Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy - ATTRibute-CM

Nov 08, 2025
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Fred M. Kusumoto, MD, FACC
Date Updated:
11/08/2025
Original Posted Date:
08/27/2023
References

Highlighted text has been updated as of Nov. 8, 2025.

Contribution To Literature:

The ATTRibute-CM trial showed that acoramidis HCl is superior to placebo for improving both hard cardiovascular endpoints as well as quality of life endpoints among patients with ATTR-CM, with beneficial effects observed consistently in ATTRwt-CM and ATTRv-CM variant groups in the open-label extension.

Description:

The goal of the trial was to compare the safety and efficacy of acoramidis compared with placebo among patients with transthyretin amyloid cardiomyopathy (ATTR-CM).

Study Design

Eligible patients were randomized in a 2:1 randomized double-blinded fashion to either acoramidis HCl (n = 421) or matching placebo (n = 211). Acoramidis was administered at a dose of 800 mg BID for 30 months. All participants in the open-label extension had open-label treatment with acoramidis from months 30-42.

  • Total number of enrollees: 632
  • Total number randomized: 611 (380 in open-label extension)
  • Duration of follow-up: 30 months; 42 months for open-label extension
  • Mean patient age: 77.3 years
  • Percentage female: 10%

Inclusion criteria:

  • Age 18-90 years
  • Met the following two criteria: diagnosed ATTR-CM (wild-type [WT] or variant); NYHA class I-III with ≥1 hospitalization for heart failure (HF); signs and symptoms of volume overload; HF that resulted in diuretic treatment; ATTR-positive biopsy or technetium-99m scintigraphy (99mTc) scan; light chain amyloidosis excluded if diagnosis by 99mTc
  • Six-minute walk distance ≥150 m
  • NT-proBNP ≥300 pg/mL
  • Left ventricular wall thickness ≥12 mm

Exclusion criteria:

  • Acute coronary syndrome, stroke, transient ischemic attack, or coronary revascularization within 90 days
  • Likely heart transplant within 1 year
  • AL amyloidosis
  • Transaminitis
  • NT-proBNP ≥8500 pg/mL
  • Estimated glomerular filtration rate <15

Other salient features/characteristics:

  • ATTRwt-CM: 90.4%
  • NT-proBNP: 2326 pg/mL
  • Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS) at baseline: 71
  • Concomitant tafamidis use: 18%

Principal Findings:

The primary endpoint, a hierarchical analysis consisting of all-cause mortality, cumulative frequency of cardiovascular-related hospitalization, change from baseline in NT-proBNP, and change from baseline in 6-minute walk distance, had an overall win ratio favoring acoramidis (win ratio 1.8, 95% confidence interval [CI] 1.4-2.2, p < 0.0001).

Secondary outcomes for acoramidis vs. placebo:

  • All-cause mortality: 19.3% vs. 25.7%; hazard ratio (HR) 0.77, 95% CI 0.54-1.10 (p = 0.15)
  • Adjusted mean factor change in NT-proBNP from baseline: 0.529 (95% CI 0.46-0.60, p < 0.05)
  • Improvement from baseline in 6-minute walk distance: 39.6 m (95% CI 21.1-58.2, p < 0.001)
  • Cardiovascular-related hospitalization: 26.7% vs. 42.6% (p < 0.0001)
  • Least means square change in KCCQ-OS: 9.94 points (95% CI 5.97-13.91, p < 0.001)

Composite of all-cause mortality and cardiovascular-related hospitalization: HR 0.65, 95% CI 0.50-0.83 (p = 0.0008; number needed to treat = 7)

Open-label extension study:

At month 30, compared with placebo, acoramidis reduced the risk of all-cause mortality/first cardiovascular hospitalization by 31% in ATTRwt-CM (HR, 0.69; 95% CI, 0.52-0.90; p=0.007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; p=0.01) groups. Through month 42, all-cause mortality was reduced with HRs of 0.70 (95% CI, 0.50-0.98; p=0.04) and 0.41 (95% CI, 0.19-0.93; p=0.03) in the ATTRwt-CM and ATTRv-CM groups, respectively.

For secondary outcomes, consistent treatment benefit was observed in patients with ATTRwt-CM and ATTRv-CM. Within variant subgroups (p.Val142Ile [n=35] vs. non-p.Val142Ile), consistent treatment benefits were observed for all-cause mortality/cardiovascular hospitalization through month 30 and all-cause mortality through month 42.

Interpretation:

The results of this trial indicate that acoramidis 800 mg BID is superior to placebo for improving both cardiovascular endpoints (primarily cardiovascular-related hospitalization) as well as surrogate (NT-proBNP) and quality of life endpoints among patients with ATTR-CM. Both tafamidis and acoramidis are stabilizers of transthyretin. Acoramidis has the potential to be an effective and safe alternative to tafamidis for the treatment of ATTR-CM. A head-to-head comparison and cost considerations are important next steps.

In the open-label extension study, acoramidis had a consistent beneficial effect in both ATTRwt-CM and ATTRv-CM groups, indicating that further studies in variant subgroups are warranted to better characterize the therapeutic benefit of acoramidis.

References:

Alexander KM, Davis MK, Akinboboye O, et al. Efficacy of Acoramidis in Wild-Type and Variant Transthyretin Amyloid Cardiomyopathy: Results From ATTRibute-CM and Its Open-Label Extension. JAMA Cardiol. Published online November 8, 2025. doi:10.1001/jamacardio.2025.4477

Presented by Margot K. Davis, MD, at the American Heart Association Scientific Sessions (AHA 2025), New Orleans, LA, Nov. 8, 2025.

Gillmore JD, Judge DP, Cappelli F, et al., on behalf of the ATTRibute-CM Investigators. Efficacy and Safety of Acoramidis in Transthyretin Amyloid Cardiomyopathy. N Engl J Med 2024;390:132-42.

Presented by Dr. Daniel Judge at the American Heart Association Scientific Sessions, Philadelphia, PA, November 12, 2023.

Presented by Dr. Julian Gillmore at the European Society of Cardiology Congress, Amsterdam, Netherlands, August 27, 2023.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: AHA23, Amyloid, Cardiomyopathies, Heart Failure, AHA Annual Scientific Sessions, AHA25


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