Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial

• Published in: Circulation (New York, N.Y.) Vol. 151; no. 9; pp. 601 - 611
• Main Authors: Judge, Daniel P., Gillmore, Julian D., Alexander, Kevin M., Ambardekar, Amrut V., Cappelli, Francesco, Fontana, Marianna, García-Pavía, Pablo, Grodin, Justin L., Grogan, Martha, Hanna, Mazen, Masri, Ahmad, Nativi-Nicolau, Jose, Obici, Laura, Hvitfeldt Poulsen, Steen, Sarswat, Nitasha, Shah, Keyur, Soman, Prem, Lystig, Ted, Cao, Xiaofan, Wang, Kevin, Pecoraro, Maria Lucia, Tamby, Jean-François, Katz, Leonid, Sinha, Uma, Fox, Jonathan C., Maurer, Mathew S.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 04.03.2025
• Subjects: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial - diagnosis; Amyloid Neuropathies, Familial - drug therapy; Amyloid Neuropathies, Familial - mortality; Benzoxazoles; Cardiomyopathies - drug therapy; Cardiomyopathies - mortality; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain - blood; Original s; Prealbumin - metabolism; Time Factors; Treatment Outcome; amyloidosis, familial; hospitalization; clinical trials as topic; mortality; exercise tolerance; quality of life; transthyretin-related heart failure
• ISSN: 0009-7322; 1524-4539; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.124.072771

BACKGROUND: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE. METHODS: Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42. RESULTS: Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46-0.72) at month 42 based on a stratified Cox proportional hazards model (P<0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47-0.88) and 0.53 (95% CI, 0.41-0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation. CONCLUSIONS: Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04988386.