1区 · 医学
Article
作者: Bettencourt, Brian R. ; Geissler, Mary ; Meyers, Rachel E. ; Borland, Todd ; Butler, James S. ; Gollob, Jared A. ; Coelho, Teresa ; Adams, David ; Sehgal, Alfica ; Mant, Timothy ; Cehelsky, Jeffrey ; Warrington, Steve ; Hutabarat, Renta M. ; Alvarez, Rene ; Hawkins, Philip N. ; Fitzgerald, Kevin ; Chiesa, Joseph ; Gamba-Vitalo, Christina ; Harrop, Jamie ; Lozeron, Pierre ; Vaishnaw, Akshay K. ; Suhr, Ole B. ; Chen, Qingmin ; Silva, Ana ; Tranter, Elizabeth ; Perez, Javier ; Nochur, Saraswathy V. ; Clausen, Valerie A. ; Munisamy, Malathy ; Sah, Dinah W. Y. ; Falzone, Rick
BACKGROUND:Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart. A therapeutic approach mediated by RNA interference (RNAi) could reduce the production of transthyretin.
METHODS:We identified a potent antitransthyretin small interfering RNA, which was encapsulated in two distinct first- and second-generation formulations of lipid nanoparticles, generating ALN-TTR01 and ALN-TTR02, respectively. Each formulation was studied in a single-dose, placebo-controlled phase 1 trial to assess safety and effect on transthyretin levels. We first evaluated ALN-TTR01 (at doses of 0.01 to 1.0 mg per kilogram of body weight) in 32 patients with transthyretin amyloidosis and then evaluated ALN-TTR02 (at doses of 0.01 to 0.5 mg per kilogram) in 17 healthy volunteers.
RESULTS:Rapid, dose-dependent, and durable lowering of transthyretin levels was observed in the two trials. At a dose of 1.0 mg per kilogram, ALN-TTR01 suppressed transthyretin, with a mean reduction at day 7 of 38%, as compared with placebo (P=0.01); levels of mutant and nonmutant forms of transthyretin were lowered to a similar extent. For ALN-TTR02, the mean reductions in transthyretin levels at doses of 0.15 to 0.3 mg per kilogram ranged from 82.3 to 86.8%, with reductions of 56.6 to 67.1% at 28 days (P<0.001 for all comparisons). These reductions were shown to be RNAi-mediated. Mild-to-moderate infusion-related reactions occurred in 20.8% and 7.7% of participants receiving ALN-TTR01 and ALN-TTR02, respectively.
CONCLUSIONS:ALN-TTR01 and ALN-TTR02 suppressed the production of both mutant and nonmutant forms of transthyretin, establishing proof of concept for RNAi therapy targeting messenger RNA transcribed from a disease-causing gene. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov numbers, NCT01148953 and NCT01559077.).