Alnylam announces complete results from ALN-RSV01 Phase IIb trial on RSV infection

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today complete results from its Phase IIb trial with ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection in lung transplant patients. The data were presented at the European Respiratory Society's (ERS) Annual Congress held in Vienna, September 1-5, 2012. As reported previously, the study narrowly missed the primary endpoint of reduced day 180 BOS in an "intent-to-treat" (ITTc) analysis of confirmed RSV infected patients, but achieved statistically significant reductions in prospectively defined analyses of ITTc patients with their "last observation carried forward" (LOCF), and of ITTc patients treated "per protocol" (PP). At the ERS meeting, new results were presented on secondary endpoints and certain post-hoc analyses that support the efficacy of ALN-RSV01 in this setting. Further, and as reported earlier, ALN-RSV01 was found to be generally safe and well tolerated in the study. Alnylam plans to discuss these complete results with U.S. and European regulatory authorities, and communicate future development plans for ALN-RSV01 at year's end.   

"Our Phase IIb study results demonstrate that inhaled ALN-RSV01 reduces the incidence of new or progressive BOS in RSV-infected lung transplant patients. The complete results presented at the ERS meeting continue to show that ALN-RSV01 is associated with a significant treatment effect, including results of a multivariate logistic regression analysis where treatment with ALN-RSV01 showed an over eight-fold reduced risk in developing day 180 BOS. Further, we showed a statistically significant effect on the secondary endpoint of day 90 BOS, and demonstrated a particularly strong effect of over 80% in patients receiving ALN-RSV01 within five days of symptom onset," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "Our plans are to discuss these results with U.S. and European regulatory authorities later this year and then communicate next steps, if any, for our ALN-RSV program. In the meanwhile, we continue to execute on our 'Alnylam 5x15' product strategy with a focus on our transthyretin-mediated amyloidosis and hemophilia programs."

"Community acquired respiratory infections, including RSV, represent a significant risk for lung transplant patients, as infection may be associated with the development of new or progressive BOS. Indeed, BOS is the leading cause of death in patients beyond the first year of transplantation," said Jens Gottlieb, M.D., principal investigator, Hannover Medical School. "Amongst other study findings, ALN-RSV01 treatment shows a clinically meaningful effect on the incidence of day 180 BOS, and these results appear to be quite robust even in the context of concomitant therapies such as ribavirin and steroids. There is clearly an unmet medical need for an effective RSV therapy for lung transplant patients, and ALN-RSV01 holds considerable potential as an innovative therapeutic for the prevention RSV-induced BOS."   

As reported previously, the Phase IIb trial was an international multi-center, randomized, double-blind, placebo-controlled study of ALN-RSV01 in RSV-infected lung transplant patients. RSV infection in lung transplant patients represents a significant unmet medical need as it can lead to the development of new or progressive BOS, an irreversible fibro-occlusive pathology of the airways that is the biggest cause of chronic allograft dysfunction and mortality in lung transplant patients, with an approximately 50% mortality within five years of onset. The primary endpoint of the Phase IIb trial was the incidence of new or progressive BOS at 180 days. The trial enrolled 87 patients who were randomized in a one-to-one, ALN-RSV01-to-placebo ratio; a total of 33 sites participated from six countries. Based on central laboratory confirmation of RSV infection, a total of 44 patients were randomized to receive ALN-RSV01 and 33 patients were randomized to receive placebo, defining the overall intent-to-treat study cohort (ITTc). Data from the study show that ALN-RSV01 missed the primary endpoint of new or progressive BOS at 180 days in the ITTc population (p=0.058). However, ALN-RSV01 treatment was associated with a statistically significant reduction in the incidence of day 180 BOS in the prospectively defined LOCF (p=0.028) and PP (p=0.025) analyses. In all analyses, treatment with ALN-RSV01, as compared with placebo, was associated with a clinically meaningful reduction in the incidence of day 180 BOS with a treatment effect of greater than 50%.

New study findings presented at the ERS meeting included results from key secondary endpoints and certain post-hoc analyses of data. As it pertains to key secondary endpoints, ALN-RSV01 treatment resulted in a statistically significant reduction in day 90 BOS as compared with placebo as measured in the ITTc population (p=0.044) with an overall effect size of 52%. Further, ALN-RSV01 showed an enhanced treatment effect size of 88% toward day 180 BOS in patients treated within five days from symptom onset (p=0.0095). Other secondary endpoints including viral parameters and symptom score were not significantly different between ALN-RSV01 and placebo. A number of post-hoc analyses were also performed. In a logistic regression analysis adjusting for multiple variables, treatment with ALN-RSV01 was found to be associated with a significantly reduced risk of developing day 180 BOS, with an odds ratio of 8.5 (95% confidence intervals of 1.7 and 41.7). Further, the effects of ALN-RSV01 on day 180 BOS persisted when controlled for the concomitant administration of pulse-dose steroids. A direct comparison of patients receiving ALN-RSV01 in the absence of ribavirin versus placebo patients receiving inhaled ribavirin, the current standard of care at some centers, showed that ALN-RSV01 was associated with a statistically significant reduction in new or progressive BOS at day 180 (p=0.022). There was a similar incidence of reported adverse events in placebo (81%) and study drug (73.3%) treatment arms. Serious adverse events were also reported with similar incidence in patients receiving placebo (9.5%) and ALN-RSV01 (11%). In aggregate, the newly presented results support the conclusion that treatment of RSV-infected lung transplant patients with ALN-RSV01 is generally safe and well tolerated and associated with a decreased incidence of new or progressive BOS.

Alnylam's RSV program is partnered with Cubist Pharmaceuticals in North America and the rest of the world outside of Asia, where the program is partnered with Kyowa Hakko Kirin Co., Ltd. These partners maintain certain opt-in rights for the development of ALN-RSV01.