Safety and Efficacy of RNAi Therapy for Transthyretin Amyloidosis.
Coelho, Teresa M.D.; Adams, David M.D., Ph.D.; Silva, Ana M.D.; Lozeron, Pierre M.D.; Hawkins, Philip N. Ph.D., F.Med.Sci.; Mant, Timothy M.B.; Perez, Javier M.D.; Chiesa, Joseph M.D.; Warrington, Steve M.D.; Tranter, Elizabeth M.B.; Munisamy, Malathy M.D.; Falzone, Rick M.P.H.; Harrop, Jamie B.A.; Cehelsky, Jeffrey M.B.A.; Bettencourt, Brian R. Ph.D.; Geissler, Mary M.P.H.; Butler, James S. Ph.D.; Sehgal, Alfica Ph.D.; Meyers, Rachel E. Ph.D.; Chen, Qingmin Ph.D.; Borland, Todd B.S.; Hutabarat, Renta M. Ph.D.; Clausen, Valerie A. Ph.D.; Alvarez, Rene Ph.D.; Fitzgerald, Kevin Ph.D.; Gamba-Vitalo, Christina Ph.D.; Nochur, Saraswathy V. Ph.D.; Vaishnaw, Akshay K. M.D., Ph.D.; Sah, Dinah W.Y. Ph.D.; Gollob, Jared A. M.D.; Suhr, Ole B. M.D.
[Article]
New England Journal of Medicine.
369(9):819-829, August 29, 2013.
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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.)
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