The future of Alnylam Pharmaceuticals Inc.'s RNAi candidate for respiratory syncytial virus (RSV), ALN-RSV01, could be either continued development or total termination, according to CEO John Maraganore, following the drug's failure to hit its primary endpoint in a Phase IIb trial against progressive bronchiolitis obliterans syndrome (BOS) in lung transplant patients.

"With these results in hand, we are planning to meet with U.S. and European regulatory authorities later this year," Maraganore said in a conference call Wednesday morning. "Pending outcomes of those discussions, we'll determine the appropriate path forward."

The Cambridge, Mass.-based company plans to have those meetings with the FDA and European Medicines Agency later this year. In the meantime, investor response was minimal, as most of Alnylam's value is perceived to be in its other programs, including ALN-TTR02 for amyloidosis.

Shares (NASDAQ:ALNY) closed Wednesday at $10.04, down 9 cents.

The randomized, double-blind, placebo-controlled Phase IIb trial enrolled 87 RSV-infected lung transplant patients at 33 sites in six countries. Ten patients were eliminated due to inability to confirm RSV infection through PCR analysis, leaving 33 patients in the placebo group and 44 in the ALN-RSV01 group, or 77 total.

A dose of 0.6 mg/kg or placebo was administered by inhalation once daily for five days through the eFlow Nebulizer System from PARI Pharma GmbH. Patients also received standard-of-care treatment according to each site's practices.

In all analyses, treatment with ALN-RSV01 was associated with a clinically meaningful reduction in the incidence of BOS, and the drug was safe and well tolerated. None of the three deaths that occurred in the study were found to be treatment-related.

However, the study narrowly missed its primary endpoint of reduction in BOS in an intent-to-treat analysis of confirmed RSV-infected patients. In that analysis, 30.3 percent of patients receiving placebo had BOS at day 180, compared to 13.6 percent of the treatment group, with a "p" value of 0.058.

Maraganore pointed out that in a prospectively defined analysis of patients with their last observation carried forward, the study did reach statistical significance. In that group, the rate of BOS in the placebo arm was 30.3 percent, and in the ALN-RSV01 arm, it was 11 .4 percent, with a "p" value of 0.028.

Alnylam said it believes the treatment effect is real and could reach statistical significance with a larger trial. Leerink Swann's Steve Yoo agreed.

"We believe that running a larger trial will allow the company to reach the efficacy endpoint if it opts to proceed with Phase III trials," Yoo wrote in a research note, adding that safety does not seem to be an issue, with the caveat that the result would not necessarily generalize to other RNAi compounds because ALN-RSV01 was given as an inhalation therapy, rather than a systemic therapy.

Analyst Michael G. King, of Rodman and Renshaw, was even more optimistic. "We see today's results as a reaffirmation of the drug's efficacy seen in the earlier studies," King wrote.

However, the market for BOS in lung transplantation may be a factor leading to a decision to terminate, according to Yoo. The patient population in the U.S. is about 16,000, with an RSV infection rate of about 5 percent.

Alnylam "may opt to move forward with the high pricing strategy, but that may cause complications in its partnership with Cubist for Aln-RSV01 which is currently being explored for pediatric RSV infections," Yoo noted.

Cubist Pharmaceuticals Inc., of Lexington, Mass., partnered with Alnylam in 2009 in a deal valued at $102.5 million to develop RNAi therapeutics for RSV. (See BioWorld Today, Jan. 12, 2009.)

The pair scored positive results in a Phase II study of ALN-RSV01 in lung transplant patients in 2009, but Cubist stepped away from that program. It has an option to step back in, but is thought to be more interested in ALN-RSV02 for pediatric indications. And even that program may not show movement from Cubist for some time.

"Currently, Cubist has placed the program on hold prior to entering clinical trials," Yoo said.

The RNAi field suffered a vote of no confidence in November 2010 when Roche AG and Novartis AG backed out of programs and partnerships in that space, leaving partners, including Alnylam, to their own devices. (See BioWorld Today, Sept. 27, 2010, and Nov. 24, 2010.)

Maraganore defended RNAi, asserting that the field was young, and, like monoclonal antibodies, would be vindicated when RNAi therapeutics began moving into advanced clinical studies. (See BioWorld Today, Nov. 29, 2010.)

To that end, Alnylam set forth its 5x15 plan to get five products into advanced trials by 2015.

ALN-RSV01 was Alnylam's most advanced product, but it has not been included as one of the five programs in that initiative.

Even though investor expectations for the Phase IIb trial were low, the necessary backburnering and reassessment of the program shifts the spotlight now to the 5x15 entities, including ALN-TTR, ALN-PCS, ALN-HPN, ALN-APC and ALN-TMP.

Most advanced among that group is ALN-TTR02 for transthyretin (TTR)-mediated amyloidosis. The company began a Phase I trial of ALN-TTR02 in March in healthy volunteers to evaluate safety and tolerability. The trial will also capture clinical activity through serium levels of TTR.

Alnylam plans to present data from the study in the third quarter and begin a pivotal trial in 2013.