Acoramidis leads to clinically meaningful improvements from baseline in NT-proBNP and 6-minute walk distance in patients with transthyretin amyloid cardiomyopathy: observations from ATTRibute-CM

Abstract Background/Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive myocardial disease that leads to repeated cardiovascular hospitalisations and death within 3 to 10 years if left untreated. A progressive rise in NT-proBNP (>30% and >300 pg/mL) can be a prognostic marker of disease progression and is associated with an increased risk of mortality in people with ATTR-CM. In addition, the 6-minute walk distance (6MWD) test is a tool for evaluating functional capacity and is associated with prognosis in patients with ATTR-CM. Although targeted therapies have shown clinical efficacy, thresholds for clinically meaningful improvements from baseline in ATTR-CM remain unclear. Acoramidis, an oral transthyretin (TTR) stabiliser that achieves near-complete (≥90%) TTR stabilisation, is approved in the US and Europe for the treatment of ATTR-CM. In the phase 3 randomised controlled study ATTRibute-CM, acoramidis demonstrated significant efficacy on the primary endpoint of all-cause mortality, cardiovascular-related hospitalization, change from baseline (CFB) in NT-proBNP, and CFB in 6MWD (p<0.0001). Purpose We assessed the capacity for acoramidis to achieve clinically meaningful improvements from baseline through 30 months in NT-proBNP and 6MWD in participants with ATTR-CM from the phase 3 ATTRibute-CM study. Methods Randomised participants in the ATTRibute-CM study received acoramidis or placebo (2:1) for 30 months. Clinically meaningful improvements from baseline for NT-proBNP were adopted as the inverse of those used to denote progression (reduction of >30% with a minimum decrease of >300 pg/mL) and defined improvement in 6MWD as an increase of >30 m. The proportion of participants who met clinically meaningful improvement in NT-proBNP and/or 6MWD were evaluated at month 30. Participants with missing assessments at month 30 were categorised as worsened. Univariate logistic regression with treatment group as an independent variable was performed to compute the odds ratio (OR) for response. Results A total of 611 participants were analysed in the modified intention-to-treat population (acoramidis: 409; placebo: 202). Participant baseline characteristics were comparable between groups. A total of 106 (25.9%) participants in the acoramidis group showed improvement in at least one parameter compared with 19 (9.4%) in the placebo group (Table 1; OR 3.4, 95% CI 2.0–5.7, p<0.0001). Among those meeting both improvement criteria, 12 (2.9%) were in the acoramidis group compared with two (1.0%) in the placebo group (Table 2; OR 3.0, 95% CI 0.7–13.6, p<0.1502). Conclusion(s) Acoramidis treatment resulted in clinically meaningful improvements from baseline in NT-proBNP and/or 6MWD across 30 months in >25% of patients with ATTR-CM, a finding inconsistent with the natural history of this progressive disease. Further studies are needed to understand patient characteristics and factors that influence these improvements on acoramidis.

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