1. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis
- Author
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Hartmut Schmidt, Jeeyoung Oh, Yesim Parman, Teresa Coelho, Byoung Joon Kim, Akshay Vaishnaw, Ole B. Suhr, Chih-Chao Yang, Scott D. Solomon, Pushkal Garg, Sunita Goyal, Ivailo Tournev, Andrew Strahs, John L. Berk, Pritesh Gandhi, Shahram Attarian, Violaine Planté-Bordeneuve, Alejandra González-Duarte, Arnt V. Kristen, William O'Riordan, Kon Ping Lin, Mitsuharu Ueda, Philip N. Hawkins, Michelle M. Mezei, Jared Gollob, Jihong Chen, David Adams, Saraswathy V. Nochur, Thomas H. Brannagan, Peter J. Dyck, Josep M. Campistol, Giuseppe Vita, Marianne T. Sweetser, Michael Polydefkis, Yoshiki Sekijima, Juan Buades, and Universitat de Barcelona
- Subjects
Male ,Tafamidis ,Administration, Intravenous ,Adult ,Aged ,Aged, 80 and over ,Amyloid Neuropathies, Familial ,Disease Progression ,Double-Blind Method ,Edema ,Female ,Gait Disorders, Neurologic ,Humans ,Infusions, Intravenous ,Least-Squares Analysis ,Middle Aged ,Polyneuropathies ,Prealbumin ,Quality of Life ,RNA, Small Interfering ,Severity of Illness Index ,Walk Test ,RNAi Therapeutics ,Medicine (all) ,030204 cardiovascular system & hematology ,chemistry.chemical_compound ,0302 clinical medicine ,Clinical trials ,RNA interference ,biology ,Amyloidosis ,General Medicine ,03 medical and health sciences ,medicine ,business.industry ,RNA ,medicine.disease ,Clinical trial ,Transthyretin ,chemistry ,biology.protein ,Cancer research ,Amiloïdosi ,Amyloid cardiomyopathy ,business ,human activities ,030217 neurology & neurosurgery ,Assaigs clínics - Abstract
Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin.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).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.In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).
- Published
- 2018