Title: Safety and Efficacy of Inotersen in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (NEURO-TTR) (N2.001)
Abstract: Objective: To report the safety and efficacy of inotersen, an antisense oligonucleotide inhibitor of transthyretin (TTR) protein production, for the treatment of patients with hereditary TTR amyloidosis (hATTR) in a global, randomized, double-blind, placebo-controlled phase 3 study (NEURO-TTR, NCT01737398). Background: hATTR is an autosomal dominant disease caused by mutations in the gene coding for the transport protein TTR. Mutations in the TTR gene cause the tetrameric protein to dissociate into free monomers, form insoluble fibril deposits, and accumulate in the nerves, heart, and other vital organs. Patients with hATTR-PN have a life expectancy of approximately 10 years from symptom onset. Design/Methods: One hundred seventy-two patients with hATTR-PN ≥18 years of age who had stage 1 or 2 disease were treated after randomization (2:1) to receive 300-mg weekly subcutaneous doses of inotersen or placebo for 15 months of treatment. The primary endpoints were change from baseline in the Norfolk Quality of Life–Diabetic Neuropathy (Norfolk QOL–DN) score and modified Neuropathy Impairment Score+7 (mNIS+7) at week 66. Results: At baseline, the study population was 69% male with a mean age of 59 years (range, 27–81 years), and 63% (108/172) patients had cardiomyopathy. The study cohort included 27 TTR mutations, with 52% of patients expressing the Val30Met mutation. Eighty percent of patients completed the 15-month treatment period. Inotersen-treated patients experienced statistically significant benefit in both primary endpoints, mNIS+7 ( P P = 0.0006), compared with placebo. Key safety findings of thrombocytopenia and renal events were monitorable and manageable. More than 95% of patients who completed treatment entered the open-label extension study. Conclusions: Inotersen demonstrated highly significant benefit on both primary clinical end points indicating quality of life improvements and prevention of neurological disease progression in patients with hATTR-PN. Study Supported by: Ionis Pharmaceuticals Disclosure: Dr. Gertz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis, Alnylam, Prothena. Dr. Wang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis. Dr. Wang has received research support from Ionis. Dr. Coelho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam, Ionis, Prothena. Dr. Coelho has received research support from Pfizer, Ionis, Alnylam. Dr. Waddington Cruz has nothing to disclose. Dr. Polydefkis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam. Dr. Dyck has nothing to disclose. Dr. Scheinberg has nothing to disclose. Dr. Plante-Bordeneuve has nothing to disclose. Dr. Berk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis, Alnylam. Dr. Berk has received research support from Ionis, Alnylam, Pfizer. Dr. Barroso has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer. Dr. Barroso has received research support from Alnylam. Dr. Adams has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam, Prothena. Dr. Adams has received research support from Ionis, Alnylam. Dr. Brannagan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Brannagan has received research support from Ionis, Alnylam. Dr. Whelan has nothing to disclose. Dr. Merlini has nothing to disclose. Dr. Drachman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam. Dr. Drachman has received research support from Pfizer, Ionis, Alnylam. Dr. Heitner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alnylam, Amgen, Takeda, MyoKardia. Dr. Conceicao has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam. Dr. Conceicao has received research support from Pfizer, Alnylam, Sanofi. Dr. Schmidt has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Pfizer, Alnylam, Ionis. Dr. Vita has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Alnylam, Pfizer. Dr. Vita has received personal compensation in an editorial capacity for Neurological Sciences. Dr. Campistol has nothing to disclose. Dr. Gamez has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ITALFARMACO. Dr. Gane has nothing to disclose. Dr. Gorevic has received personal compensation in an editorial capacity for Amyloid. Dr. Gorevic has received research support from Ionis, Alnylam, Pfizer. Dr. Oliveira has nothing to disclose. Dr. Monia has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis. Dr. hughes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis. Dr. Kwoh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis. Dr. McEvoy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis. Dr. Baker has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis. Dr. Baker holds stock and/or stock options in Ionis. Dr. Ackermann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis. Dr. Benson has received research support from Ionis.
Publication Year: 2018
Publication Date: 2018-04-10
Language: en
Type: article
Indexed In: ['crossref']
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