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N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153.

Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis.

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From Assistance Publique-Hôpitaux de Paris (APHP), National Reference Center for Familial Amyloidotic Polyneuropathy, Centre Hospitalier Universitaire (CHU) Bicêtre, INSERM Unité 1195, Université Paris-Sud, Le Kremlin-Bicêtre (D.A.), the Department of Neuromuscular Disorders and ALS, Hôpital de la Timone, Marseille (S.A.), and the Department of Neurology, Amyloid Network, CHU Henri Mondor-APHP, Créteil (V.P.-B.) - all in France; the National Institute of Medical Sciences and Nutrition-Salvador Zubiran, Mexico City (A.G.-D.); the Department of Clinical Research, eStudySite, San Diego, CA (W.D.O.); the Department of Neurology, National Taiwan University Hospital (C.-C.Y.), and the Department of Neurology, Taipei Veterans General Hospital (K.-P.L.), Taipei, Taiwan; Kumamoto University Hospital, Kumamoto (M.U.), and the Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto (Y.S.) - both in Japan; the Department of Cardiology, University of Heidelberg, Heidelberg (A.V.K.), and Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster (H.H.S.) - both in Germany; University Multiprofile Hospital for Active Treatment, Sofia, Bulgaria (I.T.); Hospital de Santo António, Centro Hospitalar do Porto, Porto, Portugal (T.C.); the Amyloidosis Center, Department of Medicine, Boston Medical Center (J.L.B.), and Harvard Medical School (S.D.S.), Boston; the Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy (G.V.); the Departments of Neurology and Medicine, Vancouver General Hospital, Vancouver, BC, Canada (M.M.M.); the Department of Nephrology, Hospital Clinic, Barcelona (J.M.C.), and the Balearic Islands Health Research Institute and Hospital Son Llatzer, Palma de Mallorca (J.B.) - all in Spain; the Department of Neurology, Columbia University, College of Physicians and Surgeons, New York (T.H.B.); Samsung Medical Center, Sungkyunkwan University School of Medicine (B.J.K.), and the the Department of Neurology, Konkuk University Medical Center (J.O.), Seoul, South Korea; the Department of Neurology, Istanbul University, Istanbul, Turkey (Y.P.); the Division of Medicine, University College London, London (P.N.H.); Johns Hopkins Bayview Medical Center, Baltimore (M.P.); the Department of Neurology, Mayo Clinic, Rochester, MN (P.J.D.); Alnylam Pharmaceuticals, Cambridge, MA (P.J.G., S.G., J.C., A.L.S., S.V.N., M.T.S., P.P.G., A.K.V., J.A.G.); and the Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden (O.B.S.).



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; 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.


In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO number, NCT01960348 .).

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