Consistent effect on Kansas City cardiomyopathy questionnaire overall summary score with acoramidis treatment compared with placebo across all subgroups in ATTRibute-CM
M Fontana, E Kastritis, J Mitchell, J Krejci, P Van Der Meer, H Falvey, C Chen, J F Tamby, J Fox, S Siddhanti, F Cappelli, A Masri, P Garcia-Pavia, J Spertus, B SperryAbstract
Background
Transthyretin amyloid cardiomyopathy (ATTR-CM), an infiltrative, restrictive, life-threatening, progressive disease caused by the destabilization of transthyretin (TTR) tetramers, is associated with impaired health status (symptoms, function and quality of life). Acoramidis, an oral, near-complete (≥90%) TTR stabilizer, is approved in the USA, Europe, Japan, and the UK for the treatment of ATTR-CM. In the 30-month phase 3 ATTRibute-CM study (NCT03860935), acoramidis treatment markedly attenuated the decline in patients’ heart failure (HF)-related health status as assessed by the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS) compared with placebo. The consistency of this benefit across clinically relevant patient subgroups has not been fully characterized.
Purpose
To evaluate the effect of acoramidis on KCCQ-OS at Month 30 across participant subgroups from ATTRibute-CM.
Methods
Participants in ATTRibute-CM were randomized 2:1 to receive acoramidis HCl 800 mg or placebo twice daily for 30 months. Concomitant tafamidis use was permitted after Month 12 at investigator discretion. Efficacy analyses were performed in the modified intention-to-treat (mITT) population (acoramidis: 409; placebo: 202). Least-squares mean (LSM) change from baseline (CFB) differences were estimated using mixed models with repeated measures, adjusted for baseline health status and stratification factors. A sensitivity analysis was performed, excluding all participants who received concomitant tafamidis at any time during the study. Efficacy analyses at Month 30 were performed in the following pre-specified subgroups: ATTR-CM genotype (wild-type vs variant), NT-proBNP (≤3000 vs >3000 ng/L), estimated glomerular filtration rate (eGFR; ≥45 vs <45 mL/min/1.73 m²), age (<78 years vs ≥78 years), country (US vs rest of world), and New York Heart Association (NYHA) class (I/II vs III).
Results
At Month 30, the LSM CFB difference in KCCQ-OS between treatment groups was 9.9 (95% confidence interval [CI]: 5.97 to 13.91; p<0.0001), favouring acoramidis over placebo (Table). The tafamidis sensitivity analysis showed LSM CFBs (standard error) in KCCQ-OS of −12.9 (1.27) in the acoramidis group and −22.6 (1.88) in the placebo group, with a LSM CFB difference between treatments of 9.7 points (95% CI, 5.26 to 14.13; p<0.0001; Table). The benefit of acoramidis on KCCQ-OS at Month 30 was observed across all pre-specified participant subgroups, with no evidence of heterogeneity of treatment effect (Figure). P values were significant (<0.05) in each participant subgroup except for eGFR <45 mL/min/1.73 m² and NYHA class III, which both favoured acoramidis but were limited by small patient numbers.
Conclusions
Acoramidis significantly attenuated the decline in HF-related health status compared with placebo in patients with ATTR-CM. This effect was observed consistently across all pre-specified participant subgroups, including those with advanced HF symptoms.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.