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Phase III APOLLO results finally give the beleagured firm the first late-stage success for an RNAi thereapeutic and potentially a strong lead in the rare hereditary disease. 





Alnylam Pharmaceuticals Inc. finally reached the event the company and its investors had been waiting for – the receipt of positive Phase III data for its RNAi candidate patisiran in transthyretin-modulated amyloidosis polyneuropathy – and the company as well as its shareholders greeted it exuberantly.



Alnylam CEO John Maraganore said during a Sept. 20 call to unveil the APOLLO study's top-line results that, “Frankly, we could not have dreamed for a better outcome here.” Patisiran met the primary endpoint, a key secondary endpoint and five other secondary endpoints by resounding margins over placebo, potentially ameliorating a pair of recent setbacks with other closely-watched drug candidates revusiran and fitusiran. Alnylam's share price posted a 51.7% increase to close at $113.84 as investors signaled their support and relief.



The Cambridge, Mass.-based biotech plans to file a new drug application (NDA) with the US FDA by the end of 2017 and hopes to bring patisiran to the European Medicines Agency early in 2018. Alnylam is developing the drug with Sanofi, which will prepare regulatory filings for patisiran in Japan, Brazil and other countries during the first half of next year. Pending approvals, Alnylam will market and sell patisiran in the US, Canada and Western Europe, with the French pharma holding rest-of-world commercial rights. [See Deal]



A day like this might have seemed never to arrive to Maraganore and his team after the biotech had to abandon then-lead candidate revusiran due to an imbalance of deaths in a Phase III trial in hereditary ATTR amyloidosis with cardiomyopathy last October. (Also see "Alnylam's 'Day After' Revusiran Failure Bad, Maybe Not Catastrophic" - Scrip, 6 Oct, 2016.) Exacerbating that setback was the news on Sept. 7 that ongoing studies of Alnylam’s hemophilia candidate fitusiran were suspended temporarily due to a death for unknown reasons in a Phase II trial. (Also see "Alnylam Hopes To Resume Fitusiran Dosing Quickly, Despite Unclear Cause Of Trial Death" - Scrip, 7 Sep, 2017.)



In both instances, market analysts cited reasons why there should not be read-through to Alnylam’s overall pipeline or the larger RNA-interference modality, but questions and doubts hung in the air nevertheless. Now, Alnylam not only has its first successful Phase III data, it appears to hold a significant edge in TTR-modulated amyloidosis polyneuropathy as competitor Ionis Pharmaceuticals Inc.'s drug inotersen met both primary endpoints in a Phase II/III study in May, but with significant safety concerns. (Also see "Ionis Touts Inotersen's Convenience As Phase III Safety Data Disappoints" - Scrip, 15 May, 2017.) GlaxoSmithKline PLC opted out of its partnership with Ionis pertaining to inotersen and another candidate a few months later. (Also see "Deal Watch: GSK Declines Option As Ionis' Inotersen Nears Finish Line" - Scrip, 11 Aug, 2017.)



With the reveal of the APOLLO data, Biomedtracker increased patisiran’s likelihood of US approval by 15 percentage points to 76%, which is 14 points higher than average for a Phase III candidate in this indication, while inotersen’s odds were downgraded four points to 58% after the May data release.



Jefferies analyst Eun Yang said in a Sept. 20 note that with both drugs on similar timelines to approval, roughly in mid-2018, Ionis may need to find a new partner for inotersen to compete effectively with Alnylam and Sanofi.



JMP analyst Michael King, meanwhile, illustrated the growing enthusiasm for Alnylam with the APOLLO data’s unveiling. He reiterated a “market outperform” rating for Alnylam shares in a same-day note, raised his price target from $101 per share to $128 and wrote that “patisiran’s success in APOLLO significantly de-risks the other assets in the company’s pipeline.”



Safety Data Offer Encouragement For RNAi Overall


While the efficacy evidence is essential, the safety data for patisiran are also important reassurance. After the revusiran shutdown and the questions surrounding fitusiran, Alnylam was able to report that in APOLLO, the treatment and placebo arms showed similar frequency of adverse events (96.6% versus 97.4%) and of serious adverse events (36.5% versus 40.3%). Deaths occurred less frequently among patients receiving patisiran (4.7%) than in the placebo arm (7.8%).



Perhaps most notable were the sizeable differences in treatment discontinuations between the arms. The overall discontinuation rate was 7.4% in the treatment arm and 37.7% in the placebo arm. For discontinuations due to adverse events, the rates were 4.7% and 14.3%, respectively.



“As we go through the safety data, the serious adverse events, the deaths, the discontinuations from treatment and the discontinuations from treatment due to adverse events were all lower for patisiran relative to placebo, and I think that’s very encouraging for the overall tolerability profile of patisiran,” Akshay Vaishnaw, Alnylam’s senior VP for R&D, told Scrip.



The combination of the efficacy and safety data point to best-in-class treatment potential for patisiran, added JMP analyst King. “Beyond the statistically significant changes in APOLLO’s primary endpoint, which demonstrate that patisiran can not only halt, but also reverse disease progression, patisiran’s safety profile is very encouraging,” he said.



When it detailed Phase II open-label extension data with patisiran in April, Alnylam asserted that the findings suggested the drug could improve sensation and possibly even regenerate nerve tissue. (Also see "Alnylam Plays Up Patisiran As Polyneuropathy Drug Nears Filings" - Scrip, 26 Apr, 2017.) The biotech only unveiled top-line Phase III data on Sept. 20, saying that it will release the full dataset this November at the first European ATTR Amyloidosis Meeting for Patients and Doctors in Paris. With 225 patients randomized two-to-one patisiran to placebo, APOLLO is the largest randomized study ever completed in this indication, Alnylam said, and nearly all eligible patients who completed the study have rolled over to an APOLLO open-label extension trial.



APOLLO dosed patisiran at 0.3 mg/kg once every three weeks for 18 months at 44 sites in 19 countries. For the primary endpoint, change from baseline in the modified neuropathy impairment score (mNIS+7) at 18 months, the study drug yielded mean and median changes in this score at negative values compared to placebo; declining scores indicate improvements for patients, and in this case the results show an improvement overall and in the majority of patients. In the key secondary endpoint, patients reported improved quality of life based on Norfolk Quality of Life Questionnaire-Diabetic Neuropathy.



Patisiran also achieved statistical significance compared to placebo on five secondary endpoints measuring muscle strength, the Rasch-built Overall Disability Score measuring daily living and disability, a 10-meter walk test, modified body mass index, and a questionnaire that assessed autonomic symptoms.



Leerink Partners analyst Paul Matteis wrote Sept. 20 that APOLLO’s safety and efficacy data represent a “best case scenario” for Alnylam, meeting a high bar the investment bank set for success of disease improvement and clean safety. He called the data a “big win” for Alnylam and RNAi, and a validation for the biotech’s platform.



Vaishnaw said the data should ameliorate safety concerns about Alnylam’s drugs, because patients receiving patisiran have been dosed for between two and three years now, depending on whether they enrolled in the Phase II or Phase III study. “The safety profile that we see, which is encouraging I think, bodes well both for patisiran and also for other RNAi therapeutics, because it shows that we can harness the RNAi pathway for long periods of time and do it with what seems to be a safe and tolerable profile,” he pointed out.



Staying The Course With GalNAc Delivery Modality

A major focus for Alnylam in recent years has been the delivery technology for its therapeutics. Patisiran uses an older modality as a liquid nanoparticle, while both the shelved revusiran and the stalled fitusiran employ newer GalNAc (N-acetylgalactosamine) delivery technology. But even with proof from APOLLO that its liquid nanoparticle technology can safely deliver effective medicines to patients, Vaishnaw indicated that the company remains committed GalNAc for future products.



Alnylam made the switch, because it wanted to offer subcutaneous administration. GalNAc has been advanced through three iterations with improved potency so that smaller doses can be used. (Also see "Alnylam Advancing From Platform Buzz To Late-Stage Clinical Work" - Scrip, 21 Dec, 2015.) The third-generation GalNAc delivery system, called enhanced stabilization chemistry-plus, “looks very encouraging today,” Vaishnaw said.



Moving forward with the intravenous RNAi therapeutic patisiran as a pioneering new modality, it would seem likely that FDA will want to convene an advisory committee before making a decision on whether to approve the drug. Vaishnaw did not deny that an advisory committee seems fairly likely.



“It’s typical for a first-in-class compound from a new class of medicines to be reviewed at an advisory committee,” he noted. “I think ultimately that’s a matter of discussion and decision the FDA would make. What we can say are that these data do look resoundingly positive, internally consistent, clinically meaningful and the safety profile looks encouraging, so we hope that for a high unmet need disease like this that the data would support approval without an advisory committee.”

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