Improvement of health status with acoramidis in patients with wild-type and variant transthyretin amyloid cardiomyopathy: KCCQ domains analysis from the ATTRibute-CM study

Background Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) occurs as wild-type (ATTRwt-CM) and variant (ATTRv-CM) forms and is associated with a progressive decline in patients’ health status. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a patient-reported measure of health status and health-related quality of life (QoL) in patients with heart failure. The questionnaire includes 23 questions that map to seven domains including the frequency and severity of heart failure symptoms, limitations of physical and social functions, and heart failure impact on QoL. Acoramidis, an oral, approved therapy for ATTR-CM, achieves near-complete (≥90%) TTR stabilization. In the phase 3 ATTRibute-CM study, acoramidis reduced mortality and cardiovascular-related hospitalizations and attenuated the decline in heart failure-related health status vs placebo. However, the effects of acoramidis on individual KCCQ domains, particularly across ATTRwt-CM and ATTRv-CM subgroups, have not been fully characterised. Purpose To evaluate the effects of acoramidis on KCCQ Overall Summary (KCCQ-OS) and domain scores in participants with ATTRwt-CM and ATTRv-CM. Methods Participants in ATTRibute-CM were randomized 2:1 to receive acoramidis HCl 800 mg or placebo twice daily for 30 months. Efficacy analyses were conducted in the modified intention-to-treat (mITT) population. KCCQ scores were evaluated at baseline, every 3 months for the first year and then every 6 months through Month 30. Summary statistics for the change from baseline in KCCQ and domain scores at Month 30 were evaluated in ATTRwt-CM and ATTRv-CM subgroups based on observed values. The minimal clinically important difference for KCCQ-OS score is ±5 points in HF patients, indicating a meaningful improvement or worsening in health status. Results Of the 611 participants in the mITT population (acoramidis, n=409; placebo, n=202), 552 had ATTRwt-CM (acoramidis, n=370; placebo, n=182) and 59 had ATTRv-CM (acoramidis, n=39; placebo, n=20). At baseline, KCCQ scores were comparable across genotypes and treatment groups. Consistent with the overall population, acoramidis attenuated the decline in KCCQ-OS and domain scores in participants with ATTRwt-CM and ATTRv-CM. For KCCQ-OS score, the mean (SE) change from baseline in acoramidis-treated participants was −3.1 (1.05) in the ATTRwt-CM subgroup (vs −10.4 [1.67] with placebo) (Figure 1) and −3.0 (3.25) in the ATTRv-CM subgroup (vs −18.4 [10.39] with placebo) (Figure 2). A numerical improvement was observed across almost all KCCQ domains in acoramidis-treated participants with ATTRwt-CM and ATTRv-CM relative to placebo, with the most pronounced improvement observed in the self-efficacy domain. Conclusions In ATTRibute-CM, acoramidis attenuated the decline in heart failure-related health status vs placebo in participants with ATTRwt-CM and ATTRv-CM, with consistent benefits observed across KCCQ-OS and individual domain scores.