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Transthyretin amyloidosis: safety and efficacy of RNAi therapy

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.

Researches have 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.

Researchers 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.

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 less than 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.

In conclusion, 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. ( Xagena )

Coelho T et al, N Engl J Med 2013; 369:819-829