Alnylam Pharmaceuticals Inc. CEO John Maraganore said the company "would like to have a complete picture here before we get into any further detail" about the 18 trial deaths that caused halting phase III development of RNA interference (RNAi) drug revusiran for hereditary transthyretin amyloidosis (ATTR) with cardiomyopathy.

Chief medical officer (CMO) Akshay Vaishnaw would only cite an "imbalance in mortality there," pointing out that the trial in 206 patients was underway on a two-for-one basis (two for revusiran and one for placebo) when the data monitoring committee (DMC) said the benefit-risk profile no longer justified continuing.

Analysts insisted that the news about revusiran had no read-through for Cambridge, Mass.-based Alnylam's patisiran, undergoing phase III trials for the treatment of ATTR amyloidosis with polyneuropathy. No other Alnylam RNAi programs are affected either, the company said.

Investors apparently felt otherwise, as shares (NASDAQ:ALNY) closed Thursday $36.21, down $34.09, or 48.5 percent. Wall Street clipped The Medicines Co., too, which uses some of Alnylam's technology, conjugating a sugar molecule N-Acetylgalactosamine (GalNAc) to the small interfering RNA molecule, and the partnered firm's stock (NASDAQ:MDCO) ended down 8.3 percent, or $3.18, at $35.33.

After reports in the revusiran phase II OLE study of new onset or worsening peripheral neuropathy, the phase III ENDEAVOUR DMC assembled to check out unblinded data there, finding no neuropathy concerns but turning up a mortality worry strong enough to stop the phase III experiment.

"Patisiran is a completely different molecule, a different approach for delivery," Maraganore said during a conference call. "We have been encouraged by the safety data we have seen in the phase II open-label study to date. Of course, the [phase III] APOLLO study is a randomized double-blind placebo-controlled study that is under the purview of a data safety and monitoring committee. We have not been notified of any concern by the DMC across that study, which has now been going on for quite some time. We obviously monitor our safety database across the entirety of the rest of our programs and feel that we have an encouraging set of data around safety there, including the recent report from The Medicines Co." Patients treated with revusiran represent "a very different population," he said. "There are a lot of concomitant meds. We don't know what drug/drug interactions might arise here, a lot of co-morbidities. And these patients do have a median survival which is relatively short."

There wasn't much else to say. In the conference call Wednesday, CMO Vaishnaw noted that the most recent analysis "has been completed within the last 24 hours. We are reporting [it] today and that led to the cessation of the program. As to all these other data points, we will have to look at them in the fullness of time." CEO Maraganore revealed that the number of deaths in the drug vs. placebo groups "wasn't 18 to zero, it was an imbalance." Cowen Co. analyst Ritu Baral, however, guessed that the imbalance of deaths in ENDEAVOUR was "profound" and may have come with "poor observed efficacy." She conceded that "cardiac symptoms are an expected part" of the natural history of the disease. "Importantly we do not think the observed potential safety signal is a platform issue, as other programs have shown solid safety," she added in a report.

PCSK9 'BLOCKBUSTER' AHEAD?

Morningstar analyst Karen Andersen lowered her fair-value estimate for Alnylam to $50 from $90.

"Before the [trial-halt] announcement, revusiran was a key revenue driver in our Alnylam model," she said. "Given the concentrated revenue drivers in early-stage biotech companies, we believe Alnylam still warrants a high uncertainty rating." She forecast "break-even operating income in 2021 on the back of the successful launch of patisiran in 2018 (80 percent probability), although top-line revenue is expected to grow much more slowly given the loss of future revusiran contributions in our model. With Alnylam's current rate of cash burn, we anticipate the company may need to raise additional capital before patisiran reaches the market."

Andersen said in a report that her firm "still believe[s] in the potential of Alnylam's remaining pipeline," which includes fitusiran in hemophilia, ALN-CC5 in complement-mediated disorders, ALN-PCSsc for high cholesterol, and ALN-AS1 for hepatic porphyrias.

Separately, Medicines provided an update on its ongoing phase II ORION-1 study with a first-in-class proprotein convertase subtilisin/kexin type 9 synthesis inhibitor (PCSK9si). The study is a placebo-controlled, double-blind, randomized experiment testing single or multiple subcutaneous injections of PCSK9si in patients with atherosclerotic cardiovascular disease (ASCVD) or ASCVD-risk equivalents (e.g., diabetes and familial hypercholesterolemia) and elevated LDL-C despite maximum tolerated doses of LDL-C-lowering therapies. Compared in the study are the effects of different doses of PCSK9si, with an eye to the potential for a quarterly or bi-annual dosing regimen. The primary endpoint of the study is the percentage change in LDL-C from baseline at day 180.

The study has exceeded its enrollment target of 480 patients ahead of schedule, Medicines noted, enrolling a total of 501 patients between Jan. 21, 2016, and June 2, 2016. An interim analysis of day 90 follow-up for all 501 patients will be conducted and presented in the late-breaking clinical trial session at the American Heart Association (AHA) Scientific Sessions 2016 on Nov. 15, in New Orleans. The company expects top-line data from day 180 follow-up for up to 200 patients will be presented then, too, and day 180 follow-up in all 501 patients will be completed and analyzed with top-line results disclosed before the end of this year.

J.P. Morgan analyst Jessica Fye said the ORION-1 update, "which was clean, came in the context of Alnylam's decision to discontinue development of revusiran. PCSK9si utilizes Alnylam's GalNAc technology; however, we believe the similarities to revusiran diminish from there," she wrote in a report, adding that she "would not be surprised" to see Medicines take a hit on the Alnylam news. "We continue to expect a positive dataset at AHA, de-risking both PCSK9si's safety and efficacy, and see both an intriguing setup in the stock and a blockbuster opportunity for the asset."

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