Key Points:
- Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the destabilization of transthyretin (TTR), leading to amyloid fibril deposition in the heart, progressive heart failure, and premature death. Acoramidis is an oral TTR stabilizer that achieves near-complete (≥90%) TTR stabilization.
- In the phase 3 ATTRibute-CM trial, acoramidis reduced the risk of all-cause mortality or first cardiovascular hospitalization versus placebo at 30 months.
- In this open-label extension, eligible participants who completed the double-blind phase all received acoramidis. Continuous acoramidis treatment was associated with a significant reduction in both all-cause mortality and cardiovascular mortality through month 54 compared with the placebo-to-acoramidis group.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease caused by destabilization of the transthyretin (TTR) protein, which misfolds and deposits as amyloid fibrils in the heart. This process leads to progressive heart failure, cardiovascular hospitalizations, and premature death. Acoramidis is an oral TTR stabilizer that achieves near-complete (≥90%) TTR stabilization and is approved for the treatment of wild-type or variant ATTR-CM. In the phase 3 ATTRibute-CM trial, acoramidis reduced the risk of all-cause mortality or first cardiovascular hospitalization compared with placebo at 30 months. However, whether these benefits continue with longer-term follow-up remains uncertain.
On March 30th, 2026, the results of “Long-Term Survival Benefits and Disease Stabilization with Acoramidis in Patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM)” were presented at ACC Scientific Sessions 2026 in New Orleans, LA, with simultaneous publication in JAMA Cardiology. The purpose of this analysis was to evaluate the long-term efficacy and safety of acoramidis through Month 54 of the ATTRibute-CM trial and its open-label extension (OLE).
In ATTRibute-CM, 632 participants with ATTR-CM were randomized in a 2:1 ratio to receive acoramidis 800 mg twice daily or placebo for 30 months. The modified intention-to-treat population included 611 participants (409 acoramidis, 202 placebo). Participants who completed the double-blind phase were invited to enroll in the OLE, in which all participants received open-label acoramidis 800 mg twice daily. Those who had previously received acoramidis continued their therapy (continuous acoramidis group), and those who had received placebo were switched to acoramidis (placebo-to-acoramidis group). Key endpoints included time to all-cause death, cardiovascular death, and first cardiovascular hospitalization, as well as changes in NT-proBNP, serum TTR, Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score, and 6-minute walk distance (6MWD). Analyses were performed using a stratified Cox proportional hazards model.
The mean age at randomization was 77.3 years, 9.8% were female, and 90.3% had wild-type ATTR-CM. Overall, 389 of 438 eligible participants enrolled in the OLE (263 continuous acoramidis, 126 placebo-to-acoramidis). At OLE entry, the continuous acoramidis group had less advanced disease, with a greater proportion in NYHA class I or II (82.1% vs. 62.7%), higher mean serum TTR levels (32.8 vs. 25.5 mg/dL), and lower median NT-proBNP levels (2094 vs. 2905 pg/mL) compared with the placebo-to-acoramidis group. The median follow-up was 53.2 months.
Through Month 54, continuous acoramidis treatment was associated with a 45% reduction in all-cause mortality compared with the placebo-to-acoramidis group (26.2% vs. 43.6%; HR 0.55 [95% CI: 0.42, 0.74]; p<0.001) as well as a 49% reduction in cardiovascular mortality (18.6% vs. 33.7%; HR 0.51 [95% CI: 0.36, 0.71]; p<0.001). Continuous acoramidis also reduced first cardiovascular hospitalization by 47% (35.2% vs. 56.9%; HR 0.53 [95% CI: 0.42, 0.69]; p<0.001). The survival benefit was consistent across all prespecified subgroups. Notably, the magnitude of risk reduction in all cause and cardiovascular mortality increased progressively from Month 30 (23% and 29%, respectively) to Month 42 (36% and 45%) to Month 54 (45% and 49%), demonstrating a durable and growing benefit with continued treatment.
Continuous acoramidis ALSO stabilized NT-proBNP concentrations and sustained higher sTTR levels through Month 54, while switching from placebo to acoramidis at Month 30 appeared to stabilize NT-proBNP and rapidly increase sTTR levels. Heart failure-related health status (KCCQ-OS) and functional capacity (6MWD) were better preserved with continuous acoramidis, though participants who switched to acoramidis also demonstrated subsequent stabilization and improvement. Acoramidis was well tolerated through Month 54, with treatment-related adverse events occurring in only 2.6% of OLE participants and no new long-term safety concerns identified. These findings demonstrate the long-term, durable clinical benefits of early and continuous acoramidis treatment in ATTR-CM and underscore the importance of early diagnosis and prompt initiation of therapy.
Limitations include the potential selection bias inherent in the OLE design, as enrollment was limited to participants who completed the double-blind phase and elected to continue. The continuous acoramidis group had less advanced disease at OLE entry compared with the placebo-to-acoramidis group, which could have influenced the estimated treatment effect. There was no concurrent placebo group during the OLE. Additionally, some participants received concomitant tafamidis, with greater use in the placebo group. SGLT2 inhibitor and mineralocorticoid receptor antagonist use was also higher in the placebo-to-acoramidis group at OLE entry. These imbalances may have led to an underestimation of acoramidis efficacy. Finally, improvements in functional outcomes among those who switched from placebo may be influenced by survivor bias.
Prem Soman, MD, PhD, of the Division of Cardiology at the University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania, concluded: “These findings demonstrate the long-term, durable clinical benefits and safety of early and continuous acoramidis treatment in patients with ATTR-CM, and underscores the importance of early diagnosis and treatment.”