Biosimilar Product Differences Will Affect US Uptake, Amgen Predicts

28 April 2017 No. 3851

Scripscrip.pharmamedtechbi.com Pharma intelligence | informa However, the US is poised for potentially significant growth in the biosimilar category in the coming year. There currently are at least six 351(k) applications and at least one resubmitted application pending with FDA. The report’s discussion of delivery device, packaging and product dosing considerations as market drivers is particularly timely in the context of FDA’s recently released draft guidance on interchangeability, which suggested that such differences from a reference product could present a hurdle to achieving an interchangeability determination. “While the biosimilar market continues to develop, we expect that the next year will bring another strong phase of growth and market maturity for biosimilars,” Amgen’s Shutterstock: spaxiax Shutterstock: Duane Barnes, vice president and general manager of US Value and Access, said in the report’s opening message. “We anticipate Biosimilar Product Differences Will additional regulatory and legal activity sur- rounding these agents across a range of Affect US Uptake, Amgen Predicts therapeutic areas.” Differences in product characteristics should be considered in formulary decisions, Amgen INDICATION BREADTH says in annual trends report that puts its biosimilars in a strong competitive light while The report discusses the FDA approval path- also bolstering the position of its reference biologics. way for 351(k) applications, evolution of the US biosimilar market, and patient and phy- SUE SUTTER [email protected] sician perceptions of the product category. It also identifies manufacturer, product iosimilar product considerations such The document marks Amgen’s fourth re- and operational considerations that pay- as delivery device, dosing and pack- port on biosimilar trends, but the first since ers and other formulary decision-makers Baging that differ from the reference the company received FDA approval last should take into account when evaluating a product may affect uptake of the follow-on September of its own biosimilar, Amjevita biosimilar and considering appropriate cov- agents in the nascent US market, a new Am- (adalimumab-atto), which references AbbVie erage criteria (see box). gen Inc. report states. Inc.’s TNF-inhibitor Humira (adalimumab). The document reiterates a point raised While a biosimilar must have no clinically The US biosimilars market is still young, in Amgen’s earlier reports regarding supply meaningful efficacy or safety differences with just four approved products. Only two chain reliability and avoiding the potential from the reference product, nonclinical dif- of these – Sandoz Inc.’s Zarxio (filgrastim- for drug shortages when making formulary and prescribing decisions about a biosimi- ferences could have implications for payers, sndz) and Celltrion Inc.’s Inflectra (infliximab- lar. It emphasizes the importance of biologic integrated delivery networks, healthcare dyyb) – have launched; commercialization manufacturing experience. providers and patients, the “2017 Trends in of Amjevita and Sandoz’s Erelzi (etanercept- Biosimilars Report” states. szzs) have been delayed by patent litigation. CONTINUED ON PAGE 8

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Market Intelligence Research & Development Company Focus Can cholesterol drug sponsors make New active substance launches UniQure gives up on Glybera, but not the case for statin intolerance? (p11) declined again in 2016 (p14) gene therapies (p18) IN THIS ISSUE

from the editor [email protected]

If a company is still assuming the value of its drug is to stretch the length of significant profitable service almost entirely tied up in the IP around its active ingre- a drug can deliver. For example, while a biologic may dient, it is probably over-zealous in its interpretation of technically be exposed to biosimilar competition, bar- the IP protection bargain between society and innova- riers to adoption are likely to be posed by peripheral tive pharma. At its extreme, this bargain entails generic elements such as the delivery device in which the origi- competition being held at bay for a limited number of nator product is packaged (see cover story). “Beyond the years of premium pricing – to generate funds to plow pill” factors can become even more important in bind- back into novel drug development – and then being ing payers to an out-of-patent branded product if the unleashed to flood the market with the same medicine originator harnesses real-world evidence to ‘accessorize’ at a fraction of the price. This frees up patient spending its offering and demonstrate how patient outcomes dollars and the cycle begins again. associated with the drug are influenced by numerous In fact, the multiple facets of digital health technol- non-pharmacological factors, from delivery devices ogy and the increasing complexity of many therapies and physician education to adherence, monitoring (from biologicals to combinations to respiratory medi- and medical support apps. Now more than ever, patent cines packaged in proprietary inhaler devices) promise expiry need not be a cliff-edge for pharma.

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2 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 NAS Launches Declined In 2016

Amgen’s study supports LDL- Emicizumab’s lowering Next Big 20Challenge 7 11 16

exclusive online content inside: COVER / Biosimilar Product Differences Will Affect US Uptake, Biomunex CEO On Earlier Deals For Cancer Drugs Amgen Predicts http://bit.ly/2pcLp8S Biomunex CEO Pierre Emmanuel Gerard discusses the 4 Veliparib Phase III Failures Strike Blow To AbbVie’s company’s founding, its pipeline of innovative bispecific Oncology Strategy antibodies being developed for oncological indications, and the partnering potential for these compounds. 5 Teva’s AirDuo Authorized Generic Priced At A 70% Discount To Advair

Newron CEO On Xadago & Upcoming Pipeline 6 Rebates, Pricing Pressure Weigh On J&J’s 1Q Pharma Sales Milestones http://bit.ly/2on4Ts9 7 Roche’s Emicizumab Progresses Against Hemophilia’s Next Newron CEO Stefan Weber joins Scrip to discuss the company’s Big Challenge recently approved Parkinson’s therapy Xadago (safinamide), as well as development timelines for Newron’s other pipeline 9 High Profile Combo Answer To Late-Stage NASH Programs? candidates. 10 AbbVie Next-Gen Combo To Target Hard-To-Cure Noxxon CEO Talks Partnering Strategy & Cancer HCV Patients Combos http://bit.ly/2pXpdQJ 10 OncoMed Trying To Regroup After Cancer Failures Aram Mangasarian, CEO of Noxxon Pharma, a biotech company focused on cancer therapies targeting the tumor 11 Can Cholesterol Drug Sponsors Make The Case For microenvironment, discusses partnering options and his Statin Intolerance? strategy for how Noxxon can compete in the busy immuno- oncology space. 14 New Active Substance Launches Declined Again In 2016

18 UniQure Gives Up On Glybera, But Not Gene Therapies India Pricing Authority Chief Says List Is No Attempt To Vilify Industry 20 Immune-Focused Discovery Firm Alpine Goes Public http://bit.ly/2oDIh1H The chair of India’s National Pharmaceutical Pricing Authority 21 Valeant Gives Siliq Competitive Price In Crowded has tried to clear the air around the regulator’s recent public Psoriasis Market notice that lists over 600 products suspected of having flouted price caps, telling Scrip the chances of error around the data 22 Pipeline Watch used to verify compliance is low, though at least half a dozen companies on the list indicate they have complied with the regulator’s norms. 23 Multispecific Approach Could Improve I-O Side Effect Profile, Says Numab

Forward Pharma Faces Uphill Struggle Appealing 23 Appointments Biogen’s Tecfidera PTAB Win http://bit.ly/2oZAzTp Forward Pharma is suspending all FP187 development pending the outcome of its legal interference appeal against Biogen – but analysts see little prospect of it overturning last month’s decision that effectively allows Biogen’s dimethyl fumarate-based drug Tecfidera to stay on the market with @scripnews /scripintelligence its own patent.

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scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 3 RESEARCH & DEVELOPMENT

Veliparib Phase III Failures Strike Blow To AbbVie’s Oncology Strategy STEN STOVALL & EMILY HAYES

The failure of veliparib in Phase III studies That would appear to be lower than com- at upcoming medical meetings or pub- of squamous NSCLC and triple-negative petitors – Rubraca comes in at $13,740 per lished in a peer-reviewed journal, the breast cancer is a blow for AbbVie’s on- month and Lynparza is reportedly priced company said. cology pipeline, but may not have impli- at from $12,400 to $13,000 per month – Analysts at BMO Capital Markets com- cations for other PARP inhibitors in new but the approved starting dose of Zejul is mented that the latest failed veliparib tumor types. actually 300 mg, which would bring the combo trials are “incrementally negative” as list price up to $14,750 per month. Tesaro they further weaken sentiment about Ab- bbVie Inc.’s oncology strategy has maintained that 200 mg is the most com- bVie’s overall pipeline being able to “mean- taken a hit with news of the failure monly administered dose. ingfully offset declining Humira sales as a Aof its investigational PARP inhibitor Tesaro’s stock price was down by 6.07% result of inevitable biosimilars competition.” veliparib in two Phase III studies that tested on April 20 to $139.01, following a close “Further, we remain cautious on the suc- the drug in combination with chemothera- of $145.52 on April 19, amid concerns cess of veliparib relative to the other PARP py in first-line squamous non-small cell lung that the price for the approved dose is inhibitors,” they added. cancer (NSCLC) and in early stage triple- too high for the market and that the need Analysts at Leerink Swann said the latest negative breast cancer. to use the lower 200 mg dose is due to failure by veliparib “is unfortunate for Ab- In one of the trials, the combination adverse events. bVie’s oncology strategy, which is ground- treatment failed to improve the overall ed in complementary contributions from survival of previously untreated meta- ABBVIE DISAPPOINTMENT both internal discovery and external ac- static, squamous NSCLC patients who had The veliparib news is a setback for AbbVie’s quisitions, and is focused on both hema- smoked within the past 12 months and ambitions in oncology, an area of intense tological and solid tumor malignancies. At had more than 100 smoking events in their research and development activity for this stage at least, the solid tumor outlook lifetime, AbbVie announced April 19. the company. The company’s BTK inhibi- and AbbVie’s internal contributions to the In the other trial, which evaluated the tor Imbruvica (ibrutinib) was its second- portfolio seem a bit more uncertain, leav- drug in 312 patients receiving neoadjuvant best seller in 2016, passing its hepatitis C ing AbbVie still likely looking for additional treatment for triple-negative breast cancer, combo Viekira Pak Viekira Pak (ombitasvir, assets in solid tumor area to bolster that veliparib did not achieve the endpoint of paritaprevir and ritonavir with dasabuvir) side of its portfolio.” improvement in complete pathologic re- sales have been declining in the face of sponse rate, a surrogate marker for survival, greater competition and AbbVie’s block- REPERCUSSIONS FORESEEN as an add-on to chemotherapy compared buster inflammatory diseases drug Humira The late-stage trial failures appear to further to chemotherapy alone. (adalimumab) is set to decline with the weaken sentiment over veliparib’s potential Veliparib is also in Phase III for ovarian introduction of biosimilar competition. relative to other PARP inhibitors, especially cancer. AbbVie told Scrip that it is con- AbbVie announced data from the Phase III as they confirm earlier disappointing results tinuing to evaluate the drug’s safety and EXPEDITION-1 study on April 20 showing in both breast and lung cancers. efficacy in Phase III studies of ovarian that its next-generation hepatitis C combi- “This is a significant setback for veliparib in cancer, non-squamous NSCLC and breast nation glecaprevir/pibrentasvir cures HCV breast cancer, but data from other PARP in- cancer with BRCA1/2 mutations. AbbVie patients with compensated cirrhosis with- hibitors in treating breast cancer patients are needed to better determine their overall role is also testing veliparib in combination out ribavirin add-on therapy. in this indication,” commented Datamonitor with Bristol-Myers Squibb Co.’s PD-1 in- AbbVie has said it hoped to differentiate Healthcare analyst Zachary McLellan. “Top- hibitor Opdivo (nivolumab) in a Phase II veliparib from other PARP inhibitors on the line results from this Phase III trial in triple- NSCLC study basis that as a potent inhibitor of PARP, it negative breast cancer seem to confirm Three drugs are currently FDA-approved combines well with multiple chemothera- veliparib’s lack of efficacy even in BRCAm+ in the PARP class, all for ovarian cancer: pies – particularly platinum chemotherapies. patients where PARP inhibitors are most ef- AstraZeneca PLC ‘s Lynparza (olaparib), In a statement about the failed Phase fective,” McLellan added. Clovis Oncology Inc.’s Rubraca (rucaparib) III trials, AbbVie said that the company Published online 20 April 2017 and Tesaro Inc. ‘s Zejula (niraparib), which had wanted to explore whether PARP in- on March 27 received the broadest ap- hibitors could augment chemotherapy proval in the indication. Tesaro announced in squamous NSCLC and triple-negative CLICK April 19 that Zejula is now available in the breast cancer by disrupting the repair of View PARP Inhibitor trials US, at the wholesale acquisition cost of cancer cells, but that the trials concluded here: http://bit.ly/2pspMCk $9,833 per month for a 200 mg/day dose. otherwise. Full results will be presented

4 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 PRICING & STRATEGY

Teva’s AirDuo Authorized Generic Priced At A 70% Discount To Advair Teva’s decision to launch an authorized generic version of AirDuo, a drug made up of the same active ingredients in GSK’s Advair, at a steep discount to typical brand drugs for asthma will help encourage use, even though it is not interchangeable.

JESSICA MERRILL [email protected]

eva Pharmaceutical Industries Ltd. has taken the interesting tially by months. Hikma’s application has a May 10 action date. step of launching AirDuo RespiClick (fluticasone/salmeterol) For Teva, the Mylan delay presents an opportunity. The Israeli T and an aggressively discounted authorized generic in the US company is continuing to develop its own AB-rated generic, but on the same day. The company announced the availability of the two now sees an chance for the AirDuo authorized generic to gain sig- products April 20, both of which are formulated with the same active nificant traction in the market. ingredients as GlaxoSmithKline PLC’s Advair Diskus, but are adminis- “The Mylan decision was beneficial to us. It confirms our ap- tered through a different device. proach could be creative and wise,” Dethlefs said. The authorized generic is priced at a steep discount to the Air- “Payers now have a choice: do we wait to get an AB-rated Advair Duo brand product – and to the leading brands in the inhaled cor- coming one day to the US or do we start working with the [fluti- ticosteroid/long-acting beta2-agonist (ICS/LABA) category, notably casone/salmeterol] generic that we have today, which is available, Advair and AstraZeneca PLC’s Symbicort (budesonide/formoterol). known, attractive and responsibly priced,” he said. The move could help the Teva franchise gain traction in a competi- Teva could use a big win on the generic side of its business. The tive therapeutic category, despite the fact the product is not con- company’s generic growth has slowed, and despite closing an sidered interchangeable to Advair. enormous deal to buy Allergan PLC’s generic drug business last “I think we established a price point that is an exclamation point year, pressure on the business contributed to the resignation of in the ICS/LABA market,” Teva’s global respiratory business head CEO Erez Vigodman last year. Sven Dethlefs said in an interview. AirDuo is priced at a wholesale acquisition cost of $285 for all SECURE FORMULARY ACCESS three strengths of the medication, while the authorized generic will The launch strategy now is a bit of a creative play for Teva, which be priced at a wholesale acquisition cost of $90. In comparison, the by launching the brand product and an authorized generic at the price of Advair Diskus is around $301 and more for higher doses same time, stands a better chance of getting the discounted drug and Symbicort is around $307, according to Teva. on formularies in 2017, rather than if it launched the brand alone “We have around a 75% price advantage,” Dethlefs said of the au- at a steep discount. This way, payers don’t have to worry about thorized generic. “If you think about patients who have to pay out impacting 2017 contracts signed with brand drug manufactur- of pocket, it is a tremendous benefit, and also if you have a copay, ers. Dethlefs said Teva ultimately decided it would be faster for the the copay is also down, because of the low price point.” product to achieve access from payers by launching it as a brand and an authorized generic. TEVA’S APPROACH VALIDATED “A generic [represents] very different formulary access,” he The launch of the two products at the same time is part of a carefully said. “We don’t touch any of the existing contracts because we plotted strategy to secure access for the product from payers, given introduce a new option.” The strategy, he added, builds off some that AirDuo is not an AB-rated, or interchangeable, version of Advair, of the experience Teva has had launching branded generics in- a blockbuster drug that is complicated to copy because it is delivered ternationally. to the lungs through a delivery device. “I think the approach we have taken is creative,” he said. “It is also AirDuo was approved for asthma in January under FDA’s 505(b)2 driven by the experience Teva has with the European launches, and pathway for new drugs that rely on data from existing medicines, we will see how it is adopted in the US market. rather than under the abbreviated new drug application (ANDA) Both drugs are “highly important” to Teva’s respiratory business. pathway for generic drugs. Teva made the decision to pursue an AirDuo will augment the company’s existing respiratory portfolio, Advair copy through the 505(b)2 pathway back in 2010, when it felt which includes the rescue inhaler ProAir (albuterol) and the in- the chance for developing an interchangeable generic through a haled corticosteroid Qvar (beclomethasone). The portfolio has not traditional ANDA were slim. Since then, however, FDA unveiled bio- included a ICS/LABA combination, however, a mainstay of mainte- equivalence guidance to sponsors to develop an interchangeable nance treatment. generic version of Advair, and Teva reprioritized the development One advantage, according to Teva, is that both ProAir and Air- of a substitutable generic. Duo are administered through the same Respiclick device, which Teva’s interchangeable generic has been behind other sponsors means patients can use both products without having to learn a like Mylan NV and Hikma Pharmaceuticals PLC, however, both of new device. ProAir generated $565m in 2016 sales and Qvar gener- which already filed ANDAs. But FDA issued a complete response ated $462m last year. letter to Mylan’s application in March, postponing a launch poten- Published online 20 April 2017 scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 5 PRICING

Rebates, Pricing Pressure Weigh On J&J’s 1Q Pharma Sales Johnson & Johnson had to offer steeper discounts in certain therapeutic categories like cardiovascular and metabolic disease, impacting first quarter sales. So far, the impact of a new biosimilar in the US has had minimal impact on Remicade.

JESSICA MERRILL [email protected]

S pricing pressure negatively im- when it comes to pricing more broadly. INFLECTRA IMPACT pacted sales of some Johnson & “The difference between list price and The company is also bracing for more pres- UJohnson products in the first quarter, net price is pretty dramatic, and we think sure on US sales of Remicade (infliximab), weighing on the pharmaceutical segment, that will continue,” he added. “We’ve had following the launch of the first biosimilar the company said April 18. Pricing pressure modest price increases on a net price ba- version of the tumor necrosis factor inhibi- was notable in more competitive therapy sis, and we think that will be the case go- tor. Pfizer Inc. launched Inflectra, a biosimilar areas like cardiovascular and metabolic dis- ing forward.” version of Remicade partnered with Cell- ease, where J&J markets the SGLT-2 inhibitor Pricing pressure has been a key discus- trion Inc., in the US Nov. 21. Invokana (canagliflozen) for diabetes and sion topic within pharma so far in the first So far, J&J said it hasn’t felt much impact the blood thinner Xarelto (rivaroxaban). part of 2017, with increased emphasis on from the US launch, but Inflectra hasn’t had “In certain parts of the portfolio, cardio- the issue coming out of the US presidential much time on the market. Remicade is fac- vascular and metabolics in particular, that election in 2016. President Trump has also ing more pressure from biosimilars in Eu- [are] a little bit more crowded, [where] it’s mentioned high drug prices on several rope. US sales of Remicade declined 2.4% not as specialty focused, more primary- occasions as part of his populist message, to $1.18bn in the first quarter, while J&J’s care focused, that’s where the payer com- putting industry on edge. US exports of Remicade declined 29.2% to munity has more influence over rebates,” $165m. US sales of Remicade reflect slightly chief financial officer Dominic Caruso said ONCOLOGY DRUGS DELIVER higher volume growth, offset by steeper dis- in a same-day conference call. J&J’s pharma segment sales were flat, up counting, the firm said. US sales of Xarelto declined 9.5% to 0.8% to $8.25bn in the first quarter, coming “There’s no interchangeability, so we $513m in the quarter, while US sales of in below analyst consensus estimates. None- certainly don’t expect that physicians will Invokana declined 16.8% to $247m. Invo- theless, new oncology drugs performed switch patients,” Caruso said of the biosimi- kana is also facing competition from Eli Lilly well, namely Darzalex (daratumumab) for lar competition. “They may start new pa- & Co.’s rival drug Jardiance (empagliflozin), multiple myeloma and Imbruvica (ibrutinib) tients on therapy, but with the long history which launched in 2014, but gained a new for chronic lymphocytic leukemia. Sales of that we have of Remicade’s efficacy and indication from FDA in December 2016 for Darzalex were $255m worldwide, more than safety, we believe patients will move slowly reducing the risk of cardiovascular death double sales in the year-ago quarter, and to switch to a biosimilar.” after the company released positive car- sales of Imbruvica increased 57% to $409m. J&J’s pharmaceutical sales should get a diovascular outcomes data. J&J plans to Sales of the prostate cancer blockbuster Zyt- boost in 2017 from the addition of Actelion release the results of its own cardiovascu- iga (abiraterone) were under pressure how- Pharmaceuticals Ltd., which the company lar outcomes trial testing Invokana at the ever, down 14.3% to $233m in the US and is in the process of acquiring for roughly American Diabetes Association Scientific down 6.3% worldwide to $523m, which the $30bn. The acquisition, which is expected Sessions in June. company attributed partly to more use of to close by the end of the second quarter, will give J&J a portfolio of drugs for pulmo- J&J’s pharma unit also faced a challeng- the drug under patient assistance programs. nary arterial hypertension, including Tra- ing comparative headwind against the Leerink device analyst Danielle Antalffy, cleer (bosentan), as well as two Phase III as- prior-year quarter related to the timing in a same-day note said, “investors are likely sets – ponesimod for multiple sclerosis and of rebate accruals, which impacted sales to focus on now the second straight quar- cadazolid, a novel antibiotic for Clostridium growth, the firm said. ter of pharma sales underperformance, difficile-associated diarrhea. But Caruso insisted pricing pressure re- while a miss in consumer could further ex- Management provided updated 2017 mains limited to specific categories. “We acerbate investor anxiety.” guidance to reflect the estimated impact have an innovative portfolio in pharma, “Given the importance of the pharma of the Actelion acquisition. and the innovation comes with greater business to J&J’s growth trajectory, this is Published online 18 April 2017 patient outcomes and therefore evidence certainly a trend we will be watching in or- that supports the pricing for the products,” der to assess the company’s ability to drive he said. “That’s the vast majority of the sustainable mid-single digit sales growth View J&J’s Caruso On The portfolio in oncology, immunology and and even faster EPS growth,” she said. Prospect Of US Tax Reform neuroscience.” Therefore, he told investors J&J’s stock fell 3% on the results, to close here: http://bit.ly/2oDak28 not to expect a dramatic change from J&J the day at $121.82.

6 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 RESEARCH & DEVELOPMENT

Roche’s Emicizumab Progresses Against Hemophilia’s Next Big Challenge JOHN DAVIS [email protected]

Interim results from the first patients enrolled in the Phase III HA- Emicizumab brings together factor IXa and factor X through its VEN 2 study suggest Roche’s potential anti-hemophilia monoclo- bispecific binding to both blood-clotting proteins, a role that is nal antibody emicizumab reduces bleeds over time in younger as usually performed by factor VIII in the human coagulation cascade, well as in older patients with inhibitors to factor VIII. and its subcutaneous mode of administration could produce savings in administration costs versus intravenous injections and infu- oche’s bispecific monoclonal antibody emicizumab has pro- sions, as well as being more convenient for patients. duced a clinically meaningful reduction in the number of The biologic also has a lengthy duration of action, and Roche Rbleeds over time in younger hemophilia A patients with in- is exploring once-weekly, every two weeks and once-monthly ad- hibitors to factor VIII, in interim results from the Phase III HAVEN 2 ministration schedules, that could have convenience and compli- study. These complement results previously released from the HA- ance benefits. However, enthusiasm for the product is likely to be VEN 1 study showing similar benefits in older hemophilia patients tempered by concerns over a recent report of a patient death in with inhibitors. the earlier HAVEN 1 clinical study of emicizumab in older patients. The results from HAVEN 2 are very early – the interim analysis was conducted after only 19 out of a likely 60 patients were enrolled in the single-arm study, and after a median 12 weeks of treatment compared with the study’s planned final analysis after 52 weeks of treatment - but are promising nevertheless, and were released on Apr. 17, 2017, World Hemophilia Day. The study design, with a single arm and no comparator, is standard for pediatric studies in hemophilia, and further details on the bleeding rates will be shared at a forthcoming medical meeting, the Swiss multinational told Scrip. This is likely to be the Interna- tional Society on Thrombosis and Hemostasis (ISTH) meeting to be held in Berlin, Germany, in July 2017. Roche says it has penciled in 2017 for the filing of marketing ap-

plications in the US and Europe for emicizumab, suggesting that it molekuul_be Shutterstock: could become available in the first half of 2018. Analysts at Informa Pharma Intelligence’s Datamonitor Healthcare believe that emici- BLEEDS OVER TIME REDUCED zumab could revolutionize the hemophilia treatment landscape. HAVEN 2 is being conducted in children aged less than 12 years Because of its long half-life and subcutaneous route of administra- with hemophilia A and factor VIII inhibitors, given emicizumab tion, emicizumab could be an attractive prophylactic therapy for pa- by subcutaneous injection once weekly. After a median 12 tients regardless of their factor VIII inhibitor status, the analysts say. weeks there was said to be a clinically meaningful reduction in the number of bleeds over time, Roche reported in a brief DIFFICULT TO TREAT statement Apr. 17. The most common adverse events associated Younger hemophilia patients with inhibitors are particularly hard with emicizumab in HAVEN 2 were injection site reactions and to treat because of the difficulty in gaining control of their bleed- nasopharyngitis. ing. Patients with inhibitors are usually first treated with immune Previously, Roche has reported results from the Phase III HAVEN tolerance induction (ITI): that is, they are given very high doses of 1 study in older patients, that is adolescents aged 12 years or over factor VIII over a long period, but this is ineffective in around 30% of and adults, who also have hemophilia A and factor VIII inhibitors, hemophilia A sufferers. showing that emicizumab prophylaxis was associated with a statis- After ITI fails, short-acting “bypassing” agents are used, including tically significant and clinically meaningful reduction in the number Shire PLC’s anti-inhibitor activated prothrombin coagulant com- of bleeds over time compared with no prophylaxis and compared plex, Feiba (factor VIII inhibitor bypassing protein), and Novo Nor- with prophylaxis with bypassing agents. disk AS’s recombinant Factor VII product, NovoSeven (eptacog alfa), Roche is conducting two further Phase III studies of emicizumab: but they require intravenous injections or infusions. HAVEN 3, evaluating once-weekly or every-two-weeks injections of The need for newer, more convenient and better therapies to emicizumab in patients aged 12 years or over with hemophilia A treat hemophilia, particularly in patients with factor VIII inhibitors, but without inhibitors of factor VIII; and HAVEN 4, evaluating emi- is being addressed by a diverse range of potential new agents cizumab every four weeks in patients aged 12 years or over with including monoclonal antibodies, longer-acting factor VIII deriva- hemophilia A with or without factor VIII inhibitors. tives, and gene therapy. Published online 18 April 2017

scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 7 FRONT COVER

CONTINUED FROM COVER tations, such as a prefilled syringe, auto- Product Considerations Similarly, the review of product consid- injector, single-use pen or vial. These can • Extrapolation erations important to formulary decision- create practical issues that affect commer- • Curative treatment vs. supportive care making would seem to put Amgen’s bio- cial utilization. • Product dosing considerations similars in a strong competitive light while “Physicians, pharmacists, nurses, patients • Delivery device also bolstering the position of the biotech and caregivers must be aware of any differ- • Formulation, storage and handling giant’s reference products. ences in indications, corresponding doses • Distribution channels Chief among these product-specific con- and available dosage forms between the siderations is whether a biosimilar can be branded reference product and the biosimi- Manufacturer Considerations used for all of the same indications as the lar product,” the report states. • Supply chain reliability reference product. Zarxio, a biosimilar to Amgen’s own Ne- • Patient support programs While the first four US biosimilars were ap- upogen (filgrastim), is approved only in pre- proved through extrapolation for all of the filled syringes, while the reference product is Operational Considerations available indications on their respective ref- also available in single-dose vials. Zarxio la- • Pharmacovigilance erence products’ labeling, some of the inno- beling contains a recommendation against • Pricing and contracting vator product indications remain protected direct administration to patients requiring • Reimbursement by exclusivity. For example, orphan-pro- doses of less than 0.3 mL due to the potential • Information technology tected indications for Janssen Biotech Inc.’s for dosing errors with the prefilled syringe. Remicade (infliximab) and AbbVie’s Humira “Some prefilled syringes, depending on Such differences in delivery device and were kept off the labels of their respective their design, may not be able to accurately product presentation may become a hurdle biosimilars, Inflectra and Amjevita. deliver the correct dose of medication to to interchangeability pursuant to an FDA some patient populations,” the report states. draft guidance released in January. Similarly, Sandoz’s Erelzi comes only in In that guidance, FDA raised concerns prefilled syringe and auto-injector presenta- about the potential risk of use-related er- tions. It is not approved in a vial formulation ror if an interchangeable with a different for use by pediatric populations, as is the delivery device were to be substituted case with the reference product, Amgen’s for a reference product without addi- Enbrel (etanercept). tional training for patients or caregivers. “Longer-term, what happens as more The agency suggested it intends to take biosimilars for the same reference product a more stringent view of differences from become available,” the report asks. “What the reference product in container closure if each one has its own particular packag- systems or delivery devices for an inter- ing that differs from that of the reference changeability determination than it does product? The question then becomes more for a biosimilar approval. complex: how many differences can a mar-

Shutterstock: Planar Shutterstock: The guidance describes the types of hu- ket accommodate and how many ‘highly similar’ products will have nonclinical differ- man factors studies or other data that may The report includes a quote from an un- ences that need to be noted and tracked in be needed to support an interchangeabil- identified distribution advisor and member electronic systems?” ity designation when there are more-than- of Amgen’s editorial council stating that minor differences in product presentation while a plan formulary “might continue INTERCHANGEABLE DEVICES? between the biosimilar and reference prod- covering a biosimilar for the larger patient The importance of a manufacturer’s uct. The document also advises against de- population, formularies will need to keep choice of delivery device and its impact on velopment of an interchangeable product some kind of relationship with the refer- patient compliance and adherence also is in a presentation for which the reference ence product manufacturer to cover these highlighted. product is not licensed. orphan indications.” “Some biosimilar manufacturers have Differences in formulation and handling Amgen’s editorial council comprises med- already chosen to use delivery devices should be taken into account in product se- ical and pharmacy directors for managed different from that of the reference prod- lection, the report states. care organizations, employer and benefit uct,” Amgen’s report states. “Whether “Distributors and healthcare professionals design consultants and patient advocates. that choice is due to patent protection who administer biosimilars need to know on the original device or to introduce about – and take precautions when dealing PRESENTATION & PACKAGING a competitive advantage (e.g., a more with – differences between a biosimilar’s Amgen’s discussion of nonclinical differenc- patient-friendly device that increases pa- storage, handling and route of administra- es reflects the company’s own experience tient adherence), patients and healthcare tion and those of the reference product,” the with biosimilar competitors in the US. professionals will require education about report states. The report notes a biological may be the different devices and their proper use A biosimilar’s distribution channel also available in a variety of forms or presen- and handling.” may impact adoption, the report suggests,

8 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 HEADLINE NEWS/RESEARCH & DEVELOPMENT

noting that while full-line wholesalers his- torically have distributed biologics, newer High Profile Combo Answer To agents are more frequently being launched through specialty distributors. Late-Stage NASH Programs? CLINICAL SETTING? SUKAINA VIRJI, [email protected] Another consideration in deciding whether to select a biosimilar is how the product will Novartis is teaming up with Allergan in a told Scrip: “Collaboration is key to developing be used in a given clinical setting. bid to get a treatment on the market for the best possible treatments that are urgent- At an October 2016 Friends of Cancer the fatty liver disease NASH, which cur- ly needed for NASH patients... A clinical col- Research meeting, Jeff Eichholz, senior rently has no approved treatments. The laboration with Allergan expands the Novar- director of drug trend solutions at Express decision by Novartis to test its lead FXR tis development program in NASH, bringing Scripts Holding Co., predicted clinicians agonist with Allergan’s cenicriviroc (CVC) together scientific innovation and expertise.” might be more inclined to use a biosimi- is interesting because Allergan’s product Allergan’s chief R&D officer, Dr. David lar to treat inflammatory disease than they reported mixed Phase II data. Nicholson, also believes a joint approach would be in a “life or death” situation like makes sense. He expects some compounds, cancer. Eichholz’s comments drew sup- ovartis AG and Allergan PLC, which including CVC, could be approved as single port from a lung cancer patient advocate are individually pursuing the po- agents, “However, we firmly believe that at the meeting. Ntentially lucrative non-alcoholic ste- given the multi-factorial nature of NASH, pa- The Amgen report appears to back up atohepatitis (NASH) market – forecast to be tients will be treated with multiple therapies that viewpoint, at least for the near-term. worth over $1bn annually – have decided to targeting different pathways, most likely in “In oncology, for example, utilization of bi- join forces and test two products in combina- combination. To establish CVC as a corner- osimilars may depend on whether the drug tion. They have entered a clinical trial agree- stone of NASH therapy, it is important to is being administered for supportive use or ment to conduct a Phase IIb study of Novar- study CVC with other therapies in develop- with curative intent,” the report states. The tis’s lead farnesoid X receptor (FXR) agonist ment,” he told Scrip. document includes a quote from an uniden- LJN452 with Allergan’s cenicriviroc (CVC). He is particularly excited about testing tified oncologist stating: “I’m more willing to Novartis has been developing FXR ago- CVC in combination with Novartis’s pro- let economics drive supportive care instead nists in-house, and its most advanced com- gram. “We are looking to combine CVC of therapeutic medications. I’d like a higher pound is the non-bile acid FXR agonist with treatments that have shown a clinical standard of data in a therapeutic indication.” LJN452, which recently received fast track benefit in NASH, and with differentiated There has also been speculation that designation from the FDA and is in a Phase II therapeutic profiles. We believe FXR is one biosimilars are more likely to be used in trial. It will be combined with CVC, which Al- of those targets and compounds. We also new patients. Interviews with US pay- lergan acquired through its purchase of Tobi- believe Novartis’s lead FXR agonist is one ers indicate they may initially try to steer ra Therapeutics Inc. last year for up to $1.7bn. of those differentiated compounds, which treatment-naïve patients toward biosimi- CVC is a once-daily, oral, immunomodu- is why we have entered into this collabora- lars rather than switching treatment-expe- lator that blocks two chemokine recep- tion, after a successful preclinical collabora- rienced patients who are stable on novel tors, CCR2 and CCR5, which are involved tion.” He revealed that Allergan has its own biologics, according to a recent Datamoni- in inflammatory and fibrogenic pathways. FXR compound ready for Phase I testing, “so tor Healthcare report. In the Phase IIb CENTAUR study, CVC dem- we are fully committed to the FXR pathway However, Amgen suggests these prevail- onstrated a clinically meaningful improve- and combinations with CVC.” ing attitudes may change once biosimilars ment in fibrosis of at least one stage without Novartis supplemented its NASH activi- for cancer treatment reach the market. worsening of NASH after one year of treat- ties last year when it paid $50m up front for The report points a 2016 survey that found ment, “one of only two approvable Phase a licence to Conatus Pharmaceuticals Inc.’s oncologists were the only specialists likely to III endpoints,” noted the companies. “With caspace inhibitor emricasan, another poten- prescribe biosimilars to the majority of their its unique mechanism of action and its fa- tial combination candidate for FXR agonists. treatment-naïve patients and treatment-ex- vorable safety profile, CVC represents an Intercept Pharmaceuticals Inc. is the cur- perienced patients who required retreatment. ideal candidate to become the backbone of rent frontrunner in the NASH space with “With access and affordability being is- NASH multi-therapy treatment.” its FXR agonist Ocaliva (obeticholic acid), sues in oncology, physicians and patients However, CVC’s Phase II data were viewed which is in the REGENERATE Phase III trial in may be willing to use therapeutic oncology skeptically by investors because the drug NASH patients; Ocaliva is already approved biosimilars once they become available,” the missed the primary endpoint assessed us- in another liver disease, the rare condition report states. ing the NAFLD Activity Score (NAS), but primary biliary cholangitis (PBC). Analysts Amgen and partner Allergan PLC have met a secondary endpoint of reducing liver have suggested that the PBC approval has a proposed biosimilar to Genentech Inc.’s fibrosis after a year on therapy. strengthened the potential for commercial Avastin (bevacizumab) pending at FDA with Novartis declined to elaborate on why it success of Ocaliva in NASH as it allows the a September user fee goal date. had decided to test its product in combina- drug to develop physician familiarity. Published online 17 April 2017 tion with CVC. In an emailed statement, it Published online 19 April 2017 scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 9 RESEARCH & DEVELOPMENT

AbbVie Next-Gen Combo To Target OncoMed Trying To Regroup After Hard-To-Cure HCV Patients Cancer Failures JOSEPH HAAS [email protected] After the Phase II failure of anti-cancer stem Data from EXPEDITION-1 show a 99% SVR a protease inhibitor and an NS5A inhibi- cell antibody tarextumab in small-cell lung rate for HCV patients with compensated tor. The new drug application (NDA) was cancer, another in a string of failures, execs cirrhosis after 12 weeks of therapy. Ab- backed by data from eight registrational highlight potential of other pipeline assets, bVie also will present data at EASL on the studies in more than 2,300 patients in including immuno-oncology targets. utility of glecaprevir/pibrentasvir in CKD, 27 countries, encompassing all six geno- OncoMed Pharmaceuticals Inc. is post-liver or kidney transplant, HIV co- types of the virus. A concomitant Euro- trying to shift focus to its earlier-stage infected and treatment-failure patients. pean filing was accepted for accelerated pipeline assets following another assessment, and an approval decision is pipeline setback – the failure of its anti- ith Viekira Pak missing sales ex- expected between Sept. 1 and Nov. 30, cancer stem cell antibody tarextumab, pectations in hepatitis C, AbbVie according to Biomedtracker, which gives which is partnered with GlaxoSmith- Inc. has placed substantial hope the combo a 99% likelihood of approval Kline PLC, in the PINNACLE study in W first-line small-cell lung cancer. on its next-generation combo glecaprevir/ in both the US and EU. pibrentasvir with a special focus on difficult- AbbVie hopes that these data and other The mid-stage PINNACLE study to-treat HCV sub-populations. At the Inter- datasets being presented during EASL tested tarextumab, which targets Notch national Liver Congress, the Chicago-area will show the next-generation regimen’s 2/3, with etoposide and cisplatin or pharma is presenting data demonstrating promise in patients with specific treat- carboplatin chemotherapy, followed the fixed-dose combo can cure many HCV- ment challenges. The firm also is unveil- by maintenance tarextumab, versus infected patients with compensated cirrho- ing updated data from the MAGELLAN-1 the same chemotherapy with placebo sis without ribavirin add-on therapy. study in genotype 1 and 4 patients who in 145 previously treated small-cell On the opening day of the European have failed prior therapy with direct-act- lung cancer (SCLC) patients. The test Association for the Study of Liver Diseases ing antiviral regimens as well as resistance drug arm failed the primary endpoint meeting in Amsterdam, AbbVie reported analysis from the trial; updated data from of median progression-free survival that the glecaprevir 300 mg/pibrentasvir the CERTAIN-1 study, which will back a (5.6 months for tarextumab versus 120 mg regimen, combining a protease regulatory filing of the doublet in Japan; 5.5 months for the comparator) and inhibitor co-developed with Enanta Phar- and top-line results from the MAGEL- secondary endpoint of median overall maceuticals Inc. and an NS5A inhibitor, LAN-2 study, investigating pan-genotypic survival (9.3 months for tarextumab produced a 99% (145/146) sustained viro- treatment of patients after liver or renal vs. 10.3 months for comparator), logic response rate at 12 weeks after the transplants. Other presentations will ad- OncoMed announced April 17. These completion of therapy (SVR12) in patients dress the combo’s efficacy in patients with survival results were statistically similar. with genotype 1, 2, 4, 5 and infections chronic kidney disease and co-infected Furthermore, an analysis of five and compensated cirrhosis (Child-Pugh with HIV, two of the subpopulations Ab- Notch biomarkers (Hes1, Hes6, Hey1, A disease). bVie wants to target with the glecaprevir/ Hey2 and Notch3) did now show a In the EXPEDITION-1 study, the combo pibrentasvir regimen. benefit for subsets. was dosed for 12 weeks without ribavirin. The US and EU filings also seek labeling Tarextumab had a similar safety pro- While the study did not include patients recommending eight-week treatment for file as the comparator arm in the study. with genotype 3 HCV infections – typically a majority of patients, which would offer OncoMed previously suspended de- the toughest to cure in general – patients a competitive advantage compared to velopment of tarextumab in pancreatic with viral strains associated with resistance Gilead Sciences Inc.’s market-dominating cancer in light of the failure of the Phase or with a high quantity of virus in their blood- regimens anchored by the nucleotide Ib/II ALPINE study in February 2016. stream were not excluded, AbbVie said. polymerase inhibitor sofosbuvir (Sovaldi In addition to the news about tarex- The combination of glecaprevir (ABT- and in the Harvoni and Epclusa combina- tumab failing in SCLC, the company 493) and pibrentasvir (ABT-530) have tion pills). Most patients are dosed for 12 also announced on April 17 plans to ter- been filed for approval at both the US weeks, but Harvoni (sofosbuvir/ledipasvir) minate a Phase Ib study of its anti-cancer FDA and the European Medicines Agen- is indicated for eight weeks of treatment stem cell antibody brontictuzumab cy. In the US, the doublet has an Aug. 18 in patients with lower viral loads. (OMP-52M51) that tested OncoMed’s action date and is being evaluated un- Published online 20 April 2017 drug in combination with Otsuka Pharmaceutical Co. Ltd.’s Lonsurf (triflu- der priority review – it obtained an FDA ridine/tipiracil) in third-line colorectal breakthrough therapy designation last For Commercial Prospect Estimates click cancer, due to problems with tolerability. September for genotype 1-infections pa- here: http://bit.ly/2pglDAw tients who failed prior therapy including [email protected], 17 April 2017

10 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 MARKET INTELLIGENCE

Can Cholesterol Drug Sponsors Make The Case For Statin Intolerance? Amgen’s FOURIER outcomes study of Repatha supports LDL-lowering in high risk patients, but price may have to come down dramatically to spur wide use of the PCSK9 inhibitors with the subjective condition of statin intolerance. EMILY HAYES [email protected]

he possibility of treating patients Amgen Inc. and Sanofi/Regeneron Phar- down dramatically to spur wide use in who cannot tolerate statins has long maceuticals Inc. had originally hoped to this population. T been eyed as a valuable segment of gain statin intolerant claims for their PCSK9 The release of Amgen’s FOURIER out- the cholesterol market, but has been a dif- inhibitors Repatha (evolocumab) and Pral- comes study of Repatha in a patient popu- ficult claim to get past regulators. However, uent (alirocumab), respectively, but hit a lation at high risk for events and well man- recent developments arguably may help roadblock at the US FDA. New outcomes aged on statins has renewed debate about build a market for what has been a hard-to- data support treatment to low LDL levels wider use of the drugs, including treating define population. and could spur broader use, plus labeling statin intolerant patients.

STATIN INTOLERANCE Datamonitor Healthcare estimates that there were 264m cases of hypercholesterolemia in adults in the US, Japan and five major EU markets in 2015. Overall, 34.4% of these cases are associated with high risk for coronary artery disease. Statin intolerance for a variety of reasons continues to represent an area of unmet need, despite many approved treatments in a highly genericized market, and a lucrative segment. According to Datamonitor’s proprietary survey of prescribers in November 2016, rates of statin intolerance ranged from 9% to 17% in the US, Japan and five major EU markets. But statin intolerance has always been a subjective term, prone to controversy. Amgen and Sanofi originally sought to get claims for treating statin intolerant patients

Shutterstock: hywards Shutterstock: included in labeling of their PCSK9 inhibitors. But instead, they both got similar la- The majority of the cholesterol market is allows for use in patients on “maximally tol- beling for use in particular populations well-served by statins, which offer effective erated statins” – which could mean none. – on top of maximally tolerated statin LDL lowering now as oral generic drugs. Recently, Esperion Therapeutics Inc. an- therapy for adults with heterozygous fa- There are still patients who can’t tolerate nounced it had worked out a plan with US milial hypercholesterolemia and for use in the side effects common to the class – in- regulators to gain a statin intolerant indi- patients with clinical atherosclerotic car- cluding muscle pain and cognitive impair- cation for its bempedoic acid, an oral in- diovascular disease who need additional ment. Off-label use in such patients helped hibitor of ATP citrate lyase, by conducting LDL lowering. Repatha is also cleared for drive Merck & Co. Inc.’s Zetia (ezetimibe) to a cardiovascular outcomes trial (CVOT) in an additional indication for use with other blockbuster status. that population. LDL lowering therapies in treating the rare Gaining an FDA approval for the indica- Amgen presented the first CVOT for genetic disease homozygous familial hy- tion has proven difficult, so later entrants the PCSK9 class at the American College percholesterolemia. to the cholesterol field have focused on of Cardiology annual meeting in March. At the time of approval in 2015, the high-risk subpopulations and those with Although Amgen’s FOURIER trial was in sponsors maintained that this labeling for rare genetic forms of hypercholesterolemia. patients taking statins, the cardiovas- “maximally tolerated” statins in effect in- But there are still hopes that with better evi- cular outcomes benefit arguably gives cludes statin intolerant patients. dence of effect on cardiovascular outcomes, a leg up to the PCSK9 inhibitor class for Statin intolerance has been a challeng- those products may get broader use, includ- treatment of statin intolerant patients – ing issue to deal with in the FDA review ing in the statin intolerant segment. though pricing may still have to come CONTINUED ON PAGE 12 scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 11 MARKET INTELLIGENCE

CONTINUED FROM FROM PAGE 11 While the agency was wary of including Requiring two or more statins, including process. In the review documents for the specific labeling for statin-intolerant label- at the lowest dose, may get around some PCSK9 inhibitors, FDA said that its working ing, FDA officials had also noted in review of FDA’s earlier concerns about re-chal- definition of statin intolerance was a pa- documents that “language that indicates lenging patients, although unlike GAUSS-3 tient who is not able to tolerate the lowest use in combination with ‘maximally tolerat- the re-challenge is not done as part of the starting daily dose of a statin, in addition to ed statin therapy’ would recognize that, for controlled trial. any dose of another statin, due to symp- some patients, maximally tolerated statin toms that began or increased during statin therapy may be no statin therapy at all.” IMPLICATIONS OF FOURIER therapy and ended when statin therapy “I think the FDA was very smart and In Amgen’s FOURIER trial, Repatha yielded stopped. gave a lot of freedom there in terms of a 15% reduction for the primary endpoint The agency questioned whether the defining the disorder. It’s a tough disorder related to major adverse cardiovascular PCSK9 sponsors were using adequate crite- to define scientifically,” said Robert Eckel, events and a 20% reduction in a secondary ria for statin intolerance in their trials; FDA director of the lipid clinic at University of endpoint related to cardiovascular death, noted that in Sanofi/Regeneron’s ALTER- Colorado Hospital. myocardial infarction or stroke. NATIVE trial, experience with a statin vali- Eckel expects that FDA will continue The level of benefit may not have lived dation arm the sponsors included showed with this approach – that is, rather than up to expectations and there was no de- that 70% of patients who were statin in- using the term “statin intolerant” in label- crease in mortality events, but follow-up tolerant due to muscle symptoms, could ing it will approve claims based on trial lasted only two years and it is possible that actually withstand treatment with a statin entry criteria. the benefit in terms of death rates would (atorvastatin at 20 mg, Pfizer Inc.’s Lipitor have been shown over a longer period. and generics) in a validation arm of the WILL IT WORK FOR ESPERION? The results from FOURIER may be in- study. The regulators argued this showed Coming late to the cholesterol market, Es- terpreted as encouraging when it comes the value of rechallenging with a statin. perion has been steering development to treating the statin intolerant popula- Since the PCSK9 inhibitor approvals, Am- of its bempedoic acid heavily toward the tion, even though the CVOT was not in a gen released a new Phase III study in statin statin-intolerant population. statin-intolerant population. To get into the intolerant patients that did include rechal- Asked to comment on Esperion’s plans in FOURIER study, patients needed to be on lenging with a statin. In the GAUSS-3 trial, January 2016, FDA confirmed that its views a maximally tolerated dose of statins and Repatha was associated with much greater on statin intolerance were in line with sen- to be at high-risk for cardiovascular events. LDL-lowering than Merck’s Zetia. Reports timents expressed during the reviews of Consequently, 69% of the study population of muscle pain were not that much lower the PCSK9 inhibitors. In an email to the Pink was on high-dose statins and the baseline than Zetia – 20.7% vs. 28.8% – but discon- Sheet at that time, the agency reiterated its LDL in the trial was 92 mg/dL. tinuation rates associated with this adverse concerns about the risk of encouraging The trial showed a reduction in events event were low at 0.7% and 7% for Repatha patients to prematurely abandon statins, regardless of the starting LDL level. And the and Zetia respectively. though this could be mitigated if a drug mechanism of action, already well accept- GAUSS-3 initially had two ten-week were to demonstrate a favorable effect on ed, was strengthened by the outcomes crossover periods, during which time the CV morbidity/mortality in an outcomes trial results. Furthermore, some experts be- 491 patients in the study were randomized trial that is applicable to a “statin-intolerant” lieve that a benefit for mortality might be to atorvastatin or placebo, followed by a population. seen if the study was longer. washout period and then, for those who The agency declined to comment fur- Eckel commented that he is excited could tolerate it, randomization to the al- ther, but Esperion recently said that FDA is about the data and that the results support ternate treatment. Cedars-Sinai’s cardiolo- on board with its plans to do an outcomes getting patients down to lower LDL levels. gist Sanjay Kaul points out that the results study specifically in statin-intolerant pa- The last version of LDL treatment guide- show the challenges of making a diagnosis tients. The initial approval would be based lines from the American College of Car- of statin intolerance – only 43% of patients on Phase III trials in high-risk patients, as diology and American Heart Association, developed statin intolerance while taking with the PCSK9 inhibitors, but by doing the issued in 2013, moved away from treating atorvastatin but not placebo, 27% while CVOT in statin-intolerant patients, an indi- to particular targets and toward a focus on taking placebo but not atorvastatin (per- cation matching that trial population could risk. The guidelines are now being revised haps related to the “nocebo” effect) and later be added to labeling. and many specialists – including Eckel, 17% while taking both treatments. The CLEAR Outcomes study tests the who was involved in writing the 2013 ver- “So only 60% (43 + 17) developed statin drug in 12,600 patients who are statin in- sion – believe it is possible there may be a intolerance to atorvastatin, even though a tolerant, which the company says for the move back toward endorsing targets. well-documented muscle-related adverse purposes of the trial is defined as “inabil- To date, 70 mg/dL has been ingrained as effect to two or more statins was an en- ity to tolerate two or more statins, one at an LDL target for patients at high risk of a try criterion. Interestingly, one-fifth of the the lowest approved daily starting dose, cardiovascular event, but the FOURIER and statin intolerant patients in GAUSS-3 still due to an adverse effect.” Participants will IMPROVE-IT study of Merck’s Zetia suggest reported muscle-related adverse effects have cardiovascular disease or be at risk an even lower target of at least 55 mg/dL while taking evolocumab,” Kaul said. for it. may be appropriate, he said.

12 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 MARKET INTELLIGENCE

A spokesperson for the AHA said that the rington, chair of the department of medi- it’s hard to make the case that PCSK9 in- process of reviewing results from relevant cine at Stanford University. hibitors provide value without a major dis- scientific research, including the results from “I suspect that there will be an increase count – at least 75%. FOURIER, has begun but that it is too early in treatment for this group although costs Eckel also felt that reimbursement is to predict when the guidelines will be com- will be an issue, as will insurance coverage,” hugely important in terms of using PCSK9 pleted or how they will change. Results from he added. inhibitors in statin intolerant patients. Typi- Sanofi/Regeneron’s ODYSSEY outcomes The expectation is that through FOU- cally, insurers want to see that the condi- study of Praluent are due later this year. RIER, Repatha will get a cardiovascular risk tion has been documented and that pa- The authors of the last version of the reduction claim. tients have tried two different statins for six guidelines took a cautious approach to- It’s unclear whether the agency would weeks. Often they will also require that a ward statin intolerance, advising prescrib- note in the phrasing of the claim on label- patient has tried Zetia. They may also want ers to investigate whether there might be ing that the drug is to be given on top of to see results from a creatine phosphoki- another cause for symptoms and whether high-intensity statins. Most, but not all of nase (CPK) test if the issue is muscle pain, patients were truly intolerant. Eckel is not the patients in the study were on high-in- but these tests are often normal, muscle expecting changes in the way statin intol- tensity statins; others were on lower doses. pain being subjective, Eckel commented. erant patients are handled in the next ver- If labeling gives a broad claim for risk re- “It’s really an art of medicine, not a sci- sion of guidelines. duction on top of statin therapy, this could ence,” he said. What FOURIER means for the market include patients who are able to take a low Payers are really looking for proof in cer- of patients who are intolerant to statins dose of a statin and yet whom may still be tain populations and have difficulty with remains to be seen. The class is certainly regarded as statin intolerant. the idea of statin intolerance, commented capable of much more dramatic LDL low- “If the FDA allows a CV risk reduction Edmond Pezalla, an independent reim- ering than alternatives like Zetia and there- claim for evolocumab based on FOURIER, bursement consultant in Hartford, Conn. fore represent a more robust option for I think the clinicians should be able to use and former policy and strategy executive statin intolerant patients. the drug in patients deemed truly statin- at Aetna Inc. And FOURIER was done in However, the injectable PCSK9 inhibi- intolerant, provided the payers allow it,” combination with statins, not as an alterna- tors also cost a lot more, with a list price of Cedars-Sinai’s Kaul commented. tive to statins, so it is questionable whether about $14,500 per year. Amgen contends Kaul expects that for a specific indication they would make the leap to assuming the that its net price of Repatha, including dis- or claim in statin intolerant patients, the results would apply to patients with statin counts, is more in the range of $7,700 to FDA would need to see outcomes data spe- intolerance, especially considering the cost $11,200 annually. The company sees the cifically in that population – like Esperion is of the drugs, he said. FOURIER results as supporting the current planning – but said that it’s unclear whether Pezalla said that it is terrific that FOU- pricing. Sanofi declined to comment on clinicians or payers really need an FDA-ap- RIER showed that getting patients down the net price for Praluent, which has a simi- proved indication for statin intolerance. to as low as 30 mg/dL still improved out- lar list price. PCSK9 inhibitors are more effective than comes, but the only way to get the drug Zetia for getting patients to target, so to a broader population is to bring the PRESCRIBERS’ RESPONSE PCSK9 inhibitors should be preferred. price down. PCSK9 inhibitors have been tightly man- “In my opinion, the cost would need to A net price closer to $4,000 per year aged by insurance companies to date, be discounted heavily for me to consider would boost uptake, he suggested. which has had a negative impact on sales. PCSK9 inhibitors ahead of ezetimibe in this The Institute for Clinical and Economic But questions have remained about wheth- patient population. Based on the FOURIER Review (ICER) announced March 17 plans er outcomes data would make a difference results, the 1.5% absolute risk reduction to update its assessment of comparative in prescribing patterns and reimbursement. in both the primary and the key second- clinical effectiveness of PCSK9 inhibitors, Roger Longman, chief executive officer of ary endpoint translates into a NNT [num- including a re-calculation of a value-based the reimbursement intelligence company ber needed to treat] of 66 over a median pricing benchmark, to take FOURIER data Real Endpoints, has noted that there are follow-up of 2.2 years. At an annual cost of for evolocumab into account. The initial management costs associated with re- $14,500, this means that the cost of pre- ICER assessment called for a 67% price jecting requests and that if demand rises venting 1 event is over $2 million. Even at reduction, which was later revised to 47% discount to the list price. enough, payers will respond. a 50% discount, the $1 million cost of pre- The ICER update, which is slated for mid- Although FOURIER was not designed venting one event does not offer a value May, could have implications for payers’ ex- to assess outcomes in statin-intolerant proposition,” Kaul commented. pectations. patients, the improvement in clinical out- Even if the FDA approved a specific indi- Published online 20 April 2017 comes with the demonstrated LDL lower- cation in statin intolerant patients (a best- ing should make patients and clinicians case scenario), the prohibitive cost and the reasonably comfortable with the choice of skepticism of payers would still pose a bar- View Statin Intolerance Rates For a PCSK9 inhibitor as an alternative for LDL rier against widespread use, Kaul added. Secondary Prevention, Major Markets here: lowering when it is required and statins Given the estimated number needed to http://bit.ly/2pVZJR5 are not tolerated, commented Robert Har- treat to prevent an event, in Kaul’s view, scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 13 RESEARCH & DEVELOPMENT

New Active Substance Launches Declined Again In 2016 2016 witnessed a second straight year of decline in the number of new active substance launches worldwide, but trend data show that this hard measure of R&D productivity was still healthy compared with industry’s performance during the first decade of the century. ALEX SHIMMINGS [email protected]

n 2016, a total of 41 new active substances KEY FACTS: launches with reformulated or non-NAS (NAS) reached the market for the first time 41 NAS launched in 2016 moieties, and biosimilars. Iworldwide – that’s an 11% drop on 2015, 11% drop on 2015’s total of 46 Looking here reveals 2016 to be the worst which was itself a 27% fall from the previ- Fewer first-in-class products year since 2009, but the tally of 34 non-vac- ous year. cine NASs still puts last year a little ahead of 20% were Orphan products 2016 wasn’t a great year for novelty either, the average throughout the noughties. Alto- Disappointing tally for Big Pharma with only nine of the products, or 22%, being gether, it makes 2014’s proud tally of 54 look first in class, compared with over 30% of the all the more freakish. 46 NAS launched in 2015. as they have been stockpiled for potential That year was boosted by a no fewer Nor did big pharma cover itself with use in the event of a pandemic. It is the lower than seven novel treatments for hepatitis glory – the company that delivered the red portion of the column representing non- C and four for SGLT2 inhibitors for type 2 most new launches was the Australian vaccine NASs that more truly reflects the un- diabetes, and bolstered further by a bum- firm CSL Limited, while many of the top derlying trend in industry innovation. per year for Japanese debuts – but has not firms managed none at all. But there was Editor’s note: The survey conducted in ushered in a vintage era for the industry. a solid performance from orphan drugs, conjunction with Pharmaprojects focuses Instead we appear to have entered a rather which consolidated their position in the exclusively on new active substances (NASs): less glamorous period characterised by new drugs lists. new chemical or biological entities where blood clotting factors and me toos, with in- The chart below of NAS launches from the active ingredient had received no prior cremental advances being the order of the the past 16 years separates out vaccines at approval for human use. This includes vac- day. 2016’s new crop of hepatitis C drugs, the top of each column. While the vaccines cines with novel antigenic components. As for example, offer improved cure rates, dos- included are strictly-speaking NASs, many such, this list represents a subset of all the ing, treatment length or side-effect profiles are just new variations of influenza vaccines, first launches which Pharmaprojects report- over their predecessors, but they do not hit some of which are only considered launched ed during 2016, excluding the 78 new drug any interesting new therapeutic targets.

NAS Launches Worldwide 2000-2016

55 6

50 45 3 40 1 35 6 3 1 8 7 30 2 3 1 4 25 1

10 5 7 2 6 8 5 7 7 3 0 6 9 9 6 1 6 6 7 4 3 2 2 2 3 3 3 4 3 2 2 2 3 2 3 5 3 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Other NASs Vaccines

Pharmaprojects®, February 2017

14 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 RESEARCH & DEVELOPMENT

Percent of NAS With Orphan Drug Status 2012-2016

5 5 1 1 2 0 . . . . . 7 7 6 2 0 9 2 2 3 5 3 2012 2013 2014 2015 2016

Pharmaprojects®, February 2017

One factor that always has a clear effect this came in at just over a third, despite a on the annual figures is what’s happening US remained the tightening up of the definitions used here at the US FDA, as the US market routinely to make the measure more relevant. In accounts for around half of all global NAS most popular choice previous years, a product was counted as first launches. 2016 was a lean year for the being an orphan if it had any ODS desig- US agency – it only approved 22 novel for a first market nation, for indication and market, but this products (NB not all of these qualify for in- launch, although year, only drugs that received orphan status clusion in our NAS list of global first launch- in the market in which it was first launched es), the lowest for some time, but it must its grip did slacken and for the disease for which it was first be noted that their average approval time launched have been counted as orphans. was shorter than ever, thanks to histori- this year Even so, the number for 2016 at 15 equates cally high proportions of priority reviews to 37% – in keeping with recent historical and first-cycle approvals. Of the 22 new And while novel drug launches are a key levels although lower than in 2015. molecular entities and novel therapeutic metric for industry innovation, this measure When the list is sorted by company, it is biologics approved by the FDA in 2016, 15 doesn’t take into account the growth that clear that big pharma’s yield in 2016 was had a priority review and seven had break- pharma sees from its increasingly quasi-pan- poor. Many top names, including Pfizer Inc., through therapy designations which sped acea approach to medicine. That the world’s Novartis AG, Sanofi and Johnson & John- them through the process. best-selling drug Humira has a US label that son, managed no NAS launches, though to The couple of years before also saw a host spans ten indications has not been lost on its be fair to Novartis, its late-stage pipeline re- of drugs being approved well ahead of their competitors. More and more products now sources were probably left rather depleted PDUFA dates which may have had an impact have more than one therapeutic string to following its four NAS launches in 2015. on the numbers coming through the system their bows, not just in the immunological/ Similarly, Allergan PLC which also managed in 2016. Faster approval times and fluctua- inflammation segment, but also in cancer. It four launches in 2015, was conspicuous by tions in the numbers of novel product going is, however, reassuring to note that the num- its absence in 2016. through the varied paths of the US regulatory ber of drugs in Phase III and currently await- But Merck & Co. Inc. is enjoying a purple system will have a knock-on effect on the ing approval are at an historic high. patch, with two NAS launches last year to NAS list, especially given that the time frame Nonetheless over the years, some broad add to the three it delivered in 2015, and four of each calendar year employed in the analy- themes can be found. The first of these is the year before that. Matching Merck with a sis is rather arbitrary, which makes it tricky to the increase in the proportion of orphan brace of launches last year were Roche and discern any clear trends. drugs reaching the market. Once again CONTINUED ON PAGE 16 scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 15 RESEARCH & DEVELOPMENT

CONTINUED FROM FROM PAGE 15 Top Company NAS Launch Performance 2016 Eli Lilly, and Shire. But it was smaller companies that really shone. Topping the list with COMPANY NUMBER OF NAS LAUNCHES 2016 POSITION BY PIPELINE SIZE IN TOP 100 three NASs was Australian firm CSL Ltd., while CSL Limited 3 41 SK Holdings Co. Ltd. produced two products. Merck & Co 2 4 Their products were either flu vaccines or blood clotting products (one of which was Roche 2 7 joint effort). Eli Lilly 2 11 Shire 2 18 THERAPY AREAS SK Holdings 2 56 The chart below breaks down the 41 NASs GlaxoSmithKline 1 2 by their primary therapeutic group, and shows some surprising changes from 2015. AstraZeneca 1 6 Removing the seven vaccines from consid- Novartis 0 1 eration leaves Neurologicals as the leading Pfizer 0 3 group with six NASs, followed by a tie for Johnson & Johnson 0 5 second place for three therapeutic groups: Sanofi 0 8 Anticancers, Anti-infectives, and Alimen- Bristol-Myers Squibb 0 9 tary/Metabolic each had five. This is a big come down for oncology, Takeda 0 10 which in 2015 was the leading source of Source: Pharmaprojects, February 2017 NASs when no fewer than fourteen new cancer drugs made their debuts. Cancer with the Phase II candidate navitoclax, currently accounts for about a third of the but no other drugs with this mechanism pipeline and the concomitant R&D effort. It are currently beyond Phase I. Venetoclax may be that here the rush to market in re- is also in development for myeloma and cent years set in train by the Breakthrough acute myelogenous leukaemia. Therapy rules has left a lag which, together Eli Lilly & Co. contributed Lartruvo (olara- with the focus on developing single drugs tumab), which targets platelet-derived for multiple indications and for combination growth factor receptor (PDGFR). Whereas use, in particular for the newer immuno-on- there have been a number of anticancer cology agents, has had a knock-on effect. It drugs hitting the PDGF kinase, this is the will be interesting to see how Anticancers first to hit the receptor. Approval came in perform in the NAS lists in future years. GongTo Shutterstock: the US in October for soft tissue sarcoma, an In contrast, it was a great year for the sec- three completely new strategies to market. orphan disease. It is one of just six monoclo- ond largest therapeutic group by pipeline With Tecentriq (atezolizumab), Roche/ nal antibody drugs first launched, fewer than size, Neurologicals, which includes all CNS Genentech Inc. brought the first PD-L1 in- the nine seen the previous year. However, drugs and psychiatrics. This area’s six novel hibitor to the market, initially for bladder biologicals overall accounted for nineteen products represents its best performance cancer, but then also for non-small cell lung of the NASs, or almost half. In keeping with in memory. But the Cardiovascular area’s fall cancer. For the former indication, it is being Neurologicals’ strong year, it matched the from fashion continued – 2015’s apparent chased by competitor drugs from Merck oncology sector in producing three first-in- renaissance with five novel products, includ- KGAA/Pfizer, whoseBavencio (avelumab) class products, although this tally does in- ing the PCSK9 inhibitors Repatha and Pralu- has just been approved and launched for clude the controversial Duchenne’ muscular ent, plus Entresto and Praxbind, looks to have merkel cell carcinoma in its first market, dystrophy treatment Exondys 51 (eteplirsen) been short lived. In 2016 there was just one the US, as well as AstraZeneca PLC whose from Sarepta Therapeutics Inc. CV product, selexipag. durvalumab is awaiting approval in blad- The others are the antisense product der cancer. Spinraza (nusinersen) from Ionis Pharma- DESPERATELY SEEKING NOVELTY Roche’s second novel NAS of year, this ceuticals Inc. and Biogen Inc. for the orphan More disappointing was the relatively poor time developed in collaboration with neurodegenerative disease spinal muscular showing for novelty in 2016. Just nine NASs, AbbVie Inc., is Venclexta (venetoclax), for atrophy, which acts to increase SMN-2 (sur- or 22%, were first-in-class, in contrast to the chronic lymphocytic leukaemia, the first vival of motor neuron-2) levels, and Biopro- 14 novel products (30%) in 2015. This means Bcl2 inhibitor to reach the market. Over- jet and Ferrer Therapeutics Inc.’s Wakix (pi- 2016 was in line with 2014 in terms of the expression of Bcl2, an anti-apoptotic pro- tolisant), a histamine H3 inverse agonist for proportion of first in class products (19%) tein, when combined with overexpres- the treatment of narcolepsy. but numerically less productive (12). sion of the proto-oncogene myc, causes In ophthalmology, Shire PLC delivered the And while cancer may have underper- aggressive B-cell malignancies. The two first lymphocyte function associated mole- formed in terms of numbers, it did produce companies are following up venetoclax cule-1 (LFA-1) inhibitor in Xiidra (lifitegrast) for

16 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 RESEARCH & DEVELOPMENT

Percent of NAS With Orphan Drug Status 2012-2016

1 2 5

6 3

1 1 2

2 5 1

Alimentary/Metabolic Blood & Clotting Cardiovascular Dermatological Genitourinary Immunological Anti-infective Anticancer Musculoskeletal Neurological Respiratory Sensory

Pharmaprojects®, February 2017 the treatment of dry eye syndrome (xeroph- become the first product to be launched Inc. added another new combination thalmia). LFA-1 is a pro-inflammatory T-cell to treat hallucinations and delusions associ- product to its armoury in Epclusa, which surface protein which mediates the chronic ated with Parkinson’s disease psychosis; the adds the NAS velpatasvir to its mainstay inflammatory cascade associated with dry company has high hopes that it will also sofosbuvir. eye disease. A filing has also been made in prove to be its first blockbuster. Canada, and an EU application is expected in MARKET OF CHOICE the third quarter of 2017. While novel drug Unsurprisingly, the US remained the most Increasing research in liver disease saw on popular choice for a first market launch, al- the first farsenoid X receptor agonist come launches are key though its grip did slacken with only around to market, as Ocaliva (obeticholic acid) was 50% of the launches this year, compared launched by Intercept Pharmaceuticals Inc. for innovation, this with 63% in 2015. for primary biliary cholangitis (PBC). This is a Nonetheless it is still streets ahead of its chronic indication in which the hepatic bile doesn’t consider rivals. Japan and South Korea were runners- ducts become damaged, leading to a build- the growth that up, with four apiece, but some of these were up of bile which can lead to cirrhosis. ‘flu vaccines. In Europe there were three UK Lastly comes Ironwood Pharmaceuticals pharma sees from debuts, one in Germany, and a further two Inc.’s URAT1 inhibitor Zurampic (lesinurad) for being reported to have occurred non-specif- hyperuricaemia. URAT1 is a urate transporter its quasipanacea ically in the EU. and urate-anion exchanger which regulates approach to medicine the level of urate in the blood and is a mem- WANT TO READ MORE? brane protein primarily found in kidney. Iron- For more information, see Pharmaprojects’ wood is following it up with a combination And it was another successful year for in-depth report Pharma R&D Annual Review drug with allopurinol, which is awaiting ap- hepatitis C, following last year’s fallow 2017 Supplement: New Active Substances proval in the US. period. Three new drugs reached the Launched During 2016 market, two of which were in a single Published online 17 April 2017 BEST OF THE REST combination product Zepatier (elbasvir Among the still interesting but perhaps less + grazoprevir), and formed part of Merck View New Active Substances Launched In novel NASs is Acadia Pharmaceuticals Inc.’s & Co’s list-topping offerings. Not to be 2016 here: http://bit.ly/2pWLmyI Nuplazid (pimavanserin tartrate), which has outdone, market-leader Gilead Sciences scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 17 COMPANY FOCUS

UniQure Gives Up On Glybera, But Not Gene Therapies MANDY JACKSON [email protected]

UniQure will not seek marketing authorization renewal for pabilities in the US. Its existing cash balance – $132.5m as of Dec. Glybera in the EU before it expires in October, but the company 31 – should be sufficient fund operations into 2019. does not see the product’s commercial failure as a sign that the “All of our manufacturing is now condensed in Lexington, which market won’t accept gene therapies or their high price tags. is not licensed to produce Glybera,” Kapusta said. “The Amsterdam facility is to be decommissioned.” niQure NV surrendered to the ultra-small market dynamics for Glybera, announcing on April 20 that it will not try to re- COST NOT NECESSARILY A DETERRENT Unew the pioneering treatment’s marketing authorization in Manufacturing for gene therapies is difficult and complicated, con- the EU, but CEO Matt Kapusta still sees a market for gene therapies as tributing to the products’ high cost along with the fact they’re usu- new data for novel product candidates emerge. ally one-time treatments; companies have to cover their manufac- The company signaled six months ago that it would no longer turing expenses and recover their research and development costs make Glybera (alipogene tiparvovec) when it revealed plans to by charging extraordinary prices – in the case of Glybera, about $1m consolidate its manufacturing capabilities in the US – at a site in per treatment. Lexington, Mass. that is not licensed to manufacture the product Product pricing is a challenge, Kapusta said, but it’s not the big- for Europe – as part of a broader effort to cut costs and keep its re- gest challenge for the gene therapy field going forward. sources focused on the three key gene therapy development pro- “There must be at least 50 ongoing clinical studies in the gene grams. The manufacturing consolidation and the decision not to therapy space now and we have more clarity on safety,” Kapusta said. pursue marketing authorization renewal for the treatment of famil- “What you don’t have a view on is the long-term durability.” ial lipoprotein lipase deficiency (LPLD) effectively removes Glybera Citeline’s TrialTrove database reveals that there are actually 443 from the market in the EU. gene therapy clinical trials under way globally as of April 20, at least UniQure closed down 2.5% at $5.42 per share on April 20 after the half of which are sponsored by research and academic centers, hos- company said it would continue to manufacture Glybera for Chiesi pitals and other institutions. A report from Pharmaprojects in Sep- Farmaceutici SPA, its commercial partner in the EU, only through tember detailed the gene therapy pipeline, with cancer treatments Oct. 25, which is when the gene therapy’s marketing authoriza- leading the way, followed closely by rare diseases. tion expires in Europe – the only market in which it was approved. UniQure has data in hemophilia B patients who’ve been treated Chiesi marketed the product in the EU under a 2013 agreement, for up to seven years, but those safety results come from very small but UniQure retained costly manufacturing responsibilities for the studies. The company and its peers don’t have long-term data from gene therapy at its Amsterdam site. large studies to confirm the ability to meaningfully improve disease burden for extended periods of time. NARROW LABEL HURT COMMERCIAL OPPORTUNITY “Today, I would not say the biggest challenge is pricing. If we Kapusta does not believe that Glybera, which had a very narrow la- had five gene therapies on the market and they were struggling bel in an extremely small indication, is a reflection of gene therapy’s despite the data, then that would be an issue,” Kapusta said. “But I commercial potential, the UniQure CEO said in an interview. He not- think there is a willingness on the part of payers.” ed that just one patient with the ultra-rare genetic disorder has been treated commercially since the European Commission approved the UNIQURE’S PROSPECTS gene therapy for the treatment of LPLD under “exceptional circum- UniQure will be able to focus all of its attention on three priorities: stances” five years ago. To date, 27 patients have been treated with moving its hemophilia B program (AMT-060) into a pivotal trial based Glybera, almost completely through participation in clinical trials. on feedback from US and EU regulators that’s expected later this “We still are immensely proud of the accomplishment of getting year; and advancing its preclinical Huntington’s disease and heart Glybera approved,” Kapusta told Scrip, even though the first ap- failure programs (AMT-130 and AMT-120, respectively) into first-in- proved gene therapy in Europe never gained commercial ground. human studies in 2018. Based on the small market and limited use of Glybera, UniQure The heart failure asset is being developed under a partnership determined that the economics do not support the costs of com- that UniQure struck with Bristol-Myers Squibb Co. in April 2015. plying with the European Medicines Agency’s (EMA’s) post-mar- “Our strategy for a couple of years has moved beyond Glybera keting requirements for the product and the expense of keeping and we’ve tried to apply the platform towards building commercial a manufacturing facility in operation for a one-time treatment that shots on goal that we can really win,” Kapusta said. European doctors are not prescribing. While hemophilia B and Huntington’s disease are rare diseases, “If we could make it available for patients with a small cost, that’s they are not as small as LPLD and represent attractive markets for something we could do,” Kapusta said. “Without seeing much pa- UniQure with easily identified patients. And, under the Bristol-My- tient need materialize, we made the decision to discontinue.” ers partnership, the company has multiple opportunities to pursue UniQure expects to save $2m annually by withdrawing Glybera treatments for bigger cardiovascular diseases, if payers are recep- from the market on top of savings that it expected from its No- tive to the high-cost, one-time treatments on a larger scale. vember decision to consolidate the company’s manufacturing ca- Published online 21 April 2017

18 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 HEADLINE NEWS

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Co-produced by scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 19 COMPANY STRATEGY

Immune-Focused Discovery Firm Alpine Goes Public JESSICA MERRILL [email protected]

Mitchell Gold, who once led Dendreon, signals simultaneously, and that multitude we expect we will be filing an IND for two will lead the company, which obtains of effects off a single native protein is what additional programs in either immuno- $90m in funding to bring forward three is so unique to Alpine,” Gold said. The plat- oncology or inflammation after our lead is potential drug candidates for inflamma- form is called variant immunoglobulin do- filed,” Gold added. tory conditions and cancer. main (vIgD). The company’s lead candidate is a dual Now, a reverse merger with the public ICOS/DC28 antagonist engineered for use lpine Immune Sciences Inc. will but troubled Nivalis presents an opportu- in autoimmune and inflammatory diseas- transform into a public company nity for Alpine to go public without an IPO es. The company expects to initiate clinical Awith $90m in funding to bring and access Nivalis’ $44m in cash. For Niva- testing in the second half of 2018. forward next-generation drugs in im- lis, the reverse merger is not a surprise. The “Its ability to blast two principal co-stim- muno-oncology and inflammation after company announced earlier this year it was ulatory signals may open up new disease completing a reverse merger with Niva- evaluating strategic options after its lead areas of interest that have been recalcitrant lis Therapeutics Inc. The companies an- drug, cavosonstat, failed to show a benefit to existing forms of treatment,” Gold said. He nounced the planned merger, expected in cystic fibrosis patients when added to declined to say what those areas might be to close in the third quarter, after market Vertex Pharmaceuticals Inc.’s Kalydeco in a during a follow-up interview, but said the close April 18. Phase II trial. company would have a better idea of where The deal marks the return of a big name the strongest signals are after Phase I testing. in immunotherapy to the helm of a public ‘We expect we will be Alpine is also exploring two programs in company. Alpine’s CEO is Mitchell Gold, the oncology that it hopes could build on the former chief executive of the triumphant filing an IND for two success of existing checkpoint inhibitors. and then failed Dendreon Corp., which additional programs in IO “While blocking single checkpoints has successfully developed the first autolo- yielded impressive efficacy data, approxi- gous cancer vaccine Provenge (sipuleucel- or inflammation after our mately 70% to 80% of patients don’t re- T) in 2010, only to see it fizzle on the mar- lead is filed’ spond to checkpoint therapy alone,” Gold ket. Dendreon eventually filed for Chapter said during the conference call. “We have 11 bankruptcy. designed a unique multi-checkpoint in- Gold started Alpine in 2015 with seed hibitor that can potentially blast multiple funding from his own investment firm Al- Following the merger, Alpine share- checkpoint pathways and perhaps expand pine BioVentures with the aim of develop- holders will own approximately 74% of the responder population.” ing therapeutics that modulate multiple the combined company and current Ni- The company also sees partnering op- targets in the immune process at the same valis shareholders will own approximately portunities for its drug discovery platform. time. Orbimed Advisors and Frazier Health- 26% of the combined company. The ex- Alpine already has one research and de- care Partners joined Alpine BioVentures in a change ratio is based on a valuation of velopment collaboration with chimeric $48m Series A financing round that closed Nivalis equal to $50m, including the $44m antigen receptor (CAR) and T-cell receptor in June 2016. in cash expected to be held by Nivalis at (TCR developer Kite Pharma Inc. The com- Gold founded the Seattle-based com- the time of closing. panies signed a research and licensing pany with two experienced biotech scien- agreement in 2015 under which Alpine tists who previously worked at Amgen Inc., 2018: LEAD DRUG IN CLINIC granted Kite the rights to develop two among other companies, Ryan Swanson “By bringing together the substantial re- programs from its transmembrane immu- and Michael Kornacker. sources of both Nivalis and Alpine, we are nomodulatory protein (TIP) technology to “We built this from scratch,” Gold said in creating a unique publicly traded company use with Kite’s CAR-T and TCR candidates, an interview. The goal was to develop a with sufficient capital to achieve meaning- in exchange for $5m up front and $535m drug discovery platform that could work to ful milestones without the near-term need in potential milestones. tamp down the immune system for auto- to raise additional capital,” Gold said during TIP is one of two platform technologies at immune and inflammatory conditions or a conference call the day the news was an- Alpine; it has the potential to help improve dial up the immune system for immuno- nounced. the efficacy and duration of engineered oncology indications. Alpine will have sufficient cash to fund T-cell therapies like those under develop- “We came up with this really unique con- operations for approximately three years, ment by Kite. TIP is based off of Alpine’s cept where we insert a new DNA sequence he said, with the goal of bringing the first primary vIgD platform, with the primary into the native immune system protein drug candidate into the clinic in the sec- difference being that vIgDs are standalone and we can build in biology that wasn’t ond half of 2018. drugs, while TIPs are designed to work with there before where these native proteins “With the additional capital on our bal- engineered cellular therapies. can now interface with multiple different ance sheet as a result of this combination, Published online 19 April 2017

20 | Scrip intelligence | 28 April 2017 © Informa UK Ltd 2017 MARKET INTELLIGENCE

Valeant Gives Siliq Competitive Price In Crowded Psoriasis Market The third IL-17 inhibitor on the US market will have a $3,500/month list price. But in a crowded, safety-conscious space like psoriasis, it’s unclear how low the discounted price will need to go and whether competitive pricing would be enough to sway prescribers.

EMILY HAYES [email protected]

aleant Pharmaceuticals Interna- Average Discounts Off WAC Prices cost (WAC) and estimated average dis- tional Inc.’s IL-17 inhibitor Siliq TNF Blockers: 30% counts, and concluded in a December V (brodalumab) may be stuck with a IL-17A inhibitors: 40% 2016 report that all of the treatments it suicidal ideation black box warning and Anti IL-12/23: 15% looked at had value-based pricing, in shackled with restricted distribution, but terms of cost per quality-adjusted life Otezla (apremilast): 20% at least the list price in the US is competi- year (QALY) ratios. Source: ICER psoriasis report, tive at $3,500 per month for the treat- December 2016 Targeted drugs offer good value for ment of psoriasis – the lowest among money compared to non-targeted ther- biologics in the crowded market, accord- apy using the organization’s discounted ing to the company. Humira (adalimumab), which will soon drug cost estimates and a range of other Valeant announced April 21 that its pa- face biosimilar competition, and two other factors, including quality of life and impact tient access and pricing committee set this IL-17 inhibitors – Novartis AG’s Cosentyx on other healthcare costs, ICER concluded. price as a means of positioning the drug as (secukinumab) and Eli Lilly & Co.’s Taltz (ix- Furthermore, ICER concluded that an option with “outstanding efficacy while ekizumab). newer IL-17A targeted agents “provide being the most affordable injectable bio- Valeant has maintained that Siliq might good economic value” compared to etan- logic for patients with moderate-to-severe have an efficacy advantage over Cosen- ercept and adalimumab, and “potentially plaque psoriasis.” The decision was one of tyx and Taltz based on its mechanism also infliximab” (Janssen’s TNF blocker the first from the company’s access com- of action. Siliq blocks the interleukin Remicade). mittee, which was created in May 2016 receptor and the other two IL-17 inhibi- Discounts vary depending on the drug in response to controversy over Valeant’s tors block activity later in the pathway. class (see box). For the analysis, ICER as- drug pricing practices. Whether the difference in mechanism of sumed an average discount of 40% for Such practices by Valeant and Turing action is clinically meaningful has been IL-17 inhibitors off the list price. For Taltz, Pharmaceuticals AG were the focus of US questioned in the past and head-to-head ICER noted a $4,469 list price per 80 mg/ Congressional hearings in April 2016. Va- trials are not available. The drug did per- ml dose (the monthly dose after initia- leant executives at the time – facing the form well in terms of skin clearance re- tion period) and an estimated net price damaging effect of the public attention sponse rates in Phase III studies against of $2,681.40. For Cosentyx, ICER assumed on the company’s stock value – pledged to Janssen Pharmaceutical Cos.’s IL-12/23 a $4,064.57 list price per 300 mg/mL dose price a number of drugs, including Nitro- inhibitor Stelara (ustekinumab). (the monthly dose after initiation) and a list press (nitroprusside) and Isuprel (isoproter- Valeant notes that other drugs approved price of $2,438.74. enol), at “meaningfully lower” levels. At the for psoriasis also have boxed warnings, “The lower initial effectiveness of etaner- time, the company also promised a more albeit not for suicidal ideation. Labeling cept and adalimumab, high long-term dis- formal process for setting prices. for both Humira and Amgen Inc.’s Enbrel continuation rates, and the need for more The US FDA approved Siliq for psoriasis (etanercept), also a TNF blocker, include expensive second-line therapy decrease in February, but the clearance had some boxed warnings for serious infections and their overall value despite lower initial drug big strings attached. FDA’s Dermatologic malignancies. However, neither Cosentyx cost,” ICER said. and Ophthalmic Drugs Advisory Commit- or Taltz have a boxed warning or REMS. Despite the challenges and amid analyst tee voted unanimously in favor of approv- Cosentyx and Taltz also have advanta- skepticism, Valeant has been positioning al, but this was conditional upon inclu- geous dosing compared to Siliq, as they Siliq as a beacon of light for the future, after sion of a boxed warning about the risk for are given every four weeks after the initial trying times. The recent decision by Persh- suicidal ideation and behavior, plus a Risk dosing initiation period versus every two ing Square Capital Management to sell off Evaluation and Mitigation Strategy (REMS) weeks for Siliq. its stake of almost 10% was the latest blow, to control distribution – recommenda- The market is very competitive in terms causing the stock price to drop by 10% on tions that the agency embraced. of the number of treatments, but also March 14 to a close of $10.86. The stock These are big disadvantages in a the pricing of those agents. The Institute price had peaked at $257 in 2015. crowded market with at least seven other for Clinical and Economic Review (ICER) On April 21, the stock price was down by treatment options available, including recently evaluated pricing of psoriasis 4.17%, closing at $8.51. workhorse TNF blockers like AbbVie Inc.’s drugs, including wholesale acquisition Published online 21 April 2017 scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 21 PIPELINE WATCH

Scrip’s weekly Pipeline Watch tabulates the most recently reported CLICK late-stage clinical trial and regulatory developments from the more Visit scrip intelligence.com than 10,000 drug candidates currently under active research worldwide. for the entire pipeline with added commentary.

Selected clinical trial developments for the week 13–20 April 2017

LEAD COMPANY/PARTNER COMPOUND INDICATION COMMENTS Updated Phase III Results GW Pharmaceuticals PLC Epidiolex (cannabidiol) Lennox-Gastaut syndrome GWPCARE3; further positive results.

Vemlidy (tenofovir Safe and effective, as was switching from Gilead Sciences Inc. hepatitis B alafenamide) tenofovir disoproxil fumarate.

Phase III Interim/Top-line Results

squamous non-small cell AbbVie Inc. veliparib (a PARP inhibitor) lung cancer (NSCLC), triple Missed primary endpoints . negative breast cancer

AbbVie Inc./Enanta hepatitis C and compen- glecaprevir/pibrentasvir EXPEDITION-1; 99% SVR at 12 weeks . Pharmaceuticals Inc. sated cirrhosis

rocapuldencel-T (AGS-003) Argos Therapeutics Inc. renal cell cancer ADAPT; mixed results but will continue the study . plus sunitinib

Zybrestat (CA4P; fosbretab- Mateon Therapeutics ovarian cancer FOCUS; PFS favored CA4P, no safety issues. ulin tromethamine)

skin and skin structure Motif Bio PLC iclaprim REVIVE-1; non-inferior to vancomycin . infections

Ultragenyx Pharmaceutical Inc./ X-linked hypophos- CL303; increased serum phosphorus, the primary burosumab (KRN23) Kyowa Hakko Kirin Co. Ltd. phatemia endpoint .

Roche emicizumab hemophilia A HAVEN 2; in pediatric patients, reduced bleeds.

Phase III Initiated

progressive fibrosing In conditions other than idiopathic Boehringer Ingelheim GMBH nintedanib interstitial lung disease pulmonary fibrosis.

Phase III Announced

CREDO 4; in patients with moderate to R-Pharm CJSC olokizumab rheumatoid arthritis severe active disease.

Oxabact (freeze dried live OxThera AB hyperoxaluria OC5-DB-02; to enrol 18 patients. Oxalobacter bacteria)

LEO 43204 (ingenol Leo Pharma AS actinic keratosis Effect on skin neoplasia. disoxate) gel

idiopathic pulmonary ProMetic Life Sciences Inc. PBI-4050 In patients treated with nintedanib. fibrosis

SB05 (EndoTAG-1; lipids SynCore Biotechnology Co. Ltd. pancreatic cancer Combined with gemcitabine. loaded with paclitaxel)

Phase II Suspended

ToleroMune (house dust Missed primary endpoint on allergy symptoms Circassia Pharmaceuticals PLC house dust mite allergy mite allergen) and use of rescue medication

OncoMed Pharmaceuticals Inc. tarextumab small cell lung cancer PINNACLE; no effect on PFS or overall survival. Source: Biomedtracker

Multispecific Approach Could Improve I-O Side Effect Profile, Says Numab SUKAINA VIRJI [email protected]

Multispecific antibody therapeutic devel- stage of its development without major cell and cancer cell, here it is extremely im- oper Numab – run by two former Esbat- outside investment. What differentiates portant to have monomeric proteins that ech executives – has come of age with Numab from more established therapeutic are stable and don’t aggregate, because a deal in the IO space that validates its antibody developers? aggregates can trigger T cell activation technology. Could this mean bispecific “Small fragments have been described even in the absence of target cells. It’s criti- programs have had their day? before but they suffered from aggrega- cal to have activation of T cells only in close tion, poor reproducibility and low potency,” proximity to cancer cells.” umab AG was known as the rabbit co-CEO and CSO David Urech told Scrip. As Numab’s molecules don’t aggregate, antibody company, but times have “With the use of rabbit antibodies and there is an important differentiator here Nmoved on. It still uses rabbits as our stable scaffold, we have largely solved between its programs and others, Urech a source of antibodies, but it can now hu- these obstacles.” Numab has been able to explained. “With multispecifics we can go manize and stabilize the variable domain of put together formats that have not previ- one step further, not just bringing two cells these antibodies, and these antibody frag- ously been available. “We can now stitch together, but adding more specificities ments can be used as building blocks for together antibody fragments with up to six that, for example, create synergistic mecha- multispecific antibody therapies. specificities in one single molecule.” nisms of action or that target a mechanism The promise of Numab’s technology was Lots of biotech companies are working on of action to a very specific environment. In recently recognized by Japan’s Ono Pharma- bispecific antibodies, and one or two have a cancer microenvironment, for example, ceutical Co. Ltd. The two companies recently even reached the market, most notably systemic side effects might no longer be entered an agreement to develop a multi- Amgen Inc. with Blincyto (blinatumomab), such a big issue.” specific antibody candidate for one of Ono’s a program it acquired when it purchased Numab is using its technology to try immune-oncology programs. Numab will re- Germany’s Micromet for $1.2bn in 2012. and counteract potential side effects of ceive research funding and up to CHF258m “But with bispecifics, there are still open checkpoint modulators in cancer drug in upfront and milestone payments plus roy- questions, particularly with regard to CMC development. “In the end it will be a more alties on any resulting product sales. (chemistry, manufacturing and controls) specific approach that holds the potential Numab was only founded in 2011 and properties,” Urech claimed. “For example, if for greater efficacy and for favorable safety has previously signed smaller revenue we talk about the T cell engaging mecha- profiles.” generating deals, enabling it to reach this nism of action, where you bring together T Published online 21 April 2017

APPOINTMENTS

Karolinska Development AB, has named RXi Pharmaceuticals Corp. has named Mustang Bio Inc. has named Manuel Li- Viktor Drvota, the company’s current dep- Gerrit Dispersyn chief development offic- tchman president, CEO and a member of uty CEO and chief investment officer, CEO er (CDO) – effective April 24, 2017. Current the company’s board of directors. Michael following the resignation of current CEO CDO, Pamela Pavco, will be retiring from S. Weiss, who oversaw Mustang’s corporate Jim Van heusden. Drvota’s appointment the business but joining the company’s operations on an interim basis, will continue will be effective from June 1, 2017 while Van scientific advisory board. Most recently, as chair of the board. Litchman joins Mustang heusden’s resignation will occur in October Dispersyn was vice president, global head from Arvinas LLC., where he was previously 2017. The company has also announced the of clinical affairs at Integra LifeSciences president and CEO. Before this he spent more resignation of its chair, Bo Jesper Hansen, Holdings Corp. Before this, he was vice than 18 years at Novartis AG, where he held who will not be standing for re-election at president, product development & portfo- positions of increasing responsibility. the 2017 annual general meeting. Heusden lio management for Barrier Therapeutics, a will be pursuing new opportunities, having GlaxoSmithKline PLC company. Sickle cell disease focused company, Modus joined Karolinska to develop and change the Therapeutics AB, has appointed Ellen K. organization. Drvota joined the company in Poxel SA, a company focused on meta- Donnelly CEO. Before joining Modus, Don- February 2016 as chief investment officer bolic disorders, has appointed Anne Re- nelly was at Pfizer Inc., where she held various and was promoted deputy CEO in March. nevot chief financial officer (CFO). She leadership positions in clinical operations, He has over 15 years’ life science investment joins the company from EOS Imaging, project and portfolio management, and re- experience and before Karolinska he worked where she was CFO and before this, she search. Most recently, she was responsible for at SEB Venture Capital, where he was head of held the same role at Cartier, a luxury clinical operations for Pfizer’s neuroscience life science and a senior investment manager. goods company. and pain therapeutics unit.

scrip.pharmamedtechbi.com 28 April 2017 | Scrip intelligence | 23 APPOINTMENTS/HEADLINE NEWS 2017

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