Highlight
Acoramidis, an oral transthyretin (TTR) kinetic stabilizer given at 712 mg twice daily, delivered consistent clinical benefit in the phase 3 ATTRibute‑CM trial and its open‑label extension across both wild‑type (ATTRwt‑CM) and variant (ATTRv‑CM) forms of transthyretin amyloid cardiomyopathy. Relative risk reductions for the composite of all‑cause mortality (ACM) and first cardiovascular hospitalization (CVH) at month 30 were 31% in ATTRwt‑CM and 59% in ATTRv‑CM; ACM reductions persisted through month 42. Post‑hoc subgroup analyses — including the US‑prevalent p.Val142Ile (V122I) variant — showed consistent directionality of benefit. These findings support further focused study of variant subgroups.
Background and Disease Burden
Transthyretin amyloid cardiomyopathy (ATTR‑CM) is a progressive, life‑limiting disease caused by misfolding of the hepatic transport protein transthyretin (TTR), resulting in cardiac deposition of insoluble amyloid fibrils. Clinical phenotypes include ATTRwt‑CM, typically affecting older adults, and hereditary ATTRv‑CM, caused by pathogenic TTR variants; p.Val142Ile (historically V122I) is the most common pathogenic variant in the United States and is associated with earlier onset and worse prognosis in some series.
Until recently, treatment was largely supportive. Pharmacologic stabilization of the TTR tetramer to prevent dissociation and amyloidogenesis is a proven disease‑modifying strategy: tafamidis, the first approved TTR stabilizer, reduced mortality and cardiovascular hospitalizations in a broad ATTR‑CM population (ATTR‑ACT; NEJM 2018). Acoramidis (AG10) is a next‑generation, oral TTR stabilizer designed to achieve near‑complete stabilization (≥90%) and to improve clinical outcomes by reducing ongoing amyloid deposition and downstream cardiac dysfunction.
Study Design and Methods
ATTRibute‑CM was an international, multicenter, randomized, placebo‑controlled phase 3 trial (NCT03860935) enrolling adults with ATTR‑CM from April 2019 to May 2023, with a planned randomized treatment period of 30 months followed by an ongoing open‑label extension (OLE) through month 42 (NCT04988386). The trial randomized participants 1:1 to oral acoramidis 712 mg twice daily or matching placebo. The modified intention‑to‑treat (mITT) population included 611 of 632 enrolled participants.
Key prespecified outcomes analyzed for the ATTRwt‑CM and ATTRv‑CM cohorts included the composite of all‑cause mortality and first cardiovascular‑related hospitalization (ACM/first CVH) through month 30 and ACM through month 42. Secondary measures included serum TTR concentration (pharmacodynamic marker of stabilization), 6‑minute walk distance (6MWD), Kansas City Cardiomyopathy Questionnaire‑Overall Summary (KCCQ‑OS) score, and N‑terminal pro B‑type natriuretic peptide (NT‑proBNP). Post‑hoc analyses examined variant subgroups: p.Val142Ile (V122I) and non‑p.Val142Ile variants.
Key Results
Population
– Total randomized in mITT: 611 participants (552 ATTRwt‑CM; 59 ATTRv‑CM). Among the 59 variant participants, 35 carried p.Val142Ile.
– Mean (SD) age: ATTRwt‑CM 78 (6.3) years; ATTRv‑CM 73 (7.7) years.
– Sex: ATTRwt‑CM 92.0% male; ATTRv‑CM 77.3% male.
– A subset of 380 participants entered the OLE after month 30 (data cut analyzed January–July 2025).
Primary composite outcome (ACM/first CVH) through month 30
– ATTRwt‑CM: Acoramidis reduced the risk of ACM/first CVH by 31% versus placebo (hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.52–0.90; P = .007).
– ATTRv‑CM: The effect was larger numerically with a 59% relative risk reduction (HR 0.41; 95% CI 0.21–0.81; P = .01).
All‑cause mortality through month 42
– ATTRwt‑CM: ACM was reduced with HR 0.70 (95% CI 0.50–0.98; P = .04), indicating a 30% relative risk reduction through month 42.
– ATTRv‑CM: ACM reduction was pronounced (HR 0.41; 95% CI 0.19–0.93; P = .03), consistent with the month‑30 composite result.
Secondary endpoints
– Measures of functional capacity (6MWD), patient‑reported health status (KCCQ‑OS), and NT‑proBNP showed consistent treatment benefit in both ATTRwt‑CM and ATTRv‑CM cohorts across timepoints, supporting a concordant effect on symptoms and surrogate biomarkers.
– Serum TTR concentrations increased toward levels consistent with ≥90% tetramer stabilization on acoramidis, consistent with the expected mechanism of action.
Variant subgroup (post‑hoc) findings
– Both p.Val142Ile and non‑p.Val142Ile subgroups demonstrated consistent directionality of benefit for ACM/first CVH through month 30 and ACM through month 42. Absolute and relative effect estimates in these small subgroups were hypothesis‑generating rather than definitive due to limited numbers (35 participants with p.Val142Ile).
Safety
– Safety data were not the focus of the summary provided here. Prior reports indicate that TTR stabilizers are generally well tolerated; the original publication should be consulted for detailed adverse event profiles and discontinuation rates.
Interpretation of effect sizes and statistical context
– The observed HRs indicate clinically meaningful relative risk reductions for the composite outcome and for mortality. The magnitude of effect appears larger in the variant cohort; however, the variant cohort was small and results were derived from post‑hoc subgroup analyses, which are subject to greater uncertainty and potential imprecision.
Expert Commentary and Clinical Context
Mechanistic plausibility
– Acoramidis stabilizes TTR tetramers, reducing dissociation into monomers that can misfold and aggregate into amyloid fibrils. Increased serum TTR measured with treatment is an expected pharmacodynamic marker of this stabilization and aligns with improved clinical outcomes.
Comparison with existing therapies
– Tafamidis demonstrated mortality and heart‑failure hospitalization benefit in the ATTR‑ACT trial (Maurer et al., NEJM 2018). Acoramidis is a second TTR stabilizer with a distinct chemical structure and high target‑engagement levels. Direct head‑to‑head comparative data are not available; cross‑trial comparisons should be made with caution because of differences in trial populations, baseline disease stage, and event rates.
Limitations and generalizability
– Variant subgroup analyses were post‑hoc and underpowered. The ATTRv‑CM cohort (n=59) — and particularly the p.Val142Ile subgroup (n=35) — are small, limiting precision and raising the risk of chance findings.
– The trial population was predominantly male and older, reflecting known epidemiology but potentially limiting applicability to underrepresented groups, including women and younger carriers of pathogenic variants.
– Owing to the open‑label nature of the extension, ascertainment and behavioral effects could influence outcomes beyond the randomized period.
– The provided summary did not detail safety outcomes comprehensively; clinicians should review the full manuscript for adverse events, interactions, and discontinuations.
Clinical implications
– The consistent signal of benefit in both ATTRwt‑CM and ATTRv‑CM supports acoramidis as a promising disease‑modifying option for ATTR‑CM. The particularly large relative risk reductions observed in the variant cohort (including p.Val142Ile) underscore the need for dedicated investigations in genetic subgroups, where disease trajectory and therapeutic responses may differ.
Conclusions and Future Directions
The ATTRibute‑CM randomized trial and its open‑label extension demonstrate that acoramidis improves clinically meaningful outcomes in transthyretin amyloid cardiomyopathy, with consistent benefit across wild‑type and variant forms through 30 months for the composite of mortality and first cardiovascular hospitalization and through 42 months for all‑cause mortality. Post‑hoc analyses in p.Val142Ile and other variant subgroups showed directionally similar benefit but are hypothesis‑generating because of small numbers.
Future priorities include randomized or adequately powered observational studies focused on variant genotypes, longer‑term safety and effectiveness surveillance in broader populations, comparative effectiveness studies versus other TTR stabilizers and TTR‑lowering therapies, and increased enrollment of women and diverse racial and ethnic groups to improve generalizability.
Funding and ClinicalTrials.gov
The trial is reported under ClinicalTrials.gov identifiers NCT03860935 and NCT04988386. Detailed funding disclosures are provided in the primary manuscript (Alexander KM et al., JAMA Cardiol. 2025 Nov 8:e254477). Please consult the original publication for sponsor and conflict‑of‑interest statements.
References
1) 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. 2025 Nov 8:e254477. doi: 10.1001/jamacardio.2025.4477. Epub ahead of print. PMID: 41205147; PMCID: PMC12596743.
2) Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018;379(11):1007‑1016. doi:10.1056/NEJMoa1805686.
3) Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State‑of‑the‑Art Review. J Am Coll Cardiol. 2019;73(22):2872‑2891. doi:10.1016/j.jacc.2019.03.009.
Practical takeaways for clinicians
– For patients with ATTRwt‑CM, acoramidis appears to offer a meaningful reduction in the combined endpoint of death and first cardiovascular hospitalization and reduces mortality through 42 months.
– For patients with ATTRv‑CM, including those with p.Val142Ile, acoramidis produced numerically larger relative risk reductions, but these subgroup findings should be interpreted cautiously and considered hypothesis‑generating pending larger, dedicated analyses.
– Clinicians should review full safety data and individual patient characteristics (disease stage, comorbidities, concomitant therapies) when considering TTR stabilization strategies and remain attentive to emerging evidence from longer‑term follow‑up and variant‑focused studies.
