Clinical benefits of long-term acoramidis treatment for ATTR-CM

In ATTRibute-CM and its open-label extension study among ATTR-CM patients, 54-month acoramidis treatment resulted in sustained risk reductions of all-cause and CV-related mortality and stabilization of biomarkers of disease progression, HF-related health status, and functional capacity.

This summary is based on the publication of Soman P, Cuddy SAM, Gillmore JD, et al. - Long-Term Durability of Acoramidis Efficacy in Transthyretin Amyloid Cardiomyopathy: Open-Label Extension of the ATTRibute-CM Randomized Clinical Trial. JAMA Cardiol. 2026 Mar 30:e260819 [Online ahead of print]. doi: 10.1001/jamacardio.2026.0819

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by destabilization of transthyretin (TTR) protein, which causes misfolding, aggregation, and deposition of TTR amyloid in the myocardium. The ATTRibute-CM trial and its open-label extension (OLE) study showed that ATTR-CM patients treated with acoramidis, a highly selective, potent, oral TTR stabilizer, for 42 months had better clinical outcomes than those who received placebo for 30 months and then were switched to acoramidis [1-4].

Aim of the study

In the current analysis of the ATTRibute-CM trial and OLE study, the authors evaluated the efficacy and safety of acoramidis up in ATTR-CM patients to 54 months.

Methods

The ATTRibute-CM trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 632 patients (aged 18–90 years) with symptomatic ATTR-CM (wild-type or variant) were randomized in a 2:1 ratio to acoramidis 800 mg twice daily or placebo for 30 months. Patients who completed the ATTRibute-CM trial could participate in the OLE study, in which all participants received acoramidis 800 mg twice daily (n=389). Median follow-up time was 53.2 months (IQR: 52.8–53.5).

Outcomes

The primary endpoints were the times to all-cause mortality, CV-related mortality (i.e., death adjudicated as CV or of undetermined cause), and first CV hospitalization, analyzed in the full analysis set (i.e., ATTRibute-CM modified intention-to-treat population; n=611). Additional endpoints were the changes from baseline up to 54 months in NT-proBNP and serum TTR levels, KCCQ – Overall Summary Score (OSS), and 6-minute walk distance (6MWD).

Safety assessment included the frequencies of any treatment-emergent adverse event, treatment-emergent serious adverse events, and treatment-related treatment-emergent adverse events.

Main results

Primary endpoints

• Up to 54 months, 107 of 409 patients (26.2%) receiving acoramidis continuously and 88 of 202 (43.6%) who switched from placebo to acoramidis died due any cause (HR: 0.55; 95%CI: 0.42–0.74; P<0.001).
• The risk of CV-related mortality was also reduced in the continuous acoramidis group compared with the placebo-to-acoramidis group (18.6% vs. 33.7%; HR: 0.51; 95%CI: 0.36–0.71; P<0.001).
• The risk of first CV hospitalization was 47% lower in the continuous acoramidis group than the placebo-to-acoramidis group (35.2% vs. 56.9%; HR: 0.53; 95%CI: 0.42–0.69; P<0.001).

Additional endpoints

• Switching from placebo to acoramidis at 30 months stabilized NT-proBNP levels. At 54 months, the median NT-proBNP change from baseline was 57 pg/mL (IQR: −572 to 918; percentage change: 39.6%) in the continuous acoramidis group and 1261 pg/mL (IQR: 253–2273; percentage change: 149.0%) in the placebo-to-acoramidis group.
• The mean serum TTR change from baseline to 54 months was 8.0 mg/dL (95%CI: 7.2–8.8; percentage change: 36.5%) for continuous acoramidis treatment and 5.5 mg/dL (95%CI: 3.8–7.3; percentage change: 25.2%) for the placebo to acoramidis switch. In both groups, serum TTR levels increased rapidly during the first month after acoramidis initiation and were sustained thereafter.
• From baseline to 54 months, the percentage change in the KCCQ-OSS was −4.7% in the continuous acoramidis group and −15.8% in the placebo-to-acoramidis group.
• The percentage 6MWD change from baseline to 54 months was −9.3% and −10.1%, respectively. Patients initially receiving placebo showed a gradual decline in 6MWD, but acoramidis initiation at 30 months led to an improvement during the following 2 years.

Safety

• The incidence of treatment-emergent adverse events was 94.3% in the continuous acoramidis group and 94.4% in the placebo-to-acoramidis group.
• The frequency of treatment-emergent adverse events leading to study drug discontinuation was also similar in the continuous acoramidis and placebo-to-acoramidis groups (2.7% vs. 2.4%), as was the frequency of treatment-emergent serious adverse events leading to study drug discontinuation (1.9% vs. 1.6%).
• Importantly, no new clinically important safety concerns were identified during the OLE period.

Conclusion

The randomized ATTRibute-CM trial and its OLE study among ATTR-CM patients demonstrated that early and continuous acoramidis treatment resulted in sustained gradual reductions in all-cause and CV-related mortality up to 54-month follow-up. Continuous acoramidis treatment was associated with durable stabilization of NT-proBNP levels, sustained higher serum TTR levels, preservation of the KCCQ-OSS, and attenuation of the decline in 6MWD. Switching from placebo to acoramidis at 30 months was associated with stabilization of NT-proBNP levels and the KCCQ-OSS and improvements in serum TTR levels and the 6MWD in the following 2 years.

According to the authors, “these findings confirm the importance of prompt diagnosis and treatment, while recognizing that patients presenting at an advanced stage may still benefit from therapy.” There were no long-term safety concerns with acoramidis.

Find this article online at JAMA Cardiol.

References

1. Gillmore JD, Judge DP, Cappelli F, et al; ATTRibute-CM Investigators. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N Engl J Med. 2024;390(2):132-142. doi:10.1056/NEJMoa2305434
2. Masri A, Judge DP, Ruberg FL, et al. Effect of acoramidis on recurrent and cumulative cardiovascular outcomes in ATTR-CM: exploratory analysis from ATTRibute-CM. J Am Coll Cardiol. 2026;87(5):490-501. doi:10.1016/j.jacc.2025.09.013
3. Judge DP, Alexander KM, Cappelli F, et al. Efficacy of acoramidis on all-cause mortality and cardiovascular hospitalization in transthyretin amyloid cardiomyopathy. J Am Coll Cardiol. 2025;85(10):1003-1014. doi:10.1016/j.jacc.2024.11.042
4. Judge DP, Gillmore JD, Alexander KM, et al. Long-term efficacy and safety of acoramidis in ATTR-CM: initial report from the open-label extension of the ATTRibute-CM trial. Circulation. 2025;151(9):601-611. doi:10.1161/CIRCULATIONAHA.124.072771