Phase 3 Multicenter Study of Revusiran in Patients with Hereditary Transthyretin-Mediated (hATTR) Amyloidosis with Cardiomyopathy (ENDEAVOUR)

• DOI: 10.1007/s10557-019-06919-4
• Publication Date: 2020-02-15T10:02:28Z
• Authors: Daniel P. Judge; Arnt V. Kristen; Martha Grogan; Mathew S. Maurer; Rodney H. Falk; Mazen Hanna; Julian Gillmore; Pushkal Garg; Akshay K. Vaishnaw; Jamie Harrop; Christine Powell; Verena Karsten; Xiaoping Zhang; Marianne T. Sweetser; John Vest; Philip N. Hawkins
• Keywords: Adult; Male; Canada; Cardiomyopathy; Revusiran; RNA interference; Cause of Death; ATTR amyloidosis; Humans; Prealbumin; Genetic Predisposition to Disease; RNA, Small Interfering; Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Exercise Tolerance; Middle Aged; 3. Good health; Europe; Phenotype; Early Termination of Clinical Trials; Mutation; Disease Progression; Original Article; Female; Cardiomyopathies

Abstract Purpose The Phase 3 ENDEAVOUR study evaluated revusiran, an investigational RNA interference therapeutic targeting hepatic transthyretin (TTR) production, for treating cardiomyopathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis. Methods Patients with hATTR amyloidosis were randomized 2:1 to receive subcutaneous daily revusiran 500 mg ( n = 140) or placebo 66) 5 days over a week followed weekly doses. Co-primary endpoints 6-min walk test distance and serum TTR reduction. Results Revusiran treatment was stopped after median of 6.71 months; the Sponsor prematurely discontinued dosing due observed mortality imbalance between arms. Eighteen (12.9%) patients on 2 (3.0%) died during on-treatment period. Most deaths in both arms adjudicated as cardiovascular heart failure (HF), consistent natural history disease. A post hoc safety investigation treated found that, at baseline, greater proportion those who ≥ 75 years showed clinical evidence more advanced HF compared alive throughout treatment. pharmacokinetic exposures lowering did not show meaningful differences alive. deleteriously affect echocardiographic parameters, cardiac biomarkers, frequency hospitalization events. Conclusions Causes associated thoroughly investigated no clear causative mechanism could be identified. Although results suggest similar progression parameters arms, role cannot excluded. Clinical Trial Registration NCT02319005 .