What Does 2017 Hold For Pharma? Scrip’s Pharma Influencers Of 2016 2017, Year Of The Dog The biopharma industry will continue The Scrip team have put their heads The biotech sector moves in cycles to lobby the UK government for together to make a list of the people and the momentum that builds up harmonization framework that averts that we believe have shaped the the peaks is driven by the generalist regulatory divergence with the EU (p4) industry in 2016 (p8) investor (p34)

6 January 2017 No. 3835

Scripscrip.pharmamedtechbi.com Pharma intelligence | informa back on high-priced drugs – evidence by the fact that and Ionis have gotten some of their biggest stock boosts in 2016 from positive Spinraza news. The companies announced the FDA ap- proval late on Dec. 23 after the stock market closed, so on Dec. 27 when trading resumed following the Christmas holiday, Biogen closed up 1.3% at $291.12 per share and Ionis rose 3.2% to $55.12. Their stocks also saw major gains in August and November when the companies reported positive re- sults from the Phase III ENDEAR clinical trial in infants with SMA and the Phase III CHER- ISH trial in SMA patients aged 2 to 12. The CHERISH results in children with type 2 and 3 SMA were particularly important for Biogen and Ionis – Ionis discovered Spinraza Shutterstock: argus Shutterstock: and granted a worldwide license to Biogen in August – because the data showed a significant improvement in developmen- Biogen/Ionis’s Spinraza Approved; tal milestones and seemed to guarantee a broad label for the drug. In fact, the FDA did approve Spinraza for both pediatric and adult Second Antisense Drug For patients, which essentially makes the drug available to individuals with any type of SMA. Neurodegeneration In 2016 “Spinraza’s label is broad – meaning that it is approved for all subtypes of SMA – which MANDY JACKSON [email protected] is likely the best case scenario from a com- mercial perspective, and was somewhat ex- Analysts expect strong uptake for the (SMA), marking the second antisense drug pected (but not guaranteed) given the suc- antisense oligonucleotide (ASO) given approved in 2016 to treat a rare neurode- cess of the Phase III ENDEAR and CHERISH generative disease. the high unmet need in SMA and posi- readouts earlier this year,” Evercore ISI analyst tive data in multiple studies, while the Spinraza follows in the footsteps of the John Scotti said in a Dec. 23 note. first ASO approved in 2016 – Sarepta’s Ex- controversial approval of Sarepta Thera- ondys 51 – has seen some pushback from peutics Inc.’s Exondys 51 (eteplirsen) for A FIRST FOR SMA, NEARLY payers despite the lack of DMD therapies. Duchenne muscular dystrophy (DMD); both GUARANTEEING UPTAKE drugs convince RNA to produce proteins Spinraza is the first medicine approved for iogen and partner Ionis Pharmaceuti- needed for proper muscle strength and SMA, a neurodegenerative disease that is cals Inc. are ended 2016 with US FDA function. Investors and analysts that follow particularly deadly for babies with type 1 Bapproval for Spinraza () in both companies have high hopes for block- SMA – it’s the leading genetic cause of death the treatment of spinal muscular atrophy buster Spinraza sales – despite payer push- CONTINUED ON PAGE 7

BROUGHT TO YOU BY THE EDITORS OF PHARMASIA NEWS, START-UP AND SCRIP INTELLIGENCE IN THIS ISSUE pulls EU application for COVER / Biogen/Ionis’s Spinraza Approved; Second Antisense Arzerra with bendamustine Drug For Neurodegeneration In 2016 Acadia’s 3 Solithera’s Prospects Look Grim Following Complete Nuplazid meets Response Letter its primary 4 What Does 2017 Hold For Pharma? endpoint 20 22 6 Was ’s Offer One That Could Refuse? J&J Back At Bargaining Table 6 Emicizumab Data Will Shake Up Hemophilia 8 Scrip’s Pharma Influencers Of 2016 9 Sanger Institute Spin-Out Microbiotica To Evaluate from the editor Bacterial Mixes [email protected] 10 Infographic Our first edition of the year is a bumper issue, 11 AbbVie Picks Up Dong-A Candidate packed with extra analysis and insights to help bring 12 Biosimilar Trends: What 2017 May Have In Store you up to speed on key industry developments over 13 Business Bulletin the festive period and to prepare for the year ahead. The end of December saw the FDA approve Biogen 14 US IPOs In Review: Relatively Muted Market In 2016 and Ionis’ antisense drug Spinraza for the rare and To Continue In 2017 deadly neurodegenerative disease spinal muscular 16 2016 Review: Refocus, Reduce, Reform The Watchwords atrophy and reject Cempra’s antibiotic Solithera. See In Japan cover story, p3 and Stockwatch on p34 for more on 17 2016 Review: Pricing, R&D Issues Dominate In China the commercial implications. 18 2016 Review: Mixed Bag Of Hope And Setbacks For We gaze into our crystal balls to consider what this Korean Pharma year holds for pharma (p4), looking more closely at 19 R&D Bites the IPO market in 2017 (p14-15) and the likely trends in the biosimilar spaces (p12); then take a deeper dive 20 Acadia’s Nuplazid Could Have The Alzheimer’s R&D Curse into the prospects for a particular generic entrant this 21 Advair: A Big Generic Opportunity And A Big Question year (p21). Looking further into the future, we high- Mark In 2017 light the challenge the industry faces in replacing lost 22 Novartis Withdraws Arzerra CLL Second-Line Use Filing in EU sales of top-selling drugs over the next few years (p10). 23 Novartis Takes On Colombia Over Glivec Pricing Scrip would like to wish its readers all the best for a 24 Ex-Sanofi Exec Stoeckli Primes Glenmark’s Cancer productive and successful 2017. Therapy Ambitions 25 Christmas Cheer For Cipla’s Seretide Equivalent In The UK 26 Policy & Regulation Briefs 27 , Ironwood Seek To Divide And Conquer IBS 28 AbbVie Makes Further Inroads In Oncology As Humira Loss Looms exclusive online content 29 Capina, Essentialis Merger To Create Rare Disease Firm 30 Expert View: The CRO View: Sharing Opportunity Vs Risk The R&D Year In Numbers, An Infographic 31 Allergan Adds Accretive Aesthetics Assets In $2.9bn A snapshot of the industry’s research and development activity LifeCell Acquisition in 2015/2016. 32 Pipeline Watch http://bit.ly/2iZTpn7 34 Stockwatch: 2017, Year Of The Dog Inositec CEO On 2017 Financing Plans Mattias Ivarsson, co-founder and CEO of Swiss biotech company 35 Appointments Inositec, talks to Lucie Ellis, senior writer at Scrip, about the company’s technology and progress since being founded in 2015. http://bit.ly/2iDmbeb AdAlta CEO On Shark Antibody Technology Sam Cobb discusses development of the company’s novel technology platform that engineers the key stability features of the antigen binding domain of shark antibodies into human @scripnews /scripintelligence proteins to create unique compounds http://bit.ly/2iPORR5 /scripintelligence /scripintelligence

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Solithera’s Prospects Look Grim Following Complete Response Letter MICHAEL CIPRIANO [email protected]

Even if Cempra has the funds to conduct another trial, there is no guarantee for approval; if approved, solithromycin’s labeling would likely limit use of the com- munity-acquired pneumonia antibiotic.

he US FDA’s complete response let- ter for Cempra Inc.’s community-ac- T quired bacterial pneumonia (CABP) antibiotic Solithera (solithromycin) puts the company on a difficult and uncertain path forward. The agency went against the recom- mendations of its advisory committee, apparently unwilling to wait until Phase IV pixelparticle Shutterstock: to sort out solithromycin’s potential hepa- totoxicity and approve the drug based on cash on hand – is likely looking at a very igation strategy (REMS). Even if the costly the limited 920 patient safety database. costly trial with no guarantee of approval. clinical trial does not find cases of Hy’s The complete response letter also cited Jeffries analysts Eun Yang and Carmen Au- Law (the measurement for drug-induced good manufacturing practices (GMP) gustine also offered a grim outlook on Soli- liver injury), FDA has already signaled that deficiencies at manufacturing facilities thera, pointing out that the additional trial, differences in transaminase elevations owned by (now Inc.) and which could require up to 18,000 people, is already seen versus moxifloxacin would Wockhardt Ltd. likely more than Cempra can accomplish on need to be in labeling, signaling the risk of Interim Cempra CEO David Zaccardelli its own. (The company did not comment on to physicians. noted in a Dec. 29 investor call that the whether it would seek a partner.) “The CRL noted that while the FDA re- company still needs to meet with FDA “While [the] CRL for Solithera (Soli) was serves comment on the proposed labeling to establish the next steps for Solithera, widely expected, FDA recommendation until the NDAs are otherwise adequate, including the specifics of a future clini- for a ~9,000+ patient comparative study to even in the absence of a case of Hy’s Law or cal study. exclude possibility of serious drug-induced of another form of serious [drug-induced “Those answers can’t be determined liver injury is impractical for a company of liver injury] in future studies, labeling will until we meet with the FDA and under- CEMP’s size,” the analysts wrote in a Dec. 29 need to include adequate information stand the study in its totality, including note. “Even if CEMP elects to run the study, about the potential for hepatotoxicity, what endpoints for safety would need it would need additional capital & there limiting use to patients who have limited to be achieved,” Zaccardelli said of So- is no guarantee for approval upon study therapeutic options and limitations regard- lithera’s prospects going forward. “Also, completion.” ing duration of therapy,” Cempra said in a what labeling would be included at the statement. “A comprehensive plan for post- end of that has not been determined. LABELING WILL BE marketing safety assessment including an And so I think more information on our ANOTHER CHALLENGE enhanced pharmacovigilance program decisions around that will come after our Even if Solithera eventually does gain ap- would also be required.” meeting with the agency.” proval – which the company does not ex- Cempra also has Solithera in develop- Zaccardelli said the company is commit- pect prior to 2018 – the drug will likely have ment for uncomplicated urogenital ure- ted to working with FDA to obtain approv- a restrictive label that limits its use. thritis caused by chlamydia in an ongoing al of Solithera, although any path forward Several members of FDA’s Antimicrobial Phase III trial. The company also has an an- for the drug appears bleak. Drugs Advisory Committee recommend- tibiotic candidate called tatska fusidic acid FDA is recommending that Cempra con- ed stringent labeling regarding the risks of that has completed Phase II development duct a study of roughly 9,000 patients ex- hepatotoxicity. One panelist recommend- for the treatment of acute bacterial skin posed to Solithera alone, nearly 10-fold the ed that the label state that, if approved, and skin structure infections and is in an company’s current safety database. Tack on Solithera should not be the first treatment ongoing a Phase II trial for patients with a comparator arm, and the clinical-stage off the shelf for run-of-the-mill CABP. An- prosthetic joint infections. company – which has around $225m in other suggested a risk evaluation and mit- Published online 30 December 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 3 HEADLINE NEWS

What Does 2017 Hold For Pharma? Few would argue that 2016 threw a number of curveballs into the global arena. With the New Year upon us, Scrip took a deep breath and asked a number of internal and external contributors across the pharma and biotech spectrum for their expectations for 2017. Scrip spoke to a range of people involved in the industry to get their take on what we can expect over the next 12 months. Their responses make for an interesting, and varied, read. SUKAINA VIRJI [email protected]

BREXIT On a more positive note, Schofield says it’s likely that the UK will The biopharmaceutical industry will continue to lobby the UK gov- stick by its decision to ratify the Unified Patent Court Agreement, ernment for some sort of harmonization framework that averts regu- which should happen next year. “This means that, all being well, phar- latory divergence with the EU. This could be looking ever so slightly ma firms will be able to take out patents with unitary effect across the more plausible given the apparent softening of UK ministers’ stances UK and the EU after all. It would also mean London gets to keep its on sectoral deals and some sort of transitional period post-Brexit. branch of the Court dealing with life science and chemical patents.” “But so much will depend on how tough the EU negotiators choose to be in offering any sort of ‘tailored’ deal to the UK, and how far the IMMUNO-ONCOLOGY European Parliament will want to have a say in the final agreement,” With major developments in 2016 – including the surprise failure of explains Scrip’s Ian Schofield. Bristol-Myers Squibb Co.’s Opdivo in first-line lung cancer and Roche’s debut of Tecentriq – 2017 will start to see some major shifts, notes Scrip’s Mary Jo Laffler. Some have been long-anticipated, like cancer heavyweight Roche’s entry into the field with approvals in breast and lung cancers for Tecentriq (atezolizumab), the slow trickle of combina- tion data, and the expected approval of CAR-T therapies. “But the bombshell failure of BMS’s CheckMate 026 trial in October 2016 has had seismic implications,” she says. BMS’s once unassailable lead (still on the order of $500m above the nearest competitor, Merck & Co. Inc.’s Keytruda) virtually disappeared overnight. The release of full results, which failed even in high-express- ing PD-L1 patients, at ESMO combined with promising chemo combo Shutterstock: oatawa Shutterstock: data for Keytruda have laid a new path for the field. Merck compound- ed its advantage when Keytruda nabbed the first approval for first-line He expects that “early-ish” in the year we should have at least an lung cancer. “The full-year earnings reports will show how the market inkling of what kind of deal the UK government will be seeking to dynamics are changing, though continuing developments through- strike with the EU, “whether paying for access to the single market, out the year could narrow the gap even more,” she states. taking out part-membership of the EU Customs Union, or pulling The PD-1/L1 market will further expand with new entrants in 2017: out of the whole thing, which would of course be the least favor- Pfizer Inc./Merck KGaA’s avelumab should be coming in Merkel cell able option for the highly regulated life science industry.” cancer and AstraZeneca PLC is due to introduce durvalumab mono- Once things become clearer, companies may begin making de- therapy for urothelial carcinoma. “AstraZeneca may wind up being cisions as to whether to continue investing in the UK or shift some last in the first wave of checkpoint inhibitors, but it is better posi- operations over to mainland Europe – or indeed Ireland. “This could tioned for combination therapy,” Laffler points out. Its MYSTIC trial of affect areas like manufacturing, research, clinical trials, distribution durvalumab plus the firm’s CTLA-4 inhibitor tremelimumab in first- networks, HQ location, etc.,” warns Schofield. line lung cancer is set to report early in the year, well ahead of BMS’s In 2017, we may also get more clarity on which EU countries are similar pairing of Opdivo and its CTLA-4 inhibitor Yervoy in lung can- likely to be in the running to host the EMA. cer (the duo is already approved for melanoma). Merck is due to re- “Given the amount of work involved in relocating the agency to an- port Phase III data for Keytruda + chemo in first-line lung cancer from other member state, preparations will have to begin well in advance KEYNOTE-189 in September. “This means, by the end of the year, we’ll so that the EMA is up and running in its new home as soon as Brexit finally see if the promise of IO combinations lives up to the hopes.” happens,” states Schofield. Once the location is decided, new prem- ises will have to be found with all the necessary infrastructure, and hundreds of jobs will have to be replicated – assuming a large propor- The diabetes market will be one to watch in 2017, with significant tion of people decide not to or are unable to follow the agency to the changes expected. Eli Lilly & Co.’s launch of the basal insulin biosimi- new location. “This work will probably have to begin in earnest next lar Basaglar will alter the landscape, most significantly for Novo Nor- year, given the tight timelines allowed by Article 50 – although this disk AS and Sanofi. In addition, the US approval of the first cardio- could be mitigated somewhat if a transitional arrangement is agreed.” vascular label expansion for an anti-diabetic medicine, Boehringer

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Ingelheim GMBH/Lilly’s Jardiance (empagliflozin), is likely to mark “Robust pipelines are increasingly critical for growth but, even then, a significant change in diabetes management, according to Data- lack of visibility on FDA approvals will likely add volatility to earnings. monitor Healthcare’s Kevin Shannon. M&A has proven to be a more reliable cushion as the contribution from acquired products has offset base erosion for most; we view ADDICTION acquired products to be the most secure buffer going forward.” Opiant Pharmaceuticals Inc.’s CEO Roger Crystal says in 2017 he ex- Therefore, the analysts expect that further consolidation in the pects there to be increasing recognition of addiction as a disease re- generics sector is “inevitable,” particularly among companies with quiring medical treatment, and better reimbursement for pharmaco- concentrated portfolios and scarce pipelines. “While and therapy. Additionally, “we anticipate increased abuse of more potent Teva are likely acquirers, we only expect bolt-ons in the near-medi- opioids such as fentanyl, but also increasing access to medical treat- um term as each focuses on de-levering. We expect Endo’s current ment for opioid addiction, especially on the back of the US Surgeon leverage to limit its capacity, though see some relative flexibility for General’s recently released report, ‘Facing Addiction in America.’ He Akorn, Mallinckrodt AG and Impax.” also foresees additional advances being made into the space, as well as the limited success of abuse-deterrent formulations in pre- JAPAN venting addiction. Scrip’s man in Japan, Ian Haydock, says the biggest pharma-related issue in the country is a reform of the reimbursement pricing sys- PRICING tem, following an urgent high-level review ordered by Prime Min- PwC Partner Rick Judy expects more pharmaceutical manufacturers ister Shinzo Abe late in 2016. This includes a shift to regular annual will develop “social contracts” with consumers as part of their pricing – rather than biennial – general price revisions, which the research- strategies, along the lines of the one Allergan PLC unveiled earlier based pharma industry has strongly opposed. Political pressure on this year. drug pricing looks set to continue given the attention it received in With the antics of former Turing CEO Martin Shkreli and the 2016 and the rise in national healthcare costs driven by high-priced outcry over Mylan NV’s price increases on EpiPen both dominant new treatments for cancer and hepatitis C. stories in 2016, industry is bracing for further pushback on drug pricing. Allergan CEO Brent Saunders and other industry CEOs are INDIA warning that drug pricing will be viewed as a populist issue. According to Scrip’s Anju Ghangurde in India, 2017 is expected to Saunders took the lead in getting ahead of the issue, with his be action-packed for the Indian pharmaceutical industry. A focus on September 2016 pledge that Allergan would only take single-digit compliance-related issues, potential consolidation triggered by mul- price increases once a year. Allergan has already been followed by tiple factors, including evolving quality standards, that could make it Novo Nordisk and other companies are likely to follow in the hopes tough for some small players to stay relevant and the playout of new that voluntary action may dissuade more direct intervention. and anticipated rules are some of the key areas that are expected to “The reality of the problem is a lot more nuanced, and biophar- engage industry in the new year. maceutical manufacturers are trying to share the blame with other Tension has been simmering over India’s recent guidelines on parts of the distribution chain, including pharmacy benefit manag- similar biologics; there are also expectations that India may make ers (PBMs),” explains Laffler. “Further Congressional noise is a surety mandatory a new Uniform Code of Pharmaceuticals Marketing – but what remains to be seen is what will come of it.” Practices (UCPMP). Price-related headwinds, both on the domestic market and in TRUMP the US, is another area that may impact industry’s fortunes. Indian Scrip’s Eleanor Malone believes it is important to consider the possibility firms are among those being probed by the US Department of Jus- that the incoming US president will enable US corporations to repatri- tice over the sharp increases in the prices of specific generic drugs. ate foreign-held cash by offering new and favorable taxation terms for The US Justice Department’s antitrust division has subpoenaed Sun overseas cash. “Many big companies have amassed sizeable amounts Pharmaceutical Industries Ltd. for information pertaining to gener- of cash abroad, which they would like to bring home if only the tax ic drugs, pricing and certain company records. burden wasn’t so onerous,” she explains. “I’m not sure how quickly he’d implement something like this, but if he did, it could be a trigger for CHALLENGES AND CHANGES more domestic M&A among the big US biopharma corporations.” Shire PLC’s CEO Flemming Ornskov highlights the “significant period of challenge” that the pharma industry is going through that will con- GENERICS tinue into 2017. Challenge “in terms of justification of prices, justifica- Generics companies have had a tough time in recent years, with tion of value, contribution to society. There is discussion about almost price erosion and FDA approval delays weighing heavily on the everything from patents to prices to drug importation or not provid- group. Jami Rubin and analysts at Goldman Sachs, in a 2017 generics ing proof of value to outcomes,” he tells Scrip. But he believes that the outlook note, believe that “pricing pressure shows no signs of abat- pharma industry is one of the most attractive industries to be in “be- ing and earnings beats will largely depend on ANDA approvals.” cause it’s about innovation, it’s about smart people working for bet- They say that companies with global diversified portfolios, such ter medicines and cures for diseases, it’s a huge employer around the as Teva Pharmaceutical Industries Ltd. and Mylan, “appear better world, it’s a big contributor to value in society. That there’s going to positioned to offset pressure” while the more “concentrated” com- be some pressure … that’s probably only going to make us all better, panies like Impax Laboratories Inc., Akorn Inc., Co. PLC and more cost efficient, more innovative.” PLC remain the most exposed. Published online 30 December 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 5 HEADLINE NEWS

Was Sanofi’s Offer One That Actelion Could Refuse? J&J Back At Bargaining Table MANDY JACKSON [email protected]

Johnson & Johnson is back at the M&A Was the amount of money offered by J&J previously said on Dec. 13 that it bargaining table with Actelion after the French big pharma much lower than its walked away from negotiations with Acte- walking away from negotiations a week American competitor or were other terms, lion when the care giant “was not able ago, raising questions about whether such as upfront cash versus future earn-outs, to reach an agreement that it believed would Sanofi’s deal terms were harder to digest a deal-breaker? Did Sanofi’s offer force Acte- create adequate value for its shareholders.” than J&J’s. lion back into the kitchen to cook up a deal Neither Actelion nor Sanofi issued state- with J&J or did the original bidder whip up a ments to confirm their talks, but various news ctelion Pharmaceuticals Ltd. and new M&A recipe on its own? outlets reported the French pharma’s interest Johnson & Johnson revealed on None of the parties are providing specifics in doing a deal with the pulmonary arterial ADec. 21 that the two companies publicly. Actelion and J&J simply said in sepa- hypertension (PAH) specialist, which has vari- are back at the M&A bargaining table with rate, similarly worded statements on Dec. 21 ous pipeline programs aimed at diversifying “exclusive negotiations” ongoing, raising the that they have “entered into exclusive negoti- its portfolio. question of whether Sanofi’s offer was un- ations” regarding a possible transaction – the The entire saga – from initial speculation palatable while J&J’s is easier to digest. word “exclusive” implying that Sanofi is out of that a big pharma was interested in buying The latest twist in Actelion’s merger and the picture – and they each made a point of Actelion to the company’s confirmation acquisition saga, raised eyebrows yet again, saying “there can be no assurance any trans- that it was talking to at least one prospec- since J&J was the first company confirmed as action will result from these discussions.” tive buyer – has been somewhat surpris- a prospective buyer for the Swiss biopharma Actelion and J&J both said they won’t make ing, because of the Swiss firm’s previous firm in late November only to walk away by any additional comments about their nego- position about remaining an independent mid-December and have its seat at the table tiations “unless and until it is appropriate to do company. taken by Sanofi. so, or a formal agreement has been reached.” Published online 22 December 2016 Emicizumab Data Will Shake Up Hemophilia Positive data from the HAVEN 1 Phase III study of ’s emicizumab put pressure on the hemophilia franchises of both Shire and Novo Nordisk.

SUKAINA VIRJI [email protected]

enentech Inc. (Roche) reports that ed with bypass agents such as Novo Nord- Novo Nordisk has said that if emicizumab the primary endpoint has been met isk AS’s NovoSeven and Shire PLC’s Feiba. is approved, around 50% of NovoSeven’s Gfor the Phase III HAVEN 1 study eval- Roche expects to file for approval of emici- $1.5bn in annual sales are at risk. uating emicizumab (ACE910) prophylaxis in zumab during 2017. The HAVEN 1 study showed a significant people 12 years of age or older with hemo- Shire’s CEO Flemming Ornskov spoke to reduction in the number of bleeds over philia A and inhibitors to Factor VIII. Scrip recently about the threat from emi- time in people treated with emicizumab Emicizumab, discovered by Chugai Phar- cizumab, and stressed Feiba’s “very strong prophylaxis compared to those receiving no maceutical Co. Ltd., is a bispecific monoclo- safety record,” noting that the product “is prophylactic treatment. The study also met nal antibody designed to bring together recognized for its many benefits and is all secondary endpoints, including a sig- Factors IXa and X, proteins required to ac- serving patients extremely well.” Shire did nificant reduction in the number of bleeds tivate the natural coagulation cascade and not provide a breakdown of Feiba revenues over time with emicizumab prophylaxis restore the blood clotting process. in its third quarter earnings statement, but treatment in an intra-patient comparison in Given once weekly subcutaneously, emi- stated that total sales for its hemophilia people who had received prior bypassing cizumab has the potential to streamline franchise in the three months ended Sept. agent prophylaxis treatment. treatment of hemophilia A as it has dem- 30 were $702m, of which inhibitor thera- Published online 22 December 2016 onstrated prophylactic efficacy regardless pies made up $182m, the majority of which of the presence of Factor VIII inhibitor an- would be from Feiba. Shire has also high- CLICK tibodies (which develop in around 30% of lighted several segments of the non-inhib- Read full story at: hemophilia A patients). Currently, patients itor market that new entrants to the hemo- http://bit.ly/2i9krsp who develop inhibitor antibodies are treat- philia market might find hard to break into.

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CONTINUED FROM COVER will give preference towards using it for a with Spinraza reached milestones and sig- among infants and toddlers. The progressive, Biogen/Ionis development program.” How- nificantly fewer died from SMA. More than debilitating muscle weakness characteristic ever, he noted the high value of PRV’s to 170 patients have been treated to date with of SMA cause infants and children to miss drug makers, such as the $350m price that Spinraza, which is administered by periodic developmental milestones and leads to early AbbVie Inc. paid United Therapeutics Corp. intrathecal injections. death, even for people with less severe forms for a PRV in 2015. “Dosing is fixed regardless of SMA sub- of the disease. type, age or weight of the patient, as 12mg “We believe the broad [Spinraza] label will NEW SCIENCE FOR UNMET doses of Spinraza are to be administered on lead to robust uptake of the drug, particu- NEURODEGENERATION NEED days 0, 14, 28 and 58 (as a series of loading larly in type 1 and type 2 patients,” William SMA is a rare genetic disease caused by doses) followed by maintenance dosing ev- Blair analyst John Sonnier wrote in a Dec. 27 a lack of or defect in the SMN1 gene that ery four months thereafter, which implies note. “Although new safety warnings were produces the survival motor neuron (SMN) that the drug will be more costly up front for disclosed in the label of the drug, includ- protein. Spinraza is an antisense oligonucle- induction and then lower for maintenance,” ing thrombocytopenia and elevated urine otide (ASO) that splices the SMN2 RNA to Evercore ISI’s Scotti wrote. protein, we believe these warrant increased make full-length, functional SMN protein. monitoring, but do not believe they will hin- Stanford’s Day said in Ionis’s announcement PAYER RESPONSE TO SPINRAZA der the drug’s uptake at this time.” of the drug’s approval that “the success of PRICE TAG UNCLEAR Thrombocytopenia and renal side effects Spinraza increases our optimism that anti- Spinraza is different from Exondys 51, be- were observed in Spinraza clinical trials, and sense oligonucleotides could also control cause it was not approved in the middle of thrombocytopenia in particular has been other neurodegenerative disorders.” Biogen’s and Ionis’s development program. a problem for other Ionis drug candidates Ionis chair and CEO Stanley Crooke said The controversial approval for Sarepta’s using a similar backbone technology, Son- in the Carlsbad, California-based com- DMD drug came at the end of a contentious nier noted. However, the analyst said in his pany’s statement: “Spinraza is truly a preci- review process that relied on data from just report, the platelet and urine protein levels sion medicine that works by altering the 12 patients. The $300,000 price tag has been did not reach numbers indicative of severe processing of a single cellular RNA. We are difficult for payers to stomach, because the adverse events. proud that Spinraza exists because Ionis cre- approval was based on a biomarker rather Multiple analysts noted the side effects in- ated and validated a new platform for drug than proof that increased production of the cluded in the Spinraza label, but concluded discovery – antisense technology.” dystrophin gene results in long-term gains that the FDA’s language would not be off- Ionis’s rare disease development pipe- in muscle strength. putting for prescribers given the severity of line includes the Phase III candidate IONIS- But while some DMD patients have been SMA for these young patients and the lack TTRRx, partnered with GlaxoSmithKline denied access to Exondys 51, Spinraza’s cost of approved or in-development treatments. PLC for familial amyloid polyneuropathy; may be easier for US payers to swallow, Only six drugs are in clinical development the Phase II assets IONIS-DMPK-2.5Rx for since the drug was approved based on pos- for SMA, including four Phase II programs, myotonic dystrophy and IONIS-SOD1Rx for itive data from several dozen symptomatic one Phase I/II and one Phase I asset, accord- amyotrophic lateral sclerosis (ALS), both of and pre-symptomatic individuals who have ing to the Biomedtracker database. which are collaborations with Biogen; and been diagnosed with or are likely to develop “Until now, we had to tell parents that the the Roche-partnered IONIS-HTTRx for Hun- SMA types 1-3. only treatment was to manage symptoms as tington’s disease in Phase II. Leerink’s Geoffrey Porges said in a Dec. their children became weaker. Now, Spinraza “Spinraza offers new hope for the SMA 26 note that “given [the] significant ben- offers patients currently living with SMA hope community and exemplifies our mission of efit shown in the trials presented or pub- for disease stabilization or improvement, and applying cutting-edge science to make a lished to date, payers seem to have limited it raises the possibility that infants with SMA meaningful difference in the lives of patients grounds for denying [patients] access” and could be prevented from developing weak- with devastating, life-altering diseases,” Bio- he predicted that there will be widespread ness if identified early enough,” John Day, di- gen CEO George Scangos said in a separate reimbursement for Spinraza by the end of rector of the Neuromuscular Disorders Clinic statement. Scangos, who will leave Biogen the first quarter of 2017. at Lucile Packard Children’s Hospital and pro- in the hands of incoming CEO Michel Vou- Pricing for Spinraza was not revealed in fessor of neurology and pediatrics at Califor- natsos on Jan. 6, thanked patients, families, Biogen’s initial approval announcement, but nia’s Stanford University School of Medicine, investigators and Ionis for their roles in Spin- the company later revealed a wholesale ac- said in a statement from Ionis. raza’s development and noted “the urgency quisition cost of $125,000 per vial, bringing The approval also gave Biogen a pediatric demonstrated by the FDA in rapidly review- the first year’s cost to $750,000 and subse- voucher (PRV), which it may ing and approving this treatment.” quent years’ costs to $375,000 annually. The sell to another company or retain to seek The agency approved the drug months price exceeds analyst estimates of $200,000 speedy approval of another drug in its pipe- earlier than expected based on interim data to $400,000 per year, so given payers’ recent line. Evercore ISI analyst Scotti pointed out from ENDEAR and results from patients sensitivity to high-cost medicines it is un- in his note to investors that Biogen “hasn’t with types 1-3 SMA who were treated in known whether there will be resisitance to yet decided how it will be used, i.e. to sell open-label clinical trials; the study showed Spinraza’s price tag. it or keep it … though Biogen did say they that significantly more patients treated Published online 28 December 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 7 HEADLINE NEWS

Scrip’s Pharma Influencers Of 2016 SUKAINA VIRJI [email protected]

The Scrip editorial team have put their was “going to bring down drug prices.” The heads together to make a list of the immediate result was the bringing down people that we believe have shaped the of share prices in the pharma industry. biopharma industry in 2016 – in terms of Obviously 2017 (and beyond) will be reputation, innovation or commercial- when Trump truly puts his stamp on the ization. In the way of Time magazine’s fortunes of the pharma industry. Expect his ‘Person of the Year’, inclusion on the list is name near the top of next year’s list. not necessarily an accolade… FLEMMING ORNSKOV Another pharma executive that put a failed BRENT SAUNDERS chase behind him was Shire PLC’s CEO Allergan PLC CEO Brent Saunders has Flemming Ornskov. AbbVie Inc.’s takeover of emerged over the past couple of years as Shire was also stymied by the US tax inver- one of the most respected leaders in the in- sion crackdown back in 2014, but Ornskov dustry, and 2016 was another positive year has gone on to build Shire’s fortunes and Merck was further boosted by BMS’s rival for him. this year completed the purchase of Baxalta drug Opdivo failing the CheckMate 026 trial The first part of 2016 saw Saunders han- Inc. for $32bn, the biggest pharma deal of in first-line non-small cell lung cancer with- dling a $160bn merger proposal from Pfizer the year. out even a trend towards efficacy in -pa Inc., which subsequently fell through after tients with high levels of PD-L1 expression. the US Treasury unveiled new rules on Apr. 4 cracking down on inversion deals that JANET WOODCOCK challenged the economics of the merger. Center for Drug Evaluation and Research di- Saunders dusted himself off got on rector Janet Woodcock has made the 2016 with the day job, leading from the front in list for her role in the controversial acceler- matters such as the drug pricing debate, ated approval of Inc.’s where he declared Allergan would limit Exondys 51 (eteplirsen) in September. Mem- price increases, and urging other compa- os released concurrent with the approval nies to do the same. He was also quick to warn drug makers of the false security of Donald Trump’s US election win. “To think President Trump isn’t a populist, that he won’t jump on the next EpiPen scandal and tweet more on a pricing scandal than Hillary Clinton tweeted or anybody else… The year has not all been plain sailing for you are fooling yourself,” he said. Shire and Ornskov but the exec’s attempt to bring confidence to its $20bn revenue target by 2020 impressed Scrip.

ROGER PERLMUTTER Scrip’s next entry is Merck & Co. Inc.’s R&D head Roger Perlmutter, for his part in the suc- cessful KEYNOTE-024 trial and the predicted erosion of market share from Bristol-Myers paint a picture of Woodcock taking a highly Squibb Co.’s market leader Opdivo (nivolum- activist role, both before and after the NDA ab) by Merck’s Keytruda (pembrolizumab) in submission, in the effort to get eteplirsen lung cancer in the coming months. approved as the first drug treatment for Merck reported positive results earlier Duchenne muscular dystrophy. this year for its PD-1 inhibitor in the KEY- FDA reviewers and managers within the NOTE-024 first-line lung cancer study in pa- Office of New Drugs raised several concerns Saunders’ warnings on Dec. 1 over tients with over 50% expression of PD-L1, about whether eteplirsen had shown enough Trump were speedily corroborated by the about 30% of the overall trial population. efficacy in clinical trials. Many argued an ap- man himself in an interview in Time maga- The drug is now under review at FDA in this proval was not appropriate, but Woodcock zine a few days later, where he stated he indication, with a Dec. 24 user fee date. overruled them and granted the approval.

8 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

HILLARY CLINTON STEVE MILLER She may have lost the US presidential elec- The US’s largest pharmacy benefits manager Sanger Institute tion, but Hillary Clinton still makes Scrip’s list Express Scripts Holding Co. threw a curve- Spin-Out as a 2016 pharma influencer. ball into the diabetes arena in August when She followed up her September 2015 it decided to exclude Sanofi’s basal insulin Microbiotica To “price gouging” tweet after Martin Shkreli’s Lantus and downgrade Novo Nordisk AS’s antics at Turing Pharmaceuticals AG with Levemir from formularies in favor of Eli Lilly & Evaluate Bacterial another market-rocking tweet about Mylan Co.’s upcoming biosimilar Basaglar. This is not NV and EpiPen pricing in August 2016. She the only decision by Express Scripts, presum- Mixes stated there was “no justification” for price ably instigated by its chief medical officer Dr. The UK Wellcome Trust Sanger Institute’s hikes for “life and death” medications. Steve Miller, that has raised eyebrows during latest spin-out has received start-up funding 2016 and sent pharmaceutical companies to exploit more than six years of gut bacterial scrambling to adjust forecasts and commer- genome sequencing in order to develop novel cialization strategies. For the power Miller bacteria-based therapies for a range of diseases. wields through his own analyses of which A UK microbiome-focused biotech, drugs deliver the best value to consumers Microbiotica Ltd., has become the – and taking that job off the hands of drug second company to be spun out of the makers and regulators – Scrip has put Miller UK-based genome sequencing research on the list for 2016. facility, Wellcome Trust Sanger Insti- tute, with financial support from local HANS BISHOP start-up investor Cambridge Innova- This time last year, the chimeric antigen tion Capital. receptor T-cell (CAR-T) therapy space was The financial firm invests in technol- full of promise and excitement. And while ogy companies set up by the University much of that promise is still alive – Novar- of Cambridge, where it has preferred tis AG and Kite Pharma Inc. plan to file their investor status, and in other opportu- Shares of Mylan dropped 6% on Aug. CD19-targeting CAR-T therapies for US FDA nities it finds in the wider Cambridge 24; the and iShares approval in early 2017 – some of that excite- Cluster region. Cambridge Innova- Nasdaq Biotechnology both tumbled 3.5%. ment turned to dread when the other CAR-T tion Capital previously invested in the frontrunner, Juno Therapeutics Inc., had two genomics analytics company Congenica SHINZO ABE clinical holds put on its lead program owing Ltd. that was spun off from the Well- Drug reimbursement prices in Japan are to unexplained deaths. come Trust Sanger Institute in 2014 to to be revised annually – rather than every work on using whole genome analysis other year – following top-level political for disease diagnosis. support. Scrip has therefore added Japan’s CIC and the UK technology transfer Prime Minister Shinzo Abe, as a represen- expert IP Group plc announced Dec. 19 tative of the collective members of the the investment of £4m each to estab- country’s Central Social Insurance Medical lish Microbiotica, which will exploit a Council (Chuikyo), as one of the top phar- “first-in-class” gut microbiome culture ma influencers of the year. collection and reference genome library Chuikyo was also behind the decision to built up by Sanger researchers, that is slash the price of Opdivo in the country by claimed to be the world’s largest culture 50%, with Merck’s Keytruda likely to see a collection of intestinal bacteria isolated lower price set at launch. from the human gut. Microbiotica’s first move is to advance existing bacte- rial mixes into preclinical development For this reason, Scrip has put the CEO of in the next 12 months. These potential Juno, Hans Bishop, onto the list of people bacteriotherapy mixes have shown strik- who have shaped the pharma industry in ing effects in novel models of disease, the 2016. Bishop is of course no stranger to dif- company says, and it has been granted ficult times: he was chief operating officer exclusive rights to those mixes. of Dendreon Corp., the cell therapy trail- [email protected], 19 Dec 2016 blazer that eventually declared bankruptcy after failing to make a commercial success CLICK of the personalized prostate cancer cell Read full story at: therapy Provenge (sipuleucel-T). http://bit.ly/2j8ggRw Published online 23 December 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 9 INFOGRAPHIC

Pharma companies with drugs ranked in the top 10 by global sales in 2015 will need to nd an extra $26bn in revenues just to make up for the TOP 10 anticipated loss in sales through to 2020. Of the ten best selling drugs of 2015, only Celgene’s Revlimid, according to Informa’s Datamonitor DRUGS Healthcare, is expected to see an increase in revenues in 2020. poised to lose $26bn by 2020

TOP 10 Selling drugs of 2015 ($m) The amount of money $26bn lost by drugs currently HALF topping the charts is $83bn forecast to slip by 2020. The number of drugs $ currently in the top ten $57bn that will still be there $48bn in 2020. 1 Humira (adalimumab) Inflammatory Abbvie Other 2015 chart toppers expected to $14,012 CURRENT 2020 2023 feature in the 2020 top ten are: Harvoni 2 (ledipasvir/sofosbuvir) Hepatitis C Avastin $13,864 The year Avastin Enbrel 3 Enbrel (etanercept) will be relegated Inflammatory Remicade from the top ten $8,697 /P zer selling drugs on 2023 Revlimid the market. 4 Remicade (iniximab) Inflammatory $8,355 J&J/MSD Mabthera/Rituxan Cumulative sales of the 5 (rituximab) TEN TOP selling drugs. Cancer #1 Humira $7,115 Roche $70.7bn will retain top spot 6 Lantus (insulin glargine) $67.6bn as best-selling drug Diabetes in 2020. $7,029 Sano 7 Avastin (bevacizumab) Cancer $6,751 Roche 8 Herceptin (trastuzumab) Harvoni will lose its Cancer runner up position, $6,603 Roche replaced by Gilead #2 Sciences’ follow-up 9 Revlimid (lenalidomide) hepatitis C drug with Blood related disorders forecast revenues of $5,801 Celgene $12.1bn (2020) and Sovaldi (sofosbuvir) $11.5bn (2023). 10 2020 2023 Hepatitis C $5,276 Gilead Sciences

Source: Datamonitor Healthcare Source: Scrip, Company lings

10 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

AbbVie Picks Up Dong-A Candidate JUNG WON Shin [email protected]

Dong-A ST has scored a major early ROAD TO INNOVATION Given that AbbVie is a major global player success in its inroads into cancer R&D Dong-A ST’s vice chair Soo Hyoung Kang in the field of immune-oncology, the drug, through a sizable immuno-oncology said the new major licensing deal marks the once it successfully completes preclinical deal with AbbVie, which also under- first real outcome from the company’s novel trials, will be in a favorable position for clini- scores the US firm’s push to expand its innovative drug research center, which was cal development. The agreement will also assets in the area. established in 2013. serve as a positive factor for Dong-A ST’s

ong-A ST Co. Ltd. has reached a co- development and licensing agree- Dment with AbbVie Biotechnology, a subsidiary of AbbVie Inc., for the South Korean pharma firm’s early stage Mer tyro- sine kinase inhibitor candidate, in an alliance potentially worth up to $525m plus sales royalties. Under the deal, Dong-A ST and AbbVie will jointly develop the still preclinical stage molecule until submission of an IND to be- gin clinical trials. After this filing, AbbVie

will exclusively own the global rights, ex- chatiyanon Shutterstock: cluding South Korea, for the development and commercialization of the asset, Dong- “We have begun to research and de- progress with its R&D pipeline and financial A said in a stock market disclosure. velop immuno-oncology drugs with the performance, Eugene Investment added. Dong-A ST will receive an upfront pay- establishment of the novel innovative drug ment of $40m and up to $485m in mile- research center. Once the institute comes ABBVIE’S ONCOLOGY PUSH stones, and will be eligible to receive royal- up with candidates, they are transferred The latest deal is in line with AbbVie’s recent ties of up to 10% of sales. to our other research centers for further moves to invest heavily in its oncology pipe- development,” explained Gi Yeop Seong, line, including through partnerships. Oncolo- NOVEL TARGET manager of Dong-A ST’s PR team. gy represents a newer, promising growth area MerTK, a type of Tyro-3, Axl, Mer fam- for the company as it prepares to face sales ily receptor, has emerged as an immune- ‘The deal size is seen as losses due to biosimilar competition with its oncology target as it is relevant to the global blockbuster Humira (adalimumab). promotion of growth and metastasis of unprecedented considering The new alliance also underscores the cancer cells through the inhibition of the ongoing robust appetite by global pharmas natural immune system. The Dong-A can- the drug candidate hasn’t for immuno-oncology and allies with views didate inhibits activation of MerTK, there- entered preclinical trials yet’ that such deals will continue to dominate by boosting the innate immune response the global pharma industry in 2017. against cancer cells and affecting malig- nant cell division. STRING OF DEALS Its complex mechanism of action is said Seong said the new research center is Dong-A ST’s recent deals include a licensing to increase in combination with existing focusing primarily on oncology and immu- out agreement reached in April this year to immuno-oncology drugs and other stan- no-oncology drugs. “The deal size is seen grant development and sales rights in the dard cancer therapies, Dong-A said in the as unprecedented considering the drug US, Europe, Canada and Australia to evo- statement. candidate hasn’t entered preclinical trials gliptin, its in-house developed DPP-4 inhibi- Given that MerTK is a novel target, it is yet,” he added. tor, to US-based Tobira Therapeutics Inc. not yet clear which types of cancer the The agreement is significant for Dong-A The leading South Korean pharma is also drug will be developed for, but NH In- ST as the company has not had much ex- looking for global partners for other pipe- vestment and Securities suggested that it perience in the development of oncology line assets including DA-9801, its herbal- could be applied to acute myeloid leuke- drugs, but “it has now gained recognition derived diabetic neuropathy drug mia, breast, gastric, and prostate cancer, from a big pharma for its very early stage, which underwent a Phase II clinical trial in and melanoma. Disclosed competition in first-in-class drug candidate,” Eugene In- the US last year. the Mer space also seems to be very lim- vestment & Securities said in a research Published online 29 December 2016 ited at present. note on Dec. 29. From the editors of PharmAsia News.

scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 11 HEADLINE NEWS

Biosimilar Trends: What 2017 May Have In Store Potential approvals for biosimilar versions of three blockbuster products in the EU and/or the US in 2017, growing prescriber confidence in such products against the backdrop of positive switching studies, and early signs of market consolidation were some of the key trends highlighted at a recent roundtable in Mumbai. ANJU GHANGURDE [email protected]

he sustained dominance of “second-wave” biosimilars in both logical products to improve pharmacovigilance and avoid any unin- development pipelines and approval flow, and a crescendo tended substitution. T in the debate around the naming of biologicals and inter- Manaktala, however, noted that based on current experience that changeability were some of the issues discussed at a recent Quintil- has been reported, there appears to have been “no confusion or con- esIMS roundtable in Mumbai on “Biosimilar Trends In 2017.” cerns” on how to track the product with the same International Non- While the year could see the approval of trastuzumab, rituximab and proprietary Name (INN). bevacizumab biosimilars in the EU and/or the US, the focus on second- “It’s been 10 long years and 25 products have been approved and wave biosimilars is a reflection, in part, of these products having been the EU hasn’t reported any adverse experience with the use of the the biopharmaceutical industry’s “top grossers” for the last few years. common INN. That is quite significant. The EU seems to be doing pret- “Wave Two will rule pipelines for some time to come; these are the ty well using just the INN,” she told Scrip. products that hold a majority of the market in dollar terms. Unless there Some industry experts and other stakeholders have opposed the is a big market, companies don’t want to invest in biosimilars develop- FDA’s suffix approach, suggesting that it would impede the uptake of ment since it isn’t like generics,” Dr. Charu Manaktala, senior medical biosimilars and do little to improve pharmacovigilance. director and head of the Asia Pacific Biosimilars Centre of Excellence, strategic drug development, QuintilesIMS Asia, said at the roundtable CONFIDENCE BUILDING on Dec. 20. On interchangeability, while guidance from the US FDA is awaited, Biologics with patents expiring between 2015 and 2020 comprise the QuintilesIMS executive referred to Sandoz’s EGALITY study that the second wave of biosimilars and include blockbuster products demonstrated switching between biosimilar etanercept and the such as Humira (adalimumab), Enbrel (etanercept), Rituxan/MabThera originator product had no impact on safety and efficacy. (rituximab), Avastin (bevacizumab), Herceptin (trastuzumab) and Remi- “Such emerging data is likely to contribute towards building confi- cade (infliximab). dence of the prescribers, patients and payers in biosimilars, and this is Informa’s Datamonitor Healthcare recently said that AbbVie Inc.’s Hu- likely to impact biosimilars’ uptake positively. We see more expert bod- mira and Roche’s Avastin and Herceptin are the lead reference biolog- ies around the world endorsing the use of biosimilars,” Manaktala said. ics with the most biosimilar candidates in development in preclinical In the EGALITY study, patients who switched treatments crossed over studies through to Phase III trials. between biosimilar etanercept and the originator product three times, In its report, Datamonitor Healthcare also noted that eight biosimi- with no clinically meaningful differences in safety and efficacy. Sandoz’s lars have been filed under the 351(k) pathway in the US and are await- biosimilar etanercept was approved by the FDA in August 2016. ing FDA approval, while there are 14 biosimilars awaiting clearance in Manaktala also added that she expected to see more products ob- the EU. Sandoz has three filings in the EU: in addition to a biosimilar taining marketing approval on the basis of “lean” clinical data packages to Amgen Inc.’s Neulasta (pegfilgrastim), which is also awaiting US ap- (especially where validated pharmacodynamic markers are available), proval, the company has submitted etanercept and rituximab biosimi- lars for approval. backed by strong quality comparability, in vitro biological activity evi- Manaktala also added that while there are now signs of develop- dence, and clinical PK-PD studies. ment of “third-wave” biosimilars, these are at best “sparse” and quite some time away from regulatory approvals. The third wave of bio- CONSOLIDATION? logics, which have patent expiries beyond 2020, includes products There are also some early signs of consolidation in the biosimilars such as Cimzia (certolizumab pegol), Lucentis (ranibizumab) and space. 2016, Manaktala noted, had seen at least two significant - Simponi (golimumab). ers exiting or then seemingly considering an exit from the biosimilars domain in favor of “other priorities.” INNS AND INTERCHANGEABILITY She referred to Shire PLC returning the rights to biosimilars that Bax- The naming of biologicals and the interchangeability of biosimilars alta Inc. was developing jointly with other companies – adalimumab are expected to continue to be strongly debated topics, the Mumbai biosimilar with Momenta Pharmaceuticals Inc. and etanercept biosimi- roundtable heard. lar with Coherus BioSciences Inc. While the European Medicines Agency has approved biosimilars In addition, Merck KGAA has been reported to be re-evaluating its under the same non-proprietary name as for the reference product, biosimilars business. In October, news agencies said that the firm had the US FDA’s 2015 draft guidance on non-proprietary naming of bio- brought in JPMorgan Chase & Co to sound out potential suitors for its similars recommends that all biologicals should have non-proprietary biosimilars business. names that include a four-letter suffix to distinguish them from each She maintained that given the nature of the biosimilars business, other. The suffix would comprise four lowercase letters and not carry partnerships will play a critical role in this domain.. any meaning. The proposed US approach aims to clearly identify bio- Published online 30 December 2016

12 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 BUSINESS BULLETIN

Sun Acquires Novartis Cancer Drug In Specialty Push Akebia Holds Development Reins Indian generic drug companies have In Anemia While Otsuka Jumps On been on an aggressive quest to build scale in the higher-margin global spe- Vadadustat Sleigh cialty drug business as generic competi- Akebia Therapeutics Inc. stresses that it will be holding the reins on impor- tion grows fiercer and Sun Pharmaceu- tant aspects of developing vadadustat for anemia in patients with chronic tical Industries Ltd. has been among kidney disease (CKD) – including pricing and reimbursement – after shift- firms leading the pack with a string of ing course on its US plans in order to bring Otsuka Pharmaceutical Co. acquisitions in the branded dermatolo- Ltd. on board in a 50-50 deal. Otsuka committed at least $265m to partner gy and ophthalmology segments. Now with Akebia, including upfront fees and development capital, in a co-devel- the company, led by billionaire founder opment and commercialization deal for vadadustat, a once-daily, oral hy- and hyperactive deal-maker Dilip Shang- poxia-inducible factor prolyl hydroxylase (HIF-PH) stabilizer in Phase IIII hvi, has announced one more purchase, for CKD-related anemia – a condition that affects some 1.8m people in the saying it will pay $175m along with un- US. The agreement announced on Dec. 20 also gives Akebia the chance to disclosed milestone payments to Swiss earn as much as $765m in milestone fees, putting the deal’s potential value giant Novartis AG for its branded skin at more than $1bn. The Japanese pharma’s initial $265m commitment to cancer drug Odomzo (sonidegib). The ac- Akebia, includes $125m at the time of signing and $35m in the first quar- quisition of Odomzo, which has been ap- ter of 2017 for co-development and commercialization rights, plus at least proved for sale in 30 countries, including $105m to cover global development costs. The partners will share all US European nations, Australia and most development and commercialization costs equally and split profits in that importantly the US, the world’s largest key pharmaceutical market on a 50-50 basis. drug market, “gives Sun its first branded [email protected], 21 Dec 2016 oncology product,” the Mumbai-based company said in a stock exchange state- ment Dec. 22. Shanghvi, who’s India’s second-wealthiest person, has been steer- pon Pharma Co. Ltd., has exclusively ing the company’s focus toward more licensed US rights to commercial- specialty therapies that can achieve ize three approved respiratory treat- Broad-Based Incyte/Merus higher margins to counter the competi- ments from Novartis AG: the LABA/ Collaboration tion squeezing the pricing power of its LAMA Utibron Neohaler (indacaterol traditional generic lines. Branded spe- and glycopyrrolate), Seebri Neohaler Incyte Corp. and Merus BV have an- cialty drugs now represent some 25% of (glycopyrrolate) and Arcapta Neohaler nounced a broad-based bispecific an- global medical spending. Sun Pharma, (indacaterol), which are all indicated tibody discovery, development and like many other big Indian drug firms, for chronic obstructive pulmonary commercialization partnership that has also been buffeted by the headwinds disease (COPD). Utibron Neohaler could include up to 11 programs, re- sult in potential earn-outs to Merus of increased US regulatory scrutiny that and Seebri Neohaler were approved of nearly $3bn and includes the flex- has revealed manufacturing shortfalls at by the US FDA in 2015, and Sunovi- ibility to move into novel targets and its plants in India, curbed earnings and on plans to bring them to market in made the company’s shares one of the novel biology. On a Dec. 21 conference 2017. Arcapta Neohaler was approved worst performing pharmaceutical stocks. call, Merus executives called the agree- in 2011 and has been on the market The purchase announcement coincided ment “truly transformative” in that since 2012. Novartis will continue to with more bad regulatory news for Sun it validates the company’s Biclonics manufacture these three medicines Pharma which has been struggling to bispecific antibody technology plat- bring some of its Indian plants up to and retains rights for the products form, while providing a major cash US FDA standards and underscored the outside of the US. Financial terms of infusion and leaving the Dutch firm company’s need to diversify. the deal remain undisclosed. Sunovi- with full rights to its two clinical can- Penelope MacRae, 22 Dec 2016 on’s COPD portfolio already includes didates and one of its most advanced the long-acting β adrenoceptor ago- preclinical candidates, all in the im- nists (LABA) Brovana (arformoterol muno-oncology space. Analysts called Sunovion To Commercialize tartrate). In addition, it filed the long- the deal a win for both companies, say- acting muscarinic receptor antagonist ing Incyte expands its R&D capacity Novartis’s COPD Products In US (LAMA) SUN-101/eFlow (glycopyrro- into one of the more promising areas Sunovion Pharmaceuticals Inc., owned late) with the FDA in July 2016. within cancer. by Japanese group Sumitomo Dainip- [email protected], 22 Dec 2016 [email protected], 21 Dec 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 13 HEADLINE NEWS

US IPOs In Review: Relatively Muted Market In 2016 To Continue In 2017 After biopharma initial public offerings in the US during 2016 outperformed the prior year’s IPOs, expect more of the same in 2017: fewer, but higher quality offerings at lower IPO share prices to keep values at acceptable levels for experienced investors.

MANDY JACKSON [email protected]

eneralist investors that gambled 2015 Versus 2016 IPO Statistics on the US biopharmaceutical initial Gpublic offering market between 2015 IPOS 2016 IPOS 2013 and mid-2015 are largely gone, leav- Number Of Companies 62 30 ing health care specialists to bet on less risky Average IPO Price Per Share $13.87 $12.03 drug developer IPOs in 2016 – a trend that’s IPO Price Range $2.75 to $68.56 $5 to $24 expected to continue in 2017. The biopharma IPO market may be Total Gross Proceeds $5.38bn $2.02bn reaching a sort of equilibrium as compa- Average Gross Proceeds $86.8m $67.4m nies vetted by experienced health care Average Return Year-End 2015 12% NA investors and perceived as relatively safe Average Return Year-End 2016 -24% 11.2% wagers will still get through the IPO win- dow at investor-friendly share prices, but not every therapeutic firm that registers a ance in 2016. Instead, proceeds fell to their forming US IPOs in 2016 credited to bio- prospective offering with the US Securities lowest level since 2003 and activity was pharma companies, but only four of the and Exchange Commission (SEC) will be the worst since 2009,” Renaissance said in year’s 10 top performing IPOs were thera- able to go public. Recent investment dis- its 2016 US IPO Market Annual Review. The peutics firms. As such, Renaissance expects cipline has paid off: the average return as firm attributed most of the drop in new venture capital-backed biopharma IPO ac- of Dec. 30 for the 62 drug developers that IPOs to postponed offerings during the tivity in 2017 to be muted relative to offer- launched IPOs in 2015 was -24% compared first quarter as well as uncertainty caused ings in other industries. with an 11.2% gain for the 30 therapeutics by the UK’s Brexit vote in the second quar- AveXis CEO Sean Nolan said his firm, firms that went public in 2016. ter and the US presidential election in the which is developing the Investors that bought into 2016 offerings fourth quarter. AVXS-101 for the rare neurodegenerative bet big on innovation and hot biopharma “Health care, down 46% from last year in disease spinal muscular atrophy, remains sectors, such as gene editing and immu- deal flow, remained the most active sec- focused on one key goal, which has res- no-oncology, but were less enthusiastic tor in the IPO market for the fourth year in onated with the company’s investors: about cancer biosimilars, enzyme replace- a row due to elevated biotech activity. It “We’re relentlessly focused on driving the ment therapies, ophthalmology, infectious was the only sector that brought compa- program forward and getting approvals disease and preclinical cancer programs. nies public during the volatile first quarter to make it available to all kids affected by Even so, per the table below, companies thanks to substantial insider buying,” Re- this disease.” launched IPOs in 2016 at lower per-share naissance noted in its annual IPO review. “VC-backed biotech IPOs numbered 20 prices and grossed less money from their Performance remained volatile through- [in 2016], down 56% compared to last year, offerings compared with their 2015 peers. out the year with nine of the worst per- and averaged a return of +32%. None priced

BIOPHARMA VS. Top Five Biopharma IPOs Of 2016 OTHER INDUSTRIES The reduced number of biopharma IPOs COMPANY SPECIALTY RETURN VS. IPO and decline in gross proceeds tracked close- Novan Inc. Topical dermatology medicines 145.6% ly with overall IPO performance in 2016, but AveXis Inc. Gene therapies for rare neurological diseases 138.9% the industry is expected to diverge from technology and other sectors in 2017, ac- Merus NV Bi-specific antibodies; immuno-oncology 111.1% cording to the IPO-tracking firm Renais- Reata Targeting cellular metabolism and inflammation in sance Capital LLC. Pharmaceuticals cardiovascular and rare diseases, ophthalmology and 98.5% “With the S&P 500 at record highs and Inc. immuno-oncology Oral peptide drugs with targeted delivery to the average IPO returns handily beating the Protagonist gastrointestinal (GI) compartment; disease targets are 83.3% broad market indices, the US IPO market Therapeutics Inc. should have produced high levels of issu- currently addressed by biologics; initial focus on GI diseases

14 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

Bottom Five IPOs of 2016 ObsEva SA looking for up to $86.25m, and Braeburn Pharmaceuticals SPRL eyeing a COMPANY SPECIALTY RETURN VS. IPO $150m offering. PhaseRx Inc. mRNA therapeutics for inherited liver diseases -69% But with 2016 IPOs outperforming bio- pharma therapeutics companies that went Moleculin Bio- Cancer therapeutics; lead product is an anthracycline for -62% tech Inc. acute myeloid leukemia public in 2015, expect 2017 to offer more of the same: fewer offerings than recent fren- Aeglea Biothera- Engineered human enzymes to treat inborn errors of -56.5% zied levels at lower share prices and gross peutics Inc. metabolism proceeds as investors focus on science, Kadmon Corp. Treatments for cancer as well as autoimmune, fibrotic and -55.4% innovation and success in the clinic. That LLC genetic diseases formula paid off in 2016 and investors will Oncobiologics Biosimilars to treat cancer -49.8% look for similar or improved returns in 2017 Inc. from companies with innovative technol- ogy and clinical programs (see table below above the [proposed IPO price] range, and six include three biopharma companies for individual 2016 IPO performance). 40% priced below it. Three prominent gene that filed for an IPO on Dec. 30 – Jounce Published online 30 December 2016 editing biotechs – Editas, Intellia and CRIS- Therapeutics Inc. seeking up to $75m, PR – went public in the US this year, but ini- 2016 IPO Performance By Company tial excitement fizzled quickly. With many of the most promising biotechs already public COMPANY IPO PRICE DEC. 30 PRICE RETURN VS. IPO and the Nasdaq Biotech Index (NBI) down 20% for the year, biotechs relied on insiders TiGenix NV (TIG) $15.50 $14.58 -5.9% to get [IPOs] done and may need to follow Motif Bio PLC (MTFB) $6.98 $6.04 -13.5% the same playbook for activity in 2017,” ac- Myovant Sciences Ltd. (MYOV) $15 $12.44 -17.1% cording to Renaissance. Ra Pharmaceuticals Inc. (RARX) $13 $15.19 16.8% The NBI is down 21.7% year-to-date – CRISPR Therapeutics AG (CRSP) $14 $20 42.9% and 33% from its July 20, 2015 peak – versus year-to-date gains of 7.5% for the broader AzurRx BioPharma Inc. (AZRX) $5.50 $4.74 -13.8% Nasdaq index and 13.4% for the Dow Jones AC Immune SA (ACIU) $11 $12.98 18% Industrial Average. That’s why Renaissance Novan Inc. (NOVN) $11 $27.02 145.6% expects biopharma IPOs to attract less in- Protagonist Therapeutics Inc. (PTGX) $12 $21.99 83.3% terest than offerings from health care com- panies in general while other industries see Gemphire Therapeutics Inc. (GEMP) $10 $7.84 -21.6% a boost in the number and size of IPOs. Kadmon Holdings Inc. (KDMN) $12 $5.35 -55.4% “Health care is a trickier call because Audentes Therapeutics Inc. (BOLD) $15 $18.27 21.8% there are many scenarios by which Obam- Syros Pharmaceuticals Inc. (SYRS) $12.50 $12.16 -2.7% acare could be repealed or partially dis- Selecta Biosciences Inc. (SELB) $14 $17.15 22.5% mantled. However, one call we can make with confidence: the biotech boom is over Clearside Biomedical Inc. (CLSD) $7 $8.94 27.7% for now because the best companies of Moleculin Biotech Inc. (MBRX) $6 $2.28 -62% the 2013-2016 vintages have already gone Reata Pharmaceuticals Inc. (RETA) $11 $21.83 98.5% public and there are an increasing number Merus NV (MRUS) $10 $21.11 111.1% of Phase III trial failures,” the IPO firm wrote in its year-end report. PhaseRx Inc. (PZRX) $5 $1.55 -69% There are not a lot of biopharma Oncobiologics Inc. (ONS) $6 $3.01 -49.8% companies waiting in line to launch Spring Bank Pharmaceuticals Inc. (SBPH) $12 $7.99 -33.4% IPOs in 2017. Of the 35 therapeutics Intellia Therapeutics Inc. (NTLA) $18 $13.11 -27.2% firms that registered prospective of- Aeglea Biotherapeutics Inc. (AGLE) $10 $4.35 -56.5% ferings with the SEC in 2016, 25 priced their offerings (the five other 2016 IPOs Corvus Pharmaceuticals Inc. (CRVS) $15 $14.30 -4.7% originally filed in 2015). Also, two com- Hutchison China MediTech Ltd. (HCM) $13.50 $13.57 0.5% panies withdrew their registrations and Syndax Pharmaceuticals Inc. (SNDX) $12 $7.17 -40.3% one was acquired. Proteostasis Therapeutics Inc. (PTI) $8 $12.26 53.3% That leaves seven biopharma IPO AveXis Inc. (AVXS) $20 $47.78 138.9% hopefuls that have yet to leave the run- way. One set a preliminary price range Editas Medicine Inc. (EDIT) $16 $16.23 1.4% but didn’t launch, and six others have yet BeiGene (Beijing) Co. Ltd. (BGNE) $24 $30.36 26.5% to outline terms for an offering, but those AVERAGES $12.03 $14.05 11.2%

scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 15 HEADLINE NEWS

2016 Review: Refocus, Reduce, Reform The Watchwords In Japan IAN HAYDOCK [email protected]

While reimbursement pricing issues and reorganization in July, under which it will sim- monitoring and compliance architecture policies dominated the Japanese pharma plify global sites and outsource much of its for dementia patients in Japan. market in 2016, there was also notable worldwide development activities. commercial activity during the year, al- PRICING UPHEAVAL though this was more about refocusing SHEDDING MATURE PRODUCTS But largely overshadowing these corporate and reducing rather than major mergers Another major area of activity by research- developments were rapid and fundamental and acquisitions. based multinationals in Japan was mature changes to the drug pricing environment, products, with several firms taking con- which has been relatively stable over the 016 was a quiet year in terms of trans- crete steps to pull out of this increasingly past few years, marked by higher fixed pric- formational mergers and acquisitions competitive and less profitable business. es for innovative new therapies along with 2in Japan, with nothing that could be While new drugs are enjoying good prices regular but predicable industry-wide reim- considered a “mega-deal” clinched during and growth, and generics are expanding at bursement revisions every other April. the calendar period. the other end of the scale, older brands are Spurred by political and public concerns Astellas Pharma Inc. was again an active faced with price cuts, competition, and are over highly effective, but also highly priced, deal maker however, signing or complet- generally stagnant. new drugs for cancer and hepatitis C - and ing several smaller acquisitions valued in In the wake of Takeda completing the the first real impact of these on the national the several hundred million dollar range, divestment of a select mature portfolio to healthcare bill - 2016 will be remembered including of Ganymed Pharmaceuticals AG a new Japan joint venture with generics gi- as a year that new waves began to roil this and Ocata, which build up its expertise and ant Teva Pharmaceutical Industries Ltd. in relatively calm sea. April 2016 saw drug re- assets in specific areas such as oncology April, major Indian firm Sun Pharmaceuti- imbursement prices under Japan’s national and ophthalmology. cal Industries Ltd. struck up an alliance with health insurance scheme cut by around 6% There was also a notable unraveling of Mitsubishi Tanabe Pharma Corp. for a basket across the board, as part of the biennial effort some alliances following disappointing clini- of older drugs acquired from Novartis AG to bring levels into line with actual (discount- cal results or to move out of deprioritized ar- Japan. Another Indian-affiliated company, ed) market prices. But on top of this, the prices eas, with Otsuka Pharmaceutical Co. Ltd. end- Lupin Ltd.’s Kyowa Pharmaceutical Industry of two new Gilead Sciences Inc. products for ing its ophthalmic partnership with Acucela Co. Ltd. operation, then picked up a group hepatitis C - Sovaldi (sofosbuvir) and Harvoni Inc., and Eisai Co. Ltd. selling AkaRx Inc. to a of older brands from Shionogi & Co. Ltd. (sofosbuvir plus ledipasvir) - were slashed by private equity group. While there was the usual panoply of li- around 32%, triggered by new provisions that Indeed for many of Japan’s top pharma censing in and out deals and R&D collabo- allow one-off reductions for products that companies, including Takeda Pharmaceutical rations during the year, it was hard to pick a have exceeded by a certain margin above of- Co. Ltd., the trend was towards continued di- stand-out therapeutic trend, although not ficial forecasts at the time of launch. vestment of non-core assets and molecules surprisingly oncology technology and mol- Later in the year, the price of Ono Phar- as they strived to sharpen their focus on se- ecules featured heavily across the board. maceutical Co. Ltd./Bristol-Myers Squibb lected therapeutic areas. This was in line with a continued effort Co.’s cancer drug Opdivo (nivolumab) also Speculation that Takeda was on the prowl by Japan’s major firms to build their pipe- came under intense public, political and for certain gastrointestinal assets from Vale- lines and expertise in this growing key mass media scrutiny as a driver of surging ant Pharmaceuticals International Inc. - or area, with Daiichi Sankyo Co. Ltd. in par- national prescription drug costs. Rapidly in- even the whole company - remained un- ticular also bringing in world-class foreign creasing use of the PD-1-targeting antibody confirmed by any deal by the end of the year. executives to help with its efforts, which in the additional indication of lung cancer But Takeda is raising a potential war chest of have been kick-started by a string of acqui- became a factor behind a 9% jump in such close to $900m from the year-end sale of its sitions over the past few years. The com- spending in the fiscal year to March 31, majority-owned Wako Pure Chemical Indus- pany is looking to generate new sources even prompting projections that it could tries Ltd. subsidiary in Japan to Fujifilm Hold- of growth amid the first loss of exclusivity effectively bankrupt the NHI system. ings Corp., and the possible deployment of during the year for its long-time top seller, Published online 29 December 2016 the proceeds will be watched with interest. the antihypertensive olmesartan. From the editors of PharmAsia News. As part of new CEO Christophe Weber’s Companies dipping a toe into novel continued efforts to fundamentally reshape digital health programs included As- CLICK Takeda and concentrate on three major fields tellas, through a new US investment Read full story at: - gastrointestinal, CNS, and oncology - Japan’s venture that will put money into broad http://bit.ly/2j57FuM biggest drugs firm unveiled a massive R&D initiatives, and Eisai, which is building a

16 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

2016 Review: Pricing, R&D Issues Dominate In China 2016 was again another busy year on the commercial front in China, with market changes, new regulations, and ongoing pricing pressures all affecting the pharma sector. Meanwhile, the push for licensing deals, innovation, and international expansion continued apace. BRIAN YANG [email protected]

JANUARY JUNE Provincial drug procurement processes became a major concern In its “most pessimistic” business confidence outlook in 13 years, the as dozens of provinces started unveiling new rules for pharma- EU Chamber of Commerce in China cautioned about a need for Chi- ceutical bidding, with companies getting ready to embrace na to implement reform measures, while EU pharma companies fore- deeper price cuts. saw their profits dropping in the world’s second-largest economy.

FEBRUARY JULY China’s ongoing economic woes were found to be denting the China’s Ministry of Industry and Information Technology (MIIT) re- pharma industry and directly impacting medical sales person- leased quarterly data showing overall growth for the drug manufac- nel, whose absolute numbers were declining despite the indus- turing sector declined to 9.6%, from 9.8% in the whole of 2015. try’s chronic need for talent, said the country’s top pharmaceuti- cal associations. AUGUST Despite China’s wider economic slowdown, investment continued to MARCH flock to the healthcare sector in the country, noted Bain & Company in Multinationals changed their traditional direction by expanding their its annual Global Healthcare Private Equity and Corporate M&A Report. footprints in the promising but challenging county-level hospital China bagged close to $1bn worth of private investments in public market, with Eli Lilly & Co. among those looking to embrace China’s equities in 2015, nearly double the previous year’s figure of $575m. lower-tier opportunities. SEPTEMBER During the annual People’s Congress, pharma industry represen- Gilead Sciences Inc. changed its business strategy in China by hir- tatives called for appropriate pricing mechanisms and the auto- ing a former Roche market access executive in a bid to develop the matic enrolling of new drugs onto the national reimbursement list scope of its local operations. to improve the innovation ecosystem. OCTOBER APRIL AstraZeneca announced the out-licensing of exclusive rights to four In a crackdown on excessive layers of sales agents and purchase cost antidiabetic products in China to Shenyang 3SBio Inc.: Byetta (exena- manipulation, China’s state regulators kicked off a new battle to com- tide), Bydureon (exenatide suspended release) single dose tray, By- bat so-called “guopiao,” or receipt inflation. The State Council issued a dureon dual chamber pen and Bydureon auto-injector, indicating a rule preventing the issue of more than two receipts during the drug strategy shift to focus more on its core respiratory franchise. procurement process. NOVEMBER MAY China’s innovation darling Betta Pharmaceuticals Co. Ltd. went public Facing increasing public complaints about the prices of medicines, on the Shanghai Stock Exchange, which may herald a new wave of cap- the Chinese government was poised to kick off a fresh round of ital inflow and renewed interest in new drug R&D in China, although probes into pricing practices. hurdles to the pursuit of original research were seen as remaining. Several drug and device manufacturers including Pfizer Inc. were To realize its ambitions for novel pharma R&D, China should step summoned by the powerful National Development and Reform up by providing timely and adequate insurance coverage to inno- Commission (NDRC) to provide information. vative new drugs, urged an industry report. A government report In an immuno-oncology gold rush, more than 50 biotechs in Chi- found that ambitious and confident Chinese pharma firms had be- na were found to be developing anti-PD1 and PD-L1 assets, quickly. gun to enter a brave new world of foreign M&A. China’s first round of national drug pricing negotiations cut the prices of selected hepatitis C and lung cancer therapies by more DECEMBER than 50%, impacting GlaxoSmithKline PLC’s Viread (tenofovir), As- A shift in dispensing patterns from hospitals to external pharmacies traZeneca PLC’s Iressa (gefitinib), and Betta Pharmaceuticals Co. led to predictions that the “direct-to-patient” sales model will be- Ltd.’s Conmana (icotinib). come important in China, but only those with the right partnerships The goal, according to the National Health and Family Planning and expertise will reap the benefits, leading pharmacy chain execu- Commission (NHFPC), was to lower the prices in China to levels tives told a conference. comparable with neighboring markets such as Hong Kong, Macau, Published online 29 December 2016 Taiwan and Japan. From the editors of PharmAsia News. scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 17 HEADLINE NEWS

2016 Review: Mixed Bag Of Hope And Setbacks For Korean Pharma JUNG WON Shin [email protected]

For the South Korean pharma industry, Agency (EMA) in October 2015. After receiv- blockbuster licensing out deals with mul- 2016 was largely about major global ad- ing the green light there, it aims to begin tinationals, hit the news again with a ma- vances for a wide range of biosimilars, ac- commercialization in the region in 2017, jor controversy over the cancellation of a companied by some setbacks in the area potentially widening the gap with its closest licensing deal for its lung cancer drug ol- of novel drug development. competitors. Celltrion has an exclusive part- mutinib. A subsequent prosecutors’ probe nership with Teva Pharmaceutical Industries looked into the company’s possible leak- he approval and launch of Celltrion Ltd., reached in October 2016, for Truxima, age of undisclosed information and if there Inc.’s biosimilar infliximab in the US under which the Israeli generics giant will was an intentional delay in disclosing the T could be seen as one of the top com- be responsible for all commercial activities negative news. mercial milestones for the South Korean for the product in the US and Canada. Prosecutors eventually concluded that pharma industry in 2016, marking as it did Celltrion plans to submit biosimilar ver- Hanmi did not deliberately put back the the first time that a monoclonal antibody bi- sions of rituximab and another cancer drug, announcement of a decision by licensee osimilar had been licensed in this key market. trastuzumab, to the US FDA in the first half Boehringer Ingelheim GMBH to end its Inflectra (infliximab-dyyb), a version of of next year. Biosimilar trastuzumab, now in olmutinib partnership, but several employ- Janssen Inc.’s Remicade, received the green late Phase III development after meeting its ees were nevertheless arrested over im- light from the US FDA on April 5, and was primary endpoint, was filed with the EMA proper information disclosure. also only the second biosimilar to be ap- in October. Meanwhile, the Ministry of Food and proved in the country after Sandoz Inc.’s Drug Safety decided to limit the usage of Zarxio (filgrastim). SAMSUNG MOVES AHEAD the EGFR inhibitor, which had been ap- The biosimilar is already widely available Celltrion’s main domestic biosimilars rival, proved in South Korea in May, solely to in Europe, as Remsima. Samsung Bioepis Co. Ltd., also made good patients who had agreed to use the drug Celltrion and commercial partner Pfizer progress with its global market entry plans after receiving thorough explanations from Inc. said they would launch Inflectra in the during the year. The FDA accepted for re- doctors on possible side effects including US in late November, and the entry into the view SB2, the firm’s biosimilar of Remicade, serious adverse skin reactions. world’s biggest pharma market is expected in May, making it the first of Samsung’s bio- Adding to the negative news amid the to give a big boost to global sales of the similar candidates to be submitted for re- country’s innovation drive, Yuhan Corp. de- product. Celltrion said the initial shipments view in the US. cided to halt clinical trials with its degen- of Inflectra to the US by the end of the In October, Samsung Bioepis then filed for erative disc therapy candidate YH14618, as year would be worth about KRW260bn the approval in Europe of its biosimilar trastu- statistical significance over placebo during ($225.9m) on a customs clearance basis. zumab, SB3, marking its fifth biosimilar can- Phase II trials was not established. The company is eventually aiming for didate to be filed for approval in this market. Green Cross Corp. ended US and Europe- annual worldwide Inflectra sales of more On top of this, the EMA accepted for re- an trials with hemophilia A therapy Green- than KRW1tn, and accumulated global ex- view a marketing authorization application Gene F after it modified strategy and de- ports to date have been in excess of this for the company’s adalimumab biosimilar cided to focus on the fast-growing China figure, making the product a key commer- candidate SB5 in July. market instead. cial pillar for Celltrion. The South Korean company received Eu- ropean Commission approval earlier in the MAJOR LICENSING DEALS CELLTRION’S RITUXIMAB year for Benepali, its biosimilar etanercept, Amid the setbacks, foreign companies con- PROGRESSES and biosimilar infliximab Flixabi. Its biosimi- tinued to show an appetite for accessing The South Korean firm is also edging ahead of lar etanercept (SB4) has already received the rising level of innovation and number of its competitors in the development of a ritux- South Korean regulatory approval and is novel drugs coming out of South Korea, as imab biosimilar. Truxima, its version of Genen- marketed there as Brensys. evidenced by a number of significant licens- tech Inc./Biogen Inc.’s monoclonal antibody ing deals during the year. MabThera/Rituxan, received regulatory ap- HARSH REMINDERS Deals reached in 2016 include CrystalGe- proval in South Korea in November, marking If 2016 was full of positive news about South nomics Inc.’s licensing out agreement with the first approval globally for the product. Korean biosimilar activities, the year also Aptose Biosciences Inc., Hanmi’s deal with The company expects the ongoing served up a stark reminder of how risky and Genentech Inc. and Kolon Life Science Inc’s regulatory process in Europe for biosimilar tough new drug development can be. deal with Mitsubishi Tanabe Pharma Corp. rituximab to progress “smoothly” following Hanmi Pharmaceutical Co. Ltd., which Published online 29 December 2016 a submission to the European Medicines had made headlines reaching a series of From the editors of PharmAsia News.

18 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 R&D BITES

Alexion’s Soliris Slips Up In Pivotal PROTECT Kidney In Novartis, Conatus Lands Experienced, Transplant Study Deep-Pocketed NASH Partner Inc. has been The broad-based competition in non-alcoholic steatohepatitis (NASH) left disappointed by top-line data from took another turn Dec. 19, as Conatus Pharmaceuticals Inc. signed an op- the Phase II/III registration trial for its tion, collaboration and commercialization agreement with Novartis AG first-in-class terminal complement in- around its caspase inhibitor emricasan, currently in Phase IIb for both hibitor Soliris (eculizumab) in prevent- NASH cirrhosis and NASH fibrosis. The deal brings Conatus $50m up ing delayed graft function (DGF) after front, a convertible loan of up to $15m from Novartis, a $7m exercise fee if kidney transplantation in adult recipi- the pharma elects its option on emricasan and up to $650m in milestones ents of a deceased donor kidney. If suc- along with potential sales royalties if the drug reaches the market as mon- cessful, the study could have paved the otherapy and/or as part of a NASH combination regimen. Novartis also way for approval in another indication has LJN-452, a non- farnesoid X receptor (FXR) agonist in Phase for Alexion’s mainstay and multibillion- II for NASH, as well as for primary biliary cirrhosis and hepatic fibrosis. dollar selling product in an area of huge While Intercept Pharmaceuticals Inc. and Genfit SA have begun pivotal unmet medical need: there are no thera- Phase III studies with their NASH candidates – FXR agonist obeticholic pies licensed to prevent or treat DGF acid (Ocaliva) and dual PPAR alpha/delta agonist elafibranor, respectively after kidney transplantation, a common – the competition to become first to market in this burgeoning indication complication. The failure adds to a dif- linked to metabolic syndrome ranges widely both in terms of targets and ficult end of year for Alexion, which has mechanisms of action as well as the companies involved. Allergan PLC, just lost its CEO David Hallal and CFO Gilead Sciences Inc. and Bristol-Myers Squibb Co. are among the more es- Vikas Sinha amid an audit investigation tablished and well-heeled players in the race, which may ultimately come and a delay to its 10-Q filing. Expand- down to combination therapy strategies as was the case previously in HIV ing Soliris approval into DGF is part of and hepatitis C. Alexion’s strategy to grow the product [email protected], 20 Dec 2016 further, and an approval had been slated for 2018 by the company. Other rare indications in late-stage testing include volanesorsen for FCS in 2017. It plans a refractory generalized myasthenia gravis subsequent filing down the road in fa- (gMG) and relapsing neuromyelitis op- milial partial lipodystrophy (FPL) for the Celgene Joins Evotec In Its tica spectrum disorder (NMOSD). The candidate, which is designed to reduce First Neurodegenerative failure is also a setback for the DGF field the production apoliprotein C-III, a pro- as a whole. Analysts at Biomedtracker tein produced in the liver that plays a role Effort have lowered their likelihood of approv- in regulation of plasma triglycerides. FCS al score by 15% to 44% as a result. Celgene Corp. has made its first big for- and FPL, both rare metabolic disorders, ay into CNS by inking a strategic drug [email protected], 23 Dec 2016 are unmet medical needs with potentially discovery and development collabora- life-threatening consequences, the com- tion with Germany’s Evotec AG to iden- Ionis Subsidiary Akcea pany notes. FCS, in which triglyceride tify disease-modifying therapeutics for a levels are 10-20 times higher than nor- broad range of neurodegenerative diseas- Encouraged By Safety Data mal, often progresses to pancreatitis, and es. Under the deal – announced Dec. 15 In FCS currently available triglyceride-lowering - the duo will focus initially on areas that therapies rarely are beneficial in these include amyotrophic lateral sclerosis, Alz- Awaiting data from its pivotal AP- patients. In the Phase III COMPASS heimer’s disease, Parkinson’s disease, and PROACH trial during the first quarter study of 113 patients with severe hyper- other neurodegenerative disorders. The of 2017, Akcea Therapeutics was encour- triglyceridemia, the 75 patients treated plan is to develop novel therapies for a aged by safety and efficacy data unveiled with volanesorsen achieved a 71.2% mean broad range of neurodegenerative diseas- Dec. 19 for lead candidate volanesorsen reduction in triglycerides from baseline es, based on Evotec’s industrialized drug from a separate Phase III study in pa- after 13 weeks of treatment, compared to screening platform using patient-derived tients with severe hypertriglyceridemia, a mean reduction of 0.9% in the placebo induced pluripotent stem cells (iPSCs) including a subset of patients with famil- group (p<0.0001). The treatment effect by which high throughput screening in ial chylomicronemia syndrome (FCS). was sustained throughout the full 26- iPS cell-derived neurons is conducted to Akcea, a subsidiary of antisense-focused week dosing period. identify new therapeutic compounds. Ionis Pharmaceuticals Inc., hopes to file [email protected], 21 Dec 2016 [email protected], 19 Dec 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 19 HEADLINE NEWS

Acadia’s Nuplazid Could Have The Alzheimer’s R&D Curse Acadia’s Nuplazid (pimavanserin) has met its primary endpoint in a Phase II study in patients with Alzheimer’s disease psychosis – but a secondary endpoint miss in the same study has triggered alarm bells for future development of the product in Alzheimer’s, a historically risky scene, marred by many Phase III failures. LUCIE ELLIS [email protected]

cadia Pharmaceuticals Inc. has re- Stephen Davis, said on a Dec. 20 confer- ciation, there are approximately 5.4 million ported mixed Phase II results for ence call. Alzheimer’s patients in the US, approxi- Aits experimental Alzheimer’s drug, Srdjan Stankovic, executive vice presi- mately one-half of whom are diagnosed pimavanserin, at a time when the diseases dent and head of R&D at Acadia, added with the disease. It is the fifth leading cause space is being watched with great interest on the conference call that he is eager to of death for people aged 65 and older. following the recent late-stage failure of Eli assess these data more before launching Acadia’s chief Davis noted on the Dec. Lilly & Co.’s solanezumab. a Phase III study for pimavanserin. “Frankly, 20 conference call about pimavanserin While Acadia presented positive data for [I am] excited about the treasure trove of that, “Today, there are no drugs approved pimavanserin, with top-line results show- information that we are able to analyze in by the FDA to treat Alzheimer’s psychosis.” ing that the drug met its primary endpoint these data,” he said. “It will certainly guide us Atypical antipsychotics are frequently used in the Phase II -019 study in patients with very well where we need to go in our next off-label to treat psychosis in Alzheimer’s Alzheimer’s disease psychosis, analysts trial and in our pivotal trial in this indication.” patients to fill the treatment void. have questioned the durability of the Stankovic said the secondary endpoint product because of a missed secondary miss was “due to improvement observed in PIMAVANSERIN’S PARKINSON’S endpoint and marginal efficacy. placebo from week six to week 12. We did APPROVAL not see a separation between placebo and Study -019 is the first to test pimavanserin, pimavanserin at that point,” he said. a selective serotonin inverse agonist (SSIA) Acadia’s CEO added that the company targeting 5-HT2A receptors, in patients with will “leverage” the Phase II data “for the Alzheimer’s disease psychosis. However, the benefit of future study designs to help us drug is already on the market, having been understand what we should do the same approved by the FDA in April 2016 for de- and what we would consider changing.” In lusions associated with Parkinson’s disease the Phase II study, Davis highlighted that psychosis, under the trade name Nuplazid. “importantly, pimavanserin was able to With the results of Study -019, pimavan- demonstrate antipsychotic effect without serin has now demonstrated an antipsy- worsening cognition.” chotic effect in three major CNS disorders: Leerink analysts also highlighted con- Parkinson’s disease psychosis, schizophre- cerns about the secondary endpoint miss nia and Alzheimer’s disease psychosis.

Shutterstock: Lightspring Shutterstock: in a Dec. 21 research note. They said key opinion leaders they had spoken to called PHASE II STUDY DETAILS In the Phase II exploratory study, pima- the Phase II data a “minor positive signal.” In the -019 study, a 3.76 point improvement vanserin met the primary endpoint, show- The KOLs had feelings of skepticism that in psychosis was observed in the pimavan- ing a significant reduction in psychosis the results would not be able to be repli- serin treatment arm at week six compared versus placebo as measured by the Neuro- cated in a large Phase III study, Leerink ana- to a 1.93 point improvement for placebo. psychiatric Inventory-Nursing Home (NPI- lysts wrote. Baseline scores were 9.52 for pimavanserin NH) Psychosis score at week six of dosing However, “with no approved treatments and 10 for placebo-treated group. (p=0.0451). Pimavanserin was generally for Alzheimer’s psychosis and meaning- On the matter of cognition, pimavanser- well tolerated and the safety profile was ful safety issues with the standard-of-care, in did not impair cognition over the course consistent with what has been observed in specialist commentary suggests that pi- of 12 weeks of treatment and was similar to previous studies. mavanserin would (even with a modest placebo as measured by the Mini-Mental However, on the study’s secondary end- effect size) still get meaningful traction in Status Exam. point of mean change in NPI-NH Psychosis Alzheimer’s in the event that it were ap- Based on a preliminary analysis of safety score at week 12, pimavanserin maintained proved,” Leerink analysts note. data, the most common adverse events the improvement on psychosis observed The unmet need in Alzheimer’s is huge reported were falls, urinary tract infection at the week six primary endpoint but did and drug development has faced many set- and agitation. The mortality rate was the not statistically separate from placebo. backs over the last decade. Most recently, same in the pimavanserin and placebo Acadia plans to continue development Lilly’s solanezumab product failed in several treatment groups. The mean age of pa- of the drug in this Alzheimer’s indication, Phase III studies in different Alzheimer’s pa- tients in the study was 86 years. the company’s president, CEO and director, tient populations. Per the Alzheimer’s Asso- Published online 21 December 2016

20 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

Advair: A Big Generic Opportunity And A Big Question Mark In 2017 JESSICA MERRILL [email protected]

Takeda’s Velcade, Pfizer’s Viagra and Gil- asking the agency not to approve generic ability of generic rivals to bring and keep ead’s Viread are among the brand drugs versions of Advair. a generic version of EpiPen on the market expected to face generic competition in because it is also complex to make. the US for the first time in 2017. One un- A MORE THAN $2BN BRAND Fueled partly by that scandal, FDA has known is Advair. OPPORTUNITY come under fire from Congress for not The opportunity is significant, despite the getting competitors to expensive drugs he launch of a generic version of fact that competition, payer pressure and like EpiPen to market faster. The agency GlaxoSmithKline PLC’s blockbuster GSK’s own new respiratory entries, including recently announced it will establish an T asthma drug Advair Diskus (flutica- Breo, have chipped away at Advair’s block- eight-month priority review path for cer- sone/salmeterol) in the US could be one of buster sales over the last five years. US sales tain high-quality ANDAs under the reau- the biggest commercial opportunities for of Advair were £1.87bn ($2.35bn) in 2015. If thorized generic drug user fee program generic manufacturers in 2017, but it is still a generic drug is indeed approved, it will ad- beginning in fiscal year 2018. uncertain whether or not FDA will pave the dress one of the biggest generic opportuni- BTTG analyst Timothy Chiang speculated way for one to reach the market. ties 2017. on the market opportunity for generic Ad- Mylan NV and Hikma Pharmaceuticals Other big sellers that are expected to vair in a Nov. 28 research note: “Assuming PLC have both confirmed FDA has accept- face their first generic competition in the there are two ANDAs approved in 2017 ed their ANDAs to market generic versions US in 2017 are Takeda Pharmaceutical Co. and pricing drops by 50%, we think the first of Advair, with action dates of March 28 Ltd.’s multiple myeloma backbone Velcade generic company to enter could generate and May 10, 2017, respectively. But Advair (bortezomib), Gilead Sciences Inc.’s HIV sta- significant sales at market formation, with is considered a complex small molecule – ple Viread (tenofovir/disoproxil) and Pfizer sales in excess of $200m within the first six a combination of two drugs delivered to Inc.’s erectile dysfunction blockbuster Vi- months of launch.” the lungs through a specific dry powder agra (). Given the potential opportunity, he said inhaler – so there is no certainty of a first- Merck & Co. Inc.’s cholesterol-lowering Mylan’s shares are attractive due to recent cycle approval by the agency, which has drug Zetia (ezetimibe) faced the first ge- devaluation of the company’s stock following struggled with the approvability require- neric rival Dec. 12 so the impact on Merck’s the backlash of the EpiPen pricing scandal. ments for respiratory generics. franchise and likely the combination pill But analysts are mixed on the chances The complexity around the development Vytorin (ezetimbe/simvastatin), now made that the first ANDA filers could receive a of a generic version of Advair is why the prod- up of two active ingredients available ge- first-cycle approval uct has maintained exclusivity beyond its nerically, will be felt throughout 2017. Vyto- Leerink analyst Jason Gerberry said in an patent life. The drug components of Advair rin also will lose patent protection in April Oct. 21 research note said that while gener- lost patent protection in 2010, though the 2017. US sales of Zetia and Vytorin were ic Advair will eventually reach the market, device only lost patent protection in 2016. $2.52bn and $1.25bn in 2015. there is a low probability of a first-round Payers are eager for a substitutable ge- Being first generic to market when it approval. The investment firm conducted neric that could help reduce costs in the comes to Advair will be important in terms an analysis of FDA approval rates for com- expensive respiratory categories, includ- of the traditional window to make the most plex generics earlier this year and found the ing asthma and chronic obstructive pul- money while the exclusivity period lasts. average review time for complex ANDAs is monary disease; they are already pitting But the high barriers to entry for rivals is in the 66-month range, 55% to 60% longer competitors against one another to secure also why GSK believes it can continue to than standard 42-month reviews. significant price concessions. The availabil- extract life out of branded Advair even af- “If we were to assume a 50% to 100% ity of a generic would likely impact other ter generics enter the market. longer review clock to Mylan’s g-Advair bronchodilators in the category beyond Mylan, during recent financial calls, said review (22 to 30 months review versus 15 branded Advair, like AstraZeneca PLC’s it feels confident about a first-round ap- months), then we estimate the earliest Symbicort (budesonide/formoterol) and proval for its generic because of encour- possible approval would occur in mid- to GSK’s next-generation, once-daily ICS/ aging dialogue with the agency. If Mylan late-2018,” Gerberry speculated. LABA Breo Ellipta (fluticasone/vilanterol). does secure an approval, it will be a big win Published online 29 December 2016 In addition to Mylan and Hikma, Teva for the company, which has faced signifi- Pharmaceutical Industries Ltd. and Novar- cant backlash and pressure from the pub- View tables showing Big Drugs Expected To Face tis AG’s Sandoz are racing to bring their lic over the price increases it has taken for Generics in 2017: own generic versions to market. In Octo- the allergy medicine EpiPen (epinephrine). http://bit.ly/2j43nIr ber, Sandoz filed a citizen petition with FDA Ironically, Mylan has benefited from the in- scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 21 HEADLINE NEWS

Novartis Withdraws Arzerra CLL Second-Line Use Filing in EU Novartis has withdrawn its label extension application in Europe for use of Arzerra in combination with bendamustine for the treatment of relapsed chronic lymphocytic leukemia, following CHMP queries over a lack of comparable data.

LUCIE ELLIS [email protected]

The committee was also concerned that Predominantly, Johnson & Johnson/AbbVie the data presented by Novartis were in a Inc.’s Imbruvica (ibrutinib) has rapidly estab- small number of CLL patients and that the lished itself as standard of care in relapsed/ number of complete responses was not refractory CLL: worldwide sales of the drug significant. “Although some patients (39 out topped $1bn in 2015. Though prognosis for of 53) responded to the combination Arz- this relapsed disease population is still poor, erra plus bendamustine, only a few patients the introduction of Imbruvica and its fellow (6 out of 53) had a complete response, and Bruton’s tyrosine kinase (BTK) inhibitors have these data were not supported by further changed treatment dynamics significantly. study results,” the CHMP noted. As such, Novartis needs to establish itself in

Shutterstock: mantinov Shutterstock: The EMA’s scientific committee did not these second- and third-line treatment set- consider the data robust enough to approve tings to stay relevant in CLL. ovartis AG has pulled its EU appli- the new combination of Arzerra and benda- However, Datamonitor Healthcare ana- cation for Arzerra (ofatumumab) in mustine as a treatment for relapsed CLL. lysts Dominique Fontanilla noted that even Ncombination with bendamustine Novartis told Scrip it was now “evaluating another approval for Arzerra in relapsed CLL for the treatment of relapsed chronic lym- its options” for Arzerra as a treatment for re- would not help the product win out against phocytic leukemia (CLL) – a setback for the lapsed CLL in Europe. However, it highlighted its increasing number of competitors. “One of company which needs to up the drug’s use that earlier this month, the European Com- the only potential areas that Arzerra had to in the second-line setting. mission granted a marketing authorization in grow in was the maintenance setting where Arzerra used with bendamustine (Teva the EU for the use of Arzerra in combination it has won approval in the US, but it was re- Pharmaceutical Industries Ltd; Treanda) is a with fludarabine and cyclophosphamide for jected in the EU based on a lack of corrobo- new combination, but the European Medi- the treatment of adult patients with relapsed rating overall survival and progression free cines Agency’s scientific committee – the chronic lymphocytic leukemia. However, this survival endpoint data,” Fontanilla said. “Arz- Committee for Medicinal Products for Hu- is not an ideal combination as many relapsed erra will be used in the third-line settings or man Use – put several questions to company CLL patients are fludarabine-refractory. later – it just hasn’t been able to demonstrate after reviewing Novartis’s filing for the prod- The Swiss big pharma picked up Arzerra, the level of clinical efficacy as other drugs uct. These queries focused why Novartis did a fully human CD20-targeting monoclo- such as Rituxan and Imbruvica.” not submit data comparing Arzerra in combi- nal antibody, from GlaxoSmithKline PLC in Arzerra needs to keep up with other avail- nation with bendamustine against any other 2014 as part of a deal for GSK’s oncology able anti-CD20 therapies, such as Roche’s CLL therapies. Had Novartis not withdrawn portfolio. Novartis has since acquired the mainstay Rituxan (rituximab) – which, in its application, the CHMP would not have ap- rights for the drug from GSK in autoim- combination with chemotherapy, has been proved the new combination at this time, the mune indications as well. physicians’ choice treatment for relapsed CLL committee said in its assessment of the filing. Arzerra has been authorized in the EU since its approval in this population. Roche’s The CHMP said that Novartis presented since April 2010; it was designated an orphan product has five approved indications, in- it with results from a study involving 53 pa- medicine for CLL in November 2008. Arzerra cluding non-Hodgkin’s lymphoma, CLL and tients with relapsed CLL. All patients received plus bendamustine is used as a combination rheumatoid arthritis; but the drug’s main Arzerra plus bendamustine in the trial and therapy already in previously untreated CLL patents start to expire in the US in 2018, fol- Arzerra was not compared with any other patients who cannot be treated with fludara- lowing expiration of some patents in Europe treatment. The main measure of effective- bine (Sanofi’sOforta ). in 2013, and biosimilars are in development. ness was based on the number of patients Roche’s follow-on product to Rituxan, Gazy- who showed a partial or complete response CLL MARKET CHANGES va (obinutuzumab), won European approval to treatment. Novartis wants to expand the use of Arzerra in combination with chlorambucil chemo- While Novartis responded to the commit- and bendamustine into relapsed CLL pa- therapy for the treatment of people with pre- tee’s initial list of questions about its filing, the tients to fill a large unmet need. The compa- viously untreated CLL in 2014 – however, the CHMP said the answers were not satisfactory. ny also needs to expand its reach for Arzerra drug has not yet won approval for relapsed Novartis then withdrew its application for a within CLL now because the therapy area CLL. Phase II studies are ongoing for Roche’s change to the marketing authorization for has seen a dramatic change in the number follow-on drug in this second-line setting. Arzerra on Nov. 8, 2016. of available therapies in the last two years. Published online 20 December 2016

22 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

Novartis Takes On Colombia Over Glivec Pricing FRANCESCA BRUCE [email protected]

Novartis is taking Colombian authorities to court over moves manded by local regulations and has already been lowered twice. to cut the price of its anticancer Glivec () and warns “In fact, the Glivec price in Colombia is one of the lowest globally,” that the intellectual property rights of other products are under said Novartis. threat. Companies selling hepatitis C drugs should pay attention The groups that initiated compulsory license proceedings say the as their products could be next to face similar measures. DPI and price reduction are necessary to protect Colombia’s public health budget. They accuse Novartis of picking and choosing its ovartis AG is fighting what it thinks are unfair tactics by the arguments for convenience. They claim that there are no generic Colombian health ministry to undermine intellectual prop- versions available on the market. “Glivec is the beta-polimorph of Nerty rights and cut the price of its anticancer Glivec (imatinib). imatinib. There are no generic versions of the beta-polimorph be- It claims it is taking action to stop the same thing happening to other cause if they were they would be infringing the patent. The generic pharmaceuticals. Indeed, pressure is mounting from civil society to versions that Novartis says that are in the market are generic of the make hepatitis C treatments, including Gilead Sciences Inc.’s Sovaldi alpha-polimorph,” they told Scrip. (sofosbuvir), Bristol-Myers Squibb Co.’s Daklinza (daclatasvir) and Although they welcome the price reduction, they would like to Merck & Co. Inc.‘s Victrelis (boceprevir) more accessible. see bigger savings for the public health system and want the pat- In the latest development in the wrangling over Glivec, the Co- ent office to proceed with a compulsory license. This could lead to lombian health ministry has announced the national pricing com- a price of just 68 pesos per mg and was the price of one of the ge- mission’s decision to cut the price of Glivec by 44%, from 368 pesos nerics available on the market before Glivec’s patent was granted. (US$0.12) per mg to 206 pesos (US$0.7 per mg). The move marks Meanwhile, the NGO, Health Action International says it “sup- a “full stop in a new chapter on pharmaceutical policy,” says the ports the move to issue a declaration of public interest for imatinib health ministry. “That chapter includes not only the first ever dec- (marketed as Glivec), which is on the WHO’s essential medicines list laration of public interest for a medicine in the country, but which and which Novartis was selling for a price in Colombia per patient also turns Colombia into a pioneer of such declarations for cancer that is approximately twice the Colombian gross national income drugs,” it said in a statement published on December 21. (GNI) per capita. Glivec, which is on the WHO essential medicines list, has been “There was no willingness from Novartis to voluntarily lower the the source of much contention in Colombia for some time. When price in Colombia and given that Novartis had already made 47bn Novartis originally brought the drug to Colombia, its request for a in global sales on Glivec there is surely no rationale for earning back patent was rejected. However, Novartis kept the drug on the mar- R&D costs. Colombia is a small market for Novartis which means it has ket, which it shared with generic rivals, until 2013 when the patent less clout in price negotiations and they are fully dependent on com- office granted the patent. In 2014, civil society groups, IFARMA, Mis- panies to lower the price of drugs voluntarily. If this does not happen ión Salud and CIMUN, brought a request that the government issue they are fully entitled to use the legal means available and compliant a compulsory license for the drug, arguing the patent was weak, with international law to lower the price of a drug,” HAI told Scrip. that the drug was expensive and that generic competition could bring the price down. The declaration of public interest (DPI) was HEPATITIS C DRUGS NEXT? published in June as the prelude to a price cut, rather than a com- Gustavo Morales, president of AFIDRO, is concerned about the prec- pulsory license. Following the DPI, the government published new edent that the DPI and price cut will set. “If Glivec is a public interest regulations outlining new methodology for fixing the price of a medicine every other medicine, especially those that are complex, medicine, which was how the new price for Glivec was formulated. high cost and innovative, could be subject to the same treatment,” he It is the declaration of public interest that Novartis is challenging says. He points to procedures to issue DPI for hepatitis C treatments and it says it has filed an annulment action. Novartis claims that that are underway. financial losses are not its main motivation for challenging the DPI, The same groups have requested that all hepatitis C treatments, in- particularly given that Glivec’s patent rights expire in 2018. “We are cluding sofosbuvir, daclatasvir simeprevir, boceprevir, and telaprevir, pursuing this case out of concern for the repercussions it could be declared of public interest. They claim such action is necessary be- have for the intellectual property system and future of innovative cause the latest treatments are unaffordable in several countries for medicines. Novartis believes that the circumstances surrounding both out of pocket payers and public healthcare systems. HAI adds: the DPI for Glivec could create a damaging precedent that could be “The prices of these new but highly effective hepatitis C treatments applied to other patent-covered treatments in Colombia and other are so high that they are unsustainable even for European countries. countries. At a stroke, this could destroy intellectual property - one For Colombia the med would be too expensive in the absence of a of the fundamental frameworks the biomedical research sector re- voluntary price reduction by the pharmaceutical company.” lies on for its existence,” said the company. AFIDRO supports Novartis’ legal action and in the new year will Novartis wants to show that there are no reasonable grounds for challenge the government on the new pricing regulations for drugs the DPI for the following reasons: there are already non-infringing that have been declared of public interest, says Morales. He claims generics on the market; there are “no access issues for Glivec in that events in Colombia may make companies think twice about Colombia”; and because Glivec’s price is lower than the price de- launching there. Published online 22 December 2016

scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 23 HEADLINE NEWS

Ex-Sanofi Exec Stoeckli Primes Glenmark’s Cancer Therapy Ambitions Glenmark’s president and chief scientific officer, Dr Kurt Stoeckli, believes that some big pharma companies may have missed the opportunity to embark on immunotherapy cancer treatment R&D “at the right time” and tells Scrip that there is room for the Indian firm to provide competitive assets in the space. Stoeckli, an ex-Sanofi senior executive, also outlines why the upside potential of Glenmark’s BEAT antibody technology platform is “remarkable.” ANJU GHANGURDE [email protected]

r Kurt Stoeckli, says that moving “Should this go on in a very successful include GBR 1342 (a CD38xCD3 bispecific to Glenmark Pharmaceuticals Ltd. way even the core segment is rich enough antibody) being developed for multiple Dfrom Sanofi was all about a “perfect to think about partnering especially in im- myeloma and potentially other malignan- match.” While the former group vice presi- munotherapies where lots of combination cies of hematopoietic origin and GBR 1372, dent for the French multinational’s global concepts are coming up. I consider this as targeting EGFR through redirected killing biopharmaceuticals division may have been very value-creating because some of these by T cells. used to big pharma R&D budgets and scale, potential partners will have complementa- Stoeckli believes GBR1372, being devel- Stoeckli says that he was drawn to the Indi- ry assets, experience and access to markets oped for colorectal cancer, represents an an firm by its sheer potential – “people, proj- and regions,” he said. “enormous opportunity” for the company. ect and science” - and what the company “KRAS mutations are one of the most “could make” in the years to come. BISPECIFIC ANTIBODIES unmet needs in cancer therapy with a Stoeckli, who also spent several years in drug broad range of carcinomas. This is ex- Dr Kurt Stoeckli, President and discovery at Novartis/Sandoz in Switzerland, actly where drugs like Erbitux (cetux- Chief Scientific Officer, Glenmark is particularly upbeat about Glenmark’s bi- imab) are not really effective enough specific antibody portfolio based on the and have limitations - where the body firm’s proprietary BEAT antibody technology has by definition designed more than 10 platform. The Bispecific Engagement by An- mechanisms of resistance and where we tibodies based on the T-cell receptor (BEAT) have mechanistically a very good way to platform facilitates the efficient develop- overcome the KRAS mutation problem,” ment and manufacture of antibodies with he explained. dual specificities. For instance, Glenmark’s HER2xCD3 bi- BEAT – RANGE OF specific antibody (GBR 1302), he explained, POSSIBILITIES has the potential to be highly active on tu- Stoeckli suggested that Glenmark’s BEAT mor cells that have low to moderate level platform has a “competitive edge” compared of expression of HER2, which is where the with others including Roche’s CrossMAb current standard of care is “just not suffi- technology invented to produce bispecific cient” and has limitations with Herceptin antibodies. (trastuzumab) or conjugates of Herceptin. Glenmark’s platform, he says, is efficient “So here is where we may be able to dif- in “playing with new targets” that come “I just found that this is a perfect match, ferentiate. For us it is the front runner, al- up and are of clinical relevance; flexibility where I could bring complementarity and ready in Phase I clinical trials; the molecule beyond CD3-mediated engagement im- experience that I have gone through in big has an important role to play for us to dem- munocytes is another plus that it brings, pharma and the portfolio is so exciting in onstrate and confirm the BEAT platform besides scalability. terms of potential for the next 5-10 years,” utility,” Stoeckli said. “The stability and robustness of BEAT Stoeckli told Scrip in an exclusive interview HER2, also known as HER2/neu, or recep- molecules is an important aspect of indus- at Glenmark’s Mumbai headquarters. tor tyrosine-protein kinase erbB-2, is the trialization. The BEAT platform is designed Stoeckli, who took charge as Glenmark’s target of the antibody cancer drugs trastu- such that you can efficiently purify what president and chief scientific officer (CSO) zumab, pertuzumab and trastuzumab em- is up-scaled and can bring it rapidly to a in October, believes that it is essential for tansine. A Glenmark investor presentation point where you can supply the clinical Glenmark to be able to move ahead with a dated Dec. 19 claimed that GBR 1302 could studies with sufficient quantity and qual- “core segment” of projects that it establish- bring about “faster and more complete” ity,” Stoeckli explained. es on its own end-to-end capabilities and killing of tumor cells as compared with cur- On whether Glenmark would consider be “independent.” Glenmark is strategically rent first- and second-line treatments. GBR an outright deal for the BEAT platform, focused on three core therapy areas - on- 1302 is also being studied in gastric can- Stoeckli said: “We do not say no to this cology, dermatology and respiratory. cer. Other BEAT-based oncology biologics upfront; we consider any sort of partner-

24 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

ing for the BEAT platform to be within the Stoeckli adds. Experts say that, theoreti- range of possibilities.” cally, an OX40-targeted drug could be Christmas Amgen Inc. acquired the BiTE [Bispecific used to stimulate an immune response Cheer For T cell engager] platform behind Blincyto and it could be combined with a PD-1/ (blinatumomab) when it snapped up Mi- PD-L1 [programmed cell death-ligand 1] Cipla’s Seretide cromet Inc. in 2012 for over $1bn. In June inhibitor that would prevent tumor cells this year, Novartis AG announced a col- from evading the generated response. Equivalent In laboration and licensing agreement with Xencor Inc. for the development of bispe- THE BIG THING The UK cific antibodies for treating cancer; the deal Stoeckli also says that the big thing with Cipla’s generic version of Seretide has finally includes rights to use Xencor’s antibody immunotherapies is its potential to reach received regulatory approval in the UK, engineering platform to develop up to 10 more patients; right now, even the “best of bringing much needed relief to investors and additional antibodies for immuno-oncolo- the best” immunotherapies, he says, reach opening up more competition for GlaxoS- gy and other diseases. only 30% response rates, at best. mithKline on its home turf. But Stoeckli clarifies that the BEAT plat- “Great progress has been made and if Cipla Ltd. has received final approval form could also be used for partnering on you look at what has happened for the pa- from the UK MHRA for its fluticasone specific projects that the Indian firm has tients [who respond] - it has really changed + salmeterol metered dose inhaler (Sere- already ongoing. their lives. They have a very different per- flo), ending several months of investor “This would be a strategic partnership. spective. But there is huge unmet medical over the product’s debut on the And this means any sort of co-develop- need for patient populations that are not British market. ment, co-marketing – but we would part- responding,” he notes. Cipla said that its Sereflo ner and it’s not just a simple out-licensing. Stoeckli says that breakthroughs in can- 25mcg/125mcg and 25mcg/250mcg In addition, we could talk with someone cer therapy will find the right combination are generic “equivalent” versions to who wants to have access to the technol- that can change the response rates. GlaxoSmithKline PLC’s Seretide inhal- ogy per se for a certain number of targets “This is what we are working on, mol- ers for asthma. Mylan NV, in June last year, launched the first bioequivalent they want to work on - we don’t purely ecules that engage and further boost, alternative to GSK’s Seretide Evohaler exclude this; it is within the range of our modulate in a positive way, the immune (salmeterol xinafoate/fluticasone propi- thoughts.” system.” onate), branded as Sirdupla in the UK. Glenmark’s new CSO also believes that Cipla said that it expects to launch COMBINATION THERAPY some big pharma companies missed the Sereflo in the UK through a partner “in Significantly, Glenmark’s Dec. 19 investor opportunity to get on board with immu- the coming weeks,” but gave no specif- presentation also highlighted a new type of notherapy cancer treatments at the right ics on the alliance. “highly potent” OX40 agonist (GBR8383). time. Details on the UK MHRA website cite Glenmark’s OX40 agonist, in combina- “So they are looking at partnerships to Fannin (UK) Ltd as the market authori- tion with programmed death (PD)-1 and replenish their own pipelines, get access to zation holder of Sereflo and lists Cipla’s other checkpoint inhibitors, is expected to competitive edge technologies. Nobody Goa unit as the manufacturing site. be potentially very active in boosting the T has, to date, been able to do everything Cipla did not immediately respond to cell response. on their own since nobody knows exactly email queries pertaining to the prod- “We consider this as a typical example which combinations will be most effective,” uct’s MHRA approval, including aspects of a combination therapy in a broad sense Stoeckli said, referring to J&J’s collaboration around substitutability with Seretide. in a variety of cancers. We have already with Genentech and how Pfizer Inc. and Industry experts tracking the devel- made clear that we see great potential Merck & Co. Inc. are going into combina- opment, however, suggested that Cip- for the OX40 agonist to boost the effect tion therapy approaches either internally la’s generic product is a substitutable of our CD3 engagers, but it goes beyond,” or via partnerships. version of GSK’s Seretide inhaler and Stoeckli said. “There is room for Glenmark to come in that the UK National Health Service Glenmark maintains that preclinical data and provide competitive assets,” he said. (NHS) now has a cost-effective asthma on GBR8383 confirms a strong agonistic In March 2016, Janssen Inc. and Genen- therapy on hand. effect upon the checkpoint OX40 in com- tech Inc., part of the Roche group, entered Cipla had earlier launched a “cost- parison with other OX40 agonists currently a clinical trial collaboration pact to initiate efficient” generic version of GlaxoS- in clinical trials. The company believes that certain studies to determine the safety mithKline’s Advair/Seretide in several GBR8383 has potential to enhance current and tolerability of daratumumab (Darza- European markets. immunotherapies (PD-1, PD-L1, CTLA4). lex), the first CD38-directed monoclonal [email protected], 23 Dec 2016 “Checkpoint inhibitors, immunothera- antibody, in combination with atezoli- pies require combination therapy in the zumab, an investigational mAb designed CLICK future because the cancer site mechanis- to bind with a programmed cell death- Read full story at: tically predicts that you have to activate ligand 1 (PD-L1). http://bit.ly/2j4jVQr the immune system in multiple ways,” Published online 23 December 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 25 POLICY & REGULATION BRIEFS

Just The Tonix: New York Biotech Has Breakthrough FDA Hold On Seattle Genetics’ Trials Drug For PTSD Clouds CD33’s Suitability for AML Tonix Pharmaceuticals Holding Corp., The suitability of CD33 as a target for acute myeloid leukemia has come founded in 2007 and based in New York, into focus again after holds were placed on early trials with Seattle Genet- spent the first ten years of its life devel- ics Inc.’s antibody drug conjugate vadastuximab talirine (SGN-CD33A). oping lead compound, TNX-102, for The clinical holds, announced Dec. 27, followed the deaths of four pa- the treatment of condition tients treated with vadastuximab talirine along with allogeneic stem cell syndrome (FMS). But after transplant (ASCT), either prior to or after treatment. The investigative a setback in Phase III for this indication freezes were imposed to assess the potential risk of hepatotoxicity, as the earlier this year and positive results in an- patients who died had veno-occlusive disease (VOD). Two other patients other of its earlier stage clinical trials for also had hepatotoxicity. Vadastuximab talirine (or SGN-CD33A) targets the same drug in post-traumatic stress the CD33 receptor, which is regularly expressed in patients with myeloid disorder, Tonix decided to shift gears and diseases such as AML and myelodysplastic syndrome (MDS). The therapy, put all its resources into the latter condi- which has orphan drug status from the US FDA and the European Medi- tion. Since committing to this change cines Agency, uses Seattle Genetics’ newest technology, comprising an en- of direction in September this year, the gineered cysteine antibody (EC-mAb) stably linked to a highly potent DNA company has won a breakthrough ther- binding agent called a pyrrolobenzodiazepine (PBD) dimer. More than 300 apy designation from the US FDA on patients have been treated with SGN-CD33A in clinical trials across mul- December 19, 2016 for the development tiple treatment settings. Enrollment continues in other ongoing trials, in- of TNX-102 in PTSD – a condition cur- cluding the Phase III CASCADE study in older patients with AML and a rently considered an urgent unmet need Phase I/II trial of patients with myelodysplastic syndrome. Seattle Genetics in the US due to a huge spike in in a statement said it is working with the FDA to determine whether there is in military veterans. CEO and principal any association between hepatotoxicity and treatment with SGN-CD33A, founder of Tonix, Dr. , and that it aims to quickly identify adequate protocol amendments for told Scrip that the FMS program “nar- patient safety if needed and thus enable continuation of the trials. rowly missed” in Phase III and still has [email protected], 28 Dec 2016 importance, but the company simply cannot afford to pursue both indications simultaneously and believes the PTSD quisition cost of $13,740 for a 30-day for use with Rubraca, the first next- program has the legs to get all the way to supply, or $164,880 for a year of treat- generation sequencing-based com- market. The FDA’s breakthrough therapy ment. The company announced the panion diagnostic approved by FDA. designation is intended to expedite the FDA approval of Rubraca under an Rubraca will be the second poly ADP- development and review of a drug candi- accelerated approval Dec. 19 for the ribose polymerase (PARP) inhibitor date. The benefits of breakthrough ther- treatment of patients with BRCA mu- approved for cancer, and it appears apy designation include the eligibility for tation (germline and/or somatic) as- that it will have an advantage over the priority review of the New Drug Applica- sociated advanced ovarian cancer who competition, AstraZeneca PLC’s Lyn- tion (NDA) within six months instead have been treated with two or more parza (olaparib), which was approved of 10 months and rolling submission of chemotherapies. CEO Patrick Ma- in December 2014 for advanced BRCA portions of the NDA, in addition to an haffy said during a same-day confer- mutation ovarian cancer after three organizational commitment involving ence call that many factors went into prior treatments. The labeling advan- the FDA’s senior managers contributing the pricing decision, including the tage for Clovis could be short-lived, significant guidance to the company. clinical benefit of the drug, the mar- however. Tesaro Inc. is also awaiting [email protected], 22 Dec 16 ket for oncology drugs and the need FDA approval of a PARP inhibitor, for the company to reinvest in devel- niraparib, in BRCA ovarian cancer. In opment to bring new innovative ther- the Phase III NOVA trial, niraparib, Clovis Transitions To apies to market. Patients should be tripled progression-free survival com- Commercial Stage On selected for treatment with Rubraca pared to placebo in patients on main- based on an FDA-approved compan- tenance therapy with platinum-based Rubraca Approval ion diagnostic developed by Founda- chemotherapy, and the news doubled Clovis Oncology Inc. will launch its tion Medicine Inc. FDA simultane- the company’s stock price when it was first commercial drug, Rubraca (ru- ously approved the FoundationFocus announced June 29. caparib), this week at a wholesale ac- CDxBRCA companion diagnostic [email protected], 19 Dec 2016

26 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

Allergan, Ironwood Seek To Divide And Conquer IBS ALEX SHIMMINGS [email protected]

Allergan and Ironwood Pharmaceuticals clotide to the distal small intestine and Topline data from the placebo-con- are beefing up the blockbuster potential of colon, where the majority of the abdomi- trolled, dose-ranging Phase IIb clinical their IBS drug Linzess with two new formu- nal pain associated with IBS-C is believed trial evaluating the CR1 formulation in 532 lations that target different disease popu- to originate. The Phase II clinical trial of adult IBS-C patients showed numerically lations showing promising Phase II data. this formulation looked at whether CR1 greater abdominal pain improvement could further decrease the activity of key with CR1 300 mcg compared with place- llergan PLC and Ironwood Pharma- pain-sensing nerves in the distal small bo and with the 290 mcg IR formulation of ceuticals Inc. have released promis- intestine and colon while maintaining an linaclotide. The companies noted that the Aing topline Phase IIb data for two effect on fluid secretion. The long-term trial was exploratory in nature and com- novel formulations of their irritable bowel aim is to have a version of Linzess with parisons to placebo were evaluated using syndrome (IBS) treatment Linzess (lina- increased pain relief for IBS-C patients nominal p-values. clotide) that they hope will boost the fran- compared with the current immediate- The most common adverse event was chise for many years to come by offering release (IR) formulation. mild-to-moderate diarrhea, which was better and faster pain relief in constipation- The colonic-release 2 (CR2) formulation reported in 10.4% of patients on CR1 300 predominant patients and opening up the delivers the drug to the proximal ileum mcg compared to 1.5% of patients on pla- product for use in other IBS subtypes, and and colon to relieve abdominal pain with- cebo and 13.6% of patients on IR 290 mcg. possibly even other GI disorders. out any of the diarrhea side-effects. This Analysts thought the data encourag- The two formulations, known as CR1 means it could be used to relieve pain in ing. Those at Biomedtracker pointed to and CR2, are designed to deliver the drug IBS patients without constipation as the the comparatively earlier onset of action at two separate locations in the gastroin- predominant symptom, thus expanding compared with the marketed formulation testinal tract where they are expected to the potential patient population for Linz- as a potential differentiator. “[The] strategy produce slightly different therapeutic ef- ess, possibly even to diseases like ulcerative appears to work as CR1 had numerically fects for different patient subgroups. colitis and diverticulitis. greater abdominal pain improvement Linaclotide is a guanylate cyclase-C (GC- Tom McCourt, Ironwood’s chief com- while retaining its efficacy on constipa- C) agonist that was first approved in the mercial officer, said: “We believe the po- tion... Linzess currently takes six weeks to US in 2012 for the treatment of adults with tentially enhanced clinical profile of lina- improve pain symptoms so a faster onset with constipa- clotide CR1 could support further growth could be clinically significant.” tion (IBS-C) or chronic idiopathic consti- of the Linzess franchise from $1bn in US Umer Raffat from Evercore ISI said pation (CIC). It is marketed by Ironwood net sales by 2020 to potentially greater he believed that the data were strong and Allergan in the US as Linzess, and by than $2bn in peak US net sales.” Ironwood enough to make the possibility of success Allergan in Europe as Constella where it is and Allergan said they were pursuing pat- over the IR version at Phase III a reason- approved for the treatment of adults with ent protection for CR1 and CR2 that, if is- able hope. moderate to severe IBS-C. sued, is expected to provide patent cover- Nevertheless, he believes that “the true Based on non-clinical studies linaclotide age into the mid-2030s. upside is on CR2 formulation”, which is be- is thought to act in two ways after binding The data are also timely, coming shortly ing positioned as a pain reliever for indica- to the GC-C receptor within the intestinal after Synergy Pharmaceuticals Inc. an- tions beyond IBS-C, but he noted that the epithelium, resulting in increased intestinal nounced that it now has positive data from data are “not super clear just yet”. fluid secretion and accelerated transit, and two Phase III trials for its rival GC-C agonist a decrease in the activity of pain-sensing plecanatide showing an efficacy that is CR2 DATA nerves in the intestine. The companies roughly comparable to Linzess but with a The double-blind, placebo-controlled, note, however, that the clinical relevance lower rate of diarrhea. dose-ranging Phase IIb trial for the CR2 for- of the effect on pain fibers has not been mulation randomized 532 adult patients established. CR1 STUDY with IBS-C. Again, the trial was exploratory “Our intent was to dial up or down the The new topline linaclotide results are in nature and comparisons to placebo were two components of the linaclotide mecha- from two Phase IIb trials – one for each evaluated using nominal p-values. nism of action – the effect on pain-sensing formulation – with the data for CR1 con- “These findings support further inves- nerves and the effect on fluid secretion sidered the most convincing by analysts. tigation of CR2 in specific GI indications – by varying where the drug is delivered,” The companies now intend to discuss where patients experience abdominal explained Dr Mark Currie, chief scientific of- their Phase III development plans with pain but are not necessarily constipated, ficer and president of research and devel- the US FDA and expect to begin a Phase such as IBS-mixed, IBS with diarrhea, ulcer- opment at Ironwood. III trial in adults with IBS-C of CR1 and a ative colitis and diverticulitis,” the compa- The colonic-release 1 (CR1) formula- further Phase IIb study of CR2 in the sec- nies said. tion is designed to target delivery of lina- ond half of 2017. Published online 23 December 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 27 HEADLINE NEWS

AbbVie Makes Further Inroads In Oncology As Humira Loss Looms EMILY HAYES [email protected]

New data position BCL-2 inhibitor Ven- The partners presented impressive long- Zeneca PLC/Merck & Co. Inc./Acerta Phar- clexta, partnered with Roche, for roles in term data for Imbruvica in CLL during the ma BV’s BTK inhibitor acalabrutinib and TG multiple myeloma and acute myeloid leu- American Society of Hematology (ASH) an- Therapeutics Inc.’s anti-CD20 ublituximab. kemia, among other indications beyond nual meeting from Dec. 3-6 in San Diego, Chase described venetoclax as an as- chronic lymphocytic leukemia. as well as Phase I/II data showing a 67% set that offers significant growth potential objective response rate in graft-versus-host over the longer term, with expansion into bbVie Inc. is making inroads in oncol- disease, a condition that may occur if do- earlier lines of therapy and other hemato- ogy, expanding the potential reach nor cells attack the body after stem cell and logic malignancies. For instance, AbbVie Aof its first approved hematological bone marrow transplants. is looking forward to results from the MU- cancer drugs Imbruvica and Venclexta while AbbVie reported sales of $659m for Im- RANO study, which tests venetoclax with advancing new pipeline candidates ahead bruvica in 2015 and partner J&J reported Roche’s Rituxan (rituximab) in second-line of patent expirations for the blockbuster tu- $689m. Each of seven new filings in com- CLL in the first half of 2017 to support mor necrosis factor inhibitor Humira. ing years will bring another $500m in rev- broader labeling. Oncology has represented a newer, enue, Abbvie estimates. Data for venetoclax in multiple my- promising growth area for AbbVie, and the Imbruvica is under FDA review for eloma generated buzz at the ASH annual company has been investing heavily in the marginal zone lymphoma; in addition to meeting. In a Phase I study of relapsed/ pipeline for this therapeutic area through graft-versus-host disease, it is in Phase refractory myeloma with the t(11;14) partnerships, in-house development and III for indolent non-Hodgkin lymphoma translocation, the most common chro- ambitious expansion plans for the first ap- (iNHL), follicular lymphoma (FL), B-cell mosomal translocation in multiple my- proved drugs. Growth in areas new and old NHL and diffuse large B-cell lymphoma eloma, the objective response rate with are important for AbbVie as the company (DLBCL). Imbruvica also is in Phase II for Venclexta as a single agent was 40%, al- prepares to face sales losses due to bio- acute myeloid leukemia (AML) and mul- most twice as high as the response in the similar products competing with Humira tiple myeloma. overall population. (adalimumab), the top-selling treatment Gary Gordon, vice president of oncology for arthritis and other autoimmune con- VENCLEXTA’S PROMISE IN development at AbbVie, said in an inter- ditions that generated sales of $6.43bn in MYELOMA view that this could be one of the first ap- this year’s third quarter. AbbVie also has high hopes for its BCL- plications of biomarkers in selecting mul- It’s not clear when biosimilars for the TNF 2 inhibitor venetoclax, partnered with tiple myeloma patients for treatment. inhibitor will hit the market, even after US Genentech Inc., which was approved for “These results are particularly striking FDA approval in September for Amjevita second-line CLL with 17p deletions in given that patients in this study were heav- (adalimumab-atto), Amgen Inc.’s biosimilar April in the US, where it is marketed as ily pre-treated with a median of five prior version of Humira. But while a patent dis- Venclexta. therapies. Subsequent biomarker analysis pute between AbbVie and Amgen will de- Venetoclax was approved this month further revealed that patients in this sub- lay Amjevita’s launch beyond 2017, com- in Europe, where is branded as Venclyxto, population with high BCL-2 to BCL-XL ra- petition clearly is nipping at Humira’s heels, for second-line treatment of CLL with tio had the highest response rates. This is and AbbVie is betting big on cancer drugs 17p deletions. Only about 10% of treat- significant in that it essentially identifies a to help fill the product’s shoes. ment naïve CLL patients have 17p dele- subset of multiple myeloma patients that Oncology is one of the company’s most tions, but the indication is a gateway into would most benefit from Venclexta mono- active areas of development. Some 13 much broader use, although it’s domi- therapy,” Biomedtracker analyst Dustin drugs are in clinical development for 22 dif- nated by Imbruvica. Phan said. ferent indications, including hematological Chief financial officer Bill Chase- ac In a separate Phase Ib study of Ven- malignancies and solid tumors. knowledged during AbbVie’s third quarter clexta with Takeda Pharmaceutical Co. AbbVie’s BTK inhibitor Imbruvica (ibru- earnings call Oct. 28 that the market for Ltd.’s flagship proteasome inhibitor Vel- tinib), which is partnered with Johnson relapsed/refractory CLL with the 17p dele- cade (bortezomib) and dexamethasone & Johnson unit Inc., has tions was small – worth about $300m in in relapsed or refractory myeloma, which proven to be a big success, with approv- sales – and Imbruvica has a strong leader- also was presented at the ASH meeting, als in chronic lymphocytic leukemia (CLL), ship position with more than a 50% share the objective response rate was 38% for mantle cell lymphoma (MCL), Walden- of that market. those who were refractory to bortezo- ström’s macroglobulinemia, and many Furthermore, new late-stage competi- mib and 89% in patients who were not more indications on the way. tors in CLL are on the near horizon – Astra- refractory to bortezomib and had previ-

28 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

ously received one to three other lines of limited options, and we are encouraged therapy. For the whole study population, by AbbVie’s early results combining Ven- Capina, the response rate was 67%. clexta plus LDAC. The ORR … in all patients Essentialis Merger Gordon noted that the combination was 61% (37/61, median age=74) and 70% data support examining the hypothesis (21/30) in those patients above age 75, To Create Rare that proteasome inhibitors modulate MCL- which compares favorably with historical 1 levels and enhance sensitivity to veneto- LDAC results in the teens range,” Meacham Disease Firm clax as a BCL-2 inhibitor commented. The combined company would advance a “The drastic difference in response be- AbbVie started a Phase III study of Ven- diazoxide choline controlled-release daily tween these bortezomib-refractory and clexta with azacitidine versus azacitidine pill for treating patients with Prader-Willi bortezomib non-refractory patient sub- alone in treatment-naïve elderly patients syndrome through pivotal Phase II/III clini- groups is not surprising given that patients with AML who are ineligible for standard cal trialing. who fail to respond to a particular drug induction therapy in December. Nasdaq-listed Capnia Inc. plans to are unlikely to benefit from additional ad- acquire privately held Essentialis Inc. VELIPARIB PROVIDES SOLID ministration. However, the fact that some through a merger designed to create TUMOR OPPORTUNITY bortezomib-refractory patients responded a combined developer of rare disease AbbVie presented mid-stage data for anoth- to the combination suggests that addition- treatments, er asset now in Phase III – the PARP inhibitor al Venclexta may have helped overcome Under the deal’s terms announced bortezomib resistance,” Biomedtracker’s veliparib – at the San Antonio Breast Cancer Dec. 27, Capnia will issue common Phan said. Symposium on December 7. stock priced at $0.96 per share to a Barclays analyst Geoff Meacham in a The Phase II study tested veliparib syndicate comprised of current and Dec. 6 note said that patients with high ex- in combination with different kinds of new investors, raising gross proceeds of pression of the BCL-2 gene had an ORR of chemotherapy in 290 breast cancer $8m for use in advancing Essentialis’ 94%, versus 59% for lower expression, plus patients with BRCA1 and BRCA2 muta- diazoxide choline controlled release improved time to progression. tions. Although patients taking veli- (DCCR) tablet for treating the rare AbbVie is running a registrational study parib with carboplatin and paclitaxel disorder Prader-Willi syndrome (PWS) of Venclexta with Velcade and dexametha- chemotherapy had a significantly bet- which causes constant hunger and vari- sone in relapsed/refractory multiple my- ter response rate compared to those ous metabolic, endocrine, cognitive and eloma (RRMM) patients who are sensitive taking carboplatin and paclitaxel with behavioral symptoms, and for which or naïve to proteasome inhibitors and who placebo (77.8% vs. 61.3%), progression- there currently are “no effective treat- have had from one to three prior lines of free survival and overall survival were ments,” Capnia’s chief executive officer treatment. The primary completion date not significantly improved compared Anish Bhatnagar said in a statement. for the trial is December 2019. to the control group. However, toxicity A pivotal Phase II/III clinical trial for “While these data support the ongoing was also not significantly increased in the drug, which was given orphan drug Phase III trial in RRMM patients, we see limi- the arm that included veliparib as part designation for the treatment of PWS tations, especially with BCL-2 expression of combination therapy. by the FDA in May 2014, would start and whether or not a patient is refractory AbbVie notes that the study was not in the second half of 2017, The com- to bortezomib,” Meacham said. powered well enough to show a differ- bined California-based company also Nevertheless, the analyst said novel ence in progression-free survival and envisions developing DCCR for other combinations seem to work well in pro- the company is now running the Phase unspecified orphan indications. longing progression-free survival and that III BROCADE study, which tests veliparib The planned merger represents a big he sees potential for the use of Venclexta with carboplatin and paclitaxel in HER2- change for Capnia, a diversified health- as well as Amgen’s proteasome inhibitor negative metastatic BRCA-associated care group which develops diagnostics Kyprolis (carfilzomib) in various combina- breast cancer. and therapeutics (drug-device combina- tions for relapsed/refractory myeloma. AbbVie is planning to differentiate ve- tions) based on a precision gas flow me- liparib from other PARP inhibitors on the tering technology. The company’s first MOVING IN ON AML basis that it is a potent inhibitor of PARP, it product, CoSense, is used to diagnose AbbVie also presented data for Venclexta combines well with multiple chemothera- hemolysis in newborns. Capnia said it with low-dose cytarabine (LDAC) in a pies – particularly platinum chemothera- would evaluate alternatives for its legacy Phase I/II study of 61 elderly patients with pies – without dramatic increases in toxic- products and product candidates. the tough to treat acute myeloid leuke- ity, and it penetrates the central nervous [email protected], 29 Dec 2016 mia (AML). Investigators reported that the system, Gordon said. ORR was 61% and that side effects were Veliparib also is in Phase III for squamous manageable. non-small cell lung cancer (NSCLC), non- CLICK “The notion of using a BCL-2 inhibitor for squamous NSCLC, triple-negative breast Read full story at: elderly AML is a potentially differentiated cancer and ovarian cancer. http://bit.ly/2iE45LK approach given the population’s more Published online 21 December 2016 scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 29 EXPERT VIEW

The CRO View: Sharing Opportunity Vs Risk Premier Research’s chief commercial officer, Sean Russell, describes how the CRO has turned risk-sharing negotiations from a black art to a predictable process.

SEAN RUSSELL

e hear a lot about risk sharing in is this: sponsors want their CROs to suc- the total contract value — or alternatively, drug development these days, ceed because successful clinical trials are our project management fee — at stake, Wand it’s a healthy trend in an in- essential to getting new drugs to market. tied to milestones such as: dustry often defined by high costs and the No risk-reward deal set up as a trip wire • Time from contract award to opening of pressure of project deadlines. Drug devel- — “you missed these deadlines and now the first study site. opment thrives on cost and schedule ad- we’re going to extract our penalty” — has • Time from contract award to first patient herence, and the inextricable link between any chance of succeeding. screened. the two leads increasingly to risk-reward • Date of database lock relative to last pa- arrangements between drug makers and THE CARROT, NOT THE STICK tient last visit (incentive rises for every their clinical research providers. So with growing frequency, we’re using a week that lock date precedes LPLV). performance-based pricing model as a tool • Percentage of sites activated within a for negotiating and managing opportunity- prescribed period. sharing agreements. Sponsors pursue these To cite a recent example, a double-blind deals hoping we reach those incentive mile- trial of a treatment for major depressive stones and happily pay for performance that disorder tied incentives and penalties to meets or exceeds targets. We share these five factors: US patient enrollment (40%), payments as project team bonuses to moti- enrollment in two other countries (7.5% vate our employees, recognizing that happy each), database lock (30%), and first patient employees are engaged and stick around — screened (10%).

Rawpixel.com even in the clinical research business, which is famous for rapid employee turnover. ASSESSING THE LEVEL OF RISK Of course, bonus payments alone cannot For a successful negotiation, the CRO and Shutterstock: Shutterstock: provide the impetus needed to motivate sponsor must agree on several fundamentals our teams to the level of performance we to ensure that both parties share equally in Having been involved in many of these, aim for. Many factors drive high-functioning the financial and performance benefits and I like to avoid “risk sharing” and other terms teams, such as the satisfaction of collaborat- risks. We’ll assume risk only at a level com- that can cast these agreements in a negative ing with talented colleagues and teaming mensurate with the control we’re allowed light. When we look at clinical development, with sponsors on work that has the poten- over the study’s execution — things like: I prefer to focus on opportunity sharing — tial to advance science and improve lives. • Protocol design and site selection, which not so much avoiding failure as improving But bonuses can be an important part of the have a significant bearing on patient re- clinical trial productivity and efficiency. mix in improving employee retention. cruitment, retention, and compliance. After all, if you start a clinical develop- We’ve come a long way in evolving • Appropriate level of feasibility assess- ment program assuming you’re going to toward this ideal in the past couple of ments to be performed. fail, you’d better find something else to do. years, leaving in the wake of risk-sharing’s • Operational strategy, such as recruit- checkered past some classic non-starter ment plans, monitoring, strategy, data FIRST, A DEFINITION ideas. They include penalties without cor- management platform and process, and Risk- and opportunity-sharing is still a pretty responding rewards (an unthinkably bad statistical analysis planning. new concept, and there are different types deal) and CROs signing up for royalties In creating this structured approach, we of these arrangements. In this article, I’m de- from future drug sales (a long wait for a have advanced risk-reward negotiation scribing agreements between drug makers very uncertain return). from a black art to a process that’s straight- and clinical research organizations under forward, predictable and repeatable. And which CROs are rewarded, or penalized, OPPORTUNITY-SHARING we’ve witnessed compelling results — for based on their performance versus contract MILESTONES example, greatly improving performance terms and milestones. These arrangements began as a sort of af- in a recent Eastern European study to As CROs increasingly assume the role terthought in the contract negotiation pro- evaluate an adult schizophrenia drug for of professional adviser as opposed to ser- cess, offered by sponsors as a way to help a biopharmaceutical customer. Our incen- vice provider, sponsors expect us to have close the deal. Recognizing the potential for tivized team moved up the timeline for some skin in the game by connecting mutual benefit, we developed a template the 400-person study and, to a person, re- performance and reward. And the basis outlining the sorts of terms we’ll consider for mained for its full 22-month duration. of a well-designed incentive arrangement inclusion. We’ll typically put a percentage of Published online 29 December 2016

30 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 HEADLINE NEWS

Allergan Adds Accretive Aesthetics Assets In $2.9bn LifeCell Acquisition MANDY JACKSON [email protected]

Allergan will pay $2.9bn in cash for Life- Inc., a deal worth about $615m up front and of investor reactions to Allergan’s LifeCell Cell, a division of Acelity, adding its first up to $1.7bn including milestone fees, for acquisition news that same morning: grati- regenerative medicine portfolio and what currently is a late Phase II liver disease tude that the assets would be immediately marking its first commercial-stage deal in program. However, the LifeCell purchase accretive to the company’s earning, satisfac- more than a year. The company hopes to gives Allergan a suite of commercial prod- tion with LifeCell’s aesthetic portfolio given exploit the surgical products for aesthetic ucts for what chief commercial officer Wil- Allergan’s strong presence in that market, uses beyond breast reconstruction. liam Meury describes as the company’s “most and concern that the company sold for important customer” – plastic surgeons. $1.2bn less eight years ago. llergan PLC will pay Acelity LP Inc. “With the acquisition of LifeCell, we prob- Acelity (formerly Inc.) $2.9bn to buy the LifeCell Corp. ably have the largest and most focused acquired LifeCell for $1.7bn in 2008, but Aportfolio of aesthetic and surgical business for aesthetics and plastic surgery,” Raffat pointed out that the business is ex- products, marking Allergan’s first regen- Meury said in an interview with Scrip. pected to generate $450m in 2016 revenue erative medicine transaction and its first Investors were somewhat skeptical, send- – representing year-over-year growth in the acquisition of a firm with commercial-stage ing Allergan’s stock down 0.6% to close at mid-single digits – versus $191m in 2007 assets since the company bought Kythera $191.33 on Dec. 20 following the LifeCell revenue. Biopharmaceuticals Inc. last year. deal announcement. Published online 21 December 2016 Investors have punished Allergan for its development-stage acquisitions this year, A COMMERCIAL PRESENCE CLICK sending the company’s stock below $200 per RIGHT FROM THE START Read full story at: share for the first time this year after Allergan Evercore ISI analyst Umer Raffat said in a http://bit.ly/2i5Tx4g closed the acquisition of Tobira Therapeutics Dec. 20 report that he heard three types

Scrip Awards Winner 2016

Best Technological (Patient-focused) Development in Clinical Trials

AiCure's technology is a new approach to artificial intelligence that uses AI to visually confirm medication ingestion on smartphones.

The platform was developed to automate directly observed therapy, the gold standard in monitoring and maximizing Winner: AiCure’s artificial intelligence adherence, by visually identifying the patient, the drug, and DOT smartphone app the act of ingestion.

"AiCure is the only clinically-validated and scalable platform to confirm medication ingestion on mobile devices. Changing patient behavior and ensuring accurate data on a dose by dose basis has the potential to transform and streamline the clinical trial process. We are very grateful to the Scrip judges for recognizing our company as best in class." Scrip Awards Pharma intelligence | informa Adam Hanina, CEO and Chairman of AiCure

scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 31 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 16–29 December 2016

LEAD COMPANY/PARTNER COMPOUND INDICATION COMMENTS Phase III Results Published Mylan NV/Biocon Ltd. biosimilar trastuzumab breast cancer HERITAGE; published in JAMA online Dec. 1. primary progressive Ocrevus (ocrelizumab), Roche/Biogen , ORATORIO, OPERA I, II; NEJM online on Dec. 21. anti-CD20 MAb relapsing MS Phase III Interim/Top-line Results Roche/Chugai Pharmaceutical Co. emicizumab (a bispecific haemophilia A with Factor HAVEN 1; met primary endpoint, reduced bleeds Ltd. MAb) VIII inhibitors when used prophylactically. irritable bowel syndrome Synergy Pharmaceuticals Inc. plecanatide IBS-C (Study 2); met primary endpoint. with constipation delayed graft function after PROTECT; missed primary endpoint in potential Alexion Pharmaceuticals Inc. Soliris (eculizumab) kidney transplant new indication. Tandem2; met primary endpoint in second pivotal Sanofi/ Inc. sotagliflozin type 1 diabetes study. SWORD-1, -2; met primary endpoint, non-inferior ViiV Healthcare dolutegravir plus rilpivirine HIV maintenance to three-or four-drug regimens. familial partial volanesorsen, an antisense lipodystrophy, familial COMPASS; met primary endpoint, reduced Ionis Pharmaceuticals Inc./Akcea drug chylomicronemia triglycerides. syndrome SOLUTION; Narrowly missed primary endpoint of Inc. Sollpura (liprotamase) cystic fibrosis non-inferiority to Pancreaze Phase III Initiated ViiV Healthcare cabotegravir HIV prevention HPTN-083; a long-acting injectable agent. fluticasone furoate, CAPTAIN; a once-daily triple combination dry GlaxoSmithKline PLC/Innoviva Inc. asthma umeclidinium, vilanterol powder inhaler. Sancilio Pharmaceuticals Co. Inc. SC411 sickle cell anemia A reformulation of docosahexenoic acid. FT218 (sodium oxybate) daytime sleepiness and Flamel Technologies SA REST-ON; in patients with narcolepsy. once-nightly formulation cataplexy AbbVie Inc./Roche Venclexta (venetoclax) acute myeloid leukemia Combined with azacitidine in elderly patients. antineutrophil cytoplasmic To induce and sustain remission versus pred- ChemoCentryx Inc./Galenica Group CCX168 (avacopan) antibodies associated nisone. vasculitis CLEAR Tranquility: as an add-on to ezetimibe Esperion Therapeutics Inc. ETC-1002 dyslipidemia therapy. COR-003 Strongbridge Biopharma PLC Cushing’s syndrome LOGICS; A second Phase III study. (levoketoconazole) Phase III Announced Vemlidy (tenofovir Gilead Sciences Inc. hepatitis B Switching from tenofovir disoproxil fumarate. alafenamide fumarate)

32 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 PIPELINE WATCH

Phase II Suspended IdeS (IgG antibody acquired thrombotic No positive effect, studies continue in other Hansa Medical AB degrading enzyme) thrombocytopenic purpura indications. Phase II Results asthma, chronic salmeterol plus fluticasone A generic version of GlaxoSmithKline’s Seretide, Orion Corp. obstructive pulmonary dry powder Easyhaler filing expected first half of 2017, in Europe. disease Leber’s hereditary optic Mixed but promising results after 78 weeks of GenSight Biologics SA GS010 (gene therapy) neuropathy follow-up. Phase II Completed BioChaperone Lispro (insu- Safe and effective in an insulin pump versus Adocia SAS/Eli Lilly & Co. type 1 diabetes lin lispro) Humalog. Phase II Interim/Top-line Results Ironwood Pharmaceuticals Inc./ linaclotide colonic release irritable bowel disease with Extending the use of linaclotide with new Allergan PLC formulations constipation formulations. Galapagos NV/AbbVie Inc. GLPG1837 cystic fibrosis SAPHIRA 1; promising efficacy, well tolerated. Alzheimer’s disease psy- Met primary endpoint against psychosis but Acadia Pharmaceuticals Inc. Nuplazid (pimavanserin) chosis mixed results on other endpoints. RespireRx Pharmaceuticals Inc. dronabinol obstructive sleep apnea PACE; improved sleepiness symptoms. Phase II Initiation CTP-656 (deuterated Concert Pharmaceuticals Inc. cystic fibrosis A potential next generation CFTR potentiator. ivacaftor) major depressive and SAGE Therapeutics Inc. SAGE-217 Four programs now underway. mood disorders Portage Biotech Inc. BHV-4157 spinocerebellar ataxia In adult patients. B244 (ammonia-oxidizing AOBiome hypertension Also being evaluated in acne. bacteria) NovaBiotics Ltd. Lynovex (cysteamine), oral cystic fibrosis For exacerbations of lung disease. LIPO-202 (salmeterol) Neothetics Inc. submental fat reduction A proof of concept study. injectable facioscapulohumeral mus- Acceleron Pharma Inc. ACE-083 A locally acting muscle agent. cular dystrophy sacituzumab govitecan triple-negative breast In patients with metastatic disease and more than Immunomedics Inc. (IMMU-132) cancer one prior therapy. Source: Biomedtracker

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scrip.pharmamedtechbi.com 6 January 2017 | Scrip intelligence | 33 STOCKWATCH

2017, Year Of The Dog ANDY SMITH

News in the life sciences sector over the holiday period was pep- Pharmaceuticals Inc., Eli Lilly & Co. and finally to Anthera where it may pered with clinical and regulatory failures at Acadia, Anthera, have another Phase III failure to go through before the product again Opko and Cempra, and a drug pricing controversy from Biogen. supports a different company’s IPO. Following underperformance in 2016 and with that sort of run- up, 2017 already looks likely to be another lost one. SOLITHERA REJECTION Other clinical trial failures that punctuated the holiday period in- he biotech sector moves in cycles and the momentum that cluded the Phase III failure of Opko Health Inc.’s long-acting human builds up the peaks is driven by the generalist investor. Gener- growth hormone. The FDA’s rejection of Cempra Inc.’s antibiotic T alists are attracted by rising stock prices, cheap valuations, in- Solithera (solithromycin) for the treatment of community-acquired creased M&A and high-profile drug approvals. In 2016, the year-long pneumonia had wider implications for the sector. 22% decline for the NASDAQ Biotech Index – as compared with the The narrative accompanying the later stages of Solithera’s develop- S&P 500’s near 10% rise – and fewer approvals by the FDA spurred on ment had been bathed in assurances of the need for new antibiotics the departure of the generalist from biotech. In the 12-year cycle of and the global implications of antibiotic resistance that help include the Chinese calendar the year of the dog is not until 2018. In biotech, incentives in the recent 21st Century Cures Act. Cempra investors however, without the generalist, 2017 looks likely to be an early dog. probably believed that all this hullaballoo would result in a free pass Acadia Pharmaceuticals Inc. got the holiday bad news ball rolling for any antibiotic in any indication. Unlike Sarepta Therapeutics Inc.’s when it reported “positive” top-line results from the placebo-controlled Exondys 51 (eteplirsen), in which approval was helped by advocate Phase II study of pimavanserin in 181 Alzheimer’s disease patients with and patient pressures, Solithera’s efficacy was not in doubt. Rather, the psychosis. With so few analysts in the market on Dec. 20 it was left to product’s approval was thwarted by the macrolide class’s hepatotoxic- social media commentators to pronounce on the trial results. Those ity and the withdrawal of another equally efficacious antibiotic, Trovan pronouncements focused on the primary endpoint of the study listed (trovafloxacin), after fatal liver toxicity emerged from an on-market and on clinicaltrials.gov measured at 12 weeks not being significant. Aca- clinical trial safety database that was nearly 3,000 times that of Soli- dia’s announcement focused on the measurement at six weeks as thera’s 920 patients. the primary endpoint and just scraped significance with a p-value of 0.0451. While Acadia will be barreling into Phase III on the basis of the SPINRAZA HANGOVER exploratory Phase II study, I liked the analogy quoted on social media The celebration of the approval of Biogen Inc.’s antisense drug Spinra- about the ice being very thin around p=0.05 in both directions. From za (nusinersen) for the treatment of the rare disease spinal muscular the day of Acadia’s announcement until the last trading day of the year, atrophy (SMA) is likely to result in a hangover that will last throughout the firm’s stock price managed a 5% increase – lackluster, maybe, but 2017. Spinraza’s approval was met with a rise of about 4% in Biogen’s then again, the study didn’t demonstrate anything conclusive. In any share price that then all but dissipated over the last trading week event, Acadia is likely to have bigger problems in 2017. With fourth- of the year. The reason for investors’ reticence to embrace Spinraza’s quarter earnings season just around the corner, the sales of Acadia’s commercial potential is probably related to the small number of SMA first drugNuplazid (also pimavanserin) in its second full quarter on the patients that can tolerate an injection into their cerebrospinal fluid market will be closely watched. After a checkered Phase III program and the implied pricing needed to move the needle in a company in psychosis associated with Parkinson’s disease – an indication I have with a $62bn market capitalization. The analysts from Leerink Part- always regarded as made up to fit the drug in the absence of patients ners started to catch this mood when they described the $750,000 – Nuplazid sales in their first full quarter were only $5.3m. Bearing in first year loading dose price as “likely to invite a storm of criticism” al- mind that it took 15 quarters from the launch of Provenge (sipuleucel- though this probably underplays the future price increases for Spin- T) before Dendreon Corp. concluded that the product was unviable raza by a company that is known to regularly poke the hornet’s nest and filed for bankruptcy, Acadia may have some time yet before suc- of drug pricing and whose sales growth last quarter was primarily cumbing to a similar fate. due to price increases and channel stuffing. The justification of value is likely to be the big cloud that hangs over SOLLPURA FAILURE the whole sector in 2017. For Acadia, the demonstration of the value A week after Acadia’s “positive” clinical trial there was an attempt to of pimavanserin, which generates a barely significant p-value after six sugar-coat Anthera Pharmaceuticals Inc.’s announcement on the weeks and declines into insignificance by week 12, will be at least chal- Phase III failure of Sollpura (liprotamase) in the SOLUTION study of lenging and probably impossible. 126 cystic fibrosis patients with exocrine pancreatic insufficiency by Published online 3 January 2017 including the word “encouraging” in the title of the announcement. Investors were not fooled and the Anthera share price finished the Andy Smith gives an investor’s view on life science companies. He has last week of 2016 down by more than 66%. Many investors prob- been lead fund manager for four life science–specific funds, including ably didn’t realize that Sollpura had already failed more than once at 3i Bioscience, International Biotechnology and the AXA Framlington Altus Pharmaceuticals Inc., forcing Altus’ bankruptcy. Sollpura then Biotech Fund, and was awarded the techMark Technology Fund Man- passed through the hands of the Cystic Fibrosis Foundation, Alnara ager of the year for 2007.

34 | Scrip intelligence | 6 January 2017 © Informa UK Ltd 2017 APPOINTMENTS

Robert Waters, Astellas Inc.’s former global American commercial operations for sor of neurology and biochemistry at the regulatory lead, has joined the Oxford- Roche. Before this, Clark held various senior University of California San Francisco (UCSF). based retinal company, Oxular Ltd., as operational, sales and marketing roles in vice president of regulatory affairs. Previ- other pharma and healthcare companies. Inc.’s senior vice ously, Waters held various key European Currently, he is non-executive director of president and chief business officer, David regulatory roles including head of ophthal- TerraVia Holdings Inc. where he is chair of Alexandre, is resigning from the company mology and head of regulatory develop- the compensation committee and mem- for personal reasons – effective Jan. 6, 2017. ment at Allergan plc. ber of the nominating and corporate gov- Alynlam has also promoted its current senior ernance committee. vice president, clinical development, Pushkal Steve Bates, CEO of the UK BioIndustry As- Garg, to the role of chief medical officer. Garg sociation, was made an OBE in the Queen’s Debra Flores has joined Astellas as di- carries over 15 years of experience acquired New Year honours list, for services to in- rector, state government affairs, in the from working at various companies includ- novation. Others in the life sciences area Midwest region. With 20 years experience ing Bristol-Myers Squibb and Millennium honoured include Shankar Balasubra- in government affairs and the healthcare Pharmaceuticals and joined Alynlam in 2014. manian, professor of medicinal chemistry industry, Flores was most recently director at the University of Cambridge, who was of state government affairs for Boehringer- Alessandro Riva, Novartis Oncology’s for- knighted; Balasubramansian co-invented Ingelheim. Before this, she was director of mer head, global oncology development, next-generation DNA sequencing. And government affairs at New Century Finan- has joined Gilead Sciences as senior vice Jim Smith, a developmental biology pro- cial Corporation. president, hematology and oncology thera- fessor, who was knighted for his role in the peutic area head. Riva will also be joining the formation of the Francis Crick Institute; he Alzheon Inc., a clinical-stage biopharma company’s executive committee. Previously, is currently director of science at the Well- company focused on Alzheimer’s disease she was a member of the Novartis Oncol- come Trust, and a group research leader at and other neurological and psychiatric dis- ogy Division executive committee, devel- the Institute. orders, has appointed Stanley B. Prusiner opment committee, translational and early chair of it scientific advisory board. Dr development committee and innovation Shire Plc. has appointed Ian Clark non- Prusiner received the Nobel Prize in physi- management board. Before Novartis, Riva executive director of the company – ef- ology and medicine in 1997 and the Albert co-founded the Breast Cancer International fective Jan. 3, 2017. Until December 2016, Lasker Award for Basic Medical Research in Research Group (BIRG) and Cancer Interna- Clark was CEO and director of Genentech 1994. He is the director of the Institute for tional Research Group (CIRG), for which he Inc., (Roche Group) and head of North Neurodegenerative Diseases and a profes- served as CEO and chief medical officer.

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