Alnylam's 'Day After' Revusiran Failure Bad, Maybe Not Catastrophic

Despite its stock price falling 48% 24 hours after the shuttering of lead candidate revusiran, Alnylam is encouraged by analyst reports indicating the failure does not read through to its overall pipeline. The biotech reaffirmed its timeline for its second Phase III candidate patisiran.

The day after announcing it had ended development of its lead candidate revusiran due to an imbalance of deaths in a Phase III trial, Alnylam Pharmaceuticals Inc. took a serious hit on its stock price, but also got reassurance that a broad array of market analysts had determined that because revusiran was substantially differentiated from the rest of Alnylam's RNA-interference pipeline, there probably would be no read-through to the larger portfolio.

Several other publicly traded companies working in the RNA space also saw their share prices decline Oct. 6, but much less so than the 48% shellacking Alnylam shares took (falling from $70.30 to $36.22) by the end of the trading day. Among those other companies, Regulus Therapeutics Inc. was down 5% on the day to $3.36 per share, Dicerna Pharmaceuticals Inc. dropped 14% to $4.68, Ionis Pharmaceuticals Inc. declined 6% to $34.26 and Arrowhead Pharmaceuticals Inc. fell 7% to $7.03.

Alnylam announced Oct. 5 that there were 18 deaths in the 206-patient Phase III ENDEAVOUR trial of revusiran, its most-advanced RNAi candidate, being investigated as a treatment for hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). (Also see "Alnylam Ends Revusiran In Phase III, But Was Failure Due To Safety Or Efficacy?" - Scrip, 6 Oct, 2016.) The ENDEAVOUR trial’s data monitoring committee (DMC) recommended ending the study after an unscheduled interim review, because “the benefit-risk profile for revusiran no longer supported continued dosing.”

Alnylam had asked the DMC to look at data from the Phase III trial following an increase in peripheral neuropathy and elevated blood lactate observed in a Phase II extension study, but the committee said the adverse events could not be attributed to revusiran. Alnylam then reviewed unblinded ENDEAVOUR data after the DMC made its recommendation to discontinue the study based on a lack of benefit-risk. The company found an imbalance in the number of deaths and decided to end revusiran development.

"We do not think the revusiran announcement is a read-through to the rest of the pipeline." – Alnylam President Barry Greene

It is unclear at present whether the deaths had anything to do with revusiran's safety or efficacy. Alnylam did not disclose during an Oct. 5 investor call how many deaths occurred in the treatment arm compared with the placebo arm (participants were randomized 2:1 to treatment or placebo) other than to say that not all 18 deaths occurred in the treatment group.

Market analysts seemed to have reached consensus by Oct. 6 that because revusiran used an earlier-stage delivery technology, there is enough differentiation to trust that the revusiran failure does not suggest read-through to the rest of Alnylam's pipeline. (Also see "Alnylam Advancing From Platform Buzz To Late-Stage Clinical Work" - Pink Sheet, 21 Dec, 2015.) Revusiran uses first-generation GalNAc delivery technology, while six other candidates are delivered via the second-generation Enhanced Stabilization Chemistry (ESC)-GalNAc technology. Meanwhile, the biotech's other Phase III candidate – patisiran for familial amyloidotic polyneuropathy (PAN) – uses a lipid nanoparticle formulation for delivery.

Alnylam President Barry Greene

Source: Alnylam Pharmaceuticals

Despite the hammering his company was taking in the stock market, Alnylam President Barry Greene said the forming consensus was reassuring. "I think we've done 30 different analyst and investor calls and the resounding sentiment is that we have an incredibly strong pipeline with patisiran and the other RNAi therapeutics and people are incredibly enthusiastic for us to move that pipeline forward," he told Scrip. "We do not think the revusiran announcement is a read-through to the rest of the pipeline."

Greene said Alnylam reaffirmed its patisiran guidance and noted that the loss of revusiran does not change Alnylam's financing window at all.

"We plan on opening the [Phase III] APOLLO envelope in mid-2017 and then, assuming positive data, filing in the US and Europe for regulatory approval with a plan to launch in 2018."

Morningstar analyst Kelsey Tsai suggested in an Oct. 6 note that due to its current cash-burn, Alnylam might need to raise funds before patisiran reaches the market in 2018. Without revusiran revenues, Tsai projects that Alnylam will reach break-even revenue status in 2021, assuming a successful launch for patisiran.

Alnylam still may pursue the hATTR-CM indication, Greene said, indicating that patisiran, which targets the protein transthyretin (TTR) just as revusiran does, eventually may offer a treatment option for some patients in the cardiomyopathy setting in addition to ATTR amyloidosis patients with polyneuropathy.

"As with many orphan diseases, they become much more clearly understood when a company starts studying them," Greene explained. "What we know now that wasn't fully appreciated five or six year ago is that hereditary ATTR is a mixed-phenotype disease, where many patients have a combination of both polyneuropathy and cardiomyopathy. In fact, in the APOLLO patisiran study, slightly more than 50% of the patients have an underlying cardiomyopathy. If we see APOLLO data that are encouraging for that patient subgroup, we may in fact be able to help a number of hereditary ATTR patients with cardiomyopathy, assuming positive data and positive regulatory interactions."

Overall, the revusiran failure does not force Alnylam to adjust its near- to mid-term performance goals, the exec added. The Alnylam 2020 goals of three products on the commercial market and 10 clinical candidates in the pipeline remains in place, he said.

Analysts Lower Target Prices, But Don't Quit On Alnylam

Across the board, following the Oct. 5 news and conference call, stock market analysts lowered target prices for Alnylam shares but most remained optimistic about the pipeline and the RNAi space in general, and multiple banks continued to give Alnylam their highest rating.

Credit Suisse slashed its target price for Alnylam from $145 per share to $50, but maintained a rating of "outperform." JMP Securities also maintained a "market outperform" rating, while lowering its target price from $127 to $69. Barclays Equity Research, however, lowered its target price from $85 to $50 and downgraded the company from "overweight" to "equal weight."

Barclays's Geoff Meacham wrote Oct. 6 that he still feels "very comfortable" with patisiran, as well as with fitusiran, its antithrombin-targeted hemophilia candidate which has completed Phase I. (Also see "Alnylam's Fitusiran Could Provide Comprehensive Hemophilia Therapy Option" - Scrip, 29 Aug, 2016.)

"Despite recent uncertainty on the safety side, we do not have broader concerns about the RNAi technology platform," Meacham said. "Of note, revusiran uniquely employed first-generation GalNAc delivery technology, which could explain toxicity, but importantly, more than 800 patients have been safely dosed using other delivery technologies such as ESC-GalNAc and lipid nanoparticle delivery."

Alethia Young of Credit Suisse pointed out that patisiran, despite also targeting TTR, is differentiated from revusiran in multiple ways, including the fact that Alnylam's more advanced delivery modalities necessitate the use of much smaller drug doses than the first-generation GalNAc technology.

"With patisiran, there has been longer exposure, steroids were given, lipid nanoparticle delivery has greater validation, and we have seen some evidence of efficacy when looking at the open-label study," she wrote Oct. 6. "However, we think the platform will now become a show-me story with a much greater focus on safety (even if the efficacy looks encouraging) and de-risking will include major readouts like Phase III or significant numbers of patients."

Jefferies Equity Research analyst Biren Amin said in an Oct. 5 note about The Medicines Co., which is partnered with Alnylam on PCSK9-targeted ALN-PCSsc for hypercholesterolemia, there should be no read-through from revusiran to this program. (Also see "Alnylam, Medicines Company PCSK9 Drug Has Quarterly Dose Potential" - Scrip, 30 Aug, 2015.)

Alnylam pointed out that it has a safety database of more than 800 patients treated with its other candidates, with follow-up out to as much as 34 months. Roughly 560 of those patients have been treated with ALN-PCSsc, Amin noted, with the longest follow-up at 12 months and no notable safety events so far.