Why Aducanumab Failure Is Not the End of Amyloid Hypothesis

29 March 2019 No. 3948

Scripscrip.pharmaintelligence.informa.com Pharma intelligence | informa

The failure of aducanumab to significantly affect even mild cognitive impairment in early-stage Alzheimer’s disease patients is not particularly surprising, since several anti-amyloid antibody candidates similarly have failed in previous clinical trials. However, Biogen has projected so much confidence in its program – and Alzheimer’s disease has so much unmet need – that there was a lot of hope despite multiple sets of evidence to the contrary that aducanumab would work. “Aducanumab now joins a long list of Alzheimer’s therapies that have failed to change the course of the disease, particularly those targeting beta-amyloid,” Wil- liam Blair analyst Matt Phipps wrote in a March 21 note. “Despite the concerns with the amyloid hypothesis, we had hoped the Phase I data with aducanumab, particularly the Why Aducanumab Failure Is Not correlation between removal of amyloid plaque as measured by PET scan and The End Of Amyloid Hypothesis slowing of cognitive decline, would prove aducanumab could succeed where oth- MANDY JACKSON [email protected] ers have failed, but this hypothesis was obviously wrong,” Phipps continued. “This iogen and Eisai Co. Ltd. will continue that the trials were unlikely to meet their is a setback for the Alzheimer’s field and to test anti-amyloid agents in the primary endpoints. patients, but will hopefully catalyze in- Btreatment of Alzheimer’s disease even A Phase II safety study and a long-term creased investment in novel targets to after the failure of their most advanced and extension of the Phase Ib study that con- treat the devastating disease.” highest-profile candidate aducanumab vinced Biogen to take aducanumab into in Phase III, but suggestions that Biogen Phase III also will be terminated. The com- BIOGEN PIPELINE DOESN’T should focus its resources elsewhere are pany and its partner will determine after EXCITE ANALYSTS, INVESTORS mounting after this latest setback. looking at the ENGAGE and EMERGE data Aducanumab’s failure leaves Biogen with The partners said on March 21 that whether to initiate a planned Phase III a research and development pipeline that they will discontinue the Phase III EN- study for the anti-amyloid-beta antibody analysts describe as unexciting – includ- GAGE and EMERGE clinical trials testing in secondary prevention of Alzheimer’s. ing multiple amyloid-targeting agents – aducanumab in patients with mild cog- Biogen closed down 29.2% at $226.88 at a time when its multiple sclerosis (MS) nitive impairment due to Alzheimer’s per share on March 21 after the announce- franchise is projected to see sales decline disease and in patients with mild Al- ment that its most advanced and closely and when its top-selling drug, Tecfidera zheimer’s disease dementia based on a watch late-stage development program (dimethyl fumarate), is facing patent chal- futility analysis by an independent data will be discontinued, wiping out $18.6bn lengers seeking to launch generics of the monitoring committee, which found worth of the company’s value. CONTINUED ON PAGE 4

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Amarin’s Efficacy Boost Huge Step Forward Merck’s China Push Vascepa CV results bolster case Zulresso approved to combat Company’s long-term digital for broader patient population (p8) postpartum depression (p13) strategy in fast-evolving market (p20) IN THIS ISSUE

from the editor [email protected]

The amyloid beta hypothesis is remarkably tenacious. De- ucanumab; see cover story), its partner Eisai announces spite the many notable failures of amyloid-targeting drug the start of a new Phase III study with another beta-am- candidates to show meaningful effects on Alzheimer’s dis- yloid-targeting candidate, BAN2401. And aducanumab ease in the clinic, companies have found reasons to justify itself has yet to be definitively buried: a planned second- ongoing trials of the failed drugs and of rival candidates. ary prevention trial is still potentially in the offing. One of the reasons the hypothesis lingers on is the be- But even if there were a point in time when targeting lief that it has yet to be thoroughly tested early enough amyloid beta peptide accumulation in a person’s brain in the disease’s course to have an influence on clinical could prevent or modify the development of Alzheimer’s outcomes. Another is the dearth of promising alterna- disease, there remains the question of how patients would tive approaches. Meanwhile, developers have highlight- be identified and treated in real-world health systems. ed distinctions between their drugs and those that have Clearly, the need for better understanding of Alzhei- failed in the clinic which could make for a difference in mer’s etiology and pathophysiology is paramount. In- clinical outcomes. Hence, firms have pressed on, homing formation sharing between industry, health systems and in on earlier, milder presentations of the disease when academia should be increased. There is no low-hanging they meet with failure in more symptomatic patients. fruit for lone companies to pluck, and team work is es- Thus, even as Biogen announces the latest failure (of ad- sential to reach further.

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EDITORS IN CHIEF Andrea Charles EDITORIAL OFFICE Ian Haydock (Asia) John Davis Christchurch Court Eleanor Malone (Europe) Kevin Grogan 10-15 Newgate Street Denise Peterson (US) Ian Schofield London, EC1A 7AZ Vibha Sharma CUSTOMER SERVICES Joanne Shorthouse EXECUTIVE EDITORS US Toll-Free: +1 888 670 8900 COMMERCIAL Sten Stovall US Toll: +1 908 547 2200 Alexandra Shimmings (Europe) UK & Europe: +44 (20) 337 73737 Mary Jo Laffler (US) US Australia: +61 2 8705 6907 Michael Cipriano POLICY AND REGULATORY Japan: +81 3 6273 4260 Derrick Gingery Maureen Kenny (Europe) Email: clientservices@ Joseph Haas Nielsen Hobbs (US) pharma.informa.com Emily Hayes ASIA Mandy Jackson Cathy Kelly TO SUBSCRIBE, VISIT Anju Ghangurde scrip.pharmaintelligence.informa.com Jung Won Shin Jessica Merrill TO ADVERTISE, CONTACT Brian Yang Brenda Sandburg Bridget Silverman [email protected] Sue Sutter EUROPE All stock images in this publication Neena Brizmohun courtesy of www.shutterstock.com Francesca Bruce unless otherwise stated

2 | Scrip | 29 March 2019 © Informa UK Ltd 2019 Avelumab Combo Halted

Chagas Treatment Shortened

20 5 10 UK’s Biotech Boost 19

exclusive online content inside: COVER / Why Aducanumab Failure Is Not The End Of Going Generic: Big Brands Poised To Lose Amyloid Hypothesis Marketing Exclusivity In The US In 2019 5 Merck KGAA/Pfizer Discontinue Phase III Avelumab/ Talazoparib Combo Study In Ovarian Cancer JESSICA MERRILL [email protected] 6 Conatus Endures Another NASH Setback With Failure To Hit Fibrosis Endpoint

8 Latest REDUCE-IT Results Bolster Case For Amarin’s Vascepa Fish Oil Pill

10 Shorter Treatment Time For Chagas Could Blunt Kissing Bug Disease

11 New CV Outcomes Study May Mean Big Boost For Amgen’s Repatha Market

13 Zulresso Is Sage’s First Step In Postpartum Several high-profile blockbuster brands are poised to Depression Treatment lose their marketing exclusivity in the US in 2019 with the 14 Dermira’s Lebrikizumab Data Set Up AD Showdown launch of the first generic versions of drugs likeAdvair With Dupixent (fluticasone/salmeterol) and Lyrica (pregabalin) and the first wave of oncology biosimilars, Herceptin (trastuzum- 15 Price ‘Anchoring’? Zolgensma And The Art Of Managing ab), Avastin (bevacizumab) and Rituxan (rituximab). Gene Therapy Sticker Shock The year is expected to be a notable one for generics 16 Pfizer Buys Option For Vivet In Latest Gene Therapy Tie-Up and biosimilars, though the commercial launch trajectory for biosimilars in the US remains unclear. The exact timing 17 Biohaven Pays $105m For Turbo Boost In Migraine Drug of generic and biosimilar launches is also uncertain, with Review Race the timelines tied to patent expirations, patent settlement 18 Cancer, Rare Disease Drugs To Be Covered As China Expands agreements, or in some cases ongoing patent challenges. Reimbursement “Since the end of the patent cliff, we have had essentially the same $15bn-$17bn of negative impact from expirees 19 What Brexit Effect? UK Biotech Start-Ups Reach in the US, and our modeling suggests that it is supposed Record Numbers to pop this year,” Research Director for the IQVIA Institute 20 Merck KGaA: China E-Health Push A ‘Long-Term Strategy’ for Human Data Science Michael Kleinrock said in an interview. But, he also pointed to uncertainties, including the 21 Celgene/Bristol’s Revlimid Patent Risk Incrementally Lower possibility that some launches are delayed or there is slow- After PTAB Denies Alvogen IPR er uptake for certain complex generics and biosimilars. 22 Pipeline Watch “You can have a generic approved. It can reach the market, and the originator can retain a fairly large share of the 23 Appointments volume of sales,” Kleinrock noted. That has been the experience with some recent entrants, such as the generic launch of Teva Pharmaceuticals USA Inc.’s Copaxone (glatiramer) or biosimilars to Johnson & Johnson’s Remicade (infliximab). Published online 20 March 2019 @PharmaScrip /scripintelligence To read the rest of this story go to: https://bit.ly/2FqsEVL

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scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 3 HEADLINE NEWS

CONTINUED FROM PAGE 1 MS drug, though probably not before “This is a setback for the Alzheimer’s field and 2020. (Also see “Going Generic: Big Brands Poised To Lose Marketing Exclusivity In The patients, but will hopefully catalyze increased US In 2019 “ - Scrip, 15 Mar, 2019.) Even its much-hyped spinal muscular investment in novel targets to treat the atrophy (SMA) drug Spinraza (nusinersen), partnered with Ionis Pharmaceuticals devastating disease.” Inc., could see its blockbuster status chal- lenged when the Novartis AG gene therapy Zolgensma for SMA launches later this “BACE inhibitors (like E2609) have not more attractive acquisition target itself year. (Also see “Novartis Pharma CEO Sees worked historically to further this argu- with the aducanumab risk removed Zolgensma Supplanting Spinraza” - Scrip, ment, and BAN2401, is another beta-am- from its pipeline, but noted the Tec- 1 Feb, 2019.)Roche also is closing in on yloid targeting compound,” Syed noted. fidera intellectual property risk and Biogen’s SMA franchise with plans for mid- (Also see “Eisai/Biogen Remain In BACE coming Spinraza competition as issues year filings seeking approvals of ridisplam. Race As Alzheimer’s Contenders Dwindle” - that may also impact the company’s (Also see “Roche Makes Case For Its Oral Scrip, 6 Jun, 2018.) value in the eyes of purchasers. SMA Drug Risdiplam As Filings Beckon” - Morningstar analyst Karen Andersen Scrip, 6 Feb, 2019.) WHO MIGHT BIOGEN BUY – was more optimistic about Biogen’s pros- Analysts expect Biogen to engage in OR BUY BIOGEN? pects going forward, however, pointing more aggressive business development Syed suggested several companies that to multiple 2019 catalysts in a March 21 as a result of the aducanumab failure on are potential acquisition targets for Bio- note – approval for the MS drug Vumer- top of the company’s other challenges to gen, including Sage Therapeutics Inc., ity (diroximel fumarate), which may show build up a more interesting pipeline. which won US FDA approval on March better gastrointestinal tolerability versus “Aducanumab was the key pipeline 19 for its first drug, the postpartum de- Tecfidera in an ongoing head-to-head tri- drug, and beyond it there was [elenbece- pression (PPD) therapy Zulresso (brexano- al, and Phase II data in treatment-resistant stat (E2609)] and BAN2401, two other be- lone). Sage also has a promising oral drug epilepsy for Tysabri (natalizumab) and for ta-amyloid related compounds,” Mizuho in Phase III development with a similar the anti-tau antibody BIIB092 in progres- Securities analyst Salim Syed said in a mechanism of action, SAGE-217, for PPD sive supranuclear palsy. March 21 note. He added that the amyloid and major depressive disorder (MDD). BTIG analyst Thomas Shrader pointed to hypothesis in Alzheimer’s disease is now (Also see “Zulresso Is Sage’s First Step In Vumerity and other R&D programs as well, dead, so investors should take elenbeces- Postpartum Depression Treatment” - Scrip, but wasn’t particularly enthusiastic about tat, which inhibits beta-secretase cleaving 19 Mar, 2019.) any of the assets in a March 21 note. enzyme (BACE) to block amyloid produc- Among other companies with late- “We like the GI friendly Tecfidera (GI tion, and the anti-amyloid beta protofibril stage and commercial neurology assets news mid-year) and the stroke drug antibody BAN2401 out of their models as- that Biogen investors may see as favor- (BIIB093; in P3), but neither is really ex- sessing Biogen’s value. able acquisition targets, Syed named citing. Most of the rest of the pipeline is Both candidates plus aducanumab are Neurocrine Biosciences Inc., Acadia novel and high-risk medicine – remyelin- being developed in partnership with Eisai Pharmaceuticals Inc., Biohaven Phar- ation [in MS] and such,” Shrader wrote. “We and the three assets are the foundation maceutical Holding Co. Ltd., Alder expect BAN2401 (always weaker data) will upon which Biogen has built its Alzheim- BioPharmaceuticals Inc. and Sarepta be stopped as well.” (Also see “Alzheimer’s er’s-lead neurology focus. Biogen recently Therapeutics Inc. The company previ- Early Approval? Skepticism Over Biogen/Ei- revealed that BAN2401 was moved from ously has noted that it wants to increase sai’s BAN2401 Data Clouds Chances” - Pink Phase II into Phase III development despite its investments in gene therapy, even Sheet, 26 Jul, 2018.) mixed mid-stage results. (Also see “Biogen after the recently announced deal to To Launch Phase III Alzheimer’s Prevention acquire Nightstar Therapeutics PLC for AMYLOID HYPOTHESIS REMAINS Study “ - Scrip, 29 Jan, 2019.) and (Also see $877m in cash. IN PLAY DESPITE SETBACKS “Biogen, Eisai Report BAN2401 Seemingly “Investors wanted Biogen to buy as- In addition to Biogen and Eisai’s part- Positive In Alzheimer’s; Others Skeptical” - sets ahead of this [aducanumab] news nered programs for the amyloid-targeting Scrip, 26 Jul, 2018.) for this very scenario. The company antibody BAN2401 and BACE inhibitor Eisai announced after the aducanumab admittedly wasn’t too active on this elebecestat, the Phase III Alzheimer’s dis- Phase III trial discontinuations were dis- front, at least not enough to move the ease pipeline includes two other amyloid- closed that the company and Biogen have needle,” he wrote. “Today’s news defi- focused programs. They are ALZT-01, a initiated the Phase III ClarityAD /Study 301 nitely weakens Biogen’s seat at the ne- small molecule designed to block amy- testing BAN2401 versus placebo in 1,566 gotiation table, and any strategics that loid beta aggregation and polymerization patients with mild cognitive impairment Biogen engages with at this point will in the brain from AZTherapeutics Inc., due to Alzheimer’s disease. know that.” Syed said Biogen may be a and Roche’s anti-amyloid antibody gan-

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tenerumab, developed in partnership with MorphoSys AG. (Also Kupiec, who was vice president and global clinical leader for see “Roche In New Phase III Bet On MorphoSys’ Anti-Amyloid Agent” Parkinson’s disease as well as clinical head of the Neuroscience Re- - Scrip, 7 Mar, 2017.) search Unit at Pfizer before he joined ProMIS last year, noted that However, Roche’s amyloid-targeting antibody crenezumab the late-stage and discontinued anti-amyloid candidates target- developed in collaboration with AC Immune SA recently came ed amyloid plaques. (Also see “Executives On The Move: Defectors to the same end as aducanumab. The partners discontinued From GSK, Pfizer, Shire, Dr Reddy’s Get New Posts” - Scrip, 27 Sep, two Phase III studies for crenezumab in January after an interim 2018.) Those antibodies were created before research showed analysis found that the antibody was unlikely to succeed if the amyloid oligomers may be a better target and before there were trials were continued to their conclusion. (Also see “AC Immune/ technology platforms, like the one used by ProMIS, that could Roche Drop Crenezumab After Phase III CREAD Alzheimer’s Failure” develop antibodies capable of precisely targeting toxic amyloid - Scrip, 30 Jan, 2019.) oligomers, he said. Aducanumab and crenezumab joined 26 other antibodies, vac- That’s what ProMIS’ lead candidate PMN310, which is in preclini- cines, peptides and small molecules seeking to block amyloid cal development, is designed to do. The company is “hoping to formation or clear it from the brain, which were all suspended at get into the clinic as soon as possible” and is in “serious discussions various stages of preclinical through Phase III development, ac- with a lot of large pharma companies,” Kupiec said. cording to a review of the Biomedtracker database. Meanwhile, AgeneBio Inc. is in Phase III testing a drug with a The Biogen/Eisai and Roche/AC Immune candidates followed completely different mechanism of action altogether. The private the same path as other high-profile, late-stage antibody thera- company has a $20m National Institutes of Health (NIH) grant to peutics. Eli Lilly & Co.’s solanezumab flopped in Phase III in 2016. help fund its 830-patient Phase III trial for AGB101, which enrolled Pfizer Inc., Johnson & Johnson and partners pulled the plug on its first patient in January. bapineuzumab in 2012. The drug is a low dose of the anti-epileptic therapy levetirace- Also, development has been suspended for 15 different tam, which targets SV2A, a synaptic vesicle membrane protein. compounds targeting BACE, including three late-stage drugs AGB101 is a proprietary, extended-release, once-daily formula- whose development ended in 2018 – Merck & Co. Inc.’s veru- tion of levetiracetam dosed at one-twelfth of what’s given to treat becestat in February, J&J and Shionogi & Co. Ltd.’s atabecestat epilepsy. in May, and AstraZeneca PLC and Lilly’s lanabecestat in June. AgeneBo’s candidate is being studied in the treatment of (Also see “M&A Pressure Mounts For Merck & Co After Alzheim- mild cognitive impairment in Alzheimer’s disease based on er’s Drug Dismissed” - Scrip, 14 Feb, 2018.) and (Also see “More research from the lab of company CEO and founder Michela Alzheimer’s Pain As J&J Pulls Plug On BACE Inhibitor” - Scrip, 18 Gallagher at Johns Hopkins University that showed restoring May, 2018.) normal brain function with AGB101 slowed the progression of Alzheimer’s. ALTERNATIVE AMYLOID, ALZHEIMER’S APPROACHES AgeneBio is talking to investors and pharma partners in an ef- ProMIS Neurosciences Inc. Chief Medical Officer James Kupiec, fort to secure more funding for the Phase III study, which may be who worked on the clinical trials for bapineuzumab during his registrational, since AGB101 is based on a known, approved drug, tenure at Pfizer, said in an interview withScrip that the now-failed Gallagher told Scrip in an interview. amyloid-targeting antibodies, including BACE inhibitors, all went after the wrong amyloid target. Published online 21 March 2019 Merck KGAA/Pfizer Discontinue Phase III Avelumab/ Talazoparib Combo Study In Ovarian Cancer

JOHN DAVIS [email protected]

erck KGaA and Pfizer Inc.’s decision to discontinue their first-line use in BRACA-mutated ovarian cancer patients in Decem- Phase III study of PD-L1 inhibitor Bavencio (avelumab) ber 2018, based on the results of the SOLO-1 study. Mplus Pfizer’s PARP inhibitor, Talzenna (talazoparib) in Lynparza’s move to become the standard-of-care in first- previously untreated advanced ovarian cancer, announced March line ovarian cancer patients is likely to be reinforced by results 19, was based partly on disappointing results from another study from the PAOLA-1 trial involving Lynparza plus Roche’s Avastin involving Bavencio reported at the end of last year. (bevacizumab), due to read-out in 2020, note analysts at Bryan Other reasons for the study discontinuation were the rapidly Garnier & Co. changing treatment landscape, including the approval of another Recent progress by other companies in the ovarian cancer field PARP inhibitor in the front-line maintenance setting, the compa- include EU approval for Clovis Oncology Inc.’s PARP inhibitor, Ru- nies say. This was AstraZeneca PLC/Merck & Co. Inc.’s PARP inhibi- braca (rucaparib) for maintenance therapy for platinum-sensitive tor Lynparza (olaparib) which was approved by the US FDA for ovarian cancer in all-comers, in January 2019.

scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 5 R&D

And Tesaro Inc.’s PARP inhibitor, Zejula (niraparib) is likely to get a boost from the proposed acquisition of Tesaro by Glaxo- SmithKline PLC. Competitive pressures can lead to a rethink of PREVIOUS STUDIES development strategies Merck KGaA/Pfizer explained that the Phase III JAVELIN Ovarian PARP 100 study was being discontinued based on several emerg- ing factors since the trial’s initiation in mid-2018, including the previously announced interim results from the Phase III JAVELIN Ovarian 100 study. “The degree of benefit observed with avelumab in front-line ovarian cancer in that study does not support continuation of JAVELIN Ovarian PARP 100 trial in an unselected patient population,” the two big pharma partners said. A planned interim analysis of JAVELIN Ovarian 100 found the addition of avelumab to study, the Phase III JAVELIN Ovarian 200 study, released in No- chemotherapy or to maintenance therapy was unlikely to affect vember 2018, indicated that avelumab monotherapy or its use progression-free survival during the first-line treatment of ovarian in combination with chemotherapy missed PFS and overall sur- cancer patients. vival endpoints when evaluated in platinum-resistant or refrac- The two companies have been collaborating on the clinical tory ovarian cancer patients. development of avelumab under a deal signed in 2014 but have The decision to discontinue JAVELIN Ovarian PARP 100 does not already been knocked back by disappointing results in gastric impact the remainder of the JAVELIN program which includes 30 cancer and lung cancer, and now in ovarian cancer. Pfizer gained clinical programs across 15 different tumor types including breast, US approval for talazoparib for the treatment of breast cancer in gastric/gastro-esophageal junction and head and neck cancers, October 2018 and is now evaluating it alone and in different com- Merkel cell carcinoma, non-small cell lung cancer and urothelial binations in a number of cancers. carcinoma, the companies said. Other combinations in other cancers have been fruitful: earlier this THE LATEST DECISION month, Merck and Pfizer completed the filing process for Bavencio JAVELIN Ovarian PARP 100 was evaluating the efficacy and safety of plus Pfizer’s tyrosine kinase inhibitor, Inlyta (axitinib), for the treat- PD-L1 inhibitor avelumab in combination with chemotherapy, fol- ment of advanced renal cell carcinoma, based on the pivotal Phase lowed by maintenance therapy of avelumab in combination with III JAVELIN Renal 101 trial, and the combination has been submitted talazoparib, versus an active comparator in treatment-naive patients for priority review in the US, with a target action date of June 2019. with locally advanced or metastatic ovarian cancer (Stage III or IV). Currently, avelumab is approved in the US, EU and elsewhere for Although checkpoint inhibitors used alone have not been the treatment of metastatic Merkel cell carcinoma, and for metastat- particularly effective in relatively non-immunogenic ovarian ic urothelial carcinoma in the US, while talazoparib was approved for cancer, it was hoped that combination therapies might fare bet- the treatment of BRCA-mutated HER2-negative locally advanced or ter, but a series of disappointing results in the JAVELIN series metastatic breast cancer in the US in October 2018. may have dashed those hopes. Top-line results from another Published online 21 March 2019 Conatus Endures Another NASH Setback With Failure To Hit Fibrosis Endpoint

JOSEPH HAAS [email protected]

he future of Conatus Pharmaceuticals Inc.’s partnership In a statement, the company said that while the study did not with Novartis AG in non-alcoholic steatohepatitis (NASH) yield the desired effect in earlier-stage NASH fibrosis patients, em- T appears uncertain after the biotech’s emricasan posted its ricasan has shown biomarker activity across a spectrum of liver second Phase IIb miss in four months. The first-in-class pan-cas- disease that suggests potential utility in later-stage patients, such pase inhibitor did not meet a fibrosis-reduction endpoint in the as those with cirrhosis. ENCORE-NF trial, the San Diego firm announced March 21. The study randomized patients with fibrosis scores ranging Conatus did not provide detailed data for the trial other than from F1 to F3 at baseline (mild fibrosis to bridging fibrosis that has to report that in 318 biopsy-confirmed NASH patients with liver spread but not become cirrhosis) on a 1:1:1 basis to 5 mg or 50 mg fibrosis, emricasan failed to produce a one-stage or greater reduc- emricasan or placebo twice-daily. A fibrosis score of F4 means the tion in fibrosis score at a statistically significant rate compared to patient has cirrhosis, which can lead to hepatocellular carcinoma placebo after 72 weeks of treatment. and/or the need for a liver transplant.

6 | Scrip | 29 March 2019 © Informa UK Ltd 2019 R&D

Reduction in fibrosis is one of the expected to report out in mid-2019, Co- measures FDA recommends using as a natus said. The firm is also conducting the primary endpoint in Phase III NASH tri- 210-patient ENCORE-LF study in NASH pa- als, per its December 2018 draft guid- tients with decompensated cirrhosis. An ance on NASH drug development. event-driven analysis of clinical outcomes However, the guidance also allows for is expected in mid-2019. improvement in steatohepatitis as a Conatus said it and Conatus said it and Novartis are primary endpoint, as long as there is no awaiting a chance to review the total- worsening of fibrosis. Novartis are awaiting ity of the data from the three ENCORE No drugs are approved as therapy for a chance to review trials to make a decision on continued NASH, although four have advanced to development of emricasan. Overall, Em- Phase III, with Intercept Pharmaceu- the totality of the ricasan has been studied in more than ticals Inc.’s obeticholic acid (OCA), a 950 patients across 19 completed clini- farnesoid x receptor (FXR) agonist, gen- data from the three cal trials in a variety of liver indications. erally considered to be the closest to ap- ENCORE trials to In ENCORE-NF, the drug was generally proval. There are 53 other candidates in well tolerated, consistent with safety the clinic. make a decision on findings from the 18 previous studies, Gilead Sciences Inc. was the first the company said. company to report out Phase III data continued development Conatus unveiled its plans for the in NASH, on Feb. 11, as its ASK1 inhibi- of emricasan. ENCORE studies at the American Asso- tor selonsertib failed to demonstrate a ciation for the Study of Liver Diseases fibrosis-reduction in patients with F4 annual meeting in 2015, saying that it fibrosis scores. Intercept then reported saw emricasan as offering potential in a data from its Phase III REGENERATE study wide swath of liver conditions from ear- of OCA on Feb. 19, showing a fibrosis ly-stage to later-stage disease. Beyond benefit in the larger of two doses tested, NASH, the company hoped to demon- but it missed an endpoint of NASH reso- strate that the candidate could benefit lution. The New York-based firm said it a range of cirrhosis patients and also will file OCA for approval in NASH during address residual liver damage in cured the second half of 2019. hepatitis C patients. Still to come is Phase III data for Gen- Novartis paid $50m up front for an op- fit SA’s PPAR alpha/delta agonist elafi- tion to license emricasan in December branor, expected during the final four 2016, under a deal that also gave Cona- months of 2019. The other Phase III can- tus a convertible loan of $15m, a poten- didate, Allergan PLC’s CCR 2/5 antago- tial option exercise fee of $7m and up nist cenicriviroc, is expected to produce to $650m in milestones as well as pos- Phase III data in 2020. sible sale royalties. The agreement gave Novartis the right to take over develop- THREE ROUNDS OF ENCORES ment of emricasan in Phase III, where it Under its 2016 option agreement with planned to test the compound in combi- Novartis, Conatus is conducting three ENCORE-PH trial in compensated NASH nation with its internal NASH candidates, Phase IIb ENCORE studies with emri- cirrhosis patients at high risk of decom- including FXR agonists. casan in different cohorts of NASH pa- pensation. (Also see “In NASH Race, Bad Combination therapy is expected to tients. This past December, Conatus re- News For Conatus, Good News For Genfit become the standard of care, as NASH is a vealed that the drug failed to meet its In PBC” - Scrip, 10 Dec, 2018.) multi-factorial disease caused by buildup primary endpoint – change in hepatic A six-month extension of ENCORE- of fat in the liver that can cause fibrosis venous pressure gradient (HVPG) from PH measuring liver function and clinical and/or inflammation. baseline to week 24 – in the 263-patient outcomes after 48 weeks of treatment is Published online 21 March 2019

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scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 7 CLINICAL TRIALS

Latest REDUCE-IT Results Bolster Case For Amarin’s Vascepa Fish Oil Pill

EMILY HAYES [email protected]

marin Corp. PLC’s latest results REDUCE-IT included about 8,000 pa- and in those with no LDL increase in the for the prescription-grade fish-oil tients with triglyceride levels between placebo group “suggests this is not a ma- Aproduct Vascepa in the REDUCE-IT 135 mg/dL and 500 mg/dL. The median jor issue,” said Kaul, who has participated cardiovascular outcomes trial presented at triglyceride level at baseline was 216 mg/ as a panelist in agency reviews of cardio- the American College of Cardiology (ACC) dL, but the study also included some pa- vascular drugs. annual meeting boost the case for the tients with triglyceride levels as low as 81 drug’s efficacy ahead of a supplemental mg/dL at baseline. The patients were well- CONSISTENT REDUCTIONS US filing in a broader patient population. controlled on statins, as evidenced by the IN RISK Vascepa is a proprietary formulation of median baseline LDL cholesterol (LDL-C) In the latest release at the ACC meeting, the omega-3 acid eicosapentaenoic acid of 75 mg/dL. investigators noted that first events were (EPA). Data released on March 18 at the reduced by 25%, second events by 32%, ACC meeting in New Orleans suggest that BUILDING ON PRIOR RELEASE, third events by 31%, and fourth or more the drug used on top of statins provides TACKLING PLACEBO QUESTION events by 48%. a significant 30% reduction in risk com- The company released data for Vascepa at The analysis of recurrent events was pared with placebo for a composite of first, the American Heart Association (AHA) an- pre-specified, but a limitation of the study subsequent and total ischemic events. In- nual meeting in November. On the primary was that it was an exploratory analysis and vestigators also reported a significant 20% efficacy endpoint of the study – the first oc- one method used to evaluate the data reduction in risk for CV death and a 13% currence of a composite of major adverse was done on a post hoc basis, the authors numerical risk reduction in total mortality cardiovascular events (MACE) – the drug acknowledged in the JACC paper. (p-value of 0.09) was associated with a significant, 25% re- A total of 159 primary endpoint events An early unedited copy of an article duction in risk compared with placebo. were prevented in the course of the five- with the data was published the same day As the first major study of a fish oil prod- year study, including 12 cardiovascular by Deepak Bhatt, executive director of in- uct to show a CV outcomes benefit, the deaths and 42 heart attacks. terventional cardiovascular programs at study was groundbreaking, though there “The times to first occurrence, second Brigham and Women’s Hospital, and col- was controversy about the use of mineral occurrence, third occurrence, or fourth leagues in the Journal of the American Col- oil as a comparator for placebo as this in- occurrence of the primary composite end- lege of Cardiology (JACC). creased LDL-C, raising questions about point were consistently reduced with icos- The primary composite endpoint in- whether this was a true placebo. apent ethyl,” Bhatt and colleagues wrote. cluded cardiovascular death, nonfatal The JACC paper by Bhatt and colleagues “Patients don’t care just about the first myocardial infarction (MI), nonfatal stroke, acknowledged that some biomarkers in event, they care about the second event coronary revascularization or hospitaliza- the placebo arm increased from baseline especially if that one happens to be a fa- tion for chest pain related to blockages. – median LDL was 5 mg/DL higher in the tal one, but even otherwise,” Bhatt said The key secondary endpoint, which is placebo group versus the Vascepa group during an ACC press briefing, adding that considered more robust, included cardio- – but added that “such changes are com- from an insurance, health economics and vascular death, nonfatal MI or nonfatal mon in statin-treated patients within car- public health perspective the intervention stroke. And on this measure, the drug was diovascular outcome studies.” would have a “very large impact.” associated with a significant 26% reduc- It’s unclear whether that statement along The wholesale acquisition cost (WAC) tion in risk. Vascepa was well-tolerated, with the consistency of the latest results for Vascepa in 2019 is $303.65 per month with a risk profile in line with the what has will be enough to reassure the cardiology and Amarin stressed there are “numerous been previously reported. community regarding a potentially nega- discounts and rebates” negotiated in the Vascepa is US FDA approved for use as tive effect in the mineral oil placebo arm supply chain as well as coupon programs an adjunctive treatment of patients with that benefited the Vascepa arm of the trial. to help patients with out-of-pocket costs. severe hypertriglyceridemia, defined as Cedars-Sinai cardiologist Sanjay Kaul Amarin reported $228m in product sales 500 mg/dL or above. Amarin plans to noted in emailed responses to questions for 2018. submit a supplemental NDA with results from Scrip that the placebo/mineral oil is- Bhatt also highlighted results for people from the REDUCE-IT outcomes study, sue has been brought up twice at the FDA in the study with a baseline triglyceride which was designed through a special with this compound and was not deemed level as low as 81 mg/dL, which is lower protocol assessment with the agency, by to be a major issue. than what might be considered the target the end of March in a bid to broaden the The fact that a benefit was consistently treatment population for the drug. Study patient population. observed in patients with an LDL increase participants with a baseline triglyceride

8 | Scrip | 29 March 2019 © Informa UK Ltd 2019 CLINICAL TRIALS

between 81 mg/dL and 190 mg/dL had a 26% reduction in risk for given that they came on top of optimal medical therapy with pre- the primary endpoint. That compares with 23% risk reduction for treatment LDL levels (75 mg/dL) among the lowest recorded in LDL those with baseline between 190 mg/dL to 250 mg/dL, and 40% trials; he said the recurrent event results were “along expected lines.” risk reduction where the baseline was between 250 mg/dL and “The results of this recurrent event analysis show that the ben- 1,401 mg/dL. efits are preserved (for the more robust secondary endpoint of Bhatt and two other clinicians – Duke Clinical Research Insti- CV death, MI or stroke), and to some degree amplified (for the tute’s Ann Marie Navar and Boston University’s William Boden – less robust primary endpoint), when all events are accounted for, questioned whether the threshold for what is considered a high thereby capturing the totality of treatment benefit,” Kaul said. level of triglycerides needs to be lowered during an investor call He added that regulatory agencies appear to be “increasingly held by Amarin on March 18 after the market closed. supportive of an analysis strategy based on recurrent events.” For Discussing the study during the press briefing, University of example, the primary endpoint of the PARAGON-HF study of No- Florida Research Professor Eileen Handberg said that patients vartis AG’s Entresto (sacubitril/valstartan) in heart failure was the with cardiovascular disease have multiple events and continuing cumulative number of primary composite events of cardiovascu- to reduce that risk over time is extremely important. lar death (first and recurrent) and total heart failure hospitaliza- These analyses are not that commonly done, but should be tions, he noted. done in all trials with MACE outcomes, Handberg said, noting Hadley Wilson, an interventional cardiologist at the Sanger that REDUCE-IT represents a kind of paradigm shift for clinical Heart and Vascular Institute and a member of the ACC Board of trial reporting. Trustees, said that the study provides evidence for another agent JACC authors credited the efficacy benefit to high EPA levels, in that can be used in people with hypertriglyceridemia and lipid contrast with other fish oil products, which are composed of EPA problems. It may also pave the way for inclusion in treatment and docosahexaenoic acid (DHA). guidelines, he said. “EPA has unique lipid and lipoprotein, anti-inflammatory, anti- The ACC/AHA released new guidelines for primary prevention platelet, anti-thrombotic, and cellular modifying effects, all of of heart disease and Vascepa was not included. The next version is which may contribute to benefits in atherosclerotic processes such may be released in a year or more. as reduced development, slowed progression, and increased stabi- Joint ACC/AHA guidelines for managing cholesterol released lization of atherosclerotic plaque,” the JACC paper noted. Kaul de- last November also left Vascepa out and it is unclear when they scribed the time-to-first events of REDUCE-IT as “quite impressive” will be revised. Published online 20 March 2019

Scrip Awards Sponsored by Winner 2018 Scrip’s Lifetime Achievement Award

Scrip’s Lifetime Achievement Award (sponsored by ICON) for 2018 was bestowed upon Sir John Bell for a career that has spanned academia and industry.

The Canadian immunologist and geneticist – who holds the Regius Chair of Medicine at the University of Oxford – studied ﬁ rst in Canada and then medicine at Oxford on a Rhodes scholarship. In 1993 he founded the Wellcome Trust Centre for Human Genetics, one of the world’s Winner: Sir John Bell leading centers for complex trait common disease genetics.

He was also a founding director of three Oxford-based biotech start-ups: Avidex, which was initially acquired by MediGene in 2006 and subsequently spawned Immunocore and Adaptimmune; Oxagen; and PowderJect Pharmaceuticals, which was acquired by Chiron Corp, now part of Novartis, in 2003.

He is non-executive chairman of Immunocore, and Sensyne Health, a clinically focused artiﬁ cial intelligence company. He also serves on the boards of Roche and Genentech and had a previous role on the scientiﬁ c advisory board at AstraZeneca.

Sir John chairs the scientifi c committee of UK Biobank and the Global Health Scientifi c Advisory Board of the Bill and Melinda Gates Foundation, as well as being an advisor to other humanitarian foundations. He served as President of the Academy of Medical Sciences from 2006 to 2011 and was responsible for the working party that produced the Academy’s highly infl uential report Strengthening Clinical Research, which highlighted the need for the UK to focus attention on developing expertise in translational research.

In 2008, he was knighted for his services to medicine, is now one of three UK life sciences champions, and in 2015 New Year Honours was appointed Knight Grand Cross of the Order of the British Empire for services to medicine, medical research and the life sciences industry.

JN1768 Scrip Awards 2018 Winner Advert S.indd 1 2019/03/25 17:45 scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 9 CLINICAL TRIALS

Shorter Treatment Time For Chagas Could Blunt Kissing Bug Disease

KEVIN GROGAN [email protected]

two-week course of drugs for treating patients with Cha- gas disease, instead of the current 60-day regimen, could Abe just as effective and safer, according to a new study which researchers believe could change the paradigm for treatment of the debilitating and potentially fatal insect-borne illness. The BENDITA study was led by the not-for-profit Drugs for Ne- glected Diseases Initiative (DNDi) and carried out at sites in Co- chabamba, Tarija and Sucre in Bolivia. It tested six treatment arms with a variety of lengths and dosages of benznidazole, the drug most commonly used to treat Chagas, both as monotherapy and in combination with Eisai Co. Ltd.’s investigational antifungal fos- ravuconazole. Some 80% of the patients assigned to the group which took the standard dose of 300mg/day of benznidazole, but for two weeks instead of the standard eight weeks, showed no sign of the parasite in their blood six and 12 months after finishing the treatment. A similar result was observed in the group that took the standard eight-week treatment. Significantly, DNDi noted, none of those in the two-week re- “We’ve shown shorter treatment could be duced duration group interrupted treatment. On average, 20% just as effective, and much safer. This could of patients who followed the standard course of treatment with benznidazole abandoned it due to side effects such as gastric in- change the paradigm for Chagas treatment, tolerance, rashes or neuromuscular problems. The side effects associated with benznidazole have “often dis- by improving adherence and encouraging couraged some people from seeking treatment and healthcare wider adoption by the medical community.” workers from recommending it,” said Joaquim Gascon, principal investigator in the trial and director of the Chagas Initiative at the Barcelona Institute for Global Health. A fellow investigator, Faustino Torrico, president of the CEADES Foundation in Bolivia, noted DNDi, and for 30-40% of people infected, most will suffer added, “We’ve shown shorter treatment could be just as effective, cardiac damage, often leading to sudden death or progressive and much safer. This could change the paradigm for Chagas treat- heart failure. ment, by improving adherence and encouraging wider adoption by the medical community.” NOVARTIS TESTS ENTRESTO FOR CHAGAS The results “bring new hope for people living with this silent CARDIOMYOPATHY disease and could change the reality of access to treatment in en- It is against this background that Novartis AG has announced demic countries. With a much simpler treatment regimen, there is that as well as joining the Global Chagas Disease Coalition as a no excuse for not treating people with Chagas,” added Sergio Sosa member, it is preparing a study to test its heart failure blockbust- Estani, head of the Chagas clinical program at DNDi. er Entresto (sacubitril/valsartan) versus enalapril in around 900 Chagas is caused by the parasite Trypanosoma cruzi and trans- patients with chronic Chagas cardiomyopathy. Recruitment is mitted to humans via the feces and urine of kissing bugs or tri- planned to commence this year and the Swiss major noted that atomines. According to the World Health Organization, 8 million it will be “the first definitive morbidity and mortality study to -as people are infected worldwide, mainly in Latin America where sess a potential therapy for cardiac disease in this underserved one quarter of the population is potentially at risk of contracting a patient population.” disease which causes incapacity and more than 10,000 deaths per The primary endpoint is time to occurrence of a composite of year. International travel and migration has meant that Chagas is cardiovascular events, including death or first hospitalization due increasingly a global health issue – according to the Centers for to heart failure. Novartis said that the study followed an explorato- Disease Control and Prevention, in the US an estimated 300,000 ry analysis from the PARADIGM-HF trial on which the appproval people are infected with T cruzi. of Entresto was based which suggested the drug may have ben- As the disease typically remains asymptomatic for years after in- eficial effects in people with chronic Chagas cardiomyopathy and fection, most people with Chagas are unaware of their condition, heart failure with reduced ejection fraction.

10 | Scrip | 29 March 2019 © Informa UK Ltd 2019 CLINICAL TRIALS

The company added that it was also “working with stake- with historical placebo control. The study was conducted at sites holders in endemic countries to co-develop tailored access-to- in Argentina, Bolivia and Colombia between 2016 and 2018. medicine programs and health system strengthening strategies For the trial, Bayer developed a new formulation of both the to help ensure lower-income patients suffering from chronic 30mg and 120mg tablets, which can be dissolved in water to form Chagas cardiomyopathy can benefit from the best available a slurry when administered to children to allow for dosing accura- treatment.” In addition, Novartis pointed out that its proteasome cy and administration to those who have difficulty swallowing tab- inhibitor LXE408 was recently advanced as a promising drug lets. Jaime Altcheh of the Ricardo Gutierrez Children’s Hospital in candidate for the treatment of visceral leishmaniasis and “this Buenos Aires and coordinating investigator of the trial, was quoted novel mechanism of action is also being explored for other indi- by Bayer as saying that “an adequate dispersable formulation of ni- cations, including Chagas.” furtimox is a big step forward toward achieving the goal of treating all infected children. Early treatment after infection is very impor- BAYER PEDIATRIC STUDY A SUCCESS tant to prevent manifestation of the disease in adulthood.” There are currently only two drugs available to treat the disease So progress is being made and pharma has been doing the – benznidazole and nifurtimox – and the latter was discovered by right thing in an area of great unmet need but not a lucrative one. Bayer AG which first introduced the drug in Argentina (market- For example, since 2002 Bayer has been providing the WHO with ed as Lampit) in the 1970s, and shortly afterwards in other Latin nifurtimox free of charge, as well as financial resources for logistics American countries. Now the German major has presented posi- and distribution and funding awareness, education and training tive data from the first part of a Phase III study of nifurtimox in pe- programs, plus surveillance activities. diatric patients at a Chagas conference in Barcelona. However much is still to be done and Bayer noted that today, less The 330-patient study met its primary endpoint, which was the than 1% of people infected with Chagas worldwide are treated due serological response at one year after end of treatment, by dem- to low disease awareness and limited access to treatment. onstrating superiority of 60-day nifurtimox treatment compared Published online 15 March 2019 New CV Outcomes Study May Mean Big Boost For Amgen’s Repatha Market

EMILY HAYES [email protected]

mgen Inc.’s plan to run a new an event were included it would add an- endpoint, a composite that included cardiovascular outcomes study other 4.5m, according to the company. cardiovascular death, myocardial infarc- Aof its PCSK9 inhibitor Repatha “Amgen and TIMI previously collabo- tion (MI), hospitalization for unstable (evolocumab) in high-risk patients who rated on the Repatha cardiovascular angina or coronary revascularization. haven’t had a cardiovascular event yet has outcomes study (FOURIER), which dem- Investigators also reported a 20% reduc- the potential to greatly broaden the target onstrated Repatha’s efficacy in reduction for the endpoint including risk for population for the drug. ing low-density lipoprotein cholesterol CV death, MI or stroke. The VESALIUS-CV trial will be done (LDL-C) levels, as well as the relative risk In VESALIUS-CV, the enrollees will not in collaboration with the Brigham and for major CV events in high-risk patients have had a heart attack or stroke, but they Women’s Hospital Thrombolysis in Myo- with a history of heart attack or stroke. do have coronary, cerebral or peripheral cardial Infarction (TIMI) Study Group and VESALIUS-CV will build on these findings arterial disease and may have had inter- will start enrolling in the second quarter, by exploring the potential benefit of Re- ventions, including a coronary arterial by- the company announced March 15. Re- patha in preventing a first heart attack pass graft (CABG) or stents and they may patha is currently approved in the US for or stroke in patients with some of the have diabetes with indicators of increased reducing the risk of myocardial infarction, most significant risk factors for a first CV risk for cardiovascular disease, the com- stroke and coronary revascularization in event,” Amgen said. pany explained. adults with established cardiovascular “The study will be the first to investigate The new study tests the drug given disease, for use as an adjunctive therapy long-term outcomes in this population every two or four weeks in 13,000 high- in treating primary hyperlipidemia (in- with Repatha for a minimum of four years,” risk patients who have not had an event cluding heterozygous familial hypercho- the company noted. Median follow-up in yet and with a baseline LDL of 100 mg/ lesterolemia), and for homozygous famil- FOURIER was 24 months. dL, whereas FOURIER tested the drug ial hypercholesterolemia. Amgen’s previous FOURIER cardio- every two or four weeks after an event With current US FDA labeling, some vascular outcomes study (CVOT) tested in 27,564 patients with a baseline LDL of 11m in the US are potentially eligible for Repatha for secondary prevention and less than 70 mg/dL treatment (including 3.4m at the high- showed the drug was associated with The primary efficacy measure also dif- est risk) and if those who had never had a 15% reduction in risk on the primary fers. FOURIER featured a five-point com- scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 11 CLINICAL TRIALS

posite of major adverse cardiovascular The primary completion date on clini- nies to establish heavy utilization man- events (MACE). The new study has two caltrials.gov for Amgen’s VESALIUS-CV agement barriers that hindered use. primary endpoints – three-point MACE study is May 2024, ahead of the ORI- However, recent price cuts for both (cardiovascular death, MI and ischemic ON-4 release. drugs, and the CVOT data, have helped stroke) and four-point MACE (cardio- to improve access in the market. (Also vascular death, MI, ischemic stroke and PCSK9S FINALLY GETTING OFF see “Sanofi/Regeneron Cut Praluent List ischemia-driven revascularization. THE GROUND Price As PBMs Look To Maintain Rebate Amgen secured the outcomes claim Status Quo” - Scrip, 12 Feb, 2019.) Amgen NOT PRIMARY PREVENTION and indication for primary hyperlip- announced plans to cut the list price Mizuho Securities analyst Salim Syed idemia at the end of 2017, which has for Repatha to $5,850 in October 2018. stressed in a March 15 note that the VESA- marked a valuable turning point for the (Also see “Amgen Drops Repatha List Price LIUS-CV study is not considered a primary drug. Payers and physicians had not 60% To Cut Medicare Co-Pays And Boost prevention trial, because the study is en- fully embraced the pricey injectable Use” - Scrip, 24 Oct, 2018.) Whereas Medi- rolling very high-risk patients, who have class ahead of outcomes data. (Also see care patients have been paying as much significant coronary disease. “Outcomes Claim May Help Amgen Make as $370 per dose out of pocket, the copay cost could come down to $150 or The VESALIUS-CV trial will be done in collaboration as low as $25. And Sanofi followed suit, announcing in February that it is cut- with the Brigham and Women’s Hospital ting the list price of Praluent by 60% to $5,850 per year. The goal for both drugs Thrombolysis in Myocardial Infarction (TIMI) was to make the drugs more accessible to Medicare Part D patients, who were Study Group and will start enrolling in the second ineligible for copay coupons. The changes have been helping. quarter, the company announced March 15. Amgen reported sales of $159m in the fourth quarter, up 62% from the year- “Primary prevention typically refers Case For PCSK9 Inhibitor Repatha” - Scrip, ago period. Sanofi/Regeneron report- to pre-clinically manifest CV disease 1 Dec, 2017.) ed sales of €82m ($92m) in the fourth (e.g. a 25-year old who is perfectly in Sanofi/Regeneron Pharmaceuticals quarter, up 51% from the same period good health taking a PCSK9 for long- Inc.’s competing PCSK9 inhibitor Pralu- of 2017. term benefit). The only place in the trial ent (alirocumab) is now under review at The consensus expectation for peak design that one can really argue this is the FDA for an outcomes claim and use in sales is $2.5bn. primary prevention is patients [with] first-line treatment of primary hyperlipid- diabetes with indicators of increased emia based on the ODYSSEY outcomes AMGEN’S COUNTING ON CVD risk, which could be considered a study, with a decision expected in April. REPATHA high-risk primary prevention population (Also see “PCSK9 Inhibitor Labeling Parity Amgen highlighted Repatha as among since they do not have a diagnosis of AS- Is Within Reach As Praluent And Repatha the products driving long-term growth, CVD [atherosclerotic cardiovascular dis- Strive To Make Commercial Case” - Pink during a presentation at the Cowen Health ease],” Syed said, which was confirmed Sheet, 20 Aug, 2018.) It is currently ap- Care Conference on March 12. by Amgen. proved for use as an adjunctive therapy Repatha sales grew 70% in 2018 and The analyst also noted that the study for heterozygous familial hypercholester- with the now-reduced price offering, design is similar to The Medicines olemia or for patients with clinical ath- Amgen is starting to see a step function Co.’s ORION-4 outcomes study of the erosclerotic cardiovascular disease who in terms of upward trajectory in terms of long-acting PCSK9 inhibitor inclisiran. need additional LDL-lowering. adoption, David Meline, executive vice (Also see “Medicines Company Gets Ag- The European Commission approved a president and chief financial officer, told gressive With Inclisiran Phase III Plans” - new indication for Praluent for reducing the meeting. Scrip, 31 Aug, 2017.) The ORION-4 study cardiovascular risk in adults with estab- BMO Capital Markets analyst Do Kim tests inclisiran in 15,000 patients who lished atheroscelerotic disease as an ad- said in a March 14 note that lowering have had an event and have baseline junct to correction of other risk factors on the list price should “align reimburse- LDL of 100 mg/dL, and features four- March 15. ment with physician enthusiasm to ac- point MACE as the primary efficacy The PCSK9 class is associated with dra- celerate uptake.” endpoint. The study started in October matic reductions in LDL on top of statins, Fourth-quarter sales figures for Pralu- 2018 and has a primary completion and consequently, hopes were high for a ent and Repatha suggest that the market date of December 2024. Top-line data blockbuster trajectory. The lack of out- is very under-penetrated, the analyst said, from a range of Phase III trials are set comes data and high price at the time of with about 106,000 in the US on therapy, for release this year and the drug is ex- launch – both initially cost about $14,500 Kim said. pected to launch by 2021. annually – prompted insurance compa- Published online 22 March 2019

12 | Scrip | 29 March 2019 © Informa UK Ltd 2019 APPROVALS

Zulresso Is Sage’s First Step In Postpartum Depression Treatment

MANDY JACKSON [email protected]

he US FDA approved Sage Ther- riencing moderate or severe PPD up to only about 100 sales reps that will cover apeutics Inc.’s Zulresso (brex- six months after giving birth; onset of this market successfully.” T anolone) on March 19 as the symptoms occurred between the third The CEO explained that Sage will first agency-endorsed treatment for trimester of pregnancy and within four have almost as many medical science postpartum depression (PPD). It’s also weeks of delivery. Efficacy was seen at liaisons to work on informing physi- Sage’s first approved product, helping the 60-hour mark, but often within the cians about the science behind Zulres- the company establish a commercial first 24 hours of starting therapy, and so and the need for proper diagnosis organization as it completes Phase III treatment effects were observed for at and rapid treatment. development for the more broadly ap- least 30 days after administration. (Also plicable postpartum and major depres- see “All Smiles At Sage As Phase III Post- IV ADMINISTRATION sion candidate SAGE-217. partum Depression Data Are Positive” - About one in nine new mothers experi- Zulresso’s 60-hour I.V. infusion and Scrip, 9 Nov, 2017.) ences PPD – about 400,000 women in the requirement for continuous inpatient Sage will launch Zulresso for PPD as US – but it’s estimated that only half of af- monitoring during administration may soon as the Drug Enforcement Adminis- fected patients are diagnosed. limit its use to the most at-risk new tration (DEA) completes scheduling for Jonas said Sage does not anticipate mothers, but it will help Sage build its the drug, an allosteric modulator of syn- that Zulresso’s I.V. administration and the presence in the PPD market ahead of aptic and extrasynaptic GABA-A recep- drug’s REMS requirements will limit its approval for SAGE-217, an oral therapy tors. The DEA process usually takes about use. Physicians and patients understand with a similar mechanism of action 90 days, but company CEO Jeff Jonas told the importance of a rapid-acting therapy that’s being developed for PPD as well Scrip that Sage is ready to launch Zulres- for a condition that, he said, “is the leading as major depressive disorder. so right away if the scheduling decision medical complication of pregnancy, and comes early. the most common cause of death after MARKET REACTION The product’s list price is $34,000 for childbirth is suicide.” Sage closed down 0.5% at $156.10 per the one-time treatment, which Jonas said In speaking with women who have par- share on March 19 as it ended the trad- Sage set after discussing a range of prices ticipated in Zulresso clinical trials, Sage ing day without a Zulresso approval an- with several payers. has found that “the opportunity of a drug nouncement on the FDA action date. “The feedback has been uniformly posi- that provides benefit within hours and is However, the company rose 5.6% to tive,” he said, noting that payer attitudes a one-time treatment that is completed in $164.80 in after-hours trading when the about Zulresso’s pricing are based on the two and a half days … is not an inconve- agency announced the drug’s approval attributes of the drug – namely its fast- nience,” Jonas said. later in the evening on March 19. acting efficacy. “We have to administer the drug prop- The FDA extended the original Dec. “Payers understand the impact [of erly, but we don’t see that as a barrier 19 user fee date for the Zulresso new PPD] on the family, the cost to society, in terms of actual administration of the drug application (NDA) by three months and the convenience of getting better drug,” he added. to consider a Risk Evaluation and Miti- in two and a half days,” the CEO said. The REMS for Zulresso requires the drug gation Strategy (REMS) proposed by the “We are expecting broad reimburse- to be administered by a health care pro- company. The REMS proposal was sub- ment for the drug.” vider in a certified health care facility. Pa- mitted to the agency after an advisory Patient assistance programs will be re- tients must be enrolled in the REMS pro- committee recommended approval vealed when Sage launches Zulresso to gram prior to administration of the drug as long as the Zulresso label included improve access for women who may not then monitored during the 60-hour I.V. a REMS requiring close monitoring of be able to afford the drug. administration for excessive sedation and patients for sedation or sudden loss of Jonas noted that PPD is a psychiatric sudden loss of consciousness with contin- consciousness, which were observed in disease that’s not often diagnosed by psy- uous pulse oximetry monitoring. Patients clinical trials. (Also see “Sage’s Brexano- chiatrists, but rather by women’s obstetri- also must be accompanied when interact- lone Could Be Transformative, But Only In cians, pediatricians treating the women’s ing with their infants during administra- Controlled Settings, US FDA Panel Says” - infants, social workers and others. tion of Zulresso. Pink Sheet, 2 Nov, 2018.) “Our focus is going to be on hospitals Patients must be counseled about the The drug rapidly and significantly im- and centers of excellence, maybe an in- risks associated with the drug and in- proved depression scores in Phase III patient unit or outpatient unit where structed about the REMS monitoring re- trials for new mothers who were expe- they can stay 24/7,” he said. “We’ll have quirements prior to administration, and scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 13 APPROVALS/DERMATOLOGY

should not drive, operate machinery, or do other potentially dangerous activi- Dermira’s Lebrikizumab Data Set ties until Zulresso-induced sleepiness has resolved. Up AD Showdown With Dupixent Analysts from Cowen wrote in a March 18 report following the investment JOSEPH HAAS [email protected] bank’s recent health care conference that investors and psychiatrists see a role for ermira Inc.’s Phase IIb data for its compared to placebo. The improvement Zulresso even for moderate PPD patients IL-13 inhibitor lebrikizumab in in EASI score was 62.3% for patients get- based on Phase III results for the drug. Datopic dermatitis showed efficacy ting a 250 mg loading dose followed The I.V. administration and the require- across three dosing regimens, with a by 125 mg every four weeks, 69.2% for ment for inpatient treatment during ad- profile similar to market leader Dupix- a 500 mg loading dose followed by 250 ministration is viewed as a limiting factor ent. Now, the company hopes to initiate mg every four weeks, and 72.1% for a for the drug, however. a Phase III study by year’s end that could 500 mg loading dose followed by 250 set up the therapy with a dosing-conve- mg every two weeks. MARKET POTENTIAL nience advantage compared to Sanofi/ Dupixent is dosed every two weeks and That’s why there’s a lot of optimism Regeneron Pharmaceuticals Inc.’s IL-4/ Dermira seeks to demonstrate that lebriki- around the oral drug SAGE-217, a next- IL-13 receptor antagonist. zumab can yield similar or better efficacy generation positive allosteric modulator Dupixent (dupilumab) became the with a monthly dose. Warning about vari- optimized for selectivity to synaptic and first biologic approved for atopic der- ables that can confound cross-trial com- extrasynaptic GABA-A receptors that matitis in 2017, and in its first full year parisons, SVB Leerink analyst Pasha Sarraf also had a rapid and significant effect on on the market in 2018 approached said in a March 18 note that lebrikizumab’s PPD – without loss of consciousness – the blockbuster sales threshold Phase IIb data appear similar to the 71% in the Phase III ROBIN trial. Somnolence (€788m/$894m), while picking up an EASI improvement shown by Dupixent in was among the most common side ef- additional US indication for moderate- its Phase IIb program. fects, however. to-severe asthma. (Also see “Dupixent The Phase IIb data, while not conclusive, Sage has completed one Phase III Approved For Severe Asthma With Broad- leave open the door for the possibility of study for SAGE-217 in major depressive er Label Than Other Biologics” - Scrip, monthly dosing, analysts agreed. disorder (MDD) and has another under 21 Oct, 2018.) Dermira executives cited way with results expected in late 2019 or multiple reasons during an investor call EASI-75 DATA COULD OFFER early 2020. March 18 as to why they think lebriki- IMPORTANT DIFFERENTIATION “Our experts and audience continued to zumab can compete viably with Dupix- Of the three doses tested by Dermira, be encouraged by the potential of SAGE- ent in dermatology’s largest indication, the two larger doses also hit statistical 217 given the promising data and [Phase predicted to reach $15bn in aggregate significance on multiple secondary end- II/III] progress in MDD and PPD,” Cowen sales by 2025. points, while the 125 mg monthly dose analysts said in the March 18 note. Lebrikizumab already demonstrated did not. Key among these might be “As the PPD treatment landscape con- proof-of-concept in a Phase II study EASI-75, which measures the percent- tinues to evolve, investors and experts at Roche when the Swiss pharma out- age of patients achieving 75% clear- increasing[ly] acknowledge the oppor- licensed the compound’s development ance of atopic dermatitis by a specified tunity for pharmacologic treatments, rights outside respiratory disease in 2017 time point. Cowen analyst Ken Cac- including that of Sage’s Zulresso, in to Dermira. The antibody yielded mixed ciatore said KOLs have pinpointed this patients whose symptoms are not well results in severe asthma, hitting its Phase measure as “an important endpoint and controlled on current treatment alter- III primary endpoint in one trial but failing differentiator of efficacy” in a March 18 natives,” they said. “Successful develop- in another. note on the data. ment of an oral formulation clearly has However, Dermira saw best-in-class In the 250 mg dosing cohorts, 56.1% a role in the minds of investors and spe- potential in atopic dermatitis because of treated monthly with lebrikizumab and cialists. Our panelists were more defini- lebrikizumab’s extended coverage and 60.6% treated every two weeks achieved tive in their view that an effective oral developed a Phase IIb protocol, includ- EASI-75, while the Dupixent Phase III could be a game changer, displacing an ing a loading dose and three different SOLO studies achieved 51% and 44% I.V. therapeutic in PPD.” dosing cohorts. EASI-75 rates. “We believe that the 250 Jonas noted that SAGE-217 is not an Dermira noted in top-line data from mg bi-weekly dosing efficacy and safety oral formulation of Zulresso but a novel the 280-patient Phase IIb study unveiled of lebrikizumab demonstrates differentia- drug with a slightly different formulation. March 18 that all three treatment arms tion, since previously our consultants have He acknowledged, however, that Zulresso achieved statistical significance on the indicated that to prove superiority to Du- will pave the way for SAGE-217 with its primary endpoint of improvement from pixent a competitor would need to dem- similar mechanism and efficacy. baseline in Eczema Area and Sever- onstrate a 60% or better EASI-75 score,” Published online 19 March 2019 ity Index (EASI) score from at 16 weeks Cacciatore wrote.

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Dermira execs said they hope to initiate zumab could prove to be both best-in- follow. (Also see “Almirall Extends Derma- a Phase III program for lebrikizumab be- class and best-in-disease, supporting a tology Reach With Dermira Lebrikizumab fore the end of 2019, pending an end-of- thesis that IL-13 inhibition can address Deal” - Scrip, 12 Feb, 2019.) Phase IIb meeting with the US FDA. Chief atopic dermatitis pathology by ame- Meanwhile, Dermira reduced its near- Development Officer Luis Pena told the liorating both skin manifestations and term costs under its agreement with call that the company’s hypothesis right itch, he said. Roche by arranging for $16m in study now is to design a protocol that would “IL-13 is a validated target and be- drug free of charge, while eliminating a include a 250 mg dose every two weeks lieved to be an important mediator in $30m milestone fee for the first regulatory during the induction phase, with flexibil- atopic dermatitis,” Pena noted. “IL-13 ex- filing of lebrikizumab in atopic dermatitis ity to continue dosing every two weeks or pression is up-regulated in AD patients and halving what was a $40m start-of- transition to monthly dosing during the and correlates with disease severity. Phase III milestone. In return, Roche ob- maintenance period. It promotes type 2 inflammation and tained rights to tiered royalties into the Chief Commercial Officer Lori Lyons- drives multiple aspects of AD patho- high teens for lebrikizumab if the drug’s Williams added, however, that dosing con- physiology such as impaired skin barrier sales exceed $3bn. venience would not come at the expense function, increased sensitivity to itch, fi- Along with a financing agreement with of efficacy. Efficacy is the most important brosis and an elevated risk of infection.” Athyrium Capital Management, these ar- factor in atopic dermatitis therapy, she Lebrikizumab appears to inhibit IL-13’s rangements could reduce Dermira’s Phase said, but a dosing edge could provide an biological effects in a targeted and effi- III costs by as much as $110m and give important measure of differentiation in a cient manner, he added. the Menlo Park, Calif.-based firm financial competitive space. Dermira previously guided that the runway into the second half of 2020, SVB “Based on extensive market research, costs of a Phase III program for lebriki- Leerink’s Sarraf pointed out. we know that, of course, efficacy is the zumab in atopic dermatitis would total Dermira investors seem enthused, as most important therapeutic attribute,” approximately $200m. The company re- the company’s stock finished trading on she said. “We really think the trial design cently has taken steps to cover some of March 18 up 82% at $12.61 per share. that [Pena] described would potentially those costs, both by selling Almirall SA The company will take advantage of allow us to have that and disease effica- an option to European commercial rights investor goodwill to raise additional cy and a more convenient maintenance to the product and also by adjusting the capital in preparation for its Phase III schedule, which, we think, would drive earnout provisions of its 2017 deal with lebrikizumab program. It announced additional commercial value. So, I mean, Roche. [See Deal] after the market closed that it may honestly, from a commercial perspec- In its deal with Almirall, Dermira got raise up to $126.5m in a forthcoming tive, this is the best outcome we could $30m up front for the option rights to leb- sale of common stock, although the to- have hoped for.” rikizumab, with the Spanish firm in line to tal could change when Dermira prices CEO Thomas Wiggans asserted that pay $50m to exercise its option with po- the offering. the Phase IIb dataset indicate lebriki- tential milestone and royalty payments to Published online 18 March 2019 Price ‘Anchoring’? Zolgensma And The Art Of Managing Gene Therapy Sticker Shock

CATHY KELLY [email protected]

ovartis AG and AveXis Inc. may be following a well-known antigen receptor T-cell (CAR-T) therapy originally launched at approach to shaping the public’s reception of the price of a list price of $475,000, well below published estimates of as Ntheir upcoming one-time gene therapy for spinal muscu- much as $650,000. lar atrophy, Zolgensma (onasemnogene abeparvovec). Although Novartis/AveXis have not announced a price for Zol- For the first cell and gene therapies, Spark Therapeutics gensma, the companies have publicly suggested a price of up to Inc.’s Luxturna (voretigene neparvovec) and Novartis’ Kymriah $5m could be considered cost effective. (tisagenlecleucel), the approach has included: 1) announcing Analysts are predicting a list price of around $2m, which still a launch price that is notably lower than forecasts; and 2) en- would put Zolgensma in the ranks of the most expensive drugs gaging with payers on novel reimbursement arrangements ever. But it’s a lot less than $5m. that make coverage feasible. Zolgensma is expected to be ap- “The psychological bias they are employing is called ‘anchor- proved in May. ing’ – once they socialize the idea of a very high price as being Spark priced its therapy for inherited blindness at $850,000 ‘worth it’ they will then settle for a lower list price (but not that (for treatment in both eyes) after widespread pre-launch specu- much lower) as being ‘reasonable’,” Boston University’s Rena Conti lation about a $1m price point. And Novartis’ Kymriah chimeric suggested in an email.

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She noted the approach has also been used in the past for ICER has begun to feature the LYG metric more prominently in cancer drugs and “in other luxury markets – most notably its reports to address concerns that use of the QALY alone could art.” Conti is associate research director for biopharma and undervalue treatments that extend length without improving public policy at the Institute for Health System Innovation quality of life. (The estimates in the report are based on a $2m and Policy at BU. “placeholder” price for Zolgensma.) With regard to Spinraza, the report concludes the therapy SUPPORT FOR HIGH PRICE FROM ICER? would require “a substantial discount to meet traditional cost-ef- During its earnings presentation Jan. 30, Novartis said that a $5m fectiveness ranges.” Biogen’s treatment has a list price of $750,000 price for Zolgensma is supported by a recent analysis by the Insti- for the first year and $375,000 per year thereafter. tute for Clinical and Economic Review. AveXis reiterated that position in a statement following an ICER-convened advisory panel NEW REIMBURSEMENT MODELS meeting on the cost effectiveness of Zolgensma and Biogen Inc.’s As with Luxturna and Kymriah, AveXis has been working with pay- Spinraza (nusinersen) March 7. ers on novel reimbursement approaches for Zolgensma. ICER challenges the characterization. While its report notes “Payers are very interested in talking with us about exploring Zolgensma could be value-priced at $5m at a willingness to pay different payment models” including “outcomes-based models to threshold of $500,000 per quality-adjusted life year (QALY), the or- ensure there’s an effective balance between high upfront costs ganization does not believe that threshold would apply to setting and managing the costs and benefits that would come down US prices. the road,” according to AveXis VP Clinical Development Douglas “Our report notes that decisionmakers often give special con- Sproule. siderations for ultra-rare diseases such as SMA, and therefore we Sproule commented on discussions with payers at the March display thresholds that range all the way up to $500,000/QALY,” an 7 meeting, which was held by ICER’s New England Comparative ICER spokesman said in an email. Effectiveness Public Advisory Council. “Our experience, however, is that public and private payers Avexis has been in negotiations with commercial payers in in the US do not typically accept cost-effectiveness thresh- Massachusetts about piloting an annuity payment model for the olds that high as appropriate, even for treatments of ultra- treatment that includes a performance-based component. (Also rare conditions.” see “Annuity Payment Model For Cures May Get Test Drive In Mas- Novartis “has a real opportunity here to demonstrate both sci- sachusetts” - Pink Sheet, 19 Feb, 2019.) entific and ethical leadership by setting the launch price of Zol- However, negotiations are still in the early stages and plans for gensma in line with the benefits patients will likely receive,” the the model may not be finalized in time for the drug’s initial launch. organization said. Sticking points include how to define outcomes and how to avoid ICER concludes that $900,000 would be a value-based price for triggering Medicaid “best price.” Zolgensma in the infantile-onset Type 1 SMA population using “Medicaid is an important issue for all companies in this space,” the traditional US cost effectiveness threshold of $150,000 per Sproule pointed out. “Certainly, we’re working with [the Centers quality-adjusted life year (QALY). for Medicare and Medicaid Services] trying to pilot an effective so- Using a complementary measure of benefit called “life year lution that would be most equitable for the system and allow ap- gained” (LYG), the report suggests that Zolgensma could be propriate flexibility to work with payers to have the most optimal priced up to $1.5m, marking the first time ICER has supported a set of scenarios for payments.” value-based price of more than $1m for a drug. Published online 19 March 2019 Pfizer Buys Option For Vivet In Latest Gene Therapy Tie-Up

JESSICA MERRILL [email protected]

he gene therapy business development space has been ac- The partnership will add a new program advancing toward clin- tive, and Pfizer Inc. is the latest to announce a deal in the re- ical development, VTX-801, a treatment for Wilson disease, a rare Tsearch area with an option to buy the privately-held French and potentially life-threatening liver disorder that causes copper gene therapy developer Vivet Therapeuticss. The companies an- poisoning. A faulty gene in liver cells encoding the ATP7B protein nounced March 20 that Pfizer has acquired a 15% equity stake reduces the ability for the liver to regulate copper levels, causing in Vivet and secured an exclusive license to acquire outstanding severe hepatic and neurological symptoms. shares in exchange for €45m ($51m) up front. There are an estimated 12,000 diagnosed patients undergoing The deal will further expand Pfizer’s footprint in gene therapy, treatment in the EU and US, but there are believed to be as many where it has been building a significant presence, with several as 8,000 undiagnosed patients, according to Pfizer. Also, more than programs now in clinical development. half of patients who are being treated aren’t compliant with their

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big pharma can exercise its option after Phase I/II data for VTX-801 Pfizer has built much of is available. Pfizer VP-Worldwide Business Development Monika its gene therapy pipeline Vnuk will join Vivet’s board of directors. through business development PFIZER’S GROWING GENE THERAPY PIPELINE Pfizer has built much of its gene therapy pipeline through business development. In 2016, the company acquired Bamboo Therapeutics Inc. for $645m, bringing in adeno-associated virus vectors for neuromuscular conditions, including what is now a clinical-stage candidate for Duchenne muscular dystrophy. Data from the first human trial is expected in the first half of 2019. The partnership with Bamboo came about in a similar manner, in that Pfizer initially acquired a 22% stake for $43m and then later the same year acquired the company outright for $150m plus $495m contingent on certain milestones. Pfizer is also partnered with Spark Therapeutics Inc.c. on the development of a gene therapy to deliver the human coagulation medications. Among the drugs approved for treating the condition factor IX gene to liver cells in patients with hemophilia B under are copper chelating therapies including Bausch Health Compa- a 2014 alliance. The program, SPK-9001, is in Phase III develop- nies Inc.’s (formerly Valeant’s) Cuprimine (penicillamine) and Syn- ment, although Spark is in the midst of an ownership transition. prine (trientine), but they are associated with serious adverse events. Big pharma rival Roche announced plans to buy Spark for $4.85bn VTX-801 uses a modified AAV vector to transport a truncated in February. functional version of the ATP7B gene to the liver cells carrying the Under another partnership, Pfizer is developing a hemophilia A defective gene. Pfizer said it expects an investigation new drug gene therapy with Sangamo under a 2017 agreement in which it (IND) application will be filed with the US FDA in the first quar- paid $70m up front. The two partners signed a second agreement ter of 2020, putting off the initiation of a human trial until at least in 2018 for a gene therapy collaboration in amyotrophic lateral some time next year. sclerosis (ALS). Vivet raised €37.5m in a Series A round in 2017, led by Novar- Business development in gene therapy has been booming tis Venture Fund and Columbus Venture Partners and including recently, as many industry observers forecast it would be as Roche Venture Fund, HealthCap, Kurma Partners and Ysios Capital, big players line up to get their foot in the maturing develop- with plans to advance VTX-801 into the clinic. The company has ment area. Roche’s deal for Spark turned out to be a competi- other gene therapy programs in development for other rare liver tive bidding process, according to filings with the Securities & disorders, including programs for progressive familial intrahepatic Exchange Commission. cholestasis type 2 (PFIC2), PFIC3 and citrullinemia type 1. Biogen revealed earlier in March a deal to buy ophthalmology Pfizer could pay up to €560m ($635.8m), including the option gene therapy developer Nightstar for $877m. to acquire Vivet outright, under the companies’ agreement. The Published online 21 March 2019 Biohaven Pays $105m For Turbo Boost In Migraine Drug Review Race

ELEANOR MALONE [email protected]

onnecticut-based Biohaven Phar- maceutical Holding Co. Ltd. has Cpaid $105m for a US FDA priority review voucher that it intends to use in the second quarter of 2019 to speed the regulatory review of its oral migraine candidate rimegepant. Use of the voucher could cut the review period from 10 to six months. Since the use of a voucher to expedite a new drug application requires 90 days’ notice, it would appear that Biohaven intends to file rimegepant in the latter part

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of June 2019. Such a filing would provide dissolving tablet formulation is preferable ceived the PRV when it won approval for for a speedy six-month review of the drug, to tablets that must be taken with water, Epidiolex (cannabidiol) in June 2018 for which is being filed as rimegepant Zydis since migraine patients often experience the treatment of seizures in two rare, se- ODT (orally disintegrating tablet) for the nausea and vomiting. vere, childhood-onset epilepsies, Lennox- acute treatment of migraine. Separately, Eli Lilly & Co.’s lasmiditan, Gastaut syndrome and Dravet syndrome. Biohaven is in a race against Allergan another oral drug candidate for the acute The UK-domiciled firm intends to invest PLC with its similar oral CGRP inhibitor treatment of migraine, was submitted for the $105m proceeds in the commercial ubrogepant. FDA review in the third quarter of 2018. launch of Epidiolex in Europe and the US, On March 13, Biohaven revealed it had Lasmiditan is a serotonin receptor ago- and in advancing its pipeline of cannabi- concluded pre-NDA meetings with the FDA nist that selectively targets 5-HT1F recep- noid product candidates. for both orally dissolving tablet and tablet tors in the trigeminal nerve pathway. An The market value of priority review formulations of rimegepant for the acute approval decision for lasmiditan is likely vouchers has fluctuated since the treatment of migraine, and planned to pro- sometime in October or November 2019. first acquisition in 2014, when Regen- ceed with a filing in the second quarter. Both Allergan and Biohaven are also de- eron Pharmaceuticals Inc. and Sano- Allergan, meanwhile, announced the veloping oral CGRP receptor antagonists fi bought BioMarin Pharmaceutical FDA’s acceptance of its own NDA for ubro- for migraine prevention, but Allergan is Inc.’s for $67.5m, still the lowest price gepant to treat acute migraine on March 11. more advanced as its atogepant is in Phase on record. The highest price paid was Ubrogepant is subject to a standard III while Biohaven plans to complete enrol- $350m, paid by AbbVie Inc. to United 10-month review period with a PDUFA ment in its Phase III trial of rimegepant for Therapeutics Corp. in 2015. date in the fourth quarter of 2019. Rimege- migraine prevention in the second quarter Details of such purchases are not always pant’s submission before the end of June of 2019, and begin a Phase II/III trial of its disclosed: Novo Nordisk AS, for example, could would potentially mean it would re- third-generation CGRP-receptor antago- recently revealed that it had booked the ceive approval in the first quarter of 2020, nist BHV-3500 in the first quarter of 2019. purchase of a PRV in fourth-quarter ac- since the six-month review period would The firms are hot on the heels of a raft of counts, to expedite the filing for its oral take effect after the 60-day filing date. recently approved injectable monoclonal GLP-1 analogue semaglutide, but it did While Allergan has talked up the lack antibody migraine prevention products not disclose the source of the voucher, nor of hepatic side effects in trials of ubroge- also targeting calcitonin gene-related the price paid. However, since 2016 the pant, something which has hampered peptide from Amgen Inc./Novartis AG going rate appears to have stabilized at previous attempts to develop oral CGRP (Aimovig/erenumab), Teva Pharmaceuti- around $100-130m, with the odd outlier. inhibitors, Biohaven has been emphasiz- cal Industries Ltd. (Ajovy/fremanezumab) Lilly managed to pick one up for $80m in ing the speed of onset of its fast-dissolv- and Lilly (Emgality/galcanezumab). November 2018, acquiring that obtained ing tablet and its long durability, claiming by Siga Technologies Inc. under the ma- that ubrogepant’s four-hour half-life com- VOUCHER MARKET terial threat medical countermeasure pro- pares unfavorably to rimegepant’s 8-12 Biohaven’s priority review voucher was gram in July 2018 with the approval of its hours. It has also talked up the fact that apparently purchased from GW Pharma- oral smallpox treatment. And Teva paid up patients treated with Zydis ODT had not ceuticals PLC, which was awarded the to $150m for a PRV in 2017, which it sub- required rescue medications or a second voucher under the FDA’s incentive pro- sequently used to expedite the approval dose, unlike ubrogepant in its Phase III gram for the development of treatments of Ajovy. program. Biohaven also believes the orally for rare pediatric diseases. GW Pharma re- Published online 21 March 2019 Cancer, Rare Disease Drugs To Be Covered As China Expands Reimbursement

BRIAN YANG [email protected]

harmaceuticals that have gained ap- Outlined in the 2019 National Health- ly to currently listed drugs, meaning that provals before Dec. 31, 2018 will be care Product coverage adjustment work the inclusion will not impact the bottom Psubject to consideration for a new plans, released by the country’s Medical line of the existing medical insurance expansion of China’s National Reimburse- Insurance and Support Administration funding pool. ment Drug List (NRDL), with priority to be (MISA), the reimbursement of the prod- The other category will be high-priced given to national essential drugs, cancer ucts will be divided into two categories products, which must go through the na- and rare disease medicines, treatments for under the list. tional price negotiation system to have chronic disorders, pediatric medications One is direct inclusion, comprising their prices lowered before they can be and urgent care products. regular products priced lower or similar- included in the NRDL.

LARGE EXPERT POOL will be divided into five phases -prepara- expansion as opening market access for To ensure a fair process, the NRDL inclu- tion, evaluation and voting, release of direct such firms. sion procedure will involve tens of thou- inclusion products, negotiations, and re- Some oncology products that are sands of experts in roles ranging from lease of the inclusion of high-priced drugs. likely to be included are: Roche’s lung consultants to selection committee mem- The preparation period will be the first cancer drug Alecensa (alectinib; li- bers, health technical assessment experts three months in 2019, requiring the selec- censed from Chugai Pharmaceutical and other negotiators. tion of the experts and setup of product da- Co. Ltd.), for anaplastic lymphoma ki- Among these, 300 will serve as consul- tabases. From April to May, the consulting nase-positive disease, Hutchison Me- tants to compile a comprehensive list of experts will compile candidate products, diPharma Ltd.’s Elunate (fruquintinib) the drugs for the initial selection process. and the 20,000 selection experts brought for colorectal cancer, and Eisai Co. After that, 20,000 experts from different together from different levels of hospitals Ltd.’s Lenvima (lenvatinib) for patients provinces and local hospitals will vote to in two-thirds of China’s 31 provinces. with inoperable hepatocellular carci- select which final products to include in Meanwhile, the consulting experts will noma who have not received any prior the NRDL. finalize the products to be included in the systemic therapy. Also, the state medical insurance agen- direct inclusion list and release the list in Domestic maker Jiangsu Hengrui cy plans to involve 30 insurance experts June. Also, consulting experts will decide Medicine Co. Ltd. has its TKI inhibitor Iru- and health technology assessment (HTA) on high-priced products that are subject ini (pyrotinib), indicated for breast cancer analysts to evaluate the cost-effective- to price negotiations, and send negotia- patients with HER2 and EGFR mutations, ness of the products and impact on in- tion requests to manufacturers. and Tianqing Chiatai Pharma’s Fuke- surance funding. Especially for the high- These discussions then kick off in July wei (anlotinib) is for lung cancer. priced drugs, past price negotiations and the final list will be released in August. Rare disease treatments could in- have seen price reductions on average Expanding patient access to innovative clude: Roche’s Hemlibra (emicizum- exceeding 50%. new drugs has been a top priority for the ab; licensed from Chugai) for hemo- For the drug price negotiation rounds, reimbursement agency, as well as one of philia, and Alexion Pharmaceuticals an unspecified number of negotiators se- the top catalysts for the development of Inc.’s Soliris (eculizumab) for parox- lected from the local and central medical the healthcare sector in China in the years ysmal nocturnal hemoglobinuria and reimbursement agencies and outside ex- to come. atypical hemolytic uremic syndrome, perts will work to oversee the negotiation as well as Actelion Pharmaceuticals process with the drug makers. WHO WILL BENEFIT? Ltd.’s Uptravi (selexipag) for pulmonary Despite the large expert pool required Since many newer oncology and rare dis- hypertension. for the NRDL expansion process, the time- eases treatments are imported by multi- Published online 15 March 2019 frame is quite tight. The whole procedure nationals, many see the NRDL coverage From the editors of PharmAsia News. What Brexit Effect? UK Biotech Start-Ups Reach Record Numbers

JO SHORTHOUSE [email protected]

espite the uncertainty over the New analysis from investment man- as well as allowing more accurate diagno- UK’s withdrawal from the Euro- ager Downing LLP suggests that 44% of sis and treatment of patient populations. Dpean Union, the number of new the total number of active biotechnology “This combination of data-driven technol- British biotechnology companies has businesses have been incorporated in ogy and healthcare also means that the soared by 65% in the last three years, and the past three years, since January 2016. pool of capital is expanding with technol- investment in the industry has reached This includes 127 in the first two months ogy funds and companies now targeting new highs. of 2019, which is the equivalent to three the healthcare sector,” he said. Official data from Companies House, every working day during January and The uncertainties of the UK’s withdraw- the UK executive agency that incorpo- February 2019. al from the European Union is clearly not rates and dissolves limited companies, One reason for this is the growth in having an impact on the confidence of show that there are 3,456 active compa- genomic and data-driven science, Will UK biotech companies to raise capital, or nies currently involved in biotech R&D Brooks, investment director at Downing to recruit employees with the right skills activities. This represents a 65% increase told Scrip, which allows more powerful from the EU. from Q1 2016, when 2,095 active com- data and computation to improve the “The government has been very proac- panies were classed as engaging in the drug development path and in doing so tive with investment in R&D spending to same activity. decreases time and cost of development, support any EU shortfall, although how

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long this may last is uncertain,” said Brooks. “There has been a lot of investment both in new funding, but also in incubators and research parks that help offset costs.” Uncertainty over EU funding such as Horizon 2020 had caused some grant funds to drop off, he said. “Traditionally, the UK has not had high levels of EU investment from venture capital and so, while some funding sources may be cautious in the short term, UK-based companies should still continue to attract investment.” London is the lead location in Britain’s biotech Echoing global trends, in which the biotech sector raised Golden Triangle $23bn in venture capital in 2018, data from the BioIndustry As- sociation (BIA) and Informa Pharma Intelligence’s report Confi- dent capital: backing UK biotech show that the UK claimed a new high of £2.2bn from investors in 2018, up by 85% from 2017. Venture capital has contributed 51% of UK biotech funding from 2016-2018, increasing by 63% from £681m in 2016 to £1.1bn in 2018. (Also see “Biotech Sector Raises $23bn In Venture Capital In to 42. BIA figures show that IPOs contributed 15% of funds raised 2018” - Scrip, 3 Jan, 2019.) by UK biotech companies from 2016-2017, increasing to 20% in Steve Bates, CEO of the BIA, told Scrip: “Our finance report shows 2018, when over £1bn was raised on public markets: £432m in ini- that the UK life sciences sector is thriving and remains attractive tial public offerings and £658m in all other public financing. to investors. This further good news shows that companies feel confident starting their business in the UK and that infrastructure THE GOLDEN TRIANGLE remains strong. Over one-third of all biotech companies are now headquartered “2018 was a record year for investment in the UK life science in the ‘Golden Triangle’ of UK innovation: London, Oxford and ecosystem and despite the uncertainty of Brexit it’s clear that the Cambridge. The number of biotech R&D businesses based in the Government’s Industrial Strategy and Life Sciences Sector Deal is capital has increased by 120% over the last three years, and it now moving our sector forward.” plays host to nearly one in four registered businesses, compared Brooks dampens the idea that this rate of funding is a bubble to fewer than one in five in 2016. that will burst shortly after Brexit is complete. Once the terms of the Cambridge ranks second after London with 7.5% of biotech Brexit withdrawal deal are understood, in whatever form it takes, he businesses located there in Q1 2019, followed by Oxford with expects funding of the British biopharma industry to continue at 2.3% – the city’s biotech business population has increased by its current rate, due to confidence in the “underlying technology”. 95% in just over three years. While private limited companies still make up a large chunk of Outside of the Golden Triangle, Nottingham and Manchester active businesses in the biotech sector – 96% – Downing’s analysis continue to make up the top five UK locations for biotech R&D shows the number of public limited companies has grown from 30 activities. Published online 21 March 2019 Merck KGaA: China E-Health Push A ‘Long-Term Strategy’ STEN STOVALL [email protected]

erck KGaA aims to position itself compliance for allergy sufferers. “China is a as a key player in China’s evolv- market I know quite well and I think what Ming digital healthcare system is often underappreciated is the sheer lev- and will use recently established alliances el of digital progress that China has made with Chinese internet giants Tencent and in its internal markets,” Chris Round said in Alibaba Health to do so, the German an interview. group’s head of international operations He said there was huge healthcare told Scrip. potential in Tencent’s WeChat platform, which offers text messaging, CHINA’S E-HEALTHCARE voice messaging, voice and video calls ‘EVOLVING FAST’ in China. Merck KGaA, which has a strategic inter- “WeChat is very widely used in China, est in chronic diseases in China, tied up perhaps by as many as 700 million Chi- with Tencent in January to explore digital nese citizens. They are using it as a form services aimed at raising awareness of al- of communication which often gets Chris Round lergic disorders and improve treatment used in group discussions and as a plat-

form for online payments and online commerce,” explained while generating consistent value for patients through a series of Round. “We’ve linked up with Tencent after trying to see if add-on services. there are ways that we can provide targeted information – in a The two companies will also explore online healthcare service compliant and appropriate way that’s not branded – to various applications, direct-to-patient models as well as artificial intelli- groups in the Chinese healthcare system, and we’re exploring gence enabled healthcare applications. opportunities for Tencent’s platform and our commercial and medical teams to come together and to figure out ways that “We’re exploring opportunities we can help support the roll-out of healthcare in China and the evolution of healthcare there.” for Tencent’s platform and our Tencent, which launched a major strategic upgrade in 2018, is now actively embracing the so-called industrial internet in commercial and medical teams China, with the healthcare field being an important focus. to come together and to figure “We’ve got some really clear, defined, concrete proposals at this stage. It’s a long-term collaboration and we’re explor- out ways that we can help ing all sorts of opportunities,” Round said. He declined to say what those proposals were, however, saying that would be support the roll-out of healthcare premature. Round has responsibility for Merck Group’s international busi- in China and the evolution of nesses, comprising China, APAC, EMEA and LATAM, a role he healthcare there.” took on under a regrouping of the family-controlled German conglomerate’s healthcare executive committee last summer. “As the environment in China gets more connected it will also Asked if a similar digital health approach could be taken in oth- become increasingly interesting what opportunities lie in the er developing regions of the world, such as Latin America, Round big databases and how they can lead to effective interaction – replied: “It’s a great idea. We would be open to taking this ap- with physicians, with patients, with payers or with others.” proach in other developing areas in theory once they are capable Merck KGaA is also developing a strategic business collabora- of doing so.” tion with Chinese internet healthcare company Alibaba Health, to He explained: “Some of the principles such as how can one provide Chinese patients and their families with improved access more efficiently use technology to communicate and disseminate to patient-centric healthcare services. the products would, in principle, be possible. But WeChat as a The collaboration will focus on the areas of drug track-and-trace platform is somewhat unique to China. We could look for ways to and internet health services, and to jointly explore areas such as replicate those aims and ambitions but essentially we’re just try- pharmaceutical e-commerce and artificial intelligence. ing to do what we’ve done in the past, but just more efficiently The collaboration will start with Alibaba Health’s drug tracking using technologies that may open up new opportunities for us as platform, combining Merck’s expertise in diabetes, thyroid dis- we move forward.” orders and cardiovascular diseases with Alibaba Health’s online healthcare services to help ensure safety and security of drug use, Published online 19 March 2019 Celgene/Bristol’s Revlimid Patent Risk Incrementally Lower After PTAB Denies Alvogen IPR

MANDY JACKSON [email protected]

he final request for aninter partes to eventually replace the loss of Revlimid’s single limited competitor in 2022 was re- review (IPR) of a Celgene Corp. Rev- blockbuster revenue stream, as an April 12 duced by the PTAB’s decision regarding T limid (lenalidomide) patent by the shareholder vote on the Celgene deal ap- an IPR sought by Alvogen Inc. The PTAB US Patent and Trademark Office (USPTO) proaches. Regardless, shareholders can’t said it was unlikely that the generic drug Patent Trial and Appeal Board (PTAB) was get over the fact that the multiple myelo- maker would prevail on at least one of the denied March 14, somewhat reducing ma drug, which will continue to account claims in a review of the 7,968,569 patent, the intellectual property risk associated for about two-thirds of Celgene’s revenue which covers administration of Revlimid with Bristol-Myers Squibb Co.’s pending for at least another year or two, will be- in combination therapy regimens to treat $74bn acquisition of the company. gin to face generic competition in the US relapsed multiple myeloma. Bristol-Myers has tried to keep inves- starting in 2022. Bernstein analyst Ronny Gal said in a tors focused on Celgene’s research and However, the risk of multiple Revlimid March 14 note that this was the last of the development pipeline, which is designed generics hitting the market before a TURN TO PAGE 23 scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 21 Pipeline Watch - March 15-21, 2019 Phase II

Lead Change To LOA Event Stage Drug Name Indication Comments Company/Partner LOA (%) (%) Phase II Recurrent Updated Regeneron Arcalyst (rilonacept) Signs Of E�cacy 0 59 Pericarditis Results Phase II Hypertrophic PIONEER-OLE; Updated MyoKardia, Inc. mavacamten 0 52 Cardiomyopathy Positive Results Results Phase II omecamtiv mecarbil Congestive Heart COSMIC-HF; Updated Amgen, Inc. 0 49 (oral) Failure Encouraging Signs Results Phase IIa PROLONG; Signs Of Updated ObsEva SA OBE022 Preterm Labor 0 24 E�cacy Results Phase I/II w/ Paclitaxel; Updated VBL Therapeutics VB-111 gene therapy Ovarian Cancer 0 35 Immune Responses Results Phase I/II bimatoprost Extended Duration Of Updated Allergan plc Glaucoma 0 59 sustained release IOP Control Results Phase IIa Top- NasoVAX Intranasal ALT-103-201; Durable Altimmune, Inc. Pandemic In�uenza 0 27 Line Results Vaccine Responses Phase IIb Top- Aerpio TIME-2b; Missed AKB-9778 Diabetic Retinopathy -24 0 Line Results Therapeutics, Inc. Endpoints Phase IIb Top- Dermira Inc. lebrikizumab Atopic Dermatitis Positive Results 4 27 Line Results Phase IIb Top- Non-Alcoholic ENCORE-NF; Mixed Novartis AG emricasan -15 10 Line Results Steatohepatitis Results Phase IIb Top- Diabetes Mellitus, DPO-203; Signs Of Opko Health OPK-88003 0 21 Line Results Type II. Obesity E�cacy Phase II Top- Puma Cervical Cancer, w/fulvestrant; Nerlynx (neratinib) 1 11 Line Results Biotechnology, Inc. HER2-Mutant Durable Responses Phase II Top- Trizell Ltd. TR002 gene therapy Mesothelioma Positive Results 10 Line Results Phase II Top- Leap Therapeutics, DKN-01 Ovarian Cancer Partial Responses 0 10 Line Results Inc. Phase II MorphoSys/I-Mab w/Dexamethasone; In MOR202 Multiple Myeloma 0 0 Initiation Biopharma Taiwan Phase II OncBioMune vs. Active ProscaVax vaccine Prostate Cancer 4 10 Initiation Pharmaceuticals Surveillance Aerie AR-1105 Phase II Following Retinal Pharmaceuticals, (dexamethasone Macular Edema 24 24 Initiation Vein Occlusion Inc. implant) Phase II Taiwan Liposome TLC590 (ropivacaine) Following Postsurgical Pain 0 21 Initiation Company liposomes Bunionectomy Phase II NCX 4251 Blepharitis Nicox S.A. Dose Finding 24 24 Initiation (�uticasone) Exacerbations Aerie Phase II Rhopressa Pharmaceuticals, Glaucoma CS208; In Japan 0 100 Initiation (netarsudil) Inc. Phase II 6019-202; In Severe Alkahest/Grifols GRF6019 Alzheimer's Disease 0 17 Initiation Disease Phase IIa Xermelo (telotristat TELE-ABC; In various Lexicon/Ipsen Biliary Tract Cancer 10 10 Initiation ethyl) combinations PIPELINEPhase IIa WATCHDURECT Proof-of-Concept DUR-928 Psoriasis 6 20 Initiation Corporation Study Phase IIa Innovent Biologics, IBI306 Dyslipidemia Conducted In China 0 0 Scrip’sInitiation weekly PipelineInc. Watch tabulates the most recently reported late-stage clinical trial and regulatory developments from the more Click here for the entire pipeline Phase I/II GlaxoSmithKline DREAMM 4; Positivewith added commentary: than 10,000 drug candidates currentlyGSK2857916 under active research Multiple worldwide. Myeloma 0 14 Initiation plc Results http://bit.ly/2mx4jY3 Phase III PIPELINE WATCH, 15–21 MARCH 2019 Search

Change Lead LOA Event Stage Drug Name Indication Comments To LOA Company/Partner (%) (%) Phase III Amarin Corporation Vascepa (icosapent Cardiovascular REDUCE-IT; Journal of the Published 0 51 plc ethyl) Disease American College of Results Cardiology, March 18, 2019 Phase III DECLARE-TIMI58 (CV AstraZeneca/Bristol- Farxiga Diabetes Published Events); Circulation, March 0 100 Myers Squibb (dapagli�ozin) Mellitus, Type II Results 18, 2019 Phase III TRANSPARENCY; Jeuveau Published Evolus, Inc. Wrinkles Dermatologic Surgery, March 0 100 (prabotulinumtoxinA) Results 21, 2019 Phase III Alzheimer's Biogen/Eisai aducanumab ENGAGE, EMERGE; Unlikely -35 19 Discontinuation Disease To Meet Primary Endpoint Leber's Phase III GenSight Biologics Hereditary REVERSE; Durable Updated GS010 0 45 S.A. Optic Responses Results Neuropathy Phase III Esperion CLEAR Wisdom; Met Updated bempedoic acid Dyslipidemia 0 84 Therapeutics, Inc. Endpoints Results Phase III Samsung Ontruzant Biosimilar, Similar E�cacy To Updated Breast Cancer 0 100 Bioepis/Merck & Co (trastuzumab) Reference Results Phase II/III Repatha TAUSSIG; Long-Term Safety Updated Amgen, Inc. Dyslipidemia 0 100 (evolocumab) Con�rmed Results Phase IIIb Top- Tecentriq Roche Holding AG Bladder Cancer SAUL; Safety Con�rmed 0 100 Line Results (atezolizumab) Stroke Phase IIIb Top- Daiichi Sankyo Co., Prevention in ELIMINATE-AF; Positive Savaysa (edoxaban) 0 100 Line Results Ltd. Atrial Results Fibrillation Phase III Top- Ameluz (5- Actinic w/BF-RhodoLED; Met Biofrontera AG 0 100 Line Results aminolevulinic acid) Keratoses Primary Endpoint Doria (risperidone Phase III Top- Farmacéuticos Rovi, ISM), once-monthly Schizophrenia PRISMA-3; Met Endpoints 2 53 Line Results S.A. Inj. Phase III Top- Urovant Sciences, Overactive vibegron EMPOWUR; Met Co-Primary 1 67 Line Results Inc. Bladder Endpoints Phase III Top- Venclexta Multiple BELLINI; Mixed Results, AbbVie/Roche -3 34 Line Results (venetoclax) Myeloma Clinical Hold Source: Biomedtracker | Informa, 2019 Phase III Emergent Anthrax NuThrax vaccine VELOCITY; Post-Exposure 34 61 Initiation BioSolutions, Inc. Prophylaxis 22Phase | Scrip III | 29 March 2019 Malignant Pleural © Informa UK Ltd 2019 Trizell Ltd. TR002 gene therapy Mesothelioma 25 35 Initiation Mesothelioma Phase III Repatha Dyslipidemia, In Amgen, Inc. VESALIUS-CV; Long-Term 0 100 Announcement (evolocumab) High CV Risk Outcomes Study Phase III Xynomic Renal Cell abexinostat RENAVIV (w/pazopanib) 0 35 Announcement Pharmaceuticals Cancer Approvals

EventType Lead Company Drug Name Indication Market Comments Zulresso In Adult Approval SAGE Therapeutics Post-Partum Depression US (brexanolone) Women Nerlynx Australia/New Adjuvant Approval Puma Biotechnology, Inc. Breast Cancer (neratinib) Zealand Therapy Sunosi Approval Jazz Pharmaceuticals plc Narcolepsy, Sleep Apnea US In Adults (solriamfetol) Iluvien Intravitreal Approval Alimera Sciences, Inc. (�uocinolone Diabetic Macular Edema Kuwait Implant acetonide) International Paroxysmal Nocturnal Elizaria Russian Approval Biotechnology Center Hemoglobinuria, Hemolytic Uremic Biosimilar (eculizumab) Federation (IBC) Generium Syndrome Approval for Tecentriq With Roche Holding AG Small Cell Lung Cancer, First-Line US sNDA/sBLA (atezolizumab) Chemotherapy Supplemental Rituxan First Biologic Roche Holding AG Pemphigus Vulgaris EU Approval (rituximab) Therapy Supplemental Praluent Reducing CV Events In In Established Regeneron/Sano� EU Approval (alirocumab) Dyslipidemia CV Disease

Source = Biomedtracker; LOA = Biomedtracker's opinion on likelihood of approval. M&A

CONTINUED FROM PAGE 21 ent (before 2023). 2) As the same argu- 2018, which was 63% of Celgene’s total outstanding IPR requests related to Rev- ments will presumably be presented at revenue of $15.28bn last year. limid, so its denial gives a little more as- trial, odds of eventual win by Celgene The company insists that Revlimid rev- surance that an additional generic launch are higher.” enue will continue to grow by double before 2023 is unlikely. The PTAB also “Critically,” he continued, “a quick read of digits annually at least through 2022, denied an IPR request in February from the IPR shows the IPR decision was made when Natco Pharma Ltd. and partner Dr. Reddy’s Laboratories Ltd. related to on the merits, i.e. the judges considered Teva Pharmaceutical Industries Ltd. are a Revlimid patent for treating myelodys- the evidence presented by Alvogen and allowed under a 2015 US patent litiga- plastic syndrome (MDS). found it insufficient to meet the minimal tion settlement to begin a limited gener- However, patent uncertainty is far threshold for review. This view (by judges ic Revlimid launch. Full generic market from erased in the US with the denial with background in the field) will have entry in the US isn’t expected until 2026. of these IPR attempts. Celgene has weight before the court.” Alvogen recently claimed a lead in multiple lawsuits pending against ge- the race to bring generics to the Eu- nerics companies that filed abbrevi- BILLIONS IN REVLIMID SALES ropean market with the first launch of ated new drug applications (ANDAs) AT STAKE Revlimid generics in Europe in Febru- with the US FDA seeking approval for What’s at stake if Celgene loses in any of ary, but this occurred in small markets – Revlimid copies. these cases is billions of dollars in sales Central and Eastern European markets, These cases will take a few more and a majority of the company’s revenue, including Romania, Croatia, Bulgaria years to work their way through the tri- which will take years to rebuild through and the Baltic states. al and appeal process unless Celgene sales of new products. None of these are Bernstein’s Gal sees US sales peaking at enters into settlement agreements guaranteed to be approved or to quickly $11.76bn in 2023 assuming no generics with its competitors, including Alvo- become big sellers. other than a Natco-Teva product launch gen and Dr. Reddy’s, the latter of which That’s why investors in both Cel- before 2027. is the plaintiff in the most advanced of gene and Bristol want to make sure, Published online 14 March 2019 these lawsuits. if the companies’ transaction closes in Even so, Gal said in his note that the the third quarter as anticipated, the benefit of the PTAB denial of Alvogen’s merged entity will be able to hold on To read this story in full IPR request “is two-fold: 1) the decision to as much Revlimid revenue as they please go to: closes the loop one of the two potential can for as long as possible. Revlimid https://bit.ly/2JJxLWu venues to invalidate the Revlimid pat- generated global sales of $9.69bn in Company Move APPOINTMENTS Search

Effective Executive To Company New Role From Company Previous Role Date Joachim BlueRock Senior Vice President, Clinical Chief Development O�cer Bioverativ 18-Mar-19 Fruebis Therapeutics Development Bryan Impax Senior Vice President and Mallinckrodt plc Chief Financial O�cer 18-Mar-19 Reasons Laboratories Chief Financial O�cer NGM Hsiao D. Chief Medical O�cer and Vice President, Early Clinical Biopharmaceuticals Genentech 20-Mar-19 Lieu Senior Vice President Development Inc Orchard Vice President, Development Ran Zheng Chief Technical O�cer Amgen 18-Mar-19 Therapeutics Supply Chain Martin B. Recursion Pfenex Inc Chief Scienti�c O�cer Chief Scienti�c O�cer 18-Mar-19 Brenner Pharmaceuticals John Atlantic President, US and Chief RDD Pharma Ltd Chief Executive O�cer 20-Mar-19 Temperato Healthcare plc Operating O�cer Andrew Chief Corporate Development Tilray Goldman Sachs Managing Director 13-Mar-19 Pucher O�cer

ClickPr hereom for allo appointments:tion https://bit.ly/2oHWRYn Source: Medtrack | Informa, 2019

Search scrip.pharmaintelligence.informa.com 29 March 2019 | Scrip | 23 Effective Executive To Company New Role Previous Role Date Philipp Allergopharma Chief Executive O�cer Chief Operating O�cer 1-Mar-19 Maerz GmbH & Co KG Marc Chief Financial O�cer and Head, Senior Vice President, Head, Strategy, ArQule 29-Mar-19 Schegerin Strategy Finance and Communications Joshua Callitas Vice President, Sales and Business Director, Sales and Marketing, Callitas 12-Mar-19 Maurice Therapeutics Inc Development Health Inc NGM Alex Chief Translational O�cer and Biopharmaceuticals Chief Medical O�cer and Vice President 20-Mar-19 DePaoli Senior Vice President Inc Yasuyushi Corporate O�cer, Senior Vice Shionogi & Co Ltd Vice President, Formulation R&D Center 31-Mar-19 Isou President, CMC R&D Division Jonathan Tyme Technologies Chief Business O�cer Chief Scienti�c Affairs O�cer 15-Mar-19 Eckard Inc Michele Tyme Technologies Chief Operating O�cer Chief Commercial O�cer 15-Mar-19 Kor�n Inc Director

Executive To Company New Role Effective Date Karen Smith Antares Pharma Director 4-Mar-19 Geoffrey A. Block Ardelyx Inc Director 14-Mar-19 Pierre Legault Bicycle Therapeutics Ltd Chairman 18-Mar-19 Christine Holman Blackmores Non-Executive Director 18-Mar-19 Rebecca Taub BriaCell Therapeutics Corp Director 18-Mar-19 Vaughn C. Embro-Pantalony BriaCell Therapeutics Corp Director 18-Mar-19 Ron Smith Covalon Technologies Ltd Director and Chairman, Audit Committee 18-Mar-19 Andrea J. Goldsmith Medtronic plc Independent Director 11-Mar-19 Raymond Schinazi Precision BioSciences Inc Director 14-Mar-19 Cynthia Smith Spero Therapeutics Director 19-Mar-19 Advisor

Executive To Company New Role Effective Date Gordon H Williams Cereno Scienti�c AB Scienti�c Advisory Board Member 11-Mar-19 Stefanie Johns Hoth Therapeutics Inc Scienti�c Advisory Board Member 19-Mar-19 Jeffrey H. Kordower Inhibikase Therapeutics Inc Scienti�c Advisory Board Member 19-Mar-19 Kenneth Marek Inhibikase Therapeutics Inc Scienti�c Advisory Board Member 19-Mar-19 Martin Tallman Moleculin Biotech Inc Scienti�c Advisory Board Member 18-Mar-19 Joshua Dunaief Mperia Therapeutics Inc Clinical Advisory Board Member 18-Mar-19 John Singerling, III Nephron Pharmaceuticals Corp Senior Advisory Board Member 12-Mar-19 Timothy M. Wright Regulus Therapeutics Scienti�c Advisor 15-Mar-19 Other

Effective Move Executive From Company Previous Role Date Type Allergopharma GmbH & Co Marco Linari Chief Executive O�cer 1-Mar-19 Resignation KG Chief Financial O�cer, Treasurer and Joseph M. Warusz Alliqua BioMedical Inc 18-Mar-19 Resignation Secretary Koert Arbutus Biopharma Corp Chief Accounting O�cer 31-Mar-19 Resignation VandenEnden Ignacio Faus Mologen AG Chairman and Chief Executive O�cer 31-Mar-19 Resignation Stewart Craig Orchard Therapeutics Chief Manufacturing O�cer 18-Mar-19 Resignation Douglas Pagan Paratek Pharmaceuticals Inc Chief Financial O�cer 5-Apr-19 Resignation Jason Laufer RDD Pharma Ltd Chief Executive O�cer 20-Mar-19 Resignation Cyril Allouche Revance Head, Finance and Corporate Controller 22-Mar-19 Resignation Chief Operating O�cer, Co-Founder, and Michael Demurjian Tyme Technologies Inc 15-Mar-19 Retirement Director

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