• Julian D Gillmore, Daniel P Judge, Francesco Cappelli, Marianna Fontana, Pablo Garcia-Pavia, Simon Gibbs, Martha Grogan, Mazen Hanna, James Hoffman, Ahmad Masri, Mathew S Maurer, Jose Nativi-Nicolau, Laura Obici, PoulsenSteen HvitfeldtSHFrom the National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London (J.D.G., M.F.); the Medical University of South Carolina, Charleston, SC (D.P.J.); Tuscan Regional Amyloidosis Centr, Frank Rockhold, Keyur B Shah, Prem Soman, Jyotsna Garg, Karen Chiswell, Haolin Xu, Xiaofan Cao, Ted Lystig, Uma Sinha, Jonathan C Fox, and ATTRibute-CM Investigators.
• From the National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London (J.D.G., M.F.); the Medical University of South Carolina, Charleston, SC (D.P.J.); Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence (F.C.), and the Amyloidosis Research and Treatment Center, IRCCS Fondazione Policlinico San Matteo, Pavia (L.O.) - both in Italy; the Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Centro de Investigacíon Biomédica en Red Enfermedades Cardiovaculares, and Centro Nacional de Investigaciones Cardiovasculares (P.G.-P.) - both in Madrid; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart, Amsterdam (P.G.-P.); the Victorian and Tasmanian Amyloidosis Service, Department of Haematology, Monash University Eastern Health Clinical School, Box Hill, VIC, Australia (S.G.); the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (M.G.); the Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland (M.H.); the Sylvester Comprehensive Cancer Center, University of Miami, Miami (J.H.), and the Amyloidosis Program, Department of Transplant, Mayo Clinic, Jacksonville (J.N.-N.) - both in Florida; the Cardiac Amyloidosis Program, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (A.M.); the Cardiac Amyloidosis Program, Division of Cardiology, Columbia College of Physicians and Surgeons, New York (M.S.M.); the Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (S.H.P.); Duke Clinical Research Institute (F.R., J.G., K.C., H.X.) and Duke University Medical Center (F.R.) - both in Durham, NC; the Pauley Heart Center, Virginia Commonwealth University, Richmond (K.B.S.); the Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh (P.S.); and Eidos Therapeutics affiliate of BridgeBio Pharma, San Francisco (X.C., T.L., U.S., J.C.F.).
• N. Engl. J. Med. 2024 Jan 11; 390 (2): 132142132-142.

BackgroundTransthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo.MethodsIn this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level.ResultsA total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients.ConclusionsIn patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).Copyright © 2024 Massachusetts Medical Society.

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