17 November 2017 No. 3880

Scripscrip.pharmaintelligence.informa.com Pharma intelligence | informa to file for approval of a CGRP therapy in the US and EU. Erenumab is on track for a po- tential first-in-class launch in 2018, with the proposed brand name Aimovig. Eli Lilly & Co. and Teva Pharmaceuti- cal Industries Ltd. are just behind with the CGRP inhibitors galcanezumab and freman- ezumab, respectively. (Also see “Lilly Breath- ing Down Amgen/Novartis’s Necks With Three Phase III Migraine Wins” Scrip, 12 May, 2017.) Teva has closed the gap, however, and may be the closest to beating Novartis and Amgen to the market. The company filed a biologic license application (BLA) with the FDA in October and used a priority review voucher to expedite the application’s review, which would position Teva’s freman- ezumab neck and neck in the US with Am- Shutterstock: Johan Swanepoel Johan Shutterstock: gen/Novartis’ erenumab. Novartis believes the value case for a product like erenumab will be enhanced Novartis Floats ‘Bold’ Value-Based if the drug can be targeted to the patients that respond the best to treatment. Some migraine sufferers responded better to Reimbursement Idea In Migraine treatment in clinical trials than others, but JESSICA MERRILL [email protected] no biomarker has been identified to help target the drug to the right patients. ovartis AG has been one of the highlighting just how critical market access For example, among patients with epi- more proactive pharmaceutical and reimbursement has become to the spe- sodic migraines – those that experience Nmanufacturers when it comes to cialty drug segment. less than 15 migraines a month – 26% in implementing value-based reimbursement “There are a lot of patients who need a Phase III trial were migraine-free after 15 agreements with payers, and now it is con- these medicines and if we can come up months of treatment while 65% had 50% sidering a “bold” idea to enhance the value with an appropriate value proposition for fewer migraines. Similar differences were of an up-and-coming drug that investors payers, I think we can be successful,” Nara- seen in patients with chronic migraine, or 15 have big expectations for – the calcitonin simhan said. or more headache days a month. Novartis gene-related peptide (CGRP) antagonist Erenumab isn’t the only CGRP inhibitor and Amgen are seeking approvals for both erenumab, partnered with Amgen Inc., for nearing the market and the class is drawing indications. migraine headaches. a lot of attention from physicians and pay- “If they are not a responder, then we While an investor briefing on Nov. 13 was ers, because of the large migraine patient can underwrite that where the reim- billed as an R&D day, the company’s incom- population and the high unmet need. Pay- bursement environment will allow. Where ing CEO and current Chief Medical Officer ers are worried about how the high volume they are a responder, they can stay on medicine,” Hudson said. “We are prepared Vasant Narasimhan and Novartis Pharma- might impact costs. to do that because we think we have to ceuticals CEO Paul Hudson put commercial Novartis and Amgen are poised to set the value front and center across the portfolio, bar on pricing, as the partners were the first CONTINUED ON PAGE 9

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Third Quarter Tail CHMP Opinions ACR Roundup AstraZeneca and Regeneron eye Committee says yes to Ocrevus Highlights of the American College growth p4-5 and others p6-7 of Rhuematology meeting p16-17 IN THIS ISSUE

from the editor [email protected]

Novartis is notably creative in reimbursement negotia- on outcomes-based reimbursement beyond the sphere tions. When it won US approval for the one-time CAR-T of high-cost cures for rare and serious diseases, whether therapy Kymriah to treat children and young adults with it be in migraine, where it is open to underwriting the acute lymphoblastic leukemia, it demonstrated flexibil- cost for non-responding patients in order to secure re- ity in its promise to work with patients and payers to imbursement for responders (see cover story), or in car- ensure market access. As well as breaking new ground diac risk reduction, where it hopes to secure a market in agreeing only to bill Medicare/Medicaid if patients for canakinumab for a subset of heart attack patients respond in the first month of treatment (with similar who can be identified with a quick, cheap test. contracts on the cards for private payers), it indicated There is still much room for innovation in reimburse- that it would consider differential pricing for the prod- ment. A case in point: Spark Therapeutics is separately uct in future indications. This could entail reduced ramping up talks with payers for its likely soon to be pricing for broader indications or for those where the approved gene therapy Luxturna to treat rare blindness cost-value benefit is calculated to be lower. disorders. As more high-cost, one-off treatments like Lux- Novartis management’s latest comments on agreeing turna and Kymriah make it to market, the need in par- value propositions for different medicines with payers ticular for options to amortize upfront therapy costs over show that the company continues to push the envelope a number of years will only become more compelling.

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EDITORS IN CHIEF Ian Schofield EDITORIAL OFFICE Eleanor Malone (Europe) Vibha Sharma Christchurch Court Denise Peterson (US) Joanne Shorthouse 10-15 Newgate Street Ian Haydock (Asia) Sten Stovall London, EC1A 7AZ US CUSTOMER SERVICES EXECUTIVE EDITORS Michael Cipriano Tel: +44 (0)20 7017 5540 COMMERCIAL Derrick Gingery or (US) Toll Free: 1 800 997 3892 Alexandra Shimmings (Europe) Joseph Haas Email: clientservices@ Mary Jo Laffler (US) Emily Hayes pharma.informa.com Mandy Jackson POLICY AND REGULATORY Cathy Kelly TO SUBSCRIBE, VISIT Maureen Kenny (Europe) Jessica Merrill scrip.pharmaintelligence.informa.com Nielsen Hobbs (US) Brenda Sandburg TO ADVERTISE, CONTACT Bridget Silverman [email protected] EUROPE Sue Sutter Neena Brizmohun Francesca Bruce ASIA John Davis Anju Ghangurde Lucie Ellis Ying Huang All stock images in this publication Kevin Grogan Jung Won Shin courtesy of www.shutterstock.com John Hodgson Brian Yang unless otherwise stated

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2 | Scrip | 17 November 2017 © Informa UK Ltd 2017 Down the drain

Boehringer’s Tangled web 20 12 CNS refresh 18 of PBMs 21

exclusive online content inside: Merck KGaA Highlights Mavenclad Advances In COVER / Novartis Floats ‘Bold’ Value-Based Reimbursement Idea Tough Quarter In Migraine http://bit.ly/2if5cQr Merck KGaA’s brace of new products started to garner sales in the 4 AZ Confident New Cancer Drugs Can Drive Return third quarter, but the big pharma maintained its 2017 guidance To Sales Growth at the lower end of the forecast range in the face of increasing competition to its established pharmaceutical products and to 5 Keeping An Eye On Regeneron: What’s Next For Growth? its liquid crystal materials, and currency headwinds. 6 European Nod For Roche’s Ocrevus Clouded By Durability Still In Question For Acadia’s Nuplazid In Patient Limitation Alzheimer’s Psychosis http://bit.ly/2hyyJYa 7 EU Confirms Sirukumab Filing Withdrawal, J&J Moves On Full Phase II data studying Acadia’s Nuplazid (pimavanserin) in patients with Alzheimer’s disease psychosis confirmed the 7 AstraZeneca’s Benralizumab Asthma Chase Underway exploratory drug met its primary endpoint, but worries remain over the drug’s durability – and hence its commercial promise 8 Novartis Back In AMD Game With Brolucizumab in dementia-related psychosis. 9 Novartis’s Kisqali Gains Traction In Pre-Menopausal Patients All Smiles At Sage As Phase III Postpartum Depression Data Are Positive 10 Sanofi Expands MS Portfolio With BTK Inhibitor http://bit.ly/2zBVf9G From Principia The company plans to file an NDA with FDA in the first half of 2018 for an intravenous formulation of brexanolone, which could 11 Spark Stands By $1m Price Possibility For Luxturna be the first treatment specifically for postpartum depression. 12 Valeant Returns $1bn Female Libido Drug For Free Five Prime Bounces Back With Good Spin On Cabiralizumab Data 13 Dermira Ends UCB Cimzia Psoriasis Pact To Focus On Its http://bit.ly/2z1tK9W Own Pipeline Bristol’s new Phase I study of Opdivo with Five Prime’s cabiralizumab in second-line pancreatic cancer restored faith 14 Forendo Pharma: Tackling The Endometriosis Challenge in the combo for some investors, as did a full presentation of pancreatic cancer data slated for SITC. 16 JAK Safety Shown Across Multiple Trials Deal Watch: Boehringer’s Hectic Stretch Adds Up To Five Deals 18 CNS Refresh: Boehringer’s New Approach To Tricky http://bit.ly/2AG4DpR Neuropsychiatry Diseases Following its partnership with Dicerna, the German pharma signs a second NASH deal with MiNA and inks three cancer- 21 Mehta Analysis: The Tangled Web Of PBMs related transactions, including divestitures. Also, Amgen buys out Kirin’s half of their joint venture for $780m. 22 Pipeline Watch

Venture Funding Deals: From ADC To Y-mAbs, Capital 23 Appointments Flows For New Platforms, Novel Approaches http://bit.ly/2zEjSlO October was an active fundraising month for both start-up biopharma companies and more established privately held firms, ranging from $3m for Appili’s drug for anaerobic infections @PharmaScrip /scripintelligence to $270m for Harmony’s rare disease programs. /scripintelligence /scripintelligence

scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 3 Q3 RESULTS

AZ Confident New Cancer Drugs Can Drive Return To Sales Growth KEVIN GROGAN [email protected]

straZeneca PLC has unveiled third-quarter results on When asked whether expectations about I-O in general and com- Nov. 9 which were in line with expectations and also fo- bos in particular have been too high, Bohen stressed that the exuber- Acused on the advances its cancer treatments have been ance in some circles that “we have somehow cured cancer” had been making in the clinic and commercially. misplaced given the amount of checkpoint inhibitor data available One treatment that received much attention on conference calls now, but it was fair to say that there were certain subsets of patients to discuss the results was the PD-1/L1 inhibitor Imfinzi (durvalumab), who are experiencing really durable effects with these new medicines. a drug that is key to AstraZeneca’s hopes to become a key player in The challenge now, he added, is to expand those groups with the immuno-oncology (I-O) space. Imfinzi got its first approval in May combinations and find which are the best. Having combos in-house, under the US Food and Drug Administration’s accelerated approval as AstraZeneca has with Imfinzi and tremelimumab is great, Bohen pathway for patients with locally advanced or metastatic urothelial said, but the company is happy to look outside, as the Incyte col- cancer, the most common form of bladder cancer, however the in- laboration shows. dication that is much more significant for the checkpoint inhibitor There is much more to cancer than I-O and AstraZeneca’s oncol- will be lung cancer and specifically the earlier stages of the disease. ogy sales in the third quarter were just under $1.03bn and newer Sales of Imfinzi year-to-date came in at just $1m but Dave Fred- products made a major contribution. Most impressive was the per- rickson, head of AstraZeneca’s oncology business unit, told Scrip that formance of the lung cancer therapy Tagrisso (omisertinib), sales of the company was reasonably pleased with the launch. He noted that which leapt 86% to $248m, boosted by higher testing rates in the Imfinzi was the fourth of the five immunotherapies approved for the US and Japan, positive reimbursement decisions in Germany, Italy, treatment of bladder cancer in the US yet still had achieved mid- Portugal and Sweden and a strong launch in China – Tagrisso was ap- single digit market share. proved there in March 2017 as the first AstraZeneca medicine under the China FDA’s priority review pathway. However, Fredrickson stressed that the bladder cancer launch rep- Tagrisso was another treatment that shone at ESMO with the full resented a strategic one designed principally to increase awareness data set from the Phase III FLAURA study which showed that the drug of the product and gain formulary access. The big prize is in locally- provided significant improvement in PFS over current standard-of- advanced, unresectable non-small cell lung cancer (NSCLC) and As- care therapies – erlotinib or gefitinib – in advanced NSCLC harboring traZeneca’s teams are actively preparing for the potential launch of EGFR mutations in the first-line setting. Filings to get first-line approv- Imfinzi for that indication in the first half of 2018. al based on FLAURA are scheduled before year-end. The company has not even filed Imfinzi for bladder cancer in Europe The other jewel in AstraZeneca’s oncology crown is the PARP in- and chief medical officer Sean Bohen toldScrip that the regulatory fo- hibitor Lynparza (olaparib). Sales were up 40% to $81m, helped by an cus firmly shifted to NSCLC, with filings on both sides of the Atlantic additional broad approval in the US, namely for patients regardless of and Japan, on the strength of the PACIFIC data presented at the Eu- BRCA-mutation status for the treatment of second-line ovarian can- ropean Society for Medical Oncology congress in Madrid in patients cer with a new tablet formulation. with unresectable Stage III NSCLC. The results showed that the drug The company also noted that Lynparza will benefit from having improved progression-free survival (PFS) by just over 11 months - 16.8 Merck & Co. Inc. sales reps helping the promotion of the drug from months in the Imfinzi arm compared with 5.6 months with placebo. the beginning of 2018. The partners inked a multi-billion dollar col- AstraZeneca will be the only I-O player in the earlier-stage lung laboration in July which sees Merck share development and com- cancer space for a couple of years and the company also highlighted mercialization of Lynparza, which also has a US priority review for use the raft of trials looking at combinations of Imfinzi and its investiga- in certain patients with breast cancer, and the investigational MEK tional CTLA-4 inhibitor tremelimumab. inhibitor selumetinib. One of them, MYSTIC, was a high-profile failure in the summer As for the overall results, third-quarter core operating profit was when the combo did not show a PFS benefit in patients with previ- up 12% to $1.85bn while total revenues actually rose 9% to $6.23bn, ously untreated Stage IV metastatic NSCLC. However, not all hope is boosted by a $997m payment from Merck in connection with the lost and Bohen said that it is “quite possible” that the overall survival Lynparza pact. Product sales were down 3% to $4.88bn, hit again data could still report positively when MYSTIC finally reads out in the by generic competition in the US to the lipid-lowerer blockbuster first half of next year. Crestor (rosuvastatin), which was down 16% but is still comfortably Bohen also spoke about the recent deal signed with Incyte Corp. AstraZeneca’s biggest earner with sales of $580m. to test its closely-watched indoleamine 2, 3-dioxygenase (IDO) Crestor goes off-patent in Europe at the end of this year and chief checkpoint inhibitor epacadostat with Imfinzi in Stage III unresect- executive Pascal Soriot told reporters that will represent the last able NSCLC. Noting that toxicity is an issue with CTLA-4 inhibitors major patent expiry for a few years. He also highlighted impressive like tremelimumab, it is logical to explore other combinations with growth in the emerging markets, especially “standout” sales in China, new immune-oncology agents such as IDO inhibitors which could and the accelerated approval in the US last week for Calquence. provide additional benefit to Imfinzi with less toxicity. Published online 9 November 2017

4 | Scrip | 17 November 2017 © Informa UK Ltd 2017 Q3 RESULTS

Keeping An Eye On Regeneron: What’s Next For Growth? JESSICA MERRILL [email protected]

ith two new drug launches under its belt in 2017 – Dupix- Sanofi, with Regeneron sharing in the profits and losses. The drug ent (dupilumab) for atopic dermatitis and Kevzara (sari- appears off to a strong launch, out-performing analyst consensus Wlumab) for rheumatoid arthritis – investors want to know estimates. Exec VP-Commercial Robert Terifay reported that 7,000 what is next on the horizon to drive growth at Regeneron Phar- healthcare providers have written prescriptions for Dupixent, and ap- maceuticals Inc. Most of the biotech’s near-term growth prospects proximately 750 new patients have been prescribed Dupixent each hinge on the continued strength of its workhorse Eylea (aflibercept), week. Market access appears to be strong, with 80% of commercial the success of the new launches and the expansion of existing drugs lives covered by health plans, he said. About half of those patients into new indications. have a prior authorization requirement, where they can receive Du- The company highlighted some pipeline developments, mainly ex- pixent after trying a topical therapy. pected to lead to indication expansion, during its third quarter earn- A direct-to-consumer advertising campaign will be launching ings call Nov. 8. The company’s third quarter sales were solid, up 23% in the US in the coming weeks to further promote awareness of to $1.5bn. The company has been a Wall Street darling, but the near- to moderate-to-severe atopic dermatitis, Tarifay added. It will be an un- mid-term growth strategy has some investors growing a little nervous, branded campaign. especially given that the one drug investors had been particularly en- But Regeneron and Sanofi are already looking ahead to expan- thusiastic about – Praluent for cholesterol – is so far a commercial dud. sion of Dupixent to other indications. The companies are poised to Barclays Geoff Meacham weighed in on Regeneron in a same-day file an sBLA for Dupixent in patients with asthma by the end of the research note. “While the quarter’s financials were relatively strong, we year. Data from two Phase III trials testing Dupixent in severe asthma continue to see longer-term issues with Street expectations around patients have read out positively, though the drug, if approved, will key revenue drivers and weakness in the late-stage pipeline,” he said. enter a crowded market. Two Phase III studies in patients with nasal polyps are fully enrolled and the companies are also moving for- WRINGING GROWTH OUT OF EYLEA ward with development of Dupixent in patients with eosinophilic The eye drug Eylea, approved for wet age-related macular degen- esophagitis, an immune-mediated disease that is strongly associ- eration, diabetic macular edema (DME) and diabetic retinopathy ated with food allergies. in patients with DME, is the drug that catapulted Regeneron into a Kevzara is expected to have a slower growth trajectory, given that standout commercial-stage biotech. But Eylea is maturing, and the it is the second IL-6 inhibitor in the market competing against a well- company remains heavily reliant on it. Although Regeneron has now entrenched rival, Roche’s Actemra (tocilizumab), in a crowded mar- launched several other new drugs in the last three years, it has yet to ket. It brought in $3m in its first full quarter on the market. recreate the Eylea success story. Sales of Eylea in the US grew 12% to $953m in the third quarter. Regeneron is partnered on the drug with PD-1 INHIBITOR POISED FOR FILING Bayer AG outside the US and received $205m for its share of profit One area where Regeneron and its partner Sanofi have been flying outside the US in the third quarter. under the radar – and also behind many rivals – is immuno-oncolo- Management believes Eylea still has plenty of room for growth, gy. The companies signed a new alliance in 2015 to collaborate on particularly in diabetic eye disease. DME represents only 25% of US the discovery, development and commercialization of new antibody Eylea sales, and the majority of patients with DME are untreated or cancer treatments in immune-oncology, including a PD-1 inhibitor. receive laser therapy, which has been shown in clinical trials to be The company’s longer-term antibody drug discovery deal is winding inferior to Eylea, CEO Leonard Schleifer said. down at the end of the year, however. The company is aiming to expand the use of Eylea to patients with Regeneron President and Chief Scientific Officer George Yanco- non-proliferative diabetic retinopathy without DME next, having poulos said the companies are poised to file their PD-1 antibody ce- completed enrollment in a Phase III trial called PANORAMA. Top-line miplimab for the treatment of cutaneous squamous cell carcinoma data is expected in the first half of 2018, with a supplemental biolog- (CSCC) in the first quarter of 2018. Interim data is expected from the ics license application (sBLA) submission expected in the second half potentially pivotal Phase II trial testing cemiplimab in patients with of 2018 if the data reads out positively. metastatic CSCC and locally advanced and unresectable CSCC later Sales of Regeneron’s PCSK9 inhibitor Praluent (alirocumab), part- this year. The companies have secured a breakthrough therapy des- nered with Sanofi, are still lagging at $49m in the quarter and pros- ignation from FDA for cemiplimab for CSCC, the second deadliest pects for broader uptake remain dim in the near-term. The results of skin cancer after melanoma. an important cardiovascular outcomes trial are expected in the first “Our PD-1 program has continued to expand,” Yancopoulos said. quarter, but even if the results are positive, market access challenges The company recently initiated a Phase III program studying ce- are expected to persist. miplimab monotherapy in first-line NSCLC, a highly sought after in- In the meantime, Dupixent is poised to be Regeneron’s next block- dication. The 300-patient trial is enrolling patients expressing greater buster brand. The IL-4/IL-13 blocker, also partnered with Sanofi, was than 50% PD-L1 and will compare cemiplimab to standard-of-care approved by the FDA as the first new systemic treatment for atopic platinum chemotherapy. The company is planning additional com- dermatitis in March; it was approved in Europe in September. Dupix- bination studies in NSCLC and in second-line NSCLC, he said. ent generated $89m in the third quarter, as previously reported by Published online 8 November 2017 scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 5 CHMP OPINIONS

European Nod For Roche’s Ocrevus Clouded By Patient Limitation KEVIN GROGAN [email protected]

oche has finally received a recom- presented with three list of outstanding is- However, when Scrip asked the company mendation for approval from Euro- sues (LoOIs) this year – in March, September about the limited PPMS license and how it Rpean regulators for Ocrevus (ocreli- and October – and has had to give two oral would be addressing the CHMP’s view that zumab). The drug, which has already explanations, on Sept. 13 and Oct. 10. None- more investigation is needed in the ad- transformed the multiple sclerosis land- theless, at the CHMP’s October meeting, the vanced stages of the disease, a spokesper- scape in the US, is expected to be available product still failed to get an opinion for the son said that at this point of time, it cannot in Europe early next year. second time in a row, a surprising move giv- provide further details but “we are looking The European Medicines Agency’s Com- en that Ocrevus was one of just three initial forward to working with all stakeholders to mittee for Medicinal Products for Human marketing authorizations that the Commit- address this in due course.” Use (CHMP) has issued a positive opinion for tee was considering. The spokesperson added that the positive the treatment of adults with either the active opinion “is consistent with the population relapsing (RMS) or the early primary progres- More investigation studied in our Phase III trials.” She said that sive (PPMS) forms for the disease. The latter is needed to better Ocrevus was effective in the overall PPMS represents around 10% of sufferers, the EMA population “and while directionally consis- states, noting that “there are currently no understand how beneficial­ tent benefits were seen in patients with or disease-modifying therapies available for without baseline inflammation, greater treat- this particular form of MS so there is a great Ocrevus might be in the ment effect was seen in those with acute in- medical need for treatment of such a relent- more advanced stages flammation at baseline.” In the US, the label less, seriously-debilitating disease.” is more general, i.e., for adults with relapsing The CHMP recommendation is based on forms of MS and patients with PPMS. data from three Phase III trials in 1,423 pa- It is also too early to say what Roche’s pric- tients (two in RMS and one in PPMS). Treat- After October’s CHMP opinions were ing strategy will be as it starts to negotiate ment with Ocrevus significantly reduced published, Roche told Scrip that it was still with payers in the EU’s 28 member states, the annualised relapse rate by 46.4% at 96 confident of getting the thumbs-up this although some observers expect the firm weeks compared with interferon beta-1a month and this view was confirmed by the to mirror the approach adopted in the US. treatment in patients with RMS, while for Swiss major’s pharmaceuticals chief Dan There, on approval, the wholesale acquisi- those with PPMS, treatment with the Roche O’Day. Speaking on a conference call for tion cost was set at $65,000, lower than therapy led to a 24% reduction in the risk of Roche’s third-quarter results, he said that the some older therapies. Ocrevus is also hurt- 12-week confirmed disability progression delay in Europe had been expected as the ing rival Sanofi, which saw a weak growth compared with placebo. company had submitted “a very large file rate for its newer MS drugs Aubagio (teriflu- However one blot regarding the approval with huge amounts of datapoints.” nomide) and Lemtrada (alemtuzumab) in is that if granted, the Ocrevus license will Since getting approval in the US in the third quarter. only cover early-stage and not all PPMS pa- March,Ocrevus has made a stunning start However, Datamonitor Healthcare analyst tients. The EMA noted in a statement that commercially. Third-quarter sales reached Daniel Chancellor told Scrip that Ocrevus data from the clinical trial in PPMS indicate CHF308m, comfortably exceeding analyst may have a higher price in Europe, certainly that patients in the early stage of disease forecasts, and O’Day noted at the time of relative to the discount that it came into the benefit more and “more investigation is the financial results that 17,000 patients US at. He noted that “pricing is more struc- needed to better understand how benefi- have been infused - the split is 60%/40% in tured in the EU with a lot more reference cial Ocrevus might be in the more advanced favor of the relapsing form of the disease. pricing, therefore as long as the relevant stages of the disease.” Now it looks like Europe will be soon be market access bodies perceive the data fa- Also, given that the most common ad- adding to those impressive sales figures for vorably, we would assume pricing on a par verse reactions observed with Ocrevus are Ocrevus, which is already approved in Can- with other benchmark therapies.” infusion-related reactions and infections, ada, some countries in South America, the In terms of sales forecasts, Datamonitor it recommends that treatment “should Middle East and eastern Europe, as well as in Healthcare estimates Ocrevus turnover in be initiated and supervised by an experi- Australia and Switzerland. Sandra Horning, 2018 for Germany, Italy and the UK will be enced healthcare professional with access Roche’s chief medical officer, said in a state- around $76m, $76m and $72m respec- to appropriate medical support to man- ment that “we are pleased that the CHMP tively, rising to $287m, $299m and $354m age severe reactions.” has recognized the clinical significance of by 2025. US sales in 2025 are forecast to The path to likely approval of Ocrevus has the Ocrevus data, particularly for people liv- reach $5.32bn. been a tough one for Roche which has been ing with PPMS.” Published online 10 November 2017

6 | Scrip | 17 November 2017 © Informa UK Ltd 2017 CHMP OPINIONS

EU Confirms Sirukumab Filing Withdrawal, J&J Moves On JOHN DAVIS [email protected]

he EU’s scientific advisory panel, the tegic decision to prioritize other assets in our US FDA in September, that asked for further Committee for Medicinal Products for portfolio, given the need for additional clini- clinical data, that in the words of J&J “would T Human Use (CHMP), has confirmed cal data that would result in significant de- have delayed the launch of sirukumab sig- that Janssen-Cilag International has with- lays to patient access to sirukumab in parts nificantly.” The regulators were primarily drawn its EU marketing application for the of the world, and the availability of other concerned about the long-term safety of interleukin-6 inhibitor Plivensia (sirukumab), treatments targeting the IL-6 pathway.” sirukumab - in August, the US FDA’s arthritis as part of the company’s decision to halt its Sirukumab was expected to be used in advisory committee voted against approval development for the treatment of moderate- adults with moderate to severe rheuma- after concerns were expressed about a mor- to-severe rheumatoid arthritis worldwide. toid arthritis when one or more disease- tality imbalance in clinical trials. The CHMP said it had expressed concern modifying antirheumatics (DMARDs) had The need to conduct further time-con- to the company that the long-term safety of not worked well enough or had to trouble- suming Phase III studies would have meant sirukumab had not been well characterized, some side effects. The compound was to be that, if sirukumab had gained an approval, it due to limitations in the design of its main used in combination with methotrexate (a would have been a late-entrant in the IL-6 studies. Like the US FDA, the committee be- DMARD), or alone if the patient could not inhibitor category. lieved that further clinical studies of siruku- take methotrexate. One IL-6 inhibitor, Roche’s Actemra (tocili- mab were needed. The Johnson & Johnson subsidiary said it zumab), has already been available on some In a market as competitive as that for the reserved the right to make further marketing markets for some years – in the US for seven treatment of active rheumatoid arthritis, the submissions in other therapeutic indications years – and another IL-6 inhibitor, Sanofi/ delay in its introduction looks to have been – the Informa Pharma database, Biomed- Regeneron Pharmaceuticals Inc.’s Kevzara one hurdle too far for the compound, that tracker, notes that sirukumab is also in Phase (sarilumab) was approved for marketing ear- also lost its licensee, GlaxoSmithKline PLC, I and II clinical studies in lupus nephritis. lier in 2017. The IL-6 inhibitors do have differ- earlier this year, and was going up against J&J announced in October it would ences – sirukumab is thought to target the newly launched biosimilars to TNF-inhibitors. withdraw regulatory filings worldwide for IL-6 cytokine directly, while tocilizumab and In a letter to the CHMP dated Oct. 26, sirukumab in rheumatoid arthritis after it re- sarilumab inhibit the IL-6 receptor. Janssen-Cilag said it had made a “global stra- ceived a complete response letter from the Published online 13 November 2017 AstraZeneca’s Benralizumab Asthma Chase Underway ALEX SHIMMINGS [email protected]

straZeneca PLC is set to give chase (olaparib), Tagrisso (osimertinib), Imfinzi in catch up its more established competitors. to GlaxoSmithKline PLC’s Nucala stage III NSCLC, plus its new mantle cell lym- It cites its differentiated mechanism of ac- A(mepolizumab) and Teva Pharma- phoma therapy Claquence (acalabrutinib). tion plus its more favorable dosing regimen ceutical Industries Ltd.’s Cinqair (respi- But respiratory is still an important area for as factors that will make the product more zumab) in the severe eosinophilic asthma new products for AstraZeneca as it weath- attractive to doctors and patients. market, with a positive approval opinion ers generic competition to its blockbusters, Benralizumab binds directly to the IL-5α from the European Medicines Agency’s Symbicort (budesonide/formoterol) and receptor on an eosinophil and unique- CHMP for its monoclonal antibody product Pulmicort (budesonide). As well as benrali- ly attracts natural killer cells to induce benralizumab (as Fasenra) at its latest meet- zumab, it is also developing what it hopes apoptosis. If approved, benralizumab will ing this week. will be a game-changer in severe asthma, be available as a once every eight week The go-ahead covers benralizumab’s the first-in-class injectable anti-thymic fixed-dose subcutaneous injection via a use as an add-on maintenance treatment stromal lymphopoietin (TSLP) monoclonal prefilled syringe. in adult patients with severe eosinophilic antibody tezepelumab. However, another By comparison, Cinqair (which was ap- asthma inadequately controlled despite product hopeful, the anti-IL13 human proved in 2015) and Nucala (which was ap- high-dose inhaled corticosteroids plus long monoclonal antibody tralokinumab, looks proved last year) target the IL-5 ligand. acting β agonists. A similar approval in the set to be dropped after a further Phase III Published online 10 November 2017 US is also expected by the end of the year. failure in severe uncontrolled asthma. Ana- At its third quarter results presentation on lysts at Leerink forecast sales of AZ’s respira- Click here for a full round up of Nov. 9, AstraZeneca emphasized an expected tory biologicals at $870m in 2022. this month’s CHMP opinions: return to sales growth in 2018 driven largely Once launched, AstraZeneca is confident http://bit.ly/2zDmuAD by its cancer portfolio, in particular, Lynparza that benralizumab will quickly be able to scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 7 R&D

Novartis Back In AMD Game With Brolucizumab STEN STOVALL [email protected]

ovartis AG expressed confidence its nAMD eye treatment eron Pharmaceuticals Inc. . in the US and Germany’s Bayer AG out- RTH258 (brolucizumab) would be approved and become side the US, or off-label with Roche’sAvastin (bevacizumab). Na blockbuster after it released further positive Phase III data Brolucizumab’s non-inferior efficacy and potentially less frequent comparing the novel anti-VEGF treatment to Eylea, using lower dosing dosing would allow Novartis to be able to compete more effectively which nonetheless showed superiority in key retinal health outcomes. in the anti-VEGF market and begin to target some of Eylea’s $5bn-and- In results from twin Phase III studies for treating neovascular age- growing sales, rather than always playing defensively. Furthermore, as related macular degeneration (nAMD), brolucizumab displayed a Narasimhan noted, Novartis would have marketing rights to an anti- potential competitive advantage for treating the condition by show- VEGF globally, whereas it splits revenues for Lucentis with Roche. ing – via fewer dosing intervals – non-inferiority to Eylea (aflibercept), “We think the dosing advantage will be particularly important for better retinal outcomes, and long-lasting effect in patients. this therapy, especially in the US where we don’t currently have an The data from the head-to-head HAWK and HARRIER trials were anti-VEGF agent. The dosing frequency matters a lot to patients, so presented at this year’s American Academy of Ophthalmology meet- that’s going to be an important differentiator,” Vas Narasimhan said. ing, held in New Orleans. Regeneron plans to defend Eylea against such encroaching com- In the trials, significantly fewer brolucizumab patients had signs of petition by filing an sBLA for quarterly dosing by the end of the year. disease activity and retinal fluid, and the drug demonstrated superior A Phase III study of Eylea in non-proliferative diabetic retinopathy is reductions in retinal thickness due to fluid accumulation versus Ey- also enrolling. lea, while overall ocular and non-ocular adverse event rates for brolu- cizumab were comparable to Eylea in both studies. The results were OTHER CONDITIONS BEING TESTED TOO achieved while most brolucizumab patients – 57% in HAWK and 52% Novartis won’t stay idle either though – it plans to explore other con- in HARRIER – were dosed on a 12-week interval for 48 weeks. The trial ditions with its newer anti VEGF treatment. data builds on top-line results released in June. “Our plan is to move it into diabetic macular edema in 2018 as well as retinal vein occlusion in 2018, so we’re moving forward now “COMPELLING” AND “STATISTICALLY SIGNIFICANT” in the conversations with the regulators to allow us to start Phase III “In summary, what we have here is a drug that can deliver higher programs in those indications next year,” Novartis’ CMO said. doses into the eye safely; you have non-inferior visual acuity improve- Brolucizumab’s prospects will not cause Novartis to abandon ef- ment after the first year; you have less frequent administration every forts to promote Lucentis either, he said. 12 weeks for most patients [with RTH258]; and you have the oppor- “We’ll continue to adhere to our partnership with regards to tunity to reduce retinal fluid at a rate that’s not been seen before,” said [Roche biologics division] Genentech Inc. and Lucentis outside of Vas Narasimhan, global head of drug development and chief medi- the US – and we will continue to ensure that Lucentis is fully sup- cal officer at Novartis, who was recently named as its CEO-designate. ported across our Novartis organization outside the US. Within the “Compared with Eylea, RTH258 had significantly fewer patients US, we’re allowed to operate with RTH258 as our lead entry into the with retinal fluid; had fewer patients at the deepest layer of the reti- VEGF market,” Narasimhan said. na, and superior reductions in retinal thickness as well as less disease The less-frequent dosing option for brolucizumab versus Eylea will activity at week 16. These are all statistically significant and will be be an important differentiator, he said. compelling,” he said in an interview with Scrip. “There is a strong desire on the part of patients and doctors to reduce “Having delivered on the non-inferiority endpoint with most of pa- injection frequency. Also, when patients are going blind, they and their tients on a 12-week interval, we now plan to file in 4Q 2018, once we doctors are looking for better efficacy. And that better efficacy in the have completed some of the manufacturing work that we’ve now long run is what will ultimately determine the patients’ quality of life.” agreed with both the FDA and EMA. We’ll then be able to bring this “We believe that showing this data where we’re able to dem- important innovation to patients,” Narasimhan said. onstrate better resolution of retinal fluid and which will hopefully “We expect this to launch in 2019 and take off from there; we con- then translate over time into better visual outcomes over the lon- tinue to believe that RTH258 will be a potential blockbuster.” ger term, will be a very compelling proposition for the patients Asked whether Novartis expects to get 12-week dosing designa- and physicians.” tion on an eventual label Narasimhan said: The FDA requires this kind RTH258, or brolucizumab, was formerly known as ESBA1008 and of randomized approach to get labeling which would allow you to is a novel, single-chain antibody fragment that Novartis brought in consider the 12-week dosing interval, so we’ve done a study in full through the acquisition of Swiss company ESBATech in 2009. alignment with the FDA and we believe the data demonstrating 52% The legacy of that transaction lies behind the extended timeframe to 57% of the patients were able to be on 12-week dosing supports for filing and launch of the therapy. the labeling that will allow physicians to determine whether they can “We inherited this program from a small company that Alcon move patients out to Q-12 weeks.” had acquired before they moved it over to Novartis and at that Neovascular age-related macular degeneration is currently treated time the Phase II program was started with the Phase II manufac- with either Lucentis (ranibizumab) which is marketed in the US by turing process.” Roche and by Novartis elsewhere, or Eylea, which is sold by Regen- Published online 12 November 2017

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Novartis’s Kisqali Gains Traction In Pre-Menopausal Patients JOHN DAVIS [email protected]

he use of cyclin-dependent kinase Kisqali was evaluated in combination matase inhibitor for the treatment of post- (CDK4/6) inhibitors in certain patients with oral hormonal therapies and goserelin menopausal women with HR+/HER2-locally Twith advanced breast cancer has quickly versus those endocrine treatments alone advanced or metastatic breast cancer. grown into a multi-billion-dollar market for big in pre- and peri-menopausal women with The treatment of HR+/HER2-advanced pharma, and Novartis AG has just announced HR+/HER2- advanced breast cancer not pre- breast cancer has rapidly become a block- Phase III data with its CDK4/6 inhibitor, Kisqali viously treated with endocrine therapy. The buster market for CDK4/6 inhibitors – the (ribociclib), that could extend its use compared MONALEESA-7 Phase III study is said by No- first marketed product, Ibrance had sales in with rivals which include Pfizer Inc.’s Ibrance (pal- vartis to be the first prospective global Phase the 2017 third quarter of $878m. bociclib) and Eli Lilly & Co.’s Verzenio (abemaciclib). III study in pre-menopausal women with ad- Lilly’s Verzenio was approved for market- The Basel, Switzerland-based company vanced breast cancer in more than 20 years. ing in the US in September, and is the only has outlined brief but positive top-line data Advanced breast cancer in younger, pre- CDK4/6 inhibitor approved as monotherapy from the MONALEESA-7 Phase III study, say- menopausal women is more aggressive (as well as in combination with fulvestrant ing Kisqali combination therapy met its pri- with a poorer prognosis than the condi- (AstraZeneca PLC’s Faslodex)). Novartis has mary endpoint of improving progression- tion in post-menopausal women. The MO- an extensive series of Phase III studies un- free survival in pre-menopausal women NALEESA-7 study involved 670 women, and derway with ribociclib in breast cancer. with hormone-receptor positive, human following the positive outcome, Novartis Published online 8 November 2017 epidermal growth factor receptor-2 negative said it planned to start discussions with (HR+/HER2-) advanced breast cancer. Fur- regulatory authorities about the potential Click here to read: Novartis Aims ther details will be reported at the San Anto- additional indication. Kisqali is currently in- Canakinumab At Targeted CV Patients nio Breast Cancer Symposium next month. dicated for use in combination with an aro-

CONTINUED FROM COVER an outcomes-based reimbursement plan “We are resolved to win,” he said. “There justify ourselves.” He suggested the idea for the heart failure drug Entresto, linking will be an absolute determination to do this of a three-month treatment window to the rebates and discounts for the treatment thing properly. … We have a worthy partner evaluate patient response. to reductions in hospitalization and death. and we both know our way around the US.” Such an offer suggests the companies are However, that value-based offer hasn’t pro- The companies are really focused on exploring a premium pricing strategy for pelled Entresto into the early blockbuster targeting specialists, those physicians who erenumab, but it also appears to be driven that some investors had imagined. treat the more severe migraine sufferers, ac- in part as a proactive measure to secure a cording to Novartis. preferred reimbursement position ahead of US COMMERCIALIZATION A “We don’t see the need, at least where Allergan PLC’s Botox (onabotulinumtoxinA), “NO-BRAINER” we are now, to go into the primary care which is approved for chronic migraine and Amgen partnered with Novartis on the setting, other than from a digital education is used to treat seriously afflicted patients. development and commercialization of perspective,” Hudson said. For Novartis, the “In early conversations with payers, they erenumab in 2015, with the two compa- commercial investment from a sales force want to see the only new medicine in epi- nies co-commercializing the drug in the perspective will not be enormous, given sodic and also chronic, but they do have US and Novartis retaining exclusive rights that the company already has a presence Botox on the horizon, and we can’t find to the drug in the rest of the world ex- in neurology through the multiple sclerosis ourselves after that,” Hudson said. Payers are cluding Japan. Under the arrangement, drug Gilenya (fingolimod). He said the deci- more worried about wasting money on the the companies will share commercial patients that don’t respond to treatment costs. Amgen will book sales in the US sion to go in on the commercialization in than paying for the ones that do, he said. and pay a royalty to Novartis on sales in the US when considering the expense to The sweet spot for erenumab in the the US, while Novartis will book sales in revenue was a “no-brainer.” minds of physicians and payers, when it the rest of the world and pay a royalty on Erenumab was just one of the drugs high- comes to episodic migraine, is the 26% of sales to Amgen. lighted by Novartis during the R&D briefing. patients who are migraine-free following Hudson acknowledged that the team’s The company also spotlighted the eye drug sustained treatment, Hudson said. “We just monopoly on the market – if erenumab is brolucizumab and the cardiovascular drug don’t know who they are up front, which is approved first, as expected – may be shorter canakinumab, highlighting new data in a why we are willing to be a little bit more cre- than originally envisioned, but he said the subset of patients that could prove a more ative,” he added. companies are gearing up for a tough com- compelling commercial opportunity. Novartis got a lot of attention for offering mercial fight. Published online 13 November 2017

scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 9 DEALS

Sanofi Expands MS Portfolio With BTK Inhibitor From Principia JOSEPH HAAS [email protected]

aving talked up its intention to invest treat the condition peripherally, rather than ly 170,000 people. In addition to the up- in neuroscience R&D, Sanofi put its directly. That makes ‘2246 a desirable asset front cash, Principia also still has proceeds Hmoney where its mouth is, agreeing for companies looking at the MS space be- from a $50m Series B financing closed in to pay $40m up front to license worldwide cause it combines blood-brain permeability 2014. Beyond BTK inhibitors, Principia is rights to PRN2246, a Bruton’s tyrosine kinase with the autoimmune and anti-inflammato- developing a Phase I FGFR1-4 inhibitor for (BTK) inhibitor just moved into clinical de- ry benefits seen with the BTK inhibitor class. solid tumors. velopment by Principia BioPharma Inc. “There have been a lot of partners inter- “We have the benefit at this point of still for multiple sclerosis. ested in this asset but we ultimately chose being private, but the way that we see this is While the upfront value is fairly low, Sanofi to go with Sanofi,” Babler said, although he that it enables us to take the upfront and ad- could also pay the San Francisco-area bio- declined to specify how many suitors ex- vance several of our programs so that we are tech milestones up to $765m and sales roy- pressed interest in ‘2246. getting to a value inflection point where we alties under the deal announced on Nov. 9. can raise money either publicly or privately Principia CEO Martin Babler told Scrip that PRINCIPIA’S QUICK-TO-MARKET within the next 12 months,” Babler said. Sanofi prevailed in a competitive process STRATEGY Principia unveiled promising Phase II to in-license PRN2246, which he says is dif- Principia decided to create additional BTK data for ‘1008 earlier this year in 12 patients ferentiated from any other BTK inhibitor in inhibitors beyond its lead candidate – and the company hopes to complete the clinical development by its ability to pen- PRN1008, in Phase II for the orphan autoim- study by mid-2018. While BTK inhibitors etrate the blood-brain barrier. According to mune dermatology indication pemphigus – could be developed in about 40 indica- Biomedtracker, Merck KGAA has the only due to a belief that there is a broad range of tions, Babler said focusing on pemphigus other BTK inhibitor in clinical development diseases where BTK inhibition can provide a was a decision rooted both in a strategy to for MS, the Phase II evobrutinib. [Editor’s benefit, the CEO said. German Merck’s evo- get to market quickly, but also to address a note: This article has been corrected in mul- brutinib offers a BTK inhibition approach to medical condition where patients current- tiple places to correct the spelling of Martin MS, but via a peripheral mechanism like cur- ly are unhappy with the standard of care, Babler’s last name.] rently available MS drugs, he noted. high-dose corticosteroids. Babler would not disclose any details of “We’re going to try to attack [the disease] “What patients want basically is a fast-act- the recently initiated Phase I study of ‘2246, centrally because in MS you have autoanti- ing oral drug that gets them into remission but said Sanofi will take over the trial upon bodies and inflammation in the brain itself, fast and helps them get off steroids,” he ex- the deal’s closing. In addition to the other so instead of just lopping off autoantibod- plained. “So anything that is steroid-sparing deal terms, Principia also gets an option to ies peripherally and therefore affecting MS, or even steroid-avoiding is what they’re co-fund Phase III development of the oral we’re hoping to be able to do that centrally, looking for.” molecule, in exchange for either increased which is where the differentiation comes royalties or a US profit-and-loss sharing ar- from,” he explained. SANOFI BUILDING OUT rangement around the drug. The idea that BTK inhibitors might offer MS FRANCHISE Principia intentionally developed utility in inflammatory disease is not new, Earlier in November, Sanofi reported third PRN2246 as an asset for partnering and to but up to now, the class mostly has been quarter sales for its MS drugs decreased cross the blood-brain barrier, the exec add- focused on cancer, with AbbVie Inc./John- from the previous quarter, although the ed, which is possible due to the molecule’s son & Johnson’s Imbruvica (ibrutinib) ap- company presented a picture of ongoing size and permeability. The privately held proved to treat several forms of non-Hodg- franchise growth. (Also see “MS Franchise A company’s Tailored Covalency platform en- kin lymphoma as well as graft-versus-host Surprising Concern For Sanofi In Q3; Dupix- ables it to design drug candidates that of- disease. A second BTK inhibitor obtained ent Out-Performs” Scrip, 2 Nov, 2017.) Auba- fer antibody-like specificity and reversible FDA approval just weeks ago, AstraZeneca gio, which targets DNA synthesis and was bonding. (Also see “Principia taps Series A PLC’s Calquence (acalabrutinib) for mantle launched in 2012, brought in €382m (about tranche to arm warheads for covalent drug cell lymphoma. (Also see “AstraZeneca’s $445m) during the third quarter, down IND” Scrip, 31 Oct, 2012.) Calquence Steps Into Blood Cancer Ring With roughly 10% from €425m during the second “One of the fascinating things about most Mighty Imbruvica” Scrip, 31 Oct, 2017.) quarter. Meanwhile, Lemtrada, an anti-CD52 of the brain diseases that [the medical field Babler said the money from Sanofi will therapy launched in 2014, yielded sales of is] trying to treat is that we’re treating them enable his company to focus its efforts on €113m, down about 8% from €124m in the peripherally, like MS,” Babler said. Current MS PRN1008 in pemphigus, a skin-blistering second quarter. therapies, including Sanofi’sAubagio (teri- disorder thought to have 40,000 US pa- Sanofi Executive VP Bill Sibold told an flunomide) and Lemtrada (alemtuzumab), tients and a worldwide caseload of rough- investor call on Nov. 2 that Aubagio is the

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fastest-growing oral MS therapy world- cade to bring the company greater success translate a given project into the clinic and wide and in the US, with year-over-year in the space. (Also see “Is Neuroscience Back where is the company lacking; and what is global patient growth greater than 25%. In Vogue? Sanofi Preps For R&D Dominance” the likelihood her team can address its tech- He said the MS space was competitive Scrip, 8 Feb, 2017.) nological gaps before a given candidate is when Sanofi entered it five years ago and Naming MS as a key indication in this ready for clinical testing. it remains that way. strategy, Balice-Gordon said better bio- Listed alongside ophthalmology, MS is Beyond its two approved drugs, Sanofi markers of neurodegenerative and neuro- one of Sanofi’s seven priority areas for R&D, has the anti-CD52 candidate GZ402668 in inflammatory processes will help accelerate according to global R&D Head Elias Zer- Phase II for MS. neuroscience R&D, along with advances in houni, along with diabetes; vaccines and In February, Rita Balice-Gordon, Sanofi’s imaging technology. In looking for licens- infectious disease; rare diseases, immunol- neuroscience R&D chief who jumped to the ing candidates to bolster the pipeline, she ogy and inflammation; cardiovascular and French pharma from Pfizer Inc. in 2016, said said she prioritizes three questions: what metabolic disease; and cancer. (Also see that while Sanofi was not known at present candidate offers the highest likelihood of “Sanofi R&D Chief Zerhouni: How I’m Doing as a neuroscience leader, her goal is to take being robustly tested in healthy volunteers More With Less” Scrip, 1 Mar, 2017.) advantage of R&D advances in the past de- and patients; what tools does Sanofi have to Published online 9 November 2017 Spark Stands By $1m Price Possibility For Luxturna JESSICA MERRILL [email protected]

s Spark Therapeutics Inc. gears up Advisory Committee unanimously rec- The economic model Marrazzo laid to launch its gene therapy Luxturna ommended approval of the gene therapy out is precisely the one that has payers so A(voretigene neparvovec) in the US, for the treatment of vision loss due to nervous, since alternative reimbursement the big question is how much the compa- confirmed biallelic RPE65-mutation-asso- structures to pay for a drug for an extended ny might charge for a one-time treatment ciated retinal dystrophy in October. (Also period of years are not in place and because that provides life-altering benefit to some see “Spark’s Gene Therapy Is On The Cusp Of insurers are bracing for the eventual launch patients with certain inherited forms of Approval; Now It Gets Interesting” Scrip, 12 of multiple gene therapies. blindness. From CEO Jeffrey Marrazzo’s com- Oct, 2017.) FDA usually accepts the rec- Spark separately announced it is ments during the company’s third quarter ommendations of its advisory panels, and amending its licensing agreement with earnings call Nov. 7, it seems the price could while the BLA has a Jan. 12 user fee date, Pfizer Inc. for the hemophilia B gene indeed be $1m or higher as some payers the agency is expected to act quickly on therapy SPK-9001. The amendment have feared. the application given the high unmet mainly relates to a change in the Phase Incorporating direct medical costs, in- need the therapy addresses. I/II clinical trial to enroll up to five ad- direct costs like lost employment and lost ditional patients to receive the treat- wages for caregivers, as well as quality of life, PRICE POINTS ment manufactured using an enhanced the economics support valuing Luxturna in Spark’s market access team has been in talks process, to test its comparability to the excess of $1m, Marrazzo said. The pharma- with all the large commercial payers, many SPK-9001 received by the first 10 patients co-economic model for gene therapy will regional insurers and the Centers for Medi- enrolled in the trial. need to incorporate the treatment impact care & Medicaid Services to try to lay out the One patient already received the en- over the patient’s lifetime due to the dura- value of Luxturna to patients, though Mar- hanced version, with comparable results on bility of effect, he added. razzo said the preliminary discussions are no Factor IX activity level out to 32 weeks post- “Additional approaches that we’ve match for the negotiations that will come infusion. tested to value Luxturna independently post-approval. “The changes, which are process related, corroborate this figure, specifically the “We have yet to set and discuss the spe- are designed to enhance scalability and compensation paid out under a long- cific price point with payers,” he said. “How- support the commercial manufacturing,” term disability policy and awards reached ever, we have tested multiple approaches Marrazzo said. in a sampling of recent state court cases to valuing the functional improvements in Pfizer will give Spark an additional $10m where individuals suffered impairment to vision that we have observed in our clini- payment upfront and an additional $15m their vision at or above the $1m mark, pro- cal trials and the positive impact on pa- in potential milestones upon completion of viding even further evidence of the sub- tients’ lives.” certain transition activities. stantial value our society already places The company pointed to data from the Spark is transferring the enhanced on sight,” he said. National Federation of the Blind, which SPK-9001 manufacturing process to Spark said it would not reveal the price shows 70% of working age Americans who Pfizer, which will use the process in the of Luxturna ahead of FDA approval, which are blind are unemployed despite federal Phase III clinical trial that it is responsible is anticipated in the days or weeks ahead. and state annual rehabilitation expenditures for running. FDA’s Cellular, Tissue and Gene Therapies of over $250m. Published online 7 November 2017 scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 11 DEALS

Valeant Returns $1bn Female Libido Drug For Free KEVIN GROGAN [email protected]

ust over two years after buying Sprout Pharmaceuticals Inc. the benefits of the company dumping Addyi. First up, the aforemen- and its controversial female sexual dysfunction drug Addyi tioned lawsuit has been dropped and the sale also means Valeant J(flibanserin) for $1bn, Valeant Pharmaceuticals International will be released from obligations of the original transaction to split Inc. has decided the deal was indeed a dud and is giving the pill back future profits with the former shareholders, or cover certain market- to the previous owners for next to nothing. ing and other expenditures. Getting rid of Addyi is the latest move by Valeant to rebuild its business following the turbulent times it suffered during the tenure of previous chief executive Michael Pearson. The com- pany had been embroiled in scandals about its high drug prices, including a questionable relationship with the specialty phar- macy Philidor Rx Services and accounting procedures that led to legal and regulatory investigations. (Also see “Valeant: Another Fine Mess” Scrip, 2 Mar, 2016.) The present management, led by CEO Joseph Papa, has been sell- ing off assets to ease the more than $30bn debt burden they were left with by the previous bosses’ acquisition sprees. Earlier this year, L’Oreal SA paid Valeant $1.3bn in cash for three skincare brands - CeraVe, AcneFree and AMBI – while the Dendreon Corp. unit was sold to closely-held Chinese conglomerate Sanpower Group Co. for about $820m. (Also see “Valeant On Track With Debt-Reduction Goals, But Will It Be Enough?” Scrip, 9 May, 2017.) Shutterstock: Sim Creative Art Creative Sim Shutterstock: Last month, Valeant completed the sale of iNova Pharmaceu- ticals Pty. Ltd. to a company jointly owned by funds managed by The Canadian drugmaker has decided to cut its considerable Pacific Equity Partners and The Carlyle Group for $930m in cash. It is losses and sell the subsidiary and Addyi to “a buyer affiliated with also in the process of selling its Obagi Medical Products Inc. subsid- former shareholders of Sprout” in exchange for a 6% royalty on iary to Haitong International Zhonghua Finance Acquisition Fund for global sales of the drug. In addition to not receiving any cash, Va- $190m in cash. (Also see “Deal Watch: Valeant Continues Divestment leant is actually providing a $25m loan to fund the buyer’s initial Spree By Selling Obagi At A Loss” Scrip, 25 Jul, 2017.) operating expenses. Sprout acquired flibanserin fromBoehringer Ingelheim BETTER-THAN-EXPECTED EARNINGS IN Q3 GMBH in 2011 after it had been rejected by the US Food and Indeed it seems that Valeant’s fortunes have taken a turn for the bet- Drug Administration the year before. Despite being resubmitted ter and on Nov.7, the company unveiled better-than-expected earn- in June 2013 with additional safety and efficacy data, the agency ings for the third quarter. issued another complete response letter five months later, citing Net income was $1.30bn compared with a loss of $1.22bn for the side effects. like, year-earlier period, although that included a tax benefit of about The drug, a multifunctional serotonin agonist and antagonist, was $1.4bn. Revenues fell 10.5% to $2.22bn. resubmitted yet again by Sprout which claimed that in three Phase III Valeant said in a statement that it had reduced total debt by trials of premenopausal women with a mean age of 36 years, fliban- about $6bn since the end of the first quarter of 2016, reducing the serin demonstrated a statistically significant difference compared total to around $27bn. Papa claimed, “Valeant is a very different with placebo on three primary endpoints – an increase of sexual de- company today than it was a year ago. Under a new management sire, a decrease in distress from the loss of desire and an increase in team, we have strengthened our balance sheet and stabilized the the frequency of satisfying sex. Despite concerns from its own staff- company by simplifying our business and allocating resources ers about safety and efficacy, the FDA stunned many observers by more efficiently. We realize there is more progress to be made, and approving Addyi in August 2015 and two days later Valeant acquired we will continue to hold ourselves accountable for delivering on Sprout. (Also see “Valeant Buyout Brings Marketing Clout To Sprout our commitments.” And Addyi” Scrip, 20 Aug, 2015.) There were a number of bright spots in the financials, nota- However, the once-a-day pill had hardly any commercial impact, bly from the Bausch + Lomb eye care business, which inched up with payers baulking at a price tag in the region of $800 for 30 tab- 1% to $1.25bn, and its Salix Pharmaceuticals unit, driven by the lets and things turned sour very quickly. Sprout’s founders, Cindy and irritable bowel syndrome drug Xifaxan (rifaximin). Valeant main- Bob Whitehead, took Valeant to court in November 2016, accusing tained its forecast for full-year adjusted earnings before interest, the firm of a botched launch. taxes, depreciation, and amortization of $3.60-$3.75bn, despite While the whole episode looks at first glance as a complete disas- its asset divestitures. ter for Valeant, its shares rose on the news of the sale as investors saw Published online 7 November 2017

12 | Scrip | 17 November 2017 © Informa UK Ltd 2017 DEALS

Dermira Ends UCB Cimzia Psoriasis Pact To Focus On Its Own Pipeline STEN STOVALL [email protected]

ermira Inc. is ending its partnership with UCB SA develop- commitment to helping successfully develop Cimzia in psoriasis and ing the Belgian company’s biologic Cimzia (certolizumab for a fruitful partnership over the past three years. UCB has a strong Dpegol) in the US, EU and Canada for the treatment of psoria- expertise in auto-immune disorders and psoriasis is an indication we sis to fully focus on its own dermatological assets, two of which are are aiming to add to our portfolio.” in pivotal Phase III trials. The US dermatology specialist pharma said its immediate focus ‍Dermira in-licensed Cimzia, a marketed rheumatoid arthritis drug, will now be a smooth and successful launch of DRM04 for treating from UCB in 2014 which Dermira has been developing for plaque excessive underarm sweating, or primary axillary hyperhidrosis, the psoriasis, an increasingly crowded market. Earlier this year, UCB sub- NDA submission for which has now been accepted by the FDA. The mitted a supplemental Biologics License Application to FDA and a PDUFA target date for the completion of a review of the New Drug regulatory filing to the European Medicines Agency to expand Cim- Application is June 30, 2018, Wiggans said. zia’s label to include moderate-to-severe chronic plaque psoriasis. As this date falls on a weekend, the PDUFA decision is likely to be Dermira has meanwhile been progressing its dermatology port- announced the Friday before – June 29. BioMedTracker rates the like- folio, notably its lead product, glycopyrronium tosylate, or DRM04, lihood of DRM04’s approval as a topical therapy for use in adult and which has completed clinical trials as a topical, once daily treatment adolescent patients suffering from primary axillary hyperhidrosis as for excessive underarm sweating (primary axillary hyperhidrosis) and 99% certain. The company said some 15 million people suffer from is under FDA review. hyperhidrosis in the US. Its other Phase III product, olumacostat glasaretil, or DRM01, is in Dermira, which is headquartered in Menlo Park, California, is also two pivotal trials and an open label long-term study, with topline developing an interleukin-13 inhibitor called lebrikizumab for the results on topical treatment of moderate-to-severe acne vulgaris ex- treatment of moderate-to-severe atopic dermatitis. pected in the first half of 2018. DERMIRA’S THREE KEY THERAPIES Dermira’s management said it had to make a choice between pro- “We believe that our therapies for hyperhidrosis, acne and atopic der- gressing its own pipeline demands and those for Cimzia, and UCB’s matitis are among the most exciting opportunities in dermatology drug lost. and that is where our focus should be as we enter a critical year of data “When we three years ago laid out the development timelines for readouts, clinical trial execution and launch preparation,” Wiggans said. DRM04 and Cimzia, both of those product approvals had landed on Top-line readouts are expected in the first quarter of 2018 for DRM01 the same place on the calendar. At the time, it was easy to say that in Phase III trialing as treatment of acne vulgaris. That same quarter will no product development program goes as you think it will. But noth- see initiation of a Phase IIb dose-ranging study of lebrikizumab for the ing did change,” Dermira CEO Tom Wiggans told an analyst call when treatment of moderate-to-severe atopic dermatitis, a therapy area that explaining the decision. is forecasted to become a multi-billion-dollar drug category. “Now, both of those approvals could very well occur close to- In August, Dermira signed a licensing deal with Roche to gain gether and when we looked at our ability to launch two products worldwide rights to develop and commercialize lebrikizumab in all effectively our determination was that the pipeline and priorities that indications outside of interstitial lung diseases such as idiopathic pul- we currently have with those three programs really takes precedent,” monary fibrosis. to find the optimal dose to move into Phase III trials. Tom Wiggans said. Dermira will therefore initiate a Phase IIb dose-ranging study test- “The opportunity from DRM04 needed to be maximized. It wasn’t ing lebrikizumab in adult patients with moderate-to-severe atopic an easy decision, but we think it was the right one,” he added. The dermatitis in the first quarter of 2018 to find the optimal dose to Cimzia partnership will therefore end Feb. 15, 2018. move into Phase III trials. Roche has already demonstrated proof of concept for the drug in atopic dermatitis in a Phase II study, TREBLE, NO PENALTIES that enrolled 209 patients. Dermira has cited market research fore- Dermira and UCB in a joint statement said no termination or penalty casting the atopic dermatitis drug market will reach $6bn in 2022. payments will be required by either party. In consideration for the “We’re very excited about lebrikizumab. The opportunity to in- repurchase of all product rights, licenses and intellectual property crease efficacy via dose or dosing schedule represent significant op- relating to Cimzia, UCB will pay to Dermira $11m by Nov. 13 and an portunities, particularly with regards to the IL-13 target. That’s why additional $39m upon approval of Cimzia in psoriasis in the US. Der- we’re doing the trials,” Wiggans said on the analyst call. mira for its part will reimburse UCB for up to $10m of development Meanwhile the atopic dermatitis drug market continues to heat up. costs incurred by UCB in connection with development of Cimzia. Regeneron Pharmaceuticals Inc. and partner Sanofi launched UCB said it remains committed to the worldwide development and the first biologic treatment for atopic dermatitis earlier this year,Du - commercialization of Cimzia. pixent (dupilumab), an IL-4 receptor antagonist that works through a Emmanuel Caeymaex, UCB’s head of immunology said in a state- different mechanism of action than lebrikizumab. ment that the Belgian group “would like to thank Dermira for their Published online 8 November 2017

scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 13 EMERGING COMPANY PROFILE Scrip Awards Forendo Pharma: Tackling The Endometriosis Challenge Finalists 2017 www.scripawards.com ELEANOR MALONE [email protected]

he CEO of a Finnish firm focused diol rather than eliminating estradiol has been the diagnosis of endometriosis. Best Technological Development in IQVIA’s Clinical Advance on developing a drug for endome- challenging, Lammintausta admits. There are DotLab’s Chief Medical Officer Hugh Clinical Trials – Sponsor-focused of the Year Award T triosis believes that treatment of 14 enzymes in the HSD17beta family and Taylor chairs the Department of Obstetrics, the disease may be “on the verge of fairly closely related family members have different Gynecology and Reproductive Sciences This award recognizes the vital importance of using the This award seeks to recognize success in a clinical trial significant change” thanks to advances in roles in steroid metabolism, he noted. And at Yale School of Medicine. Taylor also is most sophisticated platforms to catalyze and optimize of a new drug product that is expected to lead to an diagnostic technology and the results of his even after finding small molecule inhibitors of a member of Forendo’s scientific advisory clinical trial performance for products focused on advance in healthcare. company’s research and development. the relevant enzyme, the company has strug- board, although DotLab and Forendo have helping sponsors. Endometriosis is estimated to affect around gled with species specificity of the enzyme. no formal business partnership. Amgen and Novartis’ STRIVE study of erenumab Algorics’ Acuity analytics platform 10% of women of reproductive age, but there “We expect in a couple of years that there in migraine is a large unmet need for effective therapy. PHASE I ON HORIZON will be a lab test that can confirm a diag- Acuity is a regulatory-compliant, cloud-based clinical data analytics In the multinational, double-blind, placebo-controlled STRIVE trial in Furthermore, many sufferers wait years for Nevertheless, Forendo now has an HSD17B1 nosis of endometriosis as early as the first platform designed for the clinical research industry. Users can mine adults with episodic migraine, erenumab, a fully human monoclonal a diagnosis and there is no simple test; the candidate that is scheduled to progress into symptoms,” Lammintausta told Scrip. “That retrospective events, monitor real-time activity and predict future antibody targeting the calcitonin gene-related peptide, significantly clinical trial performance. They are able to make sense of clinical data lessened migraine frequency and use of migraine-specific medications, first-in-human studies in the first quarter of current gold standard requires a biopsy via would enable a shift in endometriosis drug from multiple siloed sources allowing them to focus on improved reducing migraine’s impact on physical impairment and everyday laparoscopy. But Risto Lammintausta, CEO 2018. The company hopes to begin study- therapy to a much earlier phase of the dis- quality and make informed decisions. activities. The study formed the basis for EU and US filings. of Turku-based Forendo Pharma Ltd., told ing the compound in patients in early 2019 ease, which is very different to later stages.” Centrexion Therapeutics’ TRIUMPH study of CNTX- Scrip that recent progress in understanding if the trial in healthy women proves success- Still, while the availability of such a non- ERT’s Centralized Clinical Trial Management Solution 4975 in osteoarthritis knee pain of the distribution of hormones in different ful. Meanwhile, it is doing early discovery invasive diagnostic would help reach more ERT’s Centralized Clinical Trial Management Solution harmonizes The results from Centrexion Therapeutics’ Phase IIb TRIUMPH study tissues provide the rationale for Forendo’s tar- work on another novel target. early-stage patients than is possible today, the people, processes and technologies across a trial’s multiple are the largest and most robust clinically relevant reductions in knee geted approach to endometriosis. Forendo hopes the target specificity of its Lammintausta believes that Forendo’s suc- service providers, information silos and data sources. The advanced joint pain that have been seen in any similar clinical trial to date. “Previously we lived in the ‘endocrine era’ product will mean it is suitable for chronic cess will not be dependent on the availability solution helps sponsors and CROs achieve a new level of day-to-day They show that CNTX-4975, the company’s lead candidate, has the – the thinking was that the body produced use, enabling a more effective long-term of such a tool, since even today treatment is trial management efficiency across study teams with near real-time potential to provide a truly novel non-opioid, non-addictive, non- visibility into performance and risk indicators. steroid and non-surgical approach to osteoarthritis pain relief. estrogen and distributed it evenly through- management of symptoms versus available started based on suspected endometriosis, out the body,” Lammintausta said. “Now ‘in- therapies, which include gonadotropin- without a confirmed laparoscopic diagnosis. Eli Lilly’s EVOLVE-1 and 2, and REGAIN studies of goBalto’s goBalto Select tracrinology’ is the new concept, in which releasing agonists that block estrogen syn- galcanezumab in migraine many organs are understood to locally form thesis and treat the lesions, but can only be PARTNERING HOPES goBalto’s Select mitigates risk factors for clinical trial recruitment Lilly’s galcanezumab, a once-monthly monoclonal antibody product significant levels of active hormone, which used for a few months at a time because of As for the longer term vision, Lammintausta by finding the optimum alignment for top-performing sites with against calcitonin gene-related peptide, which is believed to play a role substantial patient databases and quickly assessing which sites have in migraine and cluster headache, met its primary endpoint in these are much higher than circulating levels. In unwanted side effects, including osteoporo- recognizes that it would be tough for Foren- performed best in similar studies. Customers have been able to cut up three Phase III studies, demonstrating significant reductions in the fact, it has now been found that endometri- sis, menopausal symptoms and disruption of do to take its product all the way to market to 30% of the time required to activate sites, translating into millions number of monthly migraine headache days compared with placebo. otic lesions have continuously high levels of the menstrual cycle. on its own. “For this kind of large, global of dollars in savings. The product has been filed for US approval. estradiol leading to a continuously prolifera- patient group we are expecting to partner Genmab and Janssen Biotech’s CASTOR and POLLUX tive inflammatory situation, which is not de- EARLY INTERVENTION TARGETED with a big pharma company with lots of re- Medidata’s Medidata Synthetic Control Arm studies of daratumumab in multiple myeloma pendent on the menstrual cycle.” The local Forendo’s candidate also aims to treat sources and experience in women’s health,” formation of estrogen in those lesions is key early lesions and the associated inflamma- he said. “We are aiming to demonstrate clini- Medidata’s Synthetic Control Arm pulls actual data from past Daratumumab, a first-in-class human monoclonal antibody that studies to create well-matched controls arms. With its database of targets CD38, met its primary endpoint of improving progression- to the progression of the disease, he noted. tory pain, as opposed to the harder to treat, cal proof of efficacy and safety ourselves.” patient data from around 3,500 studies, SCA offers the possibility of free survival in these two Phase III trials testing it in combination Whereas endometriosis is treated now centrally mediated chronic pain syndrome Forendo developed its discovery and exploratory subgroup analysis, improves compound selection and the with bortezomib and dexamethasone, or lenalidomide plus with systemic hormone therapies, Forendo is associated with more advanced stages of screening technology in-house and has design of subsequent trials, and can reduce failure rates in Phase II dexamethasone, in relapsed or refractory multiple myeloma. The targeting an enzyme responsible for convert- the disease, when lesions have spread and worked in collaboration with the University and III studies. results paved the way for expanded approvals in an earlier use setting. ing low-active estrone precursor to highly become bigger. of Turku, which has a significant endome- Immunocore’s Phase I study of IMCgp100 in myClin’s myClin Clinical Trial Knowledge Platform active estradiol locally in the endometriotic “Early diagnosis is key,” emphasized Lam- triosis study group that has made important malignant melanoma lesions. In primates, the company has been mintausta. “If the disease is identified early, findings on the local formation of estradiol myClin is the first clinical trial knowledge platform, an innovative This Phase I study represents the first compelling evidence of single able to effectively treat and practically elimi- the inflammatory pain can be treated very and demonstrated the expression of the en- collaboration channel for clinical trial sites, sponsors and CROs. myClin agent efficacy in a solid, ‘cold’, low-mutation tumor. It showed a nate the lesions by inhibiting the enzyme, effectively and this has a big impact in the zyme target; two of the team’s scientists are lets clinical study teams collaborate and communicate – accessing significant survival benefit with IMCgp100 in patients with uveal training, distributing essential documents and tracking study melanoma, with a 73% survival rate at one year, compared with without having an effect on the systemic es- long run.” co-founders. milestones in a central, secure and private environment – to forge a typical rates of 20-45%. Immunocore continues to see prolonged trogen/progesterone balance and the men- Although there are no laboratory tests yet Forendo has about €9m remaining to closer team between sites. responses in both uveal and cutaneous melanoma. strual cycle. “This is really unique: for the first in clinical use, the CEO highlighted work be- draw down from a €12m funding round in Kite Pharma’s ZUMA-1 study of axicabtagene time we have a therapeutic target that is local ing done to develop a non-invasive test by 2014, which will take it through 2018. 4G Clinical’s Prancer ciloleucel in non-Hodgkin’s lymphoma to the lesions that would give the opportu- San Francisco firm DotLab, which recently “We are now looking to take one or two 4G Clinical’s fourth-generation randomization and trial supply Kite is helping to change the paradigm of cancer treatment with presented its prospective case control study nity for long-term treatment without signifi- investors on board early next year to expand management technology, Prancer, was developed using an agile the ZUMA-1 Phase II trial. This first multicenter pivotal trial in CAR-T cant systemic effects, which are considered of women undergoing laparoscopy or lapa- the program and develop a new compound software methodology and is the only 100% configurable and flexible therapy in aggressive non-Hodgkin’s lymphoma formed the basis to be side effects, as seen in earlier therapies rotomy for benign gynecologic indications for a different target,” the CEO said. It likely software solution using natural language processing and integrated for its recent US FDA approval. It showed axicabtagene ciloleucel that eliminate estrogen formation.” at the American Society of Reproductive will look for less than €10m, he added. supply forecasting. Prancer has transformed the process for designing (Yescarta) met its primary endpoint, with an impressive objective clinical systems, removing the burden from clinical study professionals. response rate of 82%, including 54% complete responses. Finding a very specific inhibitor to target Medicine Congress. The results demonstrat- Published online 9 November 2017 only the local conversion of estrone to estra- ed the value of its microRNA biomarkers in From the editors of Start-Up Headline Sponsor Social Media Sponsor

14 | Scrip | 17 November 2017 © Informa UK Ltd 2017

JN000 SCRIP Awards 2017 Preview Ad G 13-11.indd 1 2017/11/13 1:33 PM ScripHEADLINE NEWS Awards Finalists 2017 www.scripawards.com

Best Technological Development in IQVIA’s Clinical Advance Clinical Trials – Sponsor-focused of the Year Award

This award recognizes the vital importance of using the This award seeks to recognize success in a clinical trial most sophisticated platforms to catalyze and optimize of a new drug product that is expected to lead to an clinical trial performance for products focused on advance in healthcare. helping sponsors. Amgen and Novartis’ STRIVE study of erenumab Algorics’ Acuity analytics platform in migraine Acuity is a regulatory-compliant, cloud-based clinical data analytics In the multinational, double-blind, placebo-controlled STRIVE trial in platform designed for the clinical research industry. Users can mine adults with episodic migraine, erenumab, a fully human monoclonal retrospective events, monitor real-time activity and predict future antibody targeting the calcitonin gene-related peptide, significantly clinical trial performance. They are able to make sense of clinical data lessened migraine frequency and use of migraine-specific medications, from multiple siloed sources allowing them to focus on improved reducing migraine’s impact on physical impairment and everyday quality and make informed decisions. activities. The study formed the basis for EU and US filings. Centrexion Therapeutics’ TRIUMPH study of CNTX- ERT’s Centralized Clinical Trial Management Solution 4975 in osteoarthritis knee pain ERT’s Centralized Clinical Trial Management Solution harmonizes The results from Centrexion Therapeutics’ Phase IIb TRIUMPH study the people, processes and technologies across a trial’s multiple are the largest and most robust clinically relevant reductions in knee service providers, information silos and data sources. The advanced joint pain that have been seen in any similar clinical trial to date. solution helps sponsors and CROs achieve a new level of day-to-day They show that CNTX-4975, the company’s lead candidate, has the trial management efficiency across study teams with near real-time potential to provide a truly novel non-opioid, non-addictive, non- visibility into performance and risk indicators. steroid and non-surgical approach to osteoarthritis pain relief. Eli Lilly’s EVOLVE-1 and 2, and REGAIN studies of goBalto’s goBalto Select galcanezumab in migraine goBalto’s Select mitigates risk factors for clinical trial recruitment Lilly’s galcanezumab, a once-monthly monoclonal antibody product by finding the optimum alignment for top-performing sites with against calcitonin gene-related peptide, which is believed to play a role substantial patient databases and quickly assessing which sites have in migraine and cluster headache, met its primary endpoint in these performed best in similar studies. Customers have been able to cut up three Phase III studies, demonstrating significant reductions in the to 30% of the time required to activate sites, translating into millions number of monthly migraine headache days compared with placebo. of dollars in savings. The product has been filed for US approval. Genmab and Janssen Biotech’s CASTOR and POLLUX Medidata’s Medidata Synthetic Control Arm studies of daratumumab in multiple myeloma Medidata’s Synthetic Control Arm pulls actual data from past Daratumumab, a first-in-class human monoclonal antibody that studies to create well-matched controls arms. With its database of targets CD38, met its primary endpoint of improving progression- patient data from around 3,500 studies, SCA offers the possibility of free survival in these two Phase III trials testing it in combination exploratory subgroup analysis, improves compound selection and the with bortezomib and dexamethasone, or lenalidomide plus design of subsequent trials, and can reduce failure rates in Phase II dexamethasone, in relapsed or refractory multiple myeloma. The and III studies. results paved the way for expanded approvals in an earlier use setting. Immunocore’s Phase I study of IMCgp100 in myClin’s myClin Clinical Trial Knowledge Platform malignant melanoma myClin is the first clinical trial knowledge platform, an innovative This Phase I study represents the first compelling evidence of single collaboration channel for clinical trial sites, sponsors and CROs. myClin agent efficacy in a solid, ‘cold’, low-mutation tumor. It showed a lets clinical study teams collaborate and communicate – accessing significant survival benefit with IMCgp100 in patients with uveal training, distributing essential documents and tracking study melanoma, with a 73% survival rate at one year, compared with milestones in a central, secure and private environment – to forge a typical rates of 20-45%. Immunocore continues to see prolonged closer team between sites. responses in both uveal and cutaneous melanoma. Kite Pharma’s ZUMA-1 study of axicabtagene 4G Clinical’s Prancer ciloleucel in non-Hodgkin’s lymphoma 4G Clinical’s fourth-generation randomization and trial supply Kite is helping to change the paradigm of cancer treatment with management technology, Prancer, was developed using an agile the ZUMA-1 Phase II trial. This first multicenter pivotal trial in CAR-T software methodology and is the only 100% configurable and flexible therapy in aggressive non-Hodgkin’s lymphoma formed the basis software solution using natural language processing and integrated for its recent US FDA approval. It showed axicabtagene ciloleucel supply forecasting. Prancer has transformed the process for designing (Yescarta) met its primary endpoint, with an impressive objective clinical systems, removing the burden from clinical study professionals. response rate of 82%, including 54% complete responses.

Headline Sponsor Social Media Sponsor

scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 15

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JAK Safety Shown Across Multiple Trials MANDY JACKSON [email protected]

he highlights of the recent American College of Rheumatol- colitis. The pooled analysis included 5,432 patients in two cohorts – ogy (ACR)/Association of Rheumatology Health Professionals a placebo-controlled cohort for studies in which Xeljanz was com- T (ARHP) annual meeting tended to be data for approved drugs pared with placebo, and a dose-comparison cohort for studies where and therapies in later-stage development that back up previously the drug was compared with placebo, Humira and methotrexate. reported efficacy or provide assurances about safety in rheumatoid The DVT incidence rate for Xeljanz was 0 per 100 patient years in and psoriatic arthritis and other autoimmune diseases. the placebo-controlled cohort for up to three months of treatment; Those kinds of data are important for prescribers and patients, offer- 0.1 in the dose-comparison cohort at up to 24 months of treatment ing points of differentiation in indications with a growing number of in RA; and 0.5 in the dose-comparison cohort for PsA patients treated treatment options. Data of note at the ACR/ARHP meeting included up to 12 months. The PE incidence rate for Pfizer’s drug was 0 in the closer looks at safety for JAK inhibitors, including Pfizer Inc.’s Xeljanz placebo-controlled group. PE incidence rates in the dose-compari- (tofacitinib), Eli Lilly & Co.’s baricitinib and AbbVie Inc.’s upadacitinib. son cohort were 0.1 for Xeljanz 5 mg twice-daily and 0.2 for 10 mg Also, AbbVie continued to make the case for risankizumab with twice-daily in RA patients. Phase II results in psoriatic arthritis (PsA). The interleukin-23 (IL-23) No patients experienced both DVT and PE, and the incidence rates inhibitor and upadacitinib may help offset future revenue declines were consistent with DVT and PE rates reported for Xeljanz-treated when the company’s blockbuster biologic Humira (adalimumab) patients in the Corrona Registry of RA patients – the world’s largest faces biosimilar competition in the US. real-world registry of RA patients. Several biosimilar companies reported results at the ACR/ARHP Jefferies analyst Jeffrey Holford said in a Nov. 8 research note that meeting, held Nov. 4-8 in San Diego, showing that their therapies “event rates for the leading JAKs are all within the background rate were equivalent to the reference products, including Boehringer In- for rheumatoid arthritis patients.” Holford also pointed out that there gelheim GMBH with its approved – but not yet marketed – Humira were no additional PE or DVT events reported at the ACR/ARHP biosimilar Cyltezo (adalimumab-adbm). meeting for AbbVie’s Phase III JAK inhibitor upadacitinib, which is se- Additionally, companies with well-established products, including lective for JAK1. the Roche company Genentech Inc. and Bristol-Myers Squibb Some doubt has been placed on that drug’s prospects because Co., revealed data in new and approved uses, while Merck KGAA of some PE cases, including a death, disclosed in one of the two presented results for a new mechanism of action in osteoarthritis. Phase III studies that have been released to date. However, there are still four more Phase III studies with data expected over the next CARDIOVASCULAR RISK OF JAK INHIBITORS few months that will shed more light on upadacitinib’s safety – and Janus kinase (JAK) inhibitors provided RA patients with the first whether the drug provides the best-in-class efficacy touted by the effective oral drug in many years with a novel mechanism of ac- company’s executives. tion, so of course many companies have developed JAK inhibitors “We await additional [Phase] III readouts from the SELECT program for the disease. But even with Pfizer’s Xeljanz on the market for through 2018 (COMPARE, EARLY, MONOTHERAPY) and estimate peak five years and with three more in Phase III, there are still a lot of sales of $3bn for upadacitinib in RA,” Holford said. question about safety – especially cardiovascular safety, as Lilly AbbVie plans to seek FDA approval for its drug in 2018 and launch and AbbVie can attest. it in the US in 2019. Lilly’s NDA to the US FDA for baricitinib, a JAK1/2 inhibitor that is being developed with Incyte Corp., was rejected earlier this year ABBVIE’S RISANKIZUMAB when the agency requested more data on cardiovascular events. Lilly AbbVie’s other high-profile late-stage immunology program is the now plans to resubmit the application by the end of January, starting IL-23 inhibitor risankizumab, which recently showed positive efficacy a six-month clock for the FDA to complete its review, with data show- in psoriasis across three Phase III trials. ing the rates of deep vein thrombosis (DVT) and pulmonary embo- Phase II results in PsA were presented for the first time at the ACR/ lism (PE) are no different from the general population of RA patients. ARHP meeting, showing positive efficacy versus placebo at 16 weeks At the ACR/ARHP meeting, Lilly reported a greater effect on pain for for all four dosing regimens tested: 150 mg every four weeks (arm 1), RA patients with baricitinib compared to both Humira and placebo. 150 mg at baseline and at weeks 4 and 16 (arm 2), 150 mg at baseline Also, a pooled analysis of eight Phase I, II and III studies and an ongo- and week 12 (arm 3), and a single 75 mg dose at baseline (arm 4). ing extension study showed that cardiovascular incidence rates among The percentage of patients who achieved ACR 20 was 57.1% in 3,492 patients treated for at least one year as of Sept. 1, 2016, were con- arm 1 (p<0.05), 61.9% in arm 2 (p<0.01), 59% in arm 3 (p<0.05), sistent with published incidence rates for the general RA patient popu- 65% in arm 4 (p<0.05) and 35.7% for placebo (arm 5). Biomed- lation. There were 0.51 major cardiovascular events (MACE) per 100 pa- tracker noted that the positive results across dosing schedules tient years and 0.46 DVT/PE events per 100 patient years versus DVT/ support initiation of a Phase III program in PsA, which is expected PE rates of 0.29 to 0.79 per 100 patient years for RA patients in general. in 2018. The Informa Pharma Intelligence service raised its likeli- Thromboembolic event rates for Xeljanz, which preferentially hood of FDA approval for risankizumab by 2% to 22%, which is inhibits JAK1 and JAK3, were presented at the ACR/ARHP meeting 2% above average for mid-stage drugs in similar indications. “Ri- across Phase II and III clinical trials in RA, PsA, psoriasis and ulcerative sankizumab was something where we saw amazing Phase II data

16 | Scrip | 17 November 2017 © Informa UK Ltd 2017 ACR ROUNDUP

[in psoriasis from Boehringer Ingelheim],” AbbVie Vice President- in August. That approval came in conjunction with an FDA nod for Therapeutic Areas and International Development Shao-Lee Lin Novartis AG’s CAR-T therapy Kymriah (tisagenlecleucel) in pediatric said in an interview with Scrip at the ACR/ARHP meeting. “We acute lymphoblastic leukemia (ALL). courted them and there was a mutual desire to partner with us to William Reiss, associate group medical science director for rheu- try to get the most out of that molecule.” matology and inflammatory bowel diseases in US Medical Affairs at Lin said the IL-23 inhibitor “fit very nicely in the core experience Genentech, told Scrip it’s “extremely rewarding” to see therapies first we have” in rheumatic diseases, inflammatory bowel disease (Crohn’s approved for a large autoimmune indication – RA for Rituxan in 2006 disease and ulcerative colitis) and skin disease via the marketing of and for Actemra in 2010 – now approved in smaller diseases with Humira across several inflammatory and autoimmune conditions. few treatment options. “These are not very large indications, but they “The Phase II data were outstanding; it has the potential to not just have high unmet need,” he noted. be best-in-class, but the best therapeutic for skin disease,” she said. Actemra recently completed enrollment in a Phase III study test- ing the biologic in systemic sclerosis. The CD20-targeting therapy BI’S CYLTEZO EQUIVALENT TO HUMIRA Rituxan is in Phase III for pemphigus vulgaris, an indication for which Among many presentations of data for biosimilars of blockbuster bi- the FDA has granted a breakthrough therapy designation; Actemra ologics in rheumatoid arthritis during the ACR/ARHP meeting, Boeh- has a breakthrough designation in systemic sclerosis. ringer Ingelheim presented data for its Humira biosimilar Cyltezo Genentech had the first-ever breakthrough therapy designated- that showed no clinically meaningful differences in efficacy, safety drug to get FDA approval in 2013 with the company’s follow-on and immunogenicity of the two products. Results from the Phase III CD20-targeting product Gazyva (obinutuzumab) for chronic lym- VOLTAIRE-RA trial previously were reported at the Annual European phocytic leukemia. That product’s now in Phase II for lupus nephritis. Congress of Rheumatology (EULAR) in June. As for additional indications in autoimmune diseases, Reiss said, “the Cyltezo obtained FDA approval in August but has not launched, full development plan hasn’t been finalized. The lupus trial will in- since AbbVie’s Humira patents have not expired and the companies form where else we go.” are engaged in patent litigation. Amgen Inc. was the first company Also, the Bruton’s tyrosine kinase (BTK) inhibitor GDC-0853 is in to settle with AbbVie over a Humira biosimilar, pushing Amgen’s US Phase II for systemic lupus erythematosus (SLE). The BTK inhibitor is launch for Amjevita to 2023. designed to block B cell proliferation and the resulting excessive im- A recurring theme throughout the ACR/AHRP conference, how- mune response that is seen in autoimmune disorders, such as SLE. ever, was physicians’ skepticism about biosimilars. Rheumatologists scrutinized the biosimilarity of reference drugs and competitors’ cop- BRISTOL HIGHLIGHTS ORENCIA’S FAVORABLE COST ies whenever such data were presented. Bristol-Myers Squibb has multiple compounds with novel mecha- The debate may mean that Pfizer’s difficulty in sellingInflectra nisms for autoimmune diseases in early stages of development, (infliximab-dyyb) goes beyond the competitive pricing and reim- including personalized medicine approaches, Vice President and bursement agreements that Johnson & Johnson has negotiated Orencia (abatacept) Development Lead Brian Gavin told Scrip. The with payers to favorably position its originator product Remicade (in- company presented Phase I results in healthy volunteers for its Bru- fliximab) ahead of biosimilars. ton’s tyrosine kinase (BTK) inhibitor BMS-986195 at the ACR/ARHP In a Nov. 6 presentation on how biosimilars are changing the land- meeting, but most of the Bristol presentations at the conference scape, Jonathan Kay, a University of Massachusetts Medical School were for its T-cell co-stimulation modulator Orencia. professor and rheumatologist at UMass Memorial Healthcare, noted The data included a look at the cost-per-response to treatment that since the FDA hasn’t approved any biosimilars as interchangeable with Orencia versus Humira in erosive early RA. Across almost all with their reference products, states aren’t enforcing their laws that clinical measures of efficacy, Orencia had a lower cost-per-response favor the use of biosimilars. Those state laws require the use of inter- than Humira in a post-hoc analysis of 2,000 patients treated in the US, changeable biosimilars. Doctors in that and other presentations on Germany, Spain and Canada. The per-response cost was favorable for Nov. 6 and 7 seemed reluctant to use biosimilars without some kind Orencia about as often as the costs favored Humira in patients with of guarantee that the competing copies are the same as the drugs non-erosive early RA. that they’ve been prescribing for a decade or more. More than one speaker, when asked what doctors should do, said they would not A NEW KNEE INJECTION FROM MERCK KGAA switch a patient from a biologic that’s working for them to a biosimilar, Merck KGaA presented two-year results from the ongoing five-year implying that biosimilars may be reserved for new prescriptions rath- Phase II FORWARD clinical trial for sprifermin in 549 patients with er than for patients already using a brand-name antibody therapeutic. knee osteoarthritis (OA), showing an increase in cartilage thickness. The trial met its primary endpoint with the intra-articular injection ROCHE/GENENTECH EXPANDS REACH providing statistically significant increases from baseline in total fem- Genentech had multiple presentations at the meeting for Actemra (to- orotibial joint cartilage thickness. cilizumab) and Rituxan (rituximab) in the therapies’ approved and in- “These are very good results for sprifermin, although it remains vestigational indications, including RA and Takayasu arteritis for the IL-6 to be seen if the cartilage improvements lead to benefits by clinical inhibitor Actemra and ANCA-associated vasculitis and RA for Rituxan. measures. The company has not disclosed plans for a pivotal study, Actemra’s most recent FDA approvals were for giant cell arteritis in but one should be announced soon for either OA or general carti- May and for cytokine-release syndrome (CRS) experienced by can- lage repair,” Biomedtracker’s Nov. 6 analysis states. cer patients treated with chimeric antigen receptor T-cell therapies Published online 10 November 2017 scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 17 INTERVIEW March 19-20, 2018 Asia Grand Hyatt Roppongi CNS Refresh: Boehringer’s New Approach To Tricky International Conference Tokyo, Japan Neuropsychiatry Diseases LUCIE ELLIS [email protected]

Indications like Alzheimer’s disease, de- neuropsychiatry drug development. Firstly, pression and schizophrenia have largely he cited the high unmet need in its target been treated in the past as distinct physi- disease areas. “Alzheimer’s disease, schizo- ological pathologies. This has resulted in ap- phrenia, major depression and a lot of con- ACCELERATE YOUR PATHWAY proaches that are partly successful but that ditions associated with impulsivity… in all of also leave a large proportion of patients un- these indications we see vast unmet medi- treated. “Our approach is not to treat the dis- cal need. This is of course reason not to step TO PARTNERSHIPS IN ASIA ease as a syndrome in its entirety but rather out of the area and leave patients behind to focus on specific malfunctioning circuits and untreated.” involved and the symptoms related to these Secondly, Mendla said Boehringer was malfunctions,” Mendla said. enthusiastic about taking a fresh look at For example, a lot of research in Alzheim- these indications because of the tremen- er’s disease has focused on removing dous increase in the understanding of how beta amyloid or preventing it from being neuro-circuits drive certain symptoms. “This formed. However, this kind of approach, link between circuit and symptoms has en- aimed at the disease origin, has produced couraged us to take a novel approach to The BIO Asia International Conference is the best, limited success thus far. Boehringer is more treating these neuropsychiatry disorders,” interested in “the consequences of that he said. neutral partnering forum dedicated to facilitating initial disease cause, the consequence on Boehringer’s pipeline of neuropsychiatry the neuro-circuitry and the neuro-network drugs, which includes preclinical and clinical cross-border discussions of licensing, research Klaus Mendla, function,” Mendla said. “We try and interfere candidates, addresses both cognitive impair- global head, collaborations, and business development business develoment with this area, which may be downstream ment and non-cognitive symptoms like ag- and licensing, CNS of the immediate cause but is more ame- gression. The company does not publish its investments that connect the Japanese biopharma nable to treatment and has very important pipeline, but Mendla said its current assets effects on function for patients.” cover various modes of action. He added that market with international partners. n an exclusive interview with Scrip at the Boehringer’s approach in CNS drug dis- Boehringer has programs targeting cognitive BIO-Europe partnering conference in Ber- covery and development is inspired by impairment in schizophrenia, an indication for Ilin, Nov. 6-8, Klaus Mendla, Boehringer the US National Institute of Mental Health’s which there are no treatments approved. The Ingelheim GMBH’s global head of busi- Research Domain Criteria (RDoC) concept company also has programs in development 370 Attendees 230+ ness development and licensing, CNS, talks – a research framework for new ways of for so-called treatment resistant depression Companies about the private German pharma’s ap- studying mental disorders. It integrates sev- and negative symptoms of schizophrenia. 27 Countries represented proach to neurology drug discovery and eral levels of information (from genomics to Mendla highlighted that in treatment resis- development. self-reporting) to better understand basic tant depression for example, there is a major Central nervous system (CNS) drug de- dimensions of functioning underlying the proportion of patients, up to 50%, who do not velopment has not seen a huge amount of full range of human behavior from normal benefit from current treatments. success in recent years for prevalent diseas- to abnormal. According to Datamonitor Healthcare 1,200+ 40 es that affect millions of people worldwide. Boehringer’s “sweet spot” for partnering analysts, Boehringer’s pipeline includes two BIO One-on-One Spots available Due to the tough, high-risk, nature of thera- is in the early-stages of discovery and de- or more Alzheimer’s programs, including a PartneringTM for companies peutic development for CNS conditions, velopment because its “fresh thinking ap- phosphodiesterase enzyme inhibitor (PDEI to present their many companies have stepped away from proach to targeting CNS disorders requires 9) that is in Phase II; and a potential oral meetings the space. However, Boehringer is boosting new thinking that did not exist years ago,” therapy for Alzheimer’s that appears to tar- business its investment in CNS, particularly within the Mendla noted. “Boehringer Ingelheim is get glycine transporter-1 inhibitor. Glycine area of neuropsychiatry diseases. also very good at turning scientific innova- reuptake inhibitors are thought to target Mendla believes the industry in its drug tion into viable products – you can better a mechanism implicated in schizophrenia R&D has prioritized targeting the root achieve this goal if you partner early.” and dementia, and may play a role in regu- causes of particular diseases like Alzheim- lation of glycine levels in NMDA receptor- er’s disease or schizophrenia over develop- MAJOR UNMET NEED mediated neurotransmission. Informa subscribers receive $200 off the ing highly efficacious and tolerable treat- Boehringer’s business development ex- Datamonitor analysts told Scrip that Biotech/Pharma Company rate. ments for the symptoms that branch from ecutive said there were two main reasons based on current research a PDEI 9 in- these conditions. for the German firm’s increased interest in CONTINUED ON PAGE 20 Use promo code M717040712.

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CONTINUED FROM PAGE 18 of “an entirely novel target not related to nia, which is the inability to feel pleasure hibitor could have positive pro-cognitive/ the traditional antidepressants that we in normally pleasurable activities. Boeh- neuroprotective effects in Alzheimer’s, have in our therapeutic armamentarium ringer’s R&D team is trying to identify with a potential broader symptomatic today.” Hydra is a leader in the field of the underlying anhedonic phenotype in benefit over beta amyloid targeting ther- Transient Receptor Potential (TRP) chan- depressed patients to develop drugs that apies. However, “the only disease-mod- nel modulation; in April 2014, it signed a explicitly tackle this symptom. ifying mechanism with an established worldwide collaboration agreement with “We are learning, from areas like oncology proof-of-concept is provided by anti- Boehringer to jointly discover small-mole- in particular, that we need to identify specif- amyloid monoclonal antibodies, and the cule TRPC4/5 inhibitors for the treatment ic bio-types or sub-types of patients based data here are marginal,” Daniel Chancellor, of central nervous system (CNS) diseases on biomarkers, or other phenotypes, that Datamonitor Healthcare’s lead analyst for and disorders. Boehringer is responsible can be readily assessed,” Mendla said. CNS, said. “The further you remove your- for the global development and com- Using biomarkers for CNS therapies could self from this mechanistically then you’re mercialization of the inhibitors that come allow for more precise treatments for pa- really starting from scratch. Considering from the collaboration. tients, avoiding one-size-fits-all drugs. “In historical failure rates, you can therefore While Boehringer’s head of CNS licensing the future, I think we will see more and more expect likelihood of approval estimates is seeking partners to help the company fill tailored and specific approaches in patients to be extremely low, at least until some gaps in its neuropsychiatry pipeline, he said with conditions like depression or schizo- of the companies involved can build up a the company was focused on deals that phrenia,” Mendla said. body of evidence to the contrary.” can also broaden its foundations for future Boehringer is also focused on bridging development across the broad spectrum of the gap between preclinical and clini- CNS PARTNERING neuropsychiatry disorders. “It is our aim in cal work, as well as better preparation to A high proportion of Boehringer’s early- this field of neuro-circuit links to better un- move Phase I candidates into proof-of- to mid-stage CNS pipeline is based on ac- derstand underlying physiologies of neuro- concept or pivotal trials. “We need more quired or partnered innovation, including psychiatry disorders, to have better insight focus on bridging that gap by develop- collaborations with leading biotech com- to be able to develop specific and tailored ing translational approaches and trying panies and academic institutions in the approaches.” to identify physiological responses based field. “It is our thinking that the vast ma- However, Mendla added that in a certain on the mode of action of a compound,” jority of innovation originates somewhere way the group is disease-agnostic. “We are he noted, adding that Boehringer had else in the world,” Mendla said. “While we not looking at the disease nomenclature, introduced a research stage between have fantastic scientists – and are very rather we are interested in symptoms that Phase I and Phase II that it calls proof-of- proud of our leading, cutting-edge re- might be treated by a tailored therapy. So, clinical-principle. This step aims to identify search ability and capacity – we are still we will look where a single symptom might a physiological response that is linked to very much inspired by innovation in the play a role and where a treatment might both the mode of action of a candidate external environment.” create benefit.” compound and the physiology of the pa- Mendla highlighted Boehringer’s De- Given this agnostic approach, Mendla tient. “We want further confidence that cember 2013 drug discovery deal with was hesitant to name any disease areas we might expect a physiological response in patients rather than going on into big- Circuit Therapeutics Inc., a company re- within the CNS space that Boehringer has ger studies and hoping to see a response searching the connectivity between neuro- less interest in for R&D deals. However, he on a clinical, measured scale.” circuitry and symptoms that may arise from noted that the German drug maker has left As well as the use of biomarkers in CNS malfunctions in the body’s neural systems, the pain field, which he said requires a dif- drug development, Mendla expects to see as an example of its successful, long-term ferent R&D approach to what the company more combination therapies emerge in partnering activity within this space. Circuit is using in neuropsychiatry. “We are open to neuropsychiatry, “where we combine treat- Therapeutics’ key technology, optogenet- all sorts of indications as long as we under- ments for certain symptoms and in con- ics, allows the control of individual nerve stand the neuro-circuitry that might play a junction they might provide even bigger cells and circuits within the brain enabling role in the disease,” he said. benefits to the patients.” their functional identification and charac- Looking to the future, he said: “I hope terization. Under this first three-year part- CNS BIOMARKERS we will achieve a very rich armamentar- nership with Boehringer, the two compa- As an example of Boehringer’s symptom- ium of treatments for a range of symp- nies focused on novel avenues for drug based approach to neuropsychiatry, toms, similar to what we see today in on- discovery within brain disorders. In 2015, Mendla highlighted that the company is cology,” he said. the pair signed a second partnership deal, interested in the development of treat- Published online 13 November 2017 this time in the metabolic space. ments for anhedonia, a symptom in peo- Boehringer is also jointly developing ple suffering from depression. There is no CLICK a novel approach to treating depression specific treatment approved for anhe- Five Themes For and anxiety through a collaboration with donia and patients are generally treated BIO-Europe 2017: Hydra Biosciences Inc. Mendla said this with antidepressants that primarily target http://bit.ly/2yCsiH9 deal was focused on the development the depressed mood rather than anhedo-

20 | Scrip | 17 November 2017 © Informa UK Ltd 2017 OPINION

Mehta Analysis: The Tangled Web Of PBMs VIREN MEHTA [email protected]

any of my friends in the pharma PBMs stepped into a world where pre- the largest pharmacy chains; and United world feel that the evolution scription drug benefits were becoming an Health’s OptumRx, with approximately 60 Mof pharmacy benefit managers integral part of health insurance coverage, million members. Together, these three (PBMs) in the US has led to their operations just as managing a high volume of paper companies process over two-thirds of all and impact becoming increasingly mysteri- based prescription claims before the com- prescriptions dispensed in the US. The ous. While we understand in broad strokes puter-age was overwhelming insurers’ back implications of the rumored CVS merger the role they play, their business model has offices. PBMs initially processed and paid with Aetna, a leading US healthcare in- broadened to the extent it has become these paper claims. However, it did not take surer, as well as CVS servicing Anthem fuzzy – as if by design. long for them to realize the value of claims PBM members’ prescriptions, will be a We all harbor general skepticism to- data they were accumulating, as they began part of our next column. wards middlemen, and question what to develop clinically meaningful insights. At Despite the continuing market concen- actual value they add to the healthcare the same time, their growing scale enabled tration, the FTC in its review of Express system. When it comes to PBMs, views them to extract discounts from pharmaceu- Scripts’ merger with Medco in 2012 found on this question even among friends tical manufacturers on one side, and phar- that in the PBM market “competition for vary wildly. Concerns include the lack of macies on the other, in return for access to accounts is intense, has driven down transparency in the proportion of sav- their members to grow market share. prices, and has resulted in declining PBM ings the PBMs choose to share; bundled profit margins.” contracting that may perpetuate the use It is clear that PBMs do fulfill of expensive branded products at the ex- SHARING NICELY? pense of generics; and the misuse of the their role of helping lower Not surprisingly, the other three key stake- unique middleman position to disadvan- holders in this game – insurers, pharma- tage stakeholders on both sides, perfect- drug costs by extracting cists, and the pharmaceutical industry – do ing the art of moral dilemma to primarily ever larger rebates from the not see the PBM role the same way as the focus on shareholder value, rather than FTC, noting the divergence in invoice price value for all stakeholders. biopharma companies. The growth for branded drugs vs. the estimated At the same time, the PBM segment itself question of whom these net price growth and implying that a large faces increasing uncertainty, with a particu- portion of the rebate benefits accrue direct- lar threat represented by the inroads being rebates benefit is where the ly to the PBM and do not trickle down to the made by newcomers deploying the tools insurer or the patient. of technology, promising to offer benefits debate becomes­ heated However, in one of the settlement litiga- ranging from increased transparency to tions, an expert economist estimated that larger sharing of savings. Potentially disrup- about 90% of the savings that a PBM may tive entry in biopharma distribution by the choose to share (without specifying what likes of Amazon has contributed to valua- During the 1990s there was a move portion the PBMs choose to share) accrue tion collapse of PBM companies, with the by pharma companies to bring PBMs in to their third party payers and pharma- leading pure PBM, Express Scripts, having house, exemplified by Merck & Co’s ac- cists. It is also noteworthy that insurers lost a third of its value since 2015. quisition of Medco and Lilly’s acquisition and pharmacists are mum as to what por- We invite you to share your views as we of PCS. But such diversification proved to tion of their profits come from their share begin the dialog to put this important yet be short-lived amidst antitrust concerns, of the pharma company rebates to the opaque biopharma segment in a balanced conflicts of interest, and other factors. PBMs. With only about 10% of the sav- context. A brief history of PBMs may help set ings going to the uninsured consumers, the stage, and explain how they have be- THE TRIUMVIRATE in the end, it is the consumer who seems come so prominent over the last couple of Today the industry is dominated by three to get left out of this party, while each of decades. Your feedback will guide our next players: Express Scripts, the largest pure the big boys—the PBMs, pharma compa- column on the subject. play PBM with around 80 million mem- nies, third parties including insurers, and bers (though it is about to lose a quar- pharmacies—believe the other three are ONCE UPON A TIME ter of this roster that belongs to Anthem getting more than their fair share at their The first PBM started in 1968, just three with the recent announcement that An- individual expense. years after the enactment of Medicaid and them plans to set up its own PBM, coming The core of the moral dilemma that Medicare, and a year after the United Auto full circle after having divested its PBM the PBMs face is how to be transparent Workers and Ford reached an agreement to to create Express Scripts just a decade and share the details of their financial include drug coverage as part of the auto ago); CVS Caremark also with around 80 transactions without compromising their workers’ benefit package. million members and owned by one of CONTINUED ON PAGE 23

scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 21 PIPELINE WATCH

Scrip’s weekly Pipeline Watch tabulates the most recently reported late-stage clinical trial and regulatory developments from the more Click here for the entire pipeline than 10,000 drug candidates currently under active research worldwide. with added commentary: http://bit.ly/2mx4jY3 Selected clinical trial developments for the week 3–9 November 2017

LEAD COMPANY/PARTNER COMPOUND INDICATION COMMENTS Phase III Results Published polycystic kidney disease, Otsuka Pharmaceutical Co. Ltd. tolvaptan REPRISE; NEJM online, Nov. 4, 2017. autosomal dominant Sanofi/Drugs for Neglected human African fexinidazole The Lancet online, Nov. 4, 2017. Diseases initiative trypanosomiasis Vertex Pharmaceuticals Inc. VX-661 plus ivacaftor cystic fibrosis EVOLVE, EXPAND; NEJM online, Nov. 3, 2017. Phase III Interim/Top-line Results advanced breast cancer, MONALEESA-7; PFS improved in HR+/HER2- Novartis AG Kisqali (ribociclib) premenopausal disease. Otonomy Inc. Otividex (dexamethasone) Meniere’s disease AVERTS-2; achieved primary endpoint. Seikagaku Corp./Ferring BV SI-6603 (condoliase) lumbar disc herniation Missed primary endpoint. Novartis AG Cosentyx (secukinumab) psoriatic arthritis FUTURE 5; reduced symptoms, joint damage. pneumonia, TaiGen Biotechnology Co. Ltd. Taigexyn (nemonoxacin), iv Met co-primary endpoints. community-acquired Updated Phase III Results Eli Lilly & Co. Taltz (ixekizumab) psoriatic arthritis, psoriasis SPIRIT-P2, IXORA-S; sustained improvement. AbbVie Inc. upadacitinib rheumatoid arthritis SELECT-BEYOND, -NEXT; symptoms improved. AMAG Pharmaceuticals Inc. Feraheme (ferumoxytol) iron-deficiency anemia FIRM; reduction in hypophosphatemia. Evenity (romosozumab) post-menopausal UCB SA FRAME Ext; reduced fracture risk. then denosumab osteoporosis Cyltezo (adalimumab- rheumatoid arthritis, Boehringer Ingelheim GMBH VOLTAIRE-RA; efficacy similar to Humira. adbm) biosimilar switch study CT-P10 (rituximab) rheumatoid arthritis, Celltrion Inc. Comparable to reference rituximab. biosimilar switch study CheckMate 025; durable overall survival rate at Bristol-Myers Squibb Co. Opdivo (nivolumab) renal cell carcinoma 3 years. lysosomal acid lipase Alexion Pharmaceuticals Inc. Kanuma (sebelipase alfa) Infants survived beyond one year of age. deficiency secondary hyper- Kyowa Hakko Kirin Co. Ltd. evocalcet Non-inferior to cinacalcet. parathyroidism Ardelyx Inc. tenapanor hyperphosphatemia Decreased potassium, well tolerated. Clovis Oncology Inc. Rubraca (rucaparib) ovarian cancer ARIEL3; improved PFS. Phase III Initiated homozygous familial Sanofi Praluent (alirocumab) In patient aged more than 12 years. hypercholesterolemia Zosano Pharma Corp. M207 (zolmitriptan) migraine A long-term safety study. Alnylam Holding Co. givosiran acute hepatic porphyria ENVISION; in more than 20 countries. hypercholesterolemia and Esperion Therapeutics Inc. bempedoic acid/ ezetimibe A non-statin therapy. atherosclerosis Monofer hypophosphatemia Pharmacosmos AS PHOSHARE; versus Injectafer /Ferinject. (iron isomaltoside) induced by iron therapy primary mitochondrial Stealthyx Therapeutics Ltd. elamipretide MMPOWER-3; daily sc injections. myopathy SM-1 (zolpidem, loraz- Sequential Medicine Ltd. transient insomnia A randomized study. epam, diphenhydramine) Source: Biomedtracker

22 | Scrip | 17 November 2017 © Informa UK Ltd 2017 OPINION

CONTINUED FROM PAGE 21 dleman role with substantial clout, seem- intelligence has great promise to pro- negotiating power. The question of just ingly able to retain a large share of the mote evidence based prescribing not who is right in this matter is surprisingly savings they are able to negotiate with only to save the system money, but also difficult to answer, as the first two Con- both the drug makers at one end and the to improve health outcomes. All the PBMs gressional hearings on drug pricing, re- pharmacies at the other. The third-party have increasingly active ‘research labs’ bates, and the role of various stakehold- payers in the middle are increasingly de- working towards these objectives and ers have underscored. pendent on the so-called PBM consul- they publish some of their findings, and tants, whose role and objectivity are even are starting to push for outcomes-based ENFORCED OPACITY less well understood. agreements that link reimbursement to PBM contracts are opaque by design and PBMs also use their size to influence successful patient outcomes. all parties are prohibited from discussing clinical practice and seem to enable the Initial benefits so far, it seems, have terms. On the one hand, this lack of trans- use of higher priced brands via negoti- centered on maximizing cash flow, even parency on pricing makes the value ques- ated bundling and other incentives long if it means continuing use of expensive tion difficult to satisfy empirically, but on the after their patents have expired. In the branded though now off-patent prod- other hand lack of transparency could make end, these primarily benefit the PBM and ucts. Let us hope that convincing and the system more competitive, since forced the manufacturers. objective studies from the PBM intelli- disclosure of pricing terms in a consolidated It is clear that PBMs do fulfill their role gence about the overall value contribu- industry makes collusion easier, and has of helping lower drug costs by extracting tion to society – both about the savings been shown in other industries to at least ever larger rebates from the biopharma benefiting society, and better patient lower pricing variability and could lead to companies, now about a third of the care with improved outcomes – will be- higher prices overall. retail prices posted by the biopharma gin to demonstrate the merits of this im- Generally, all parties in the pharmaceu- companies. The question of whom these portant industry segment. tical product chain, from manufacturers rebates benefit is where the debate be- Published online 8 November 2017 to PBMs to insurers to pharmacies, have comes heated. repeatedly argued and generally won the Viren Mehta founded and is managing mem- right to variable pricing, as well as lack of DATA TROVE ber of Mehta Partners, LLC, a globally inte- transparency, in proportion to their mar- Another positive resource of course is the grated boutique providing strategic insights ket power over captive consumers, but treasure trove of PBM data and potential to senior management teams in the biophar- PBMs have carved out the ultimate mid- intelligence their analytics can yield. This maceutical sector for nearly 30 years.

APPOINTMENTS

The UK’s exosome therapeutics company Philip Johnson has been appointed senior Biohaven Pharmaceuticals Holding Co. Evox Therapeutics has appointed Dr vice president, finance and treasurer of Eli Ltd. has named Scott Phillips senior vice Antonin “Tony” de Fougerolles CEO, tak- Lilly & Co., effective Jan. 1, 2018. Johnson is president of finance. Phillips was previously ing over from acting CEO Per Lundin who currently vice president of investor relations chief accounting officer and then senior will continue as COO. De Fougerolles joins at the Indianapolis-headquartered com- vice president of global business finance from Ablynx NV where he was chief scien- pany, and he will continue to lead Lilly’s in- at Alexion Pharmaceuticals. Biohaven is tific officer for four years, and before that vestor relations efforts. Johnson will report developing product candidates for neu- he was CSO at Moderna Therapeutics. Evox to Joshua Smiley, who will become senior rological diseases, including rare disorders. is harnessing extracellular vesicles – ex- vice president and chief financial officer on osomes – as natural delivery vehicles for a Jan. 1, 2018. Lilly announced in June that Syros Pharmaceuticals Inc. has named new class of biotherapeutics. Derica Rice, Lilly’s current CFO, would retire Jeremy Springhorn chief business officer. at the end of 2017. He was most recently partner of corporate Pfizer Inc.has named Albert Bourla development at Flagship Pioneering, and COO, a new position, effective Jan. 1, 2018. CVC Capital Partners has named Fred Has- before spent 20 years at Alexion, where he Bourla has been group president of Pfizer’s san chairman of a new company, Theramex, was one of the original scientists. Syros is de- Innovative Health business since the start which will be the name of Teva Pharmaceu- veloping medicines to control the expres- of 2016, and will be replaced in that role ticals Industries Ltd.’s international women’s sion of disease-driving genes in non-coding by John Young, currently group president health business upon completion of its ac- regions of the genome. of Pfizer Essential Health. In turn, Angela quisition by CVC Fund VI. Hassan, the chair- Hwang, currently global president and man and CEO of Schering-Plough Corp from San Francisco-based Spruce Biosciences general manager of Pfizer Inflammation & 2003 to 2009, will continue to serve as special has announced that Camilla Simpson, Immunology, will become group president limited partner at Warburg Pincus. Anish Me- senior vice president and head of product of Pfizer Essential Health. Young, Hwang hta joined Theramex as CEO in October 2017, portfolio development at BioMarin Phar- and three other members of Pfizer’s execu- having previously been head of international maceutical Inc., has joined Spruce’s board tive leadership team will report to Bourla. business development at Allergan plc. of directors. scrip.pharmaintelligence.informa.com 17 November 2017 | Scrip | 23 scrip_press_ad_297x210_v7_HR.pdf 1 2017/11/09 12:57 PM

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Book your table at the awards ceremony of the year, visit scripawards.com for details.

29 November 2017 | London Hilton on Park Lane

General Enquiries: Natalia Kay | Tel: +44 (0) 20 7017 5173 | Email: [email protected]

Sponsorship and Table Booking Enquiries: Chris Keeling | Tel: +44 (20) 337 73183 | Mobile: +44 (0) 7917 647 859 Email: [email protected]

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