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

Authors, Journal, Affiliations, Type, DOI

• Gillmore JD, Judge DP, Cappelli F, Fontana M, Garcia-Pavia P, Gibbs S, Grogan M, Hanna M, Hoffman J, Masri A, Maurer MS, Nativi-Nicolau J, Obici L, Poulsen SH, Rockhold F, Shah KB, Soman P, Garg J, Chiswell K, Xu H, Cao X, Lystig T, Sinha U, Fox JC; for the ATTRibute-CM Investigators
• New England Journal of Medicine, January 11, 2024; 390(2):132–142
• Multi-national, multi-centre; lead institutions: National Amyloidosis Centre UCL/Royal Free Hospital London; Medical University of South Carolina; Mayo Clinic; Cleveland Clinic; Oregon Health & Science University; Eidos Therapeutics/BridgeBio Pharma (sponsor representatives)
• Phase 3 double-blind RCT
• DOI: https://doi.org/10.1056/NEJMoa2305434

Overview

ATTRibute-CM is the pivotal Phase 3 trial of acoramidis (AG10), a second-generation TTR tetramer stabilizer that mimics the naturally protective T119M variant through enthalpic hydrogen bonding, achieving >90% TTR stabilization across the dosing interval. In 632 patients with ATTR-CM (90% wild-type), acoramidis 800 mg BID for 30 months produced a significantly better 4-step hierarchical primary outcome (death, CV hospitalization, NT-proBNP, 6MWT) compared with placebo, with a win ratio of 1.8 (P<0.001). Key secondary endpoints — 6MWT, KCCQ-OS, serum TTR, and CV hospitalization rate — were all significantly improved. Mortality trended numerically better (80.7% vs 74.3% 30-month survival) but did not achieve formal statistical significance; curves diverged only after ~19 months, recapitulating the delayed benefit pattern observed with tafamidis. Adverse event rates were similar; serious adverse events were less frequent with acoramidis.

Keywords

Transthyretin amyloid cardiomyopathy, ATTR-CM, acoramidis, AG10, TTR stabilizer, win ratio, Finkelstein-Schoenfeld, NT-proBNP, 6-minute walk distance, KCCQ

Key Takeaways

Background and Mechanism

• ATTR-CM results from TTR tetramer destabilization → monomer misfolding → myocardial amyloid deposition → restrictive cardiomyopathy
• Tafamidis established TTR stabilization as a valid therapeutic strategy (ATTR-ACT, NEJM 2018); dose-related mortality reduction with higher stabilization seen in long-term extension (median 58 months)
• T119M TTR variant confers natural protection via unique hydrogen bonding; acoramidis was rationally designed to mimic this variant
• Acoramidis achieves >90% TTR stabilization (ex vivo, across the dosing interval) through enthalpic hydrogen bonding — primarily enthalpic (H-bond) vs predominantly entropic (hydrophobic) binding of tafamidis/diflunisal
• X-ray crystallography confirmed acoramidis binding to the T4 thyroid hormone-binding sites on TTR
• More potent than tafamidis and diflunisal in potency, binding affinity, binding-site occupancy, and TTR stabilization across assay methods

Study Design

• Phase 3, double-blind, placebo-controlled; BridgeBio Pharma–funded
• N=632; acoramidis 800 mg BID (n=421) vs placebo (n=211); 2:1 randomization
• Modified ITT population: 611 patients (eGFR ≥30 excluded stage 4 CKD patients); safety population: 632
• Stratified by TTR genotype (WT vs variant), NT-proBNP (≤3000 or >3000 pg/mL), eGFR (<45 or ≥45)
• 30-month treatment duration; last patient completed April 28, 2023
• Eligibility: confirmed ATTR-CM (endomyocardial biopsy or Tc-99m scintigraphy Perugini grade ≥2 + AL exclusion); clinical HF; 6MWT ≥150 m × 2; NT-proBNP ≥300 pg/mL; LVWT ≥12 mm; eGFR ≥15
• Tafamidis use prohibited in first 12 months; permitted thereafter

Patient Characteristics

• Mean age 77±6.6 years; 90.2% men; 90.3% wild-type TTR
• NYHA class II 72.0%, class III 17.2%
• NAC staging: stage I 57%, stage II 32%, stage III 11%

Primary Outcome

• 4-step hierarchical composite (death from any cause, CV hospitalization, NT-proBNP change, 6MWT change) — Finkelstein-Schoenfeld method
• Finkelstein–Schoenfeld test statistic 5.015; P<0.001
• Win ratio 1.8 (95% CI 1.4–2.2): 63.7% pairwise comparisons favored acoramidis, 35.9% favored placebo
• Component contributions: death 28.8%, CV hosp 27.0%, NT-proBNP 30.2%, 6MWT 14.3%; 0.4% ties
• 2-component hierarchy (death + CV hosp): win ratio 1.5 (95% CI 1.1–2.0)
• 3-component (death + CV hosp + 6MWT): win ratio 1.4 (95% CI 1.1–1.8)
• Note: primary endpoint was amended during the trial from 2-component → 3-component → 4-component (timing/rationale in Supplementary Appendix)

Secondary Outcomes

• CV-related hospitalization: relative risk ratio 0.496 (95% CI 0.355–0.695) in favor of acoramidis
• NT-proBNP at 30 months: ratio of adjusted geometric mean factor change 0.529 (95% CI 0.463–0.604)
• 6MWT: least-squares mean difference +39.6 m (95% CI 21.1–58.2; P<0.001)
• KCCQ-OS: least-squares mean difference +9.94 points (95% CI 5.97–13.91; P<0.001)
• Serum TTR level: +7.01 mg/dL (95% CI 5.79–8.40; P<0.001) — serum TTR typically below normal or low-normal in ATTR-CM; consistently higher throughout trial in acoramidis group
• Death from any cause: 30-month survival 80.7% vs 74.3%; Cox proportional-hazards model showed deviation from model assumptions (formal result not reported); log-rank test (prespecified sensitivity analysis) not significant; curves crossed multiple times early before separating at ~19 months

Safety

• Adverse events during treatment: 98.1% (acoramidis) vs 97.6% (placebo) — similar
• Serious adverse events: 54.6% vs 64.9% — fewer with acoramidis
• Discontinuation due to adverse events: similar in both arms (excluding death)
• 17.5% of primary analysis patients received tafamidis during the trial (permitted after month 12): 14.9% in acoramidis group, 22.8% in placebo group; median time to initiation 17.2 months; median exposure 11.4 months

12-Month Interim Analysis

• Primary (6MWT at 12 months): least-squares mean −26.51 m (acoramidis) vs −24.54 m (placebo) — NOT significant; alpha penalty of 0.01 applied to final analysis
• KCCQ-OS trend at 12 months: −7.00 (acoramidis) vs −10.21 (placebo)

Limitations of the document

• Protocol amendments: Primary endpoint changed three times during the trial (2-component → 3-component → 4-component); introduces questions about pre-specification rigor
• Industry-funded: BridgeBio Pharma designed the trial, analyzed data in parallel with independent reporting center; first draft written by last author; potential sponsor bias
• Mortality not formally significant: Cox model violated proportional hazards assumption; prespecified sensitivity log-rank test NS; survival curves diverged only at ~19 months (late-separating curves reduce power)
• 90% wild-type TTR: generalizability to ATTRv patients limited
• Tafamidis crossover: 17.5% received tafamidis post-month 12, potentially biasing outcomes toward the null (more crossover in placebo arm 22.8%)
• No active comparator: no head-to-head with tafamidis or vutrisiran
• Win ratio interpretation: non-proportional hazards, crossing curves, and composite hierarchy make absolute mortality benefit difficult to quantify
• 12-month endpoint missed: pre-specified 12-month 6MWT analysis was negative, suggesting benefit accrues over longer periods

Key Concepts Mentioned

• concepts/TTR-Stabilizer-Therapy — acoramidis mechanism and class comparison
• entities/ATTR-Amyloidosis — disease context, staging, diagnosis criteria

Key Entities Mentioned

• entities/ATTR-Amyloidosis — disease being treated
• entities/Vutrisiran — comparator context (RNAi class; HELIOS-B 2025)

Wiki Pages Updated

• Created wiki/sources/acoramidis-attrcm-attributecm-nejm-2024.md
• Created wiki/concepts/TTR-Stabilizer-Therapy.md
• Updated wiki/entities/ATTR-Amyloidosis.md — added acoramidis/ATTRibute-CM data to Management and Contradictions
• Updated wiki/sourceindex.md
• Updated wiki/wikiindex.md