Acoramidis treatment attenuates the rise in N-terminal pro-B-type natriuretic peptide from baseline to month 30 compared with placebo across participant subgroups in ATTRibute-CM
P Soman, N Sarswat, A Masri, K Bhatt, M Fontana, P Garcia-Pavia, O Akinboboye, R K Cheng, C Chen, J F Tamby, J C Fox, J D Gillmore, D P Judge, J L Januzzi Jr, M G KhouriAbstract
Background
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an infiltrative, restrictive, life threatening, progressive disease caused by the destabilization of transthyretin (TTR) tetramers. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of disease progression, and progressive rises in its levels are associated with increased mortality. Acoramidis, an oral, near-complete (≥90%) TTR stabilizer, is approved in the US, Europe, Japan, and UK for the treatment of ATTR-CM. In the 30-month, phase 3 ATTRibute-CM study, acoramidis treatment significantly attenuated the rise in NT-proBNP levels compared with placebo (p<0.0001). Additionally, at Month 30, 45% of acoramidis recipients who had NT-proBNP data available at both baseline and Month 30 experienced a net decrease from baseline in their NT-proBNP levels, compared with 9% of those receiving placebo.
Purpose
To evaluate the effect of acoramidis on NT-proBNP levels across patient subgroups in 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's discretion. Efficacy analyses of NT-proBNP levels at Month 30 were conducted in 595 randomized participants (acoramidis, n=397; placebo, n=198) with baseline estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m². The adjusted geometric mean (AGM) fold change from baseline to Month 30 in NT-proBNP level was analysed in the acoramidis and placebo treatment groups, using a mixed effects model for repeated measures. The AGM fold change ratio (acoramidis vs placebo) was calculated for the following pre-specified participant subgroups: ATTR-CM genotype (wild-type vs variant), NT-proBNP (≤3000 vs >3000 ng/L), eGFR (<45 vs ≥45 mL/min/1.73 m²), age (<78 vs ≥78 years), country (USA vs rest of world), and New York Heart Association class (I/II vs III). The change from baseline to Month 30 in NT-proBNP levels in participants who received acoramidis alone or placebo alone (i.e. who did not receive open-label concomitant tafamidis) was also assessed.
Results
In all participant subgroups assessed, the NT-proBNP AGM fold change ratio from baseline to Month 30 favoured acoramidis over placebo (all p<0.001), with no heterogeneity of treatment effect noted in any of the subgroups (Figure). In participants who received acoramidis alone (n=232), the median (Q1, Q3) change from baseline in NT-proBNP at Month 30 was 436 (−431, 617) ng/L, compared with 2532 (440, 2634) ng/L in those who received placebo alone (n=98).
Conclusions
In ATTRibute-CM, acoramidis consistently blunted the 30-month increase in NT-proBNP by about 50% across all participant subgroups assessed, including advanced disease, compared with placebo, demonstrating its robust efficacy on a key biomarker of ATTR-CM disease progression.For image description, please refer to the figure legend and surrounding text.