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Alnylam RSV Drug Fails in Phase IIb; Company to Weigh Options with Regulators

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In another setback to its respiratory syncytial virus program, Alnylam Pharmaceuticals announced this week that its RSV therapeutic candidate ALN-RSV01 failed to meet the primary endpoint in a phase IIb trial.

Company officials said during a conference call that no decision on the fate of the drug will be made until they meet with US and European regulators later this year. However, Alnylam CEO John Maraganore indicated that the termination of the program altogether is a possibility.

If Alnylam chooses this route, ALN-RSV01 will join a growing list of RNAi candidates that the company has dropped over the years, including a follow-up RSV treatment, a flu therapy, and a drug for wet age-related macular degeneration.

Alnylam began developing the RSV treatment in 2005, and later found a partner for the drug in Cubist Pharmaceuticals. However, in 2009, Alnylam reported phase II data showing that while the drug was safe and well tolerated, hints of efficacy were “exploratory” at best given the small size of the study.

In the trial, 24 lung-transplant patients with confirmed RSV infections were randomized to receive inhaled ALN-RSV01 or placebo once daily for three consecutive days. The drug was shown to significantly decrease the incidence of new or progressive bronchiolitis obliterans syndrome, or BOS, a non-reversible obstructive lung disease, at day 90.

Cubist later dropped out of the deal for the drug, although it maintained the right to opt in to its development down the road, instead partnering with Alnylam on a follow-on drug called ALN-RSV02 geared to pediatric RSV patients (GSN 11/12/2009).

To keep ALN-RSV01 moving forward, Alnylam initiated on its own the phase IIb trial in order to “repeat and extend the clinical results observed in the original phase II study,” Maraganore said at the time.

In the newest study, 87 lung-transplant patients were randomized in a one-to-one drug-to-placebo ratio, with 45 patients receiving ALN-RSV01 and 42 receiving placebo, defining the overall intent-to-treat study cohort, Alnylam said.

The trial did not achieve its primary endpoint of reduced incidence of new or progressive BOS at 180 days, the company said this week. However, ALN-RSV01 treatment was associated with “a statistically significant reduction in the incidence of day 180 BOS” in certain subsets of enrolled patients.

During this week's call, Alnylam officials tried to put a positive spin on the news, with CMO Akshay Vaishnaw touting the encouraging body of data that has “culminated from this robust clinical effort.”

He added that the data from Alnylam's RSV efforts as a whole have been “very informative for our broader development efforts in RNAi therapeutics.”

Maraganore said that next steps for ALN-RSV01 will be disclosed in the second half of the year once Alnylam has discussed the trial data with the US Food and Drug Administration and the European Medicines Agency.

“Pending the outcome of those discussions, we will determine the appropriate path forward for this program,” he said. “We could decide to continue development of ALN-RSV01 toward regulatory approval or … we could decide to terminate all further development efforts.”

Should Alnylam take the latter route, it would be holding steady with a recently unveiled strategy called Alnylam 5x15 that has the firm focusing on "genetically defined diseases" offering the potential for "early commercialization opportunities" (GSN 1/13/2011).

Under the initiative, Alnylam aims to have five drugs in “advanced clinical development” by 2015. Included in this is its phase I transthyretin-mediated amyloidosis drug ALN-TTR; its phase I hypercholesterolemia treatment ALN-PCS; and preclinical programs in hemophilia, refractory anemia, and hemoglobinopathies.

Notably absent is its phase I liver cancer drug ALN-VSP, which the company said it would only advance with a partner, and ALN-RSV02, which remains on hold indefinitely following a “portfolio decision” by Alnylam and Cubist.

If terminated, the ALN-RSV01 program would also be put alongside a variety of other drug candidates that the company abandoned since its founding in 2002.

One of the company's first programs was in influenza, and in 2005 it added pandemic flu to its formal drug-development pipeline with the goal of filing an investigational new drug application by the end of 2006 after securing US government funding.

However, by mid-2007 the company put the effort on hold, with Maraganore saying that “we have just not been satisfied with the level of in vivo efficacy we’re seeing related to specific RNAi effects” (GSN 8/16/2007). The program has since quietly disappeared from Alnylam's disclosed pipeline.

Alnylam also had a fledgling effort in wet AMD, and in 2004 partnered with Merck on the program. The next year, however, Maraganore gave hints that the firm was planning to end the program in light of strong data from more-developed treatments under development by other drug makers (GSN 8/5/2005). Alnylam did so a few months later.

Meanwhile, little has been said about Alnylam's collaboration with Biogen Idec since the companies announced their alliance in 2006. At the time, the firms said they were aiming to use Alnylam's RNAi technology to treat progressive multifocal leukoencephalopathy, an opportunistic viral infection of the brain that has been associated with Biogen Idec's multiple sclerosis drug Tysabri (GSN 9/21/2006).

Alnylam still lists the alliance on its website, but has not mentioned the arrangement since it was first announced.

More recently, Alnylam disclosed that it has dropped out of its partnership with Medtronic to develop an RNAi-based treatment for Huntington's disease (GSN 5/10/2012). Once structured as a 50/50 arrangement, Medtronic will now be responsible for all development and commercialization of the candidate, with Alnylam receiving only milestones and royalties.

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