Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Journal
The New England Journal of Medicine
Journal Volume
379
Journal Issue
1
Start Page
11
End Page
21
ISSN
1533-4406
Date Issued
2018-07-05
Author(s)
Adams, David
Gonzalez-Duarte, Alejandra
O'Riordan, William D
Ueda, Mitsuharu
Kristen, Arnt V
Tournev, Ivailo
Schmidt, Hartmut H
Coelho, Teresa
Berk, John L
Lin, Kon-Ping
Vita, Giuseppe
Attarian, Shahram
Planté-Bordeneuve, Violaine
Mezei, Michelle M
Campistol, Josep M
Buades, Juan
Brannagan, Thomas H
Kim, Byoung J
Oh, Jeeyoung
Parman, Yesim
Sekijima, Yoshiki
Hawkins, Philip N
Solomon, Scott D
Polydefkis, Michael
Dyck, Peter J
Gandhi, Pritesh J
Goyal, Sunita
Chen, Jihong
Strahs, Andrew L
Nochur, Saraswathy V
Sweetser, Marianne T
Garg, Pushkal P
Vaishnaw, Akshay K
Gollob, Jared A
Suhr, Ole B
Abstract
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; P<0.001) 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; P<0.001) 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; P<0.001), 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; P<0.001). 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. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).
SDGs
Type
other