Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication of complete study results from Phase I trials with ALN-TTR01 and ALN-TTR02 in the New England Journal of Medicine. The paper, titled “ Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis” (Coelho et al., N Engl J Med 2013;369:819-29), shows that RNAi therapeutics targeting transthyretin (TTR) achieved rapid, dose-dependent, durable, and specific knockdown of TTR, the disease-causing protein in TTR-mediated amyloidosis (ATTR). These results document the most robust proof of concept for RNAi therapy in man to date, including knockdown of serum TTR protein levels of up to 94% after just a single dose of drug.
“Our ATTR program is the lead effort in our ‘Alnylam 5x15’ product development and commercialization strategy, which is focused on advancing innovative RNAi therapeutics toward genetically defined targets for the treatment of diseases with high unmet medical need. Our overall clinical trial experience with RNAi therapeutics for the treatment of ATTR now includes a Phase I trial with ALN-TTR01, Phase I and II trials with ALN-TTR02, and a Phase I trial with ALN-TTRsc, a subcutaneously administered RNAi therapeutic utilizing our proprietary GalNAc conjugate delivery platform,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “The Phase I studies of ALN-TTR01 and ALN-TTR02 demonstrate key human proof of concept for RNAi therapeutics targeting TTR but also for liver-expressed target genes in general, and we are thrilled to be publishing these landmark data in the New England Journal of Medicine. Notably, this is the first time that clinical results with an RNAi therapeutic have been published in the Journal, and we are proud to be associated with this milestone as we lead the clinical translation of RNAi therapeutics as a whole new class of innovative medicines.”
“This new paper describes our clinical trial experience with ALN-TTR01 and ALN-TTR02, which utilize first- and second-generation lipid nanoparticle formulations, respectively. Relative to ALN-TTR01, the results for ALN-TTR02 showed exceptional improvement in potency, without any apparent loss in tolerability, thus documenting the important advances made by Alnylam scientists and collaborators on systemic delivery of RNAi therapeutics. Indeed, with ALN-TTR02 we achieved very robust effects, including up to 94% reduction of serum TTR and a nearly 80% level of suppression sustained at one month with just a single dose. Further, ALN-TTR02 was also found to be generally safe and well tolerated,” said Jared Gollob, M.D., Vice President, Clinical Research at Alnylam. “Knockdown of circulating TTR is expected to result in improved clinical outcomes for patients with ATTR based on data from patients receiving liver transplants. Further, evidence from other systemic amyloidotic diseases shows that as little as a 50% reduction of the disease-causing protein can result in disease improvement or stabilization. Accordingly, we believe the findings published today in the New England Journal of Medicine suggest that the robust, sustained knockdown of TTR levels observed in our clinical trials with ALN-TTR02 may ameliorate the course of disease in patients with ATTR.”
ALN-TTR01 and ALN-TTR02 are systemically delivered RNAi therapeutics using first- and second-generation lipid nanoparticle (LNP) formulations, respectively, that encapsulate an identical siRNA targeting both wild-type and mutant TTR mRNA. The ALN-TTR01 Phase I trial enrolled participants from July 2010 through September 2011, and the ALN-TTR02 Phase I trial enrolled participants from March through May 2012. Both trials were designed as multi-center, randomized, single-blind, placebo-controlled, dose-ranging studies in patients with ATTR (n=32) – in the case of ALN-TTR01, or in healthy adult volunteers (n=17) – in the case of ALN-TTR02. The primary objective of each study was to evaluate the safety and tolerability of a single dose of ALN-TTR01 or ALN-TTR02. In addition, preliminary clinical activity of each drug was evaluated based on measurements of serum TTR protein levels.