time on the application and imposed remained mum on the agency’s verdict – not implementation processes of establishing a three-month delay, Christl told Scrip in an disclosing whether the company has heard policies and regulations, those latter activities interview. from the FDA. remain ongoing, Christl said. Unfortunately, she said, “There’s a lot of Apotex also revealed in February it has The agency is working on completing speculation” when the 351(k) application an application under review at the FDA for three much-anticipated guidance action date has arrived, based on the the company’s version of filgrastim, which if documents: interchangeability, labeling and information a company has publicly disclosed, approved would be the second Neupogen statistical approaches to analytical similarity, and there’s been no word from the FDA or the biosimilar on the US market, competing with she said, although she admitted “I can’t say firm about the status of the biosimilar. Zarxio, which launched in September – six with any certainty whether they will be out “People should not default” to the idea it months after its approval after getting hung by the end of the year.” is “automatically due to biosimilarity,” Christl up in a lawsuit filed by Amgen. Nonetheless, Christl explained the FDA put insisted, adding that by doing so, it can be FDA’s Christl said that as of Oct. 31, there those three guidances on its 2015 agenda “disheartening” to the sponsor and patients were 58 “proposed” biosimilars referenced on so regulators have the ability to discuss their awaiting the drug. 17 different innovator biologics enrolled in plans publicly. There’s been at least four companies that the agency’s Biosimilar Product Development “This gives us an opportunity to let have publicly disclosed they’ve submitted (BPD) program, which was created as a part stakeholders know we are working on six 351(k) biosimilar applications to the of Biosimilar User Fee Act (BsUFA) to provide something,” she said. “If it’s not on the FDA for proposed biosimilars, Christl said, a mechanism and structure for collecting the guidance agenda, we typically don’t or can’t noting the agency has approved only one development-phase user fees. say we are working on it.” so far – Sandoz Inc.’s Zarxio (filgrastim-sndz), She also noted that’s “not an absolute With biosimilars being a new space for which is referenced on Amgen Inc.’s human number” of all programs, since there are some industry and the FDA, “there’s lessons to be granulocyte colony-stimulating factor in early development that have yet to enroll in learned all around” – the most critical of which Neupogen (filgrastim). the BPD program. has been the importance of communication, Sandoz, a subsidiary of Novartis AG, “We have a very active development Christl said. revealed on Oct. 2 the FDA had accepted space for biosimilars,” Christl said during the One group that required some additional the firm’s 351(k) application for its etanercept Biopharma Congress conference. attention in communicating the fact that biosimilar of Amgen’s tumor necrosis factor But she also acknowledged the FDA biosimilars is a different development alpha inhibitor Enbrel, which reported $9bn in missed its fiscal year 2014 BsUFA meeting paradigm was the FDA’s outside expert global sales in 2014, with close to half of that goals and likely has done the same for 2015 – advisers, she said. coming from the U.S. attributing that failure to more meetings with Christl said the FDA is anticipating that at Pfizer Inc. disclosed during its Oct. 27 quarterly biosimilar firms than the agency anticipated. least one biosimilar application per referenced earnings call, however, its subsidiary Hospira Inc. “We didn’t expect quite as many product will go before a panel. had received a CRL from the FDA on Oct. 16 for interactions,” Christl said, noting there had been [email protected] the firm’s 351(k) application for its biosimilar of a projection of about seven BPD enrollments Amgen’s epoetin alfa product Epogen. for 2014, when in fact there were about 50. For all Capitol Capsule articles visit The FDA’s outside expert advisers were “We underestimated what’s happening in scripintelligence.com/capitolcapsule due in March to review South Korea-based the space,” she admitted.

22 November 20th 2015 @scripnews scripintelligence.com © Informa UK Ltd 2015 pipeline watch

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

Late-stage clinical developments for the week 6-12 November 2015 Lead Company Partner Company Drug Indication Market Comments REGULATORY APPROVAL

Roche Holding AG Exelixis Cotellic (cobimetinib) melanoma US For the treatment of people with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma in combination with Zelboraf (vemurafenib). Cotellic and Zelboraf are not used to treat melanoma with a normal BRAF gene. The NDA was originally filled in December 2014.

Collegium – Xtampza ER (oxycodone) chronic pain US The FDA has granted tentative approval for the management of pain severe Pharmaceutical extended-release capsules enough to require daily, around-the-clock, long-term opioid treatment and for Inc. which alternative treatment options are inadequate. With a tentative approval, it is subject to an automatic stay of up to 30 months as a result of patent litigation filed by Purdue Pharma in March 2015.

RedHill IntelGenx Rizaport (RHB-103) 5mg migraine Germany The Federal Institute for Drugs and Medical Devices of Germany (BfArM) has Biopharma Ltd. and 10mg, an oral thin granted marketing authorization of for the treatment of acute migraines. The film formulation of national approval was granted under the European Decentralized Procedure, in rizatriptan benzoate which Germany served as the Reference Member State. This authorization is the (VersaFilm) first national marketing approval of Rizaport. Marketing authorization in Luxemburg, the Concerned Member State, is expected to follow.

REGULATORY FILING ACCEPTED

Amgen Inc. Ono etelcalcetide (formerly hyperparathyroidism US For the treatment of secondary hyperparathyroidism in patients with chronic AMG 416) kidney disease on hemodialysis. The FDA has set a PDUFA target action date of Aug. 24, 2016, for the etelcalcetide application.

ORPHAN DRUG DESIGNATION

Johnson & Genmab daratumumab diffuse large B-cell US For the treatment of diffuse large B-cell lymphoma. Johnson lymphoma

BREAKTHROUGH THERAPY DESIGNATION

Teva – SD-809 (deutetrabenazine) tardive dyskinesia US For the treatment of patients with moderate to severe tardive dyskinesia. For Pharmaceutical Austedo SD-809, the designation request included results from Teva’s Phase II/III study, Industries Ltd. Aim to Reduce Movements in Tardive Dyskinesia (ARM-TD). In the ARM-TD study, SD-809 was compared to placebo for change in abnormal involuntary movement scale (AIMS) score from baseline to end of therapy.

COMPLETE RESPONSE LETTER

Neos Therapeutics – Cotempla XR-ODT attention-deficit US The CRL for Cotempla XR-ODT requires the Company to conduct a bridging study Inc. (methylphenidate hyperactivity disorder to demonstrate bioequivalence between the clinical trial material and to-be- extended-release orally marketed drug product, including an assessment of food effect, and to provide disintegrating) 10mg, validation and three months of stability data. The FDA did not raise any safety 20mg and 30mg tablets. or efficacy issues with the clinical data previously provided beyond the need for an adequate bridge between the clinical trial material and the to-be-marketed drug product.

PHASE III TRIAL INITIATION

Novavax Inc. – RSV F Vaccine (Novavax) respiratory syncytial virus – Novavax announced the initiation of a Phase III clinical trial, known as Resolve, of its respiratory syncytial virus F-protein nanoparticle vaccine candidate (RSV F Vaccine) in older adults (60 years of age and older). Top-line results are expected in the second half of 2016.

Paratek – omadacycline community-acquired – Paratek announced the dosing of the first patient in its Phase III clinical study of Pharmaceuticals pneumonia its lead drug candidate, omadacycline, for the treatment of community-acquired Inc. bacterial pneumonia (CABP). The CABP study is the second of two planned Phase III registration studies of omadacycline. Top-line data from this pivotal study is projected to be available in the second half of 2017.

PRODUCT LAUNCH

Amgen Inc. – Imlygic (talimogene melanoma US For the treatment of unresectable cutaneous, subcutaneous and nodal lesions in laherparepvec) patients with melanoma recurrent after initial surgery.

Source: BioMedTracker

The Precision Medicine Catapult (PMC) has cooperation and Francophony, minister of national Prior to joining National Jewish Health in 2010, he appointed Sir John Bell, Sir Leszek Borysiewicz, education and then minister of labor, social affairs, held appointments as professor of medicine at Mayo Dame Julie Moore and Dr Mene Pangalos to family solidarity and cities. Darcos has also been an Medical School and the University of Pittsburgh. its board of directors. Bell is Regius professor of ambassador, representing France with the OECD medicine at Oxford University and chair of the UK’s and then from 2010 to 2015 he was ambassador for C4X Discovery Holdings plc, a drug discovery office for strategic coordination of health research. France’s foreign cultural policy. and design company, has appointed Dr. Clive Dix Borysiewicz is vice-chancellor of the University executive chair. Dix was previously non-executive of Cambrige and prior to this he was CEO of the Proteus Digital Health, a company creating a new chair of C4XD’s board of directors; now as executive UK Medical Research Council. Moore is chief category of therapy known as digital medicines, has chair he will build upon the strong achievements executive of University Hospitals Birmingham NHS appointed Molly O’Neill chief commercial officer C4XD has made to date in fulfilling its ambition to foundation trust and since October 2015, interim (CMO), Shumeet Banerji to its board of directors become “one of the world’s leading hubs for the chief executive of Heart of English NHS Foundation and Jonathan Symonds as chair. O’Neill brings discovery of novel drugs against critical therapeutic Trust. Pangalos is executive vice president of 30 years of experience to Proteus and is joining targets.” Recent achievements include advances in AstraZeneca’s innovative medicines and early from Tenet Health, where she was vice president its Orexin-1, IL-17, GPR142 and NRF-2 programs and development biotech unit. of business development. Symonds is currently the signing of a collaboration with the Structural chair of HSBC Bank Plc., chair of the supervisory Genomics Consortium at Oxford University. Crescendo Biologics Ltd. has appointed Kevin board of Innocoll AG and non-executive director of Johnson non-executive chair of the board of Genomics England. Previously he was chief financial Idera Pharmaceuticals Inc., a clinical-stage directors – effective immediately. Johnson has officer (CFO) of Novartis, partner and managing biopharmaceutical company developing toll-like 27 years’ experience in antibody development director of Goldman Sachs and CFO of AstraZeneca receptor and RNA therapeutics for cancer and rare and previously was CEO of Netherlands- Plc. Banerji is founder and partner of Condorcet, an diseases, has named Dr. Joanna Horobin senior based PanGenetics, an antibody development investment and advisory firm, and he retired from vice president and chief medical officer. Horobin company. He also held various roles at Cambridge Booz & Company Inc. having served as its founding was most recently chief medical officer of Verastem Antibody Technology, which eventually led to CEO. He previously held leadership roles at Allen Inc. and previously served as CEO of Syndax his appointment as research director and chief & Hamilton in India, UK and globally. Currently he Pharmaceuticals. Prior to her positions at Verastem technology officer. Since 2003 he has been working serves on the board of HP, Inc. and Innocoll, AG. and Syndax, she held several roles of increasing in the life science team at Index Ventures. responsibility at global pharmaceutical corporations Oncimmune, a leader in early cancer detection, such as Rhône-Poulenc Rorer (now Sanofi), where Sanofi has appointed French academic, civil servant has named Dr. James Jett chief medical officer. Jett she spearheaded the global oncology business and politician, Xavier Darcos, president of the is currently professor of medicine in the division of unit’s launches of Taxotere (docetaxel) in breast Sanofi Espoir Foundation. Over the years, Darcos oncology at National Jewish Health in the US, where cancer and Campto/Camptosar (CPT11) for has been senator and mayor of Périgueux, minister his research includes conducting clinical trials related colorectal cancer. Horobin’s appointment with Idera of school education, minster of development, to the screening and early detection of lung cancer. will commence on November 30, 2015.

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