Key Information
Background:
Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.
Methods:
In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters]*albumin level in grams per liter; lower values indicated worse nutritional status).
Results:
A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+-SD) mNIS+7 at baseline was 80.9+-41.5 in the patisiran group and 74.6+-37.0 in the placebo group; the least-squares mean (+-SE) change from baseline was -6.0+-1.7 versus 28.0+-2.6 (difference, -34.0 points; P0.001) at 18 months. The mean (+-SD) baseline Norfolk QOL-DN score was 59.6+-28.2 in the patisiran group and 55.5+-24.3 in the placebo group; the least-squares mean (+-SE) change from baseline was -6.7+-1.8 versus 14.4+-2.7 (difference, -21.1 points; P0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08+-0.02 m per second with patisiran versus -0.24+-0.04 m per second with placebo (difference, 0.31 m per second; P0.001), and the least-squares mean change from baseline in the modified BMI was -3.7+-9.6 versus -119.4+-14.5 (difference, 115.7; P0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups.
Conclusions:
In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.