Efficacy of Acoramidis in Wild-Type and Variant Transthyretin Amyloid Cardiomyopathy: Results From ATTRibute-CM and Its Open-Label Extension

Kevin M Alexander; Margot K Davis; Olakunle Akinboboye; John Berk; Kunal Bhatt; Francesco Cappelli; Sarah AM Cuddy; Marianna Fontana; Pablo Garcia-Pavia; Julian D Gillmore; Jan M Griffin; Justin L Grodin; Daniel P Judge; Michel G Khouri; Kaitlyn Lam; Ahmad Masri; Mathew S Maurer; Laura Obici; Frederick L Ruberg; Nitasha Sarswat; Keyur Shah; Prem Soman; Lily Stern; Richard Wright; Kuangnan Xiong; Xiaofan Cao; Ted Lystig; Jean-François Tamby; Adam Castaño; Leonid Katz; Uma Sinha; Jonathan C Fox; Scott D Solomon; Martha Grogan

doi:10.1001/jamacardio.2025.4477

. 2025 Nov 8:e254477. Online ahead of print. doi: 10.1001/jamacardio.2025.4477

Efficacy of Acoramidis in Wild-Type and Variant Transthyretin Amyloid Cardiomyopathy

Results From ATTRibute-CM and Its Open-Label Extension

Kevin M Alexander ^1,^✉, Margot K Davis ², Olakunle Akinboboye ³, John Berk ⁴, Kunal Bhatt ⁵, Francesco Cappelli ⁶, Sarah AM Cuddy ⁷, Marianna Fontana ⁸, Pablo Garcia-Pavia ⁹, Julian D Gillmore ¹⁰, Jan M Griffin ¹¹, Justin L Grodin ¹², Daniel P Judge ¹¹, Michel G Khouri ¹³, Kaitlyn Lam ¹⁴, Ahmad Masri ¹⁵, Mathew S Maurer ¹⁶, Laura Obici ¹⁷, Frederick L Ruberg ¹⁸, Nitasha Sarswat ¹⁹, Keyur Shah ²⁰, Prem Soman ²¹, Lily Stern ²², Richard Wright ²³, Kuangnan Xiong ²⁴, Xiaofan Cao ²⁴, Ted Lystig ²⁴, Jean-François Tamby ²⁴, Adam Castaño ²⁴, Leonid Katz ²⁴, Uma Sinha ²⁴, Jonathan C Fox ²⁴, Scott D Solomon ²⁵, Martha Grogan ²⁶

¹Stanford Amyloid Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, Palo Alto, California

²Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada

³Laurelton Heart Specialists, Queens Heart Institute, Rosedale, New York, New York

⁴Boston Medical Center, Boston University, Boston, Massachusetts

⁵Division of Cardiology of the Department of Medicine at Emory University, Emory Healthcare, Atlanta, Georgia

⁶Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence, Italy

⁷Heart and Vascular Center, Brigham and Women’s Hospital, Boston, Massachusetts

⁸National Amyloidosis Centre, Division of Medicine, University College London, London, United Kingdom

⁹Hospital Universitario Puerta de Hierro Majadahonda, IDIPHISA, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain

¹⁰Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, London, United Kingdom

¹¹Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston

¹²Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas

¹³Division of Cardiology, Department of Medicine, Duke University Health System, Durham, North Carolina

¹⁴Western Australia Advanced Heart Failure and Cardiac Transplant Service, Fiona Stanley Hospital, Western Australia, Australia

¹⁵Division of Cardiology, Oregon Health & Science University, Portland

¹⁶Department of Medicine, Columbia University Irving Medical Center, New York, New York

¹⁷Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

¹⁸Boston University Chobanian & Avedisian School of Medicine, Boston Medical Center, Boston, Massachusetts

¹⁹Division of Cardiovascular Medicine, University of Chicago Medicine, Chicago, Illinois

²⁰Pauley Heart Center, Virginia Commonwealth University, Richmond

²¹Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

²²Department of Cardiology, Smidt Heart Institute, Cedars Sinai, Los Angeles, California

²³Pacific Heart Institute and Providence, St. John’s Health Center, Santa Monica, California

²⁴BridgeBio, San Francisco, California

²⁵Heart and Vascular Center, Brigham and Women’s Hospital, Boston, Massachusetts

²⁶Cardiovascular Medicine, Mayo Clinic Rochester, Minnesota

Accepted for Publication: October 14, 2025.

Published Online: November 8, 2025. doi:10.1001/jamacardio.2025.4477

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2025 Alexander KM et al. JAMA Cardiology.

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Corresponding Author: Kevin M. Alexander, MD, Stanford University, 300 Pasteur Dr, Floor 2, Room A260, Palo Alto, CA 94305 (kevalex@stanford.edu).

Author Contributions: Drs Alexander and Tamby had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Alexander and Davis contributed equally to this work.

Concept and design: Alexander, Davis, Bhatt, Cappelli, Griffin, Grodin, Masri, Maurer, Sarswat, Stern, Wright, Tamby, Castaño, Katz, Sinha, Fox, Solomon, Grogan.

Acquisition, analysis, or interpretation of data: Alexander, Davis, Akinboboye, Berk, Bhatt, Cuddy, Fontana, Garcia-Pavia, Gillmore, Judge, Khouri, Lam, Masri, Maurer, Obici, Ruberg, Sarswat, Shah, Soman, Stern, Wright, Xiong, Cao, Lystig, Tamby, Castaño, Katz, Sinha, Fox, Grogan.

Drafting of the manuscript: Alexander, Davis, Fontana, Grodin, Sarswat, Shah, Stern, Wright, Tamby, Castaño, Sinha, Fox.

Critical review of the manuscript for important intellectual content: Alexander, Davis, Akinboboye, Berk, Bhatt, Cappelli, Cuddy, Garcia-Pavia, Gillmore, Griffin, Grodin, Judge, Khouri, Lam, Masri, Maurer, Obici, Ruberg, Sarswat, Shah, Soman, Stern, Wright, Xiong, Cao, Lystig, Tamby, Castaño, Katz, Fox, Solomon, Grogan.

Statistical analysis: Akinboboye, Sarswat, Xiong, Cao, Lystig.

Obtained funding: Fox, Solomon.

Administrative, technical, or material support: Alexander, Cuddy, Grodin, Katz, Sinha, Fox.

Supervision: Alexander, Davis, Bhatt, Cappelli, Fontana, Griffin, Judge, Masri, Maurer, Sarswat, Soman, Stern, Castaño, Katz, Sinha, Fox, Solomon, Grogan.

Other: Shah.

Other - Clinical trial data generation: Berk.

Conflict of Interest Disclosures: Dr Alexander reported consulting fees from Alexion, Arbor Biotechnologies, Alnylam, and BridgeBio and personal fees from Bayer, Novo Nordisk, and Pfizer outside the submitted work. Dr Davis reported nonfinancial support from BridgeBio during the conduct of the study and grants from Pfizer and personal fees from Pfizer, AstraZeneca, Novo Nordisk, and Alnylam outside the submitted work. Dr Akinboboye reported personal fees from BridgeBio, Alnylam Pharmaceuticals, AstraZeneca, and Pfizer outside the submitted work. Dr Berk reported committee or advisory membership fees from Intellia, BridgeBio, AstraZeneca and Alnylam outside the submitted work; in addition, Dr Berk had a patent for Diflunisal pending. Dr Bhatt reported consulting fees from BridgeBio during the conduct of the study. Dr Cappelli reported personal fees from Pfizer, Alnylam, BridgeBio, AstraZeneca, and Bayer outside the submitted work. Dr Cuddy reported personal fees from BridgeBio, Pfizer, Alexion, AstraZeneca, Intellia, and Alnylam outside the submitted work. Dr Fontana reported consulting fees for Alnylam, Alexion/Caelum Biosciences, AstraZeneca, BridgBio/Eidos, Prothena, Attralus, Intellia Therapeutics, Ionis Pharmaceuticals, Cardior, Lexeo Therapeutics, Janssen Pharmaceuticals, Prothena, Pfizer, Novo Nordisk, Bayer, and MyCardium, research grants from Alnylam, BridgBio, AstraZeneca, and Pfizer and share options in LexeoTherapeutics and MyCardium outside the submitted work. Dr Garcia-Pavia reported speaking fees from Alnylam Pharmaceuticals, AstraZeneca, Bayer, BridgeBio, Intellia, Ionis Pharmaceuticals, Novo Nordisk and Pfizer, grants from Alnylam Pharmaceuticals and Pfizer, consulting fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, ATTRalus, Bayer, BridgeBio, Intellia, Ionis Pharmaceuticals, Life Molecular Imaging, Pfizer, Neuroimmune, and Novo Nordisk, and research/educational support to their institution from Alnylam Pharmaceuticals, AstraZeneca, Bayer, BridgeBio, Intellia, Novo Nordisk, and Pfizer outside the submitted work. Dr Gillmore reported consultancy fees from Alnylam, ATTRalus, AstraZeneca, BridgeBio, Lycia, Intellia, Ionis, and Pfizer and grants from Alnylam outside the submitted work. Dr Griffin reported personal fees and grants from BridgeBio and Pfizer and personal fees from Astra Zeneca outside the submitted work. Dr Grodin reported grants from Pfizer and BridgeBio, personal fees from Pfizer, BridgeBio, AstraZeneca, Alnylam, Alexion, Intellia, Novo Nordisk, Tenax Therapeutics DSMC, Lumanity, and Ultromics outside the submitted work. Dr Judge reported personal fees from Alnylam, Attralus, Bayer, BridgeBio, Lexeo Therapeutics, Novo Nordisk, Rocket Therapeutics, and Alexion during the conduct of the study. Dr Khouri reported grants and personal fees from BridgeBio, Alnylam Pharmaceuticals, AstraZeneca, and Alexion Pharmaceuticals, personal fees from Pfizer, and grants from Intellia Therapeutics outside the submitted work. Dr Lam reported funds to their institution from Eidos during the conduct of the study and personal fees from Pfizer and Nova Nordisk outside the submitted work. Dr Masri reported personal fees from Cytokinetics, Bristol Myers Squibb, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Edgewise, Rocket, Lexeo, Prothena, BioMarin, AstraZeneca, Avidity, Neurimmune, and Tenaya, and grants from Pfizer, Ionis, Attralus, Cytokinetics, and Janssen outside the submitted work. Dr Maurer reported personal fees from Pfizer, Alnylam, BridgeBio, Intellia, AstraZeneca, and Ionis, and grants from Attralus during the conduct of the study. Dr Obici reported personal fees from Alnylam, Pfizer, Bayer, Novo Nordisk, AstraZeneca, BridgeBio, and Purpose Pharma outside the submitted work. Dr Ruberg reported grants from BridgeBio, Pfizer, Anumana, TriNetX/AstraZeneca, Alnylam, the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL139671), and National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL177670) and personal fees from Attralus and eMyosound outside the submitted work. Dr Sarswat reported giving talks regarding amyloidosis that were sponsored by BridgeBio (no compensation). Dr Shah reported consulting fees from AstraZeneca and BridgeBio outside the submitted work. Dr Soman reported personal fees from BridgeBio, Alnylam, and Pfizer during the conduct of the study and personal fees from Spectrum Dynamics outside the submitted work. Dr Stern reported grants from Pfizer and Intellia Therapeutics and personal fees from BridgeBio and Pfizer outside the submitted work. Dr Wright reported personal fees from BridgeBio, Alnylam, AstraZeneca, and Pfizer outside the submitted work. Dr Xiong reported being an employee and stockholder of BridgeBio. Dr Cao reported employment from BridgeBio outside the submitted work. Dr Lystig reported employment and shareholding BridgeBio. Dr Castaño reported employment and stock holding from Bridgebio. Dr Katz reported employment and stock holding from BridgeBio outside the submitted work. Dr Sinha reported employment from BridgeBio outside the submitted work; in addition, Dr Sinha had a patent for BridgeBio. Dr Fox reported employment from BridgeBio during the conduct of the study. Dr Solomon reported grants from Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Boston Scientific, Cardior, Cytokinetics, Edgewise, BridgeBio, Gossamer, GSK, Ionis, Lilly, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo NordiskRespicardia, Sanofi Pasteur, Tenaya, Theracos, and US2.AI, and grants and personal fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, Askbio, AstraZeneca, Bayer, Bristol Myers Squibb, BridgeBio, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Intellia, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, Valo, Synhale, Recordati outside the submitted work. Dr Grogan reported grants, personal fees, and nonfinancial support from BridgeBio during the conduct of the study, grants from Astra Zeneca, Janssen, Novo Nordisk, Alnylam, and Pfizer outside the submitted work. No other disclosures were reported.

Funding/Support: The ATTRibute-CM and open-label extension studies were funded by BridgeBio, San Francisco, California. Medical writing support for this manuscript was funded by BridgeBio. Under the guidance from the authors, medical writing and editorial assistance were provided by Joaquin Jaramillo, MD, of Caudex, an IPG Health company, and funded by BridgeBio. The ATTRibute-CM study and its open-label extension were funded by BridgeBio.

Role of the Funder/Sponsor: The interpretation of the data and the decision to submit the manuscript to the journal were done independently by the authors without any influence from the sponsor of the study. BridgeBio was involved in the design, data collection, and study management, and also conducted the statistical analysis. In their role as authors, employees of BridgeBio involved in the analysis, interpretation of the data, writing, reviewing, and approving the manuscript for submission. Additionally, BridgeBio was also involved in reviewing the manuscript for scientific and medical accuracy, approving from an intellectual property perspective, and ensuring adherence with Good Publication Practice guidelines and International Committee of Medical Journal Editors recommendations, but had no right to veto the publication or submission of this manuscript. The sponsor of the study (BridgeBio) backs the fidelity of this report and the data presented in this manuscript.

Meeting Presentation: This paper was presented at the AHA Scientific Sessions 2025; November 8, 2025; New Orleans, Louisiana.

Data Sharing Statement: See Supplement 4.

Additional Contributions: The authors thank the participants, their families, and caregivers who made this study possible, and the investigators and study center staff for their participation. The authors thank Souhiela Fawaz, PhD, Gillian Murtagh, MD, PhD, and Shweta Rane, PhD, BCMAS, CMPP from BridgeBio for critical review and editorial support.

^✉

Corresponding author.

PMCID: PMC12596743 PMID: 41205147

This study evaluates the efficacy of acoramidis in transthyretin amyloid cardiomyopathy with wild-type, transthyretin amyloid cardiomyopathy with variant, and variant subgroups (p.Val142Ile and non-p.Val142Ile).

Key Points

Question

Is the efficacy of acoramidis similar between those with transthyretin amyloid cardiomyopathy with wild-type (ATTRwt-CM) and with a pathogenic/likely pathogenic variant (ATTRv-CM)?

Finding

Among 611 participants, in this study, 9.6% had ATTRv-CM with similar reduction in all-cause mortality and first cardiovascular hospitalization compared with ATTRwt-CM at 30-month trial completion. Of 380 participants who continued in the open-label extension, 7.1% had ATTRv-CM with a similar reduction in all-cause mortality at 42-month follow-up.

Meaning

In patients randomized to acoramidis and followed up in the open-label extension, reduction in all-cause mortality and cardiovascular hospitalization was similar in those with ATTRv-CM and ATTRwt-CM.

Abstract

Importance

Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE).

Objective

To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile).

Design, Setting, and Participants

This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025.

Interventions

Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment.

Main Outcomes and Measures

All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile.

Results

Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42.

Conclusions and Relevance

The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups.

Trial Registration

ClinicalTrials.gov Identifiers: NCT03860935; NCT04988386

Introduction

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and underdiagnosed cause of heart failure, resulting from deposition of misfolded transthyretin (TTR) protein in the myocardium due to a pathogenic mutation in the TTR gene (hereditary or variant disease [ATTRv-CM]) or without a TTR mutation, in older adults (wild-type disease [ATTRwt-CM]). Although the precise prevalence of ATTR-CM is unknown, it is estimated that ATTRv-CM comprises about 20% of patients with ATTR-CM.

To date, over 130 pathogenic destabilizing TTR variants have been identified, resulting in amyloid fibril formation and tissue deposition, primarily in the heart and peripheral nerves. TTR destabilization in ATTRv-CM leads to lower serum TTR ([sTTR] also known as prealbumin) concentration, which has been associated with an earlier onset and a more aggressive disease phenotype than ATTRwt-CM. Lower sTTR levels are also associated with increased risk of mortality and adverse outcomes in patients with ATTRwt-CM or ATTRv-CM, and in the general population.

The p.Val142Ile variant (updated nomenclature, previously known as V122I) is the most prevalent cause of ATTRv-CM worldwide, affecting predominantly individuals of Western African ancestry, with a carrier frequency of 3% to 4% in the Black US population. The p.Val142Ile mutation exhibits variable penetrance, with homozygous individuals often experiencing earlier disease onset. However, once clinical manifestations appear, the disease tends to progress rapidly, with 2-year to 3-year mortality exceeding 50% in untreated affected individuals.

Acoramidis is a novel, orally administered TTR stabilizer that achieves near-complete (≥90%) TTR stabilization. The phase 3 ATTRibute-CM trial (NCT03860935), performed in a contemporary ATTR-CM population, demonstrated that acoramidis significantly improved all-cause mortality (ACM) and cardiovascular-related hospitalizations (CVH), with benefits observed as early as 3 months into treatment. Acoramidis has received regulatory approval in the US, European Union, United Kingdom, and Japan for the treatment of adults with ATTR-CM.

In this study, we evaluated the clinical efficacy of acoramidis observed in ATTRibute-CM in participants with ATTRwt-CM and ATTRv-CM, including the p.Val142Ile participant subgroup.

Methods

Study Design and Participant Population

The ATTRibute-CM and open-label extension (OLE) study designs have been published previously. Briefly, ATTRibute-CM study was a phase 3, randomized, double-blind, 30-month study. Participants were randomly assigned 2:1 to receive either acoramidis, 712 mg (equivalent to 800 mg acoramidis hydrochloride), or matching placebo tablets administered orally twice daily for 30 months. Stratification was based on TTR genotype, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, and estimated glomerular filtration rate (eGFR) levels, according to the National Amyloidosis Centre staging criteria. During the double-blind study, participants were permitted to initiate tafamidis, if available, and at the discretion of the investigator, as a concomitant medication after they had completed 12 months of the blinded study treatment. All randomized participants received at least 1 dose of blinded study treatment. After completing treatment in the ATTRibute-CM study, participants were invited to participate in the OLE study. In the OLE, all participants received open-label acoramidis: those who had previously received acoramidis during the ATTRibute-CM study continued to receive it (continuous acoramidis) and those who had received placebo were switched to acoramidis-only treatment (placebo to acoramidis). Participants who had received concomitant tafamidis at some point during the ATTRibute-CM study were required to discontinue it prior to entering the OLE. Efficacy analyses were conducted in the prespecified modified intention-to-treat (mITT) population (n = 611), which consisted of all randomized participants with a baseline eGFR level of 30 or more mL/min/1.73 m². Safety and tolerability were assessed in the safety population, which consisted of all randomized participants (n = 632).

The completed ATTRibute-CM study was conducted and the ongoing OLE study is being conducted, in accordance with the International Council for Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The studies were approved by the independent review board or ethics committee at each participating site. All participants provided written informed consent. The Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines were followed.

Prespecified efficacy analyses were performed within the ATTRwt-CM and ATTRv-CM subgroups, based on the genotype stratification factor (ATTRwt-CM or ATTRv-CM) recorded at randomization. At month 30, efficacy analyses compared acoramidis and placebo. For the month 42 analyses, a data cut was conducted after all OLE participants had completed at least 12 months in the OLE (or had discontinued early) and observations were analyzed comparing the continuous acoramidis and placebo with acoramidis cohorts. The composite of time to ACM or first CVH is reported at month 30 and month 42, the annual frequency of CVH is reported at month 30, and ACM is reported at month 42. Additional details of evaluation of ACM and CVH are provided in the eMethods in Supplement 1.

Other efficacy end points are reported through month 30, including the primary end point using a 4-component hierarchical Finkelstein and Schoenfeld analysis, previously described and change from baseline in sTTR, NT-proBNP, 6-minute walk distance (6MWD), and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score.

The following additional post hoc efficacy analyses were performed within the ATTRv-CM population, according to the actual variant reported (p.Val142Ile or non-p.Val142Ile subgroups): composite of time to ACM or first CVH and annual frequency of CVH at month 30, ACM at month 42, and change from baseline in sTTR at day 28 and month 30.

The Interactive Voice and Web Response System was used for the prespecified genotype stratum (ATTRwt-CM vs ATTRv-CM); however, it did not capture variant-specific data. Therefore, post hoc analyses within the variant subgroup—stratified by individual variants—were conducted using the Electronic Data Capture system, which captured detailed variant-level information.

Statistical Analysis

The primary end point was analyzed using the stratified Finkelstein and Schoenfeld method, supplemented by win-ratio estimates, which have been described previously. Time-to-first-event analyses (composite of ACM or first CVH) were performed using a stratified Cox proportional hazards model. The annualized frequency of CVH was analyzed using a negative binomial regression model.

The change from baseline in 6MWD, KCCQ-OS score, NT-proBNP (in log-scale), and sTTR level were analyzed using a mixed model for repeated measures. In general, statistical analyses were conducted using consistent methodology as the prespecified analyses in ATTRibute-CM, with appropriate considerations for the reduced sample size in the variant, p.Val142Ile and non-p.Val142Ile subgroups. Additional details of statistical analyses are provided in the eMethods in Supplement 1.

This article includes several prespecified and post hoc analyses that are outside the scope of our alpha-controlled testing scheme covering the primary and key secondary end points in the overall mITT population. Two-sided P values less than .05 are taken to indicate nominal statistical significance. Interaction P values were calculated to compare the heterogeneity of treatment effect in key clinical end points between genotypic classifications at randomization (ATTRwt-CM vs ATTRv-CM) and within the variant subgroup by mutation status, as recorded in the clinical database (p.Val142Ile vs non-p.Va142Ile variant). In addition, interaction P values were calculated between p.Val142Ile vs non-pVal142Ile in the mITT population. Statistical analysis was performed using SAS software version 9.4 (SAS Institute).

Results

Study Population and Baseline Characteristics

Among the 611 participants in the mITT population enrolled in ATTRibute-CM (Table; eFigure 1 in Supplement 1), 59 (9.7%) were categorized as having ATTRv-CM at randomization. Of these, 39 were randomized to acoramidis and 20 to placebo. The 3 most common ATTRv-CM variants recorded in the clinical database were p.Val142Ile (n = 35; including 4 homozygotes), p.Ile88Leu (n = 7), and p.Thr80Ala (n = 5) (eTable 1 in Supplement 1). Compared with ATTRwt-CM, participants with ATTRv-CM were younger (mean age, 74 vs 78 years for acoramidis; mean age, 71 vs 78 years for placebo), had lower baseline sTTR levels (17.8 vs 23.5 mg/dL for acoramidis; 17.2 vs 24.3 mg/dL for placebo), and had lower KCCQ-OS scores (68.5 vs 72.1 for acoramidis; 63.2 vs 71.3 for placebo). Other baseline parameters, including NT-proBNP, 6MWD, New York Heart Association class distribution, and duration of ATTR-CM, were comparable between ATTRv-CM and ATTRwt-CM populations. In both the ATTRwt-CM and ATTRv-CM subgroups, concomitant tafamidis use was about 8% to 10% lower in acoramidis-treated participants vs placebo-treated participants.

Table. Demographics and Baseline Characteristics in Participants of ATTRibute-CM by Genotype^a.

Characteristic	No. (%)
	ATTRv-CM (n = 59)^b		ATTRwt-CM (n = 552)^b
	Acoramidis (n = 39)	Placebo (n = 20)	Acoramidis (n = 370)	Placebo (n = 182)
Age, mean (SD), y	74 (7.6)	71 (7.8)	78 (6.2)	78 (6.3)
Sex
Male	33 (84.6)	14 (70.0)	341 (92.2)	167 (91.8)
Female	6 (15.4)	6 (30.0)	29 (7.8)	15 (8.2)
Self-reported race or ethnicity
Asian	2 (5.1)	0	8 (2.2)	3 (1.6)
Black	14 (35.9)	7 (35.0)	5 (1.4)	3 (1.6)
White	18 (46.2)	11 (55.0)	340 (91.9)	168 (92.3)
Other^c	5 (12.8)	1 (5.0)	2 (0.5)	2 (1.1)
Not reported	0	1 (5.0)	15 (4.1)	6 (3.3)
NT-proBNP, median (IQR), pg/mL	2326 (1312-4567)	2341 (1521.5-3534)	2265 (1315-3729)	2274 (1105-3590)
eGFR, mean (SD), mL/min/1.73 m²	65.0 (21.0)	64.0 (14.5)	62.0 (16.9)	62.4 (17.9)
NAC stage
I	28 (71.8)	14 (70.0)	213 (57.6)	182 (58.2)
II	8 (20.5)	5 (25.0)	122 (33.0)	61 (33.5)
III	3 (7.7)	1 (5.0)	35 (9.5)	15 (8.2)
Duration of ATTR-CM, mean (SD), y	1.3 (1.06)	1.5 (1.07)	1.2 (1.22)	1.1 (1.21)
NYHA class
I	2 (5.1)	1 (5.0)	49 (13.2)	16 (8.8)
II	35 (89.7)	16 (80.0)	253 (68.4)	140 (76.9)
III	2 (5.1)	3 (15.0)	68 (18.4)	26 (14.3)
sTTR level, mean (SD), mg/dL	17.8 (5.1)	17.2 (5.2)	23.5 (5.3)	24.3 (5.8)
6MWD, mean (SD), m	364.6 (94.93)	354.7 (97.07)	362.6 (104.49)	351.2 (93.74)
KCCQ-OS, mean (SD)	68.5 (17.2)	63.2 (24.7)	72.1 (19.6)	71.3 (20.1)
Atrial fibrillation diagnosis^d	26 (66.7)	8 (40.0)	229 (61.9)	121 (66.5)
Tafamidis drop-in^e	4 (10.3)	4 (20.0)	57 (15.4)	42 (23.1)

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Abbreviations: 6MWD, 6-minute walk distance; ATTR-CM, transthyretin amyloid cardiomyopathy; ATTRv-CM, variant transthyretin amyloid cardiomyopathy; ATTRwt-CM, wild-type transthyretin amyloid cardiomyopathy; eGFR, estimated glomerular filtration rate; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire Overall Summary; NAC, National Amyloidosis Centre; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; sTTR, serum transthyretin.

^{^a}

Modified intention-to-treat population.

^{^b}

Values vary slightly for various characteristics based on available data.

^{^c}

Includes America Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, other, and multiple races.

^{^d}

Diagnosis at baseline is defined as medical history of atrial fibrillation and/or presence of atrial fibrillation or atrial flutter on baseline electrocardiogram.

^{^e}

Tafamidis drop-in was allowed after month 12.

Primary Efficacy and Clinical Outcome End Points

A consistent treatment effect of acoramidis was observed in the ATTRwt-CM and ATTRv-CM subgroups for each end point assessed: primary 4-component hierarchical end points (Figure 1A), composite of ACM or first CVH (Figure 1B), and frequency of CVH, all at month 30 (Figure 1C), and ACM at month 42 (Figure 1D). There was no significant evidence of heterogeneity of treatment effect for any of the clinical outcome end points analyzed according to parametric models (interaction P values > .05; Figure 1B-D).

Figure 1. — Forest plots of the modified intention-to-treat population by ATTR-CM genotype for the primary 4-component hierarchical end point at month 30 (A), time to all-cause mortality (ACM) or first cardiovascular hospitalization (CVH) from baseline through month 30 (B), frequency of CVH from baseline through month 30 (C), and time to ACM from baseline through month 42 (D). ACM included 1 participant with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) in the placebo arm who received an implanted cardiac mechanical assist device and 1 participant with variant transthyretin amyloid cardiomyopathy (ATTRv-CM) in the placebo arm who received a heart transplant. F-S indicates Finkelstein and Schoenfeld.

^aP value from testing the interaction of subgroup × treatment and other P values are for testing the treatment difference at a given value of subgroup variable.

For the primary 4-component hierarchical end point at month 30 in the overall population, the win ratio for acoramidis vs placebo was 1.8 (95% CI, 1.40-2.24; P < .001). Win ratios were 1.8 (95% CI, 1.40-2.21; P < .001) in the ATTRwt-CM subgroup and 2.5 (95% CI, 1.30-4.91; P = .006) in the ATTRv-CM subgroup (Figure 1A).

The hazard ratio (HR) for the composite end point of ACM or first CVH (ACM/first CVH) at month 30 in acoramidis recipients was 0.69 (95% CI, 0.52-0.90; P = .007) in the ATTRwt-CM subgroup and 0.41 (95% CI, 0.21-0.81; P = .01) in the ATTRv-CM subgroup; interaction P = .17 (Figure 1B). This corresponds to a 31% and 59% risk reduction vs placebo. The Kaplan-Meier curves for this end point are shown in Figures 2A and B. Of note, in the ATTRv-CM placebo group, the event rate for ACM/first CVH was 75.0% (15 of 20) through month 30, compared with 46.2% (18 of 39) in the ATTRv-CM acoramidis group (Figure 2B). The rate in the ATTRv-CM acoramidis group is comparable with that of the ATTRwt-CM population (eFigure 2 in Supplement 1).

Figure 2. — Kaplan-Meier curves of the modified intention-to-treat population for time to ACM or first CVH from baseline through month 30 in the ATTRwt-CM subgroup (A) and the ATTRv-CM subgroup (B), and time to ACM from baseline through month 42 in the ATTRwt-CM subgroup (C) and the ATTRv-CM subgroup (D).

Risk reduction for the annual frequency of CVH with acoramidis was 49% in the ATTRwt-CM subgroup (relative risk ratio, 0.51; 95% CI, 0.36-0.73; P < .001) and 62% in the ATTRv-CM subgroup (relative risk ratio, 0.38; 95% CI, 0.14-1.03; P = .06; interaction for P = .57) (Figure 1C).

The HR for ACM at month 42 in participants receiving acoramidis was 0.70 (95% CI, 0.50-0.98; P = .04) in the ATTRwt-CM subgroup and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRv-CM subgroup, corresponding to 30% and 59% observed risk reductions, respectively; the interaction P value was .24 (Figure 1D).

The Kaplan-Meier curves for this end point are shown in Figure 2C and D. Of note, in the ATTRv-CM group the event rate for ACM was 60.0% (12 of 20) through month 42 with placebo vs 30.8% (12 of 39) with acoramidis (Figure 2C and D). This latter rate is comparable with the ACM event rates observed in the ATTRwt-CM population (eFigure 3 in Supplement 1). The corresponding HR values for the composite end point of ACM or first CVH through month 42 were 0.60 (95% CI, 0.47-0.77; P < .001) for participants with ATTRwt-CM and 0.35 (95% CI, 0.18-0.67; P = .002) for the ATTRv-CM population (eFigure 4 in Supplement 1).

Biomarkers, Functional Assessment, and Quality of Life

In participants with ATTRv-CM receiving acoramidis, sTTR increased at day 28 (first assessment postrandomization) to levels comparable with those achieved in participants with ATTRwt-CM receiving acoramidis (Figure 3A). This occurred despite approximately 25% lower sTTR levels in the ATTRv-CM population at baseline. At day 28, acoramidis treatment resulted in an observed mean (SD) sTTR increase from baseline of 8.9 (4.4) mg/dL in ATTRwt-CM participants and 12.4 (6.7) mg/dL in participants with ATTRv-CM. These observed changes were sustained through month 30 (Figure 3A). The least-squares mean difference in sTTR increase at month 30 among those receiving acoramidis vs placebo was 6.6 mg/dL (P < .001) and 12.0 mg/dL (P < .001) in ATTRwt-CM and ATTRv-CM, respectively.

Figure 3. — Mean serum transthyretin (TTR) levels change from baseline to month 30 (A) in geometric mean fold change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) (from mixed model for repeated measures) (B), 6-minute walk distance (6MWD) (C), and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score in the wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) and variant transthyretin amyloid cardiomyopathy (ATTRv-CM) subgroups (D). Observed values are displayed. Among the 7 participants with ATTRv-CM who received placebo and completed the month 30 visit, 2 received concomitant tafamidis treatment after month 12. In the 5 participants who received placebo without concomitant tafamidis and who completed the month 30 visit, mean (SD) serum TTR was 18.4 (3.32) mg/dL at baseline and 19.0 (4.20) mg/dL at month 30. LS indicates least squares.

An increase in NT-proBNP was observed over 30 months in participants receiving placebo. The increase was numerically greater in the placebo ATTRv-CM population than the placebo ATTRwt-CM population (Figure 3B). The ratio (acoramidis to placebo) for NT-proBNP adjusted geometric mean fold-change at month 30 was 0.55 (95% CI, 0.48-0.64; P < .001) in the ATTRwt-CM population and 0.35 (95% CI, 0.23-0.54; P < .001) in ATTRv-CM. The greater relative effect of acoramidis in attenuating the increase in NT-proBNP in the ATTRv-CM population mitigated the 30-month rise in NT-proBNP, yielding levels comparable with those observed in acoramidis-treated participants with ATTRwt-CM.

A decline in 6MWD over 30 months was observed in participants receiving placebo, with a numerically greater reduction in the placebo ATTRv-CM group than the placebo ATTRwt-CM group (Figure 3C). Relative to placebo, acoramidis treatment resulted in a least-squares mean difference in 6MWD at month 30 of 34.4 m (P = .001) in the ATTRwt-CM group and 86.7 m (P = .005) in the ATTRv-CM group. The 6MWD change from baseline at month 30 in the ATTRv-CM acoramidis group was comparable with that observed in the ATTRwt-CM acoramidis group (Figure 3C).

Health-related quality of life, as measured by KCCQ-OS, declined over 30 months, with numerically greater worsening in the placebo ATTRv-CM group than the placebo ATTRwt-CM group (Figure 3D). Relative to placebo, acoramidis treatment resulted in a least-squares mean difference through month 30 of 8.8 points (P < .001) in participants with ATTRwt-CM and 20.3 points (P = .002) in those with ATTRv-CM (Figure 3D). The mean change from baseline at month 30 in the ATTRv-CM acoramidis group was comparable with that observed in ATTRwt-CM acoramidis group.

Misclassification of ATTRv-CM Population

Fifty-nine participants were categorized as having ATTRv-CM based on stratification at randomization, whereas a variant was subsequently identified and reported in the clinical database in 56 participants (additional details are provided in the eAppendix in Supplement 1). A sensitivity analysis conducted in those 56 participants across all efficacy end points demonstrated treatment effects with acoramidis that were consistent with those observed with the prespecified analyses on the 59 participants (eTable 2 in Supplement 1).

Efficacy in the p.Val142Ile Variant Subpopulation

Baseline characteristics within the ATTRv-CM population (p.Val142Ile variant [n = 35] and non-p.Val142Ile subgroups [n = 21]) are shown in eTable 3 in Supplement 1. Homozygosity for p.Val142Ile was reported in 1 participant in the acoramidis group and 3 participants in the placebo group. The non-p.Val142Ile subgroup is a small, heterogeneous subgroup encompassing 9 different TTR variants (eTable 1 in Supplement 1).

Subgroup analysis comparing participants with p.Val142Ile variant to non-p.Val142Ile variants showed no significant heterogeneity of treatment effect. Interaction P values were .75 for the composite ACM/first CVH end point through month 30 and .64 for ACM through month 42, indicating consistent treatment effects between p.Val142Ile and non-p.Val142Ile variants (eTable 4 in Supplement 1). In addition, there was no significant heterogeneity of treatment effect in ACM/first CVH through month 30 (interaction P = .05) and for ACM through month 42 (interaction P = .17) between the p.Val142Ile (n = 35) and the rest of the mITT ATTRibute-CM participant population (n = 576).

At month 30, 43.5% (10 of 23) of acoramidis recipients with p.Val142Ile variant experienced the composite of ACM or first CVH, compared with 83.3% (10 of 12) of those in the placebo group, corresponding to an observed 69% risk reduction (HR, 0.31; 95% CI, 0.12-0.81). At month 42, 26.1% of acoramidis recipients (6 of 23) with p.Val142Ile variant experienced ACM compared with 66.7% of those in the placebo group (8 of 12), corresponding to an observed 69% risk reduction (HR, 0.31; 95% CI, 0.10-0.97) (Figure 4; eTable 4 in Supplement 1). A 71% risk reduction in the annual frequency of CVH at month 30 was observed with acoramidis (eTable 4 in Supplement 1). The effects on sTTR at day 28 and month 30 in p.Val142Ile and non-p.Val142Ile subgroups are shown in eTable 4 in Supplement 1.

Figure 4. — Kaplan-Meier curves for time to ACM or first CVH from baseline through month 30 (A) and time to ACM from baseline through month 42 in participants with p.Val142Ile ATTRv-CM (B).

Safety

The safety profile of acoramidis in participants with ATTRv-CM in ATTRibute-CM was consistent with that observed in the safety population (n = 632). Treatment-emergent adverse events occurred in 100.0% of participants with ATTRv-CM treated with acoramidis compared with 95.0% of the placebo group (eTable 5 in Supplement 1). In the ATTRv-CM subgroup, serious adverse events were reported in 56.1% of participants receiving acoramidis vs 80.0% receiving placebo (eTable 5 in Supplement 1). Treatment-emergent adverse events related to study drug were infrequent (n = 4 [9.8%] acoramidis vs n = 0 [0%] placebo), and none of these events were categorized as serious (eTable 5 in Supplement 1). The safety profile in the ATTRwt-CM population was consistent with the previously reported safety profile in the overall population (eTable 5 in Supplement 1).

Discussion

Several key insights emerge from the results presented in this article. First, consistent efficacy of acoramidis was observed in both ATTRwt-CM and ATTRv-CM populations in prespecified analyses. In addition, a post hoc analysis revealed similar treatment effects within the ATTRv-CM subgroup, in p.Val142Ile and non-p.Val142Ile variants. While the point estimates were suggestive of potentially greater treatment benefit within the variant participants, we observed no statistically significant heterogeneity of effects, and the number of variant participants was small. These findings have biological plausibility. Acoramidis was rationally designed to mimic the protective p.Thr139Met variant and stabilized wild-type and variant TTR equally. It achieves this through enthalpically driven binding involving hydrogen bonds, ionic interactions, and engagement with multiple TTR subunits. This distinct mechanism has been shown to result in near-complete (≥90%) TTR stabilization in experimental studies involving multiple TTR variants, including p.Val142Ile.

Second, the efficacy observed in ATTRv-CM is of clinical relevance given the high unmet medical need. Findings from ATTRibute-CM confirm the particularly adverse natural history previously described in these populations, with approximately 75% of participants with ATTRv-CM treated with placebo experiencing death or CVH within 30 months and a similar proportion in the p.Val142Ile subgroup dying by 42 months.

Third, our findings underscore the importance of genetic testing when making a diagnosis of ATTR-CM, particularly to identify individuals carrying the p.Val142Ile variant, who remain frequently underdiagnosed despite substantial disease burden and the availability of an effective treatment option. A recent epidemiological study highlighted the high prevalence and public health implications of the p.Val142Ile variant in the Black population in the US. This study estimated that over 400 000 Black individuals in the US aged 50 to 95 years carry the p.Val142Ile variant, with a projected cumulative loss of nearly 1 million life-years due to heart failure. If the treatment effects observed in this subgroup within ATTRibute-CM are confirmed in larger, adequately powered clinical trials or real-world settings, the implications could be meaningful at both the individual and public health levels. Such findings would support efforts to improve the identification of at-risk individuals and expand access to disease-modifying therapies like acoramidis in this underserved high-risk population. In addition, our observations of consistent efficacy across both wild-type and variant ATTR-CM emphasize the importance of broad disease awareness and maintaining clinical suspicion irrespective of genotype, followed by appropriate diagnostic testing to enable timely diagnosis and initiation of treatment.

Lastly, these findings in a limited number of patients with ATTRv-CM provide support for further clinical investigations. Acoramidis may have the potential for ATTR disease primary prevention in carriers of pathogenic TTR variants. This concept is currently being evaluated in the ACT-EARLY clinical trial (NCT06563895). In addition, further studies are warranted to evaluate the efficacy of acoramidis in transthyretin-mediated polyneuropathy, based on the assumption that near-complete TTR stabilization may confer therapeutic benefits similar to those observed in ATTR-CM.

Limitations

Our results have important limitations. Several of the analyses presented here are post-hoc, such as those involving participants with the p.Val142Ile variant. The sample sizes were also small for the various subgroups. While we conducted heterogeneity tests to identify meaningful treatment effect differences between subgroups, such tests are known to have low power and the lack of significant findings that do not necessarily support a conclusion of complete absence of heterogeneous effects. Accordingly, our observations in the p.Val142Ile and non-p.Val142Ile subgroups are hypothesis generating and should encourage further investigation in larger variant-specific studies with acoramidis. Our study has also not addressed previously described barriers affecting efficacy in participants with p.Val142Ile ATTR-CM, such as comorbidities that may influence the heart failure syndrome or social determinants of health. In our study, variant misclassification occurred due to discrepancies between the recorded variant status reported at randomization and the variants subsequently recorded in the clinical database. However, sensitivity analyses showed consistent efficacy across clinical end points in both populations. In addition, concomitant tafamidis was initiated in a subset of participants at variable times during the study with an imbalance toward greater use in the placebo group than the acoramidis group, which may have led to an underestimation of the effect of acoramidis. Our study did not include a standalone tafamidis subgroup, as this would have introduced bias (concomitant tafamidis could only be initiated if a participant had survived for 12 months). Lastly, baseline imbalances between participants who received acoramidis during the 30-month ATTRibute-CM trial and those entering the OLE—driven by prior treatment benefit in the acoramidis group and greater disease progression in the placebo group—may have influenced the observed treatment effect.

Conclusions

Prespecified analyses from the ATTRibute-CM study provide evidence that acoramidis confers consistent clinical benefit across multiple end points, including ACM, CVH, key biomarkers (NT-proBNP, serum TTR), functional status, and quality of life in both the ATTRwt-CM and ATTRv-CM groups. Taken together, these results reinforce the therapeutic benefit of near-complete TTR stabilization by acoramidis in both ATTRwt-CM and ATTRv-CM.

Supplement 1.

eMethods.

ATTRibute-CM Study Design

Efficacy Endpoints: All-Cause Mortality (ACM) and Cardiovascular-Related Hospitalization (CVH)

Statistical Analysis

eAppendix. Misclassification of Variants in ATTRibute-CM

eTable 1. List of TTR Variant Genotypes, mITT Population (n = 56)^a

eTable 2. Sensitivity Analysis of Clinical Efficacy, Biomarkers, Functional Assessments, and Quality of Life Outcomes in the ATTRv-CM Subgroup in ATTRibute-CM through Month 30^a

eTable 3. Demographics and Baseline Characteristics of Participants in the TTR Variant Subgroup in ATTRibute-CM^a

eTable 4. Summary of Efficacy Results within the TTR Variant Subgroup (n = 56) for Acoramidis vs Placebo^a

eTable 5. Safety Summary of Participants in ATTRibute-CM by Genotypea

eFigure 1. CONSORT Study Flow Diagram

eFigure 2. Kaplan-Meier Curves for Time to ACM or First CVH from Baseline through Month 30 by ATTR-CM Genotype^a

eFigure 3. Kaplan–Meier Curves for Time to ACM from Baseline through Month 42 by ATTR-CM Genotype^a

eFigure 4. Forest Plot of Composite Endpoint of ACM/CVH through Month 42 in the OLE by ATTR-CM Genotype^a

jamacardiol-e254477-s001.pdf^{(640.6KB, pdf)}

Supplement 2.

Study protocol

jamacardiol-e254477-s002.pdf^{(1.2MB, pdf)}

Supplement 3.

Statistical analysis plan

jamacardiol-e254477-s003.pdf^{(16MB, pdf)}

Supplement 4.

Data sharing statement

jamacardiol-e254477-s004.pdf^{(19.1KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods.

ATTRibute-CM Study Design

Efficacy Endpoints: All-Cause Mortality (ACM) and Cardiovascular-Related Hospitalization (CVH)

Statistical Analysis

eAppendix. Misclassification of Variants in ATTRibute-CM

eTable 1. List of TTR Variant Genotypes, mITT Population (n = 56)^a

eTable 2. Sensitivity Analysis of Clinical Efficacy, Biomarkers, Functional Assessments, and Quality of Life Outcomes in the ATTRv-CM Subgroup in ATTRibute-CM through Month 30^a

eTable 3. Demographics and Baseline Characteristics of Participants in the TTR Variant Subgroup in ATTRibute-CM^a

eTable 4. Summary of Efficacy Results within the TTR Variant Subgroup (n = 56) for Acoramidis vs Placebo^a

eTable 5. Safety Summary of Participants in ATTRibute-CM by Genotypea

eFigure 1. CONSORT Study Flow Diagram

eFigure 2. Kaplan-Meier Curves for Time to ACM or First CVH from Baseline through Month 30 by ATTR-CM Genotype^a

eFigure 3. Kaplan–Meier Curves for Time to ACM from Baseline through Month 42 by ATTR-CM Genotype^a

eFigure 4. Forest Plot of Composite Endpoint of ACM/CVH through Month 42 in the OLE by ATTR-CM Genotype^a

jamacardiol-e254477-s001.pdf^{(640.6KB, pdf)}

Supplement 2.

Study protocol

jamacardiol-e254477-s002.pdf^{(1.2MB, pdf)}

Supplement 3.

Statistical analysis plan

jamacardiol-e254477-s003.pdf^{(16MB, pdf)}

Supplement 4.

Data sharing statement

jamacardiol-e254477-s004.pdf^{(19.1KB, pdf)}

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PERMALINK

Efficacy of Acoramidis in Wild-Type and Variant Transthyretin Amyloid Cardiomyopathy

Kevin M Alexander, MD

Margot K Davis, MD

Olakunle Akinboboye, MD, MPH, MBA

John Berk, MD

Kunal Bhatt, MD

Francesco Cappelli, MD, PhD

Sarah AM Cuddy, MD

Marianna Fontana, MD, PhD

Pablo Garcia-Pavia, MD, PhD

Julian D Gillmore, MD, PhD

Jan M Griffin, MD

Justin L Grodin, MD, MPH

Daniel P Judge, MD

Michel G Khouri, MD

Kaitlyn Lam, MBBS

Ahmad Masri, MD, MS

Mathew S Maurer, MD

Laura Obici, MD

Frederick L Ruberg, MD

Nitasha Sarswat, MD

Keyur Shah, MD

Prem Soman, MD, PhD

Lily Stern, MD

Richard Wright, MD

Kuangnan Xiong, PhD

Xiaofan Cao, PhD

Ted Lystig, PhD

Jean-François Tamby, MD

Adam Castaño, MD, MS

Leonid Katz, MD

Uma Sinha, PhD

Jonathan C Fox, MD, PhD

Scott D Solomon, MD

Martha Grogan, MD

Key Points

Question

Finding

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Interventions

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Participant Population

Statistical Analysis

Results

Study Population and Baseline Characteristics

Table. Demographics and Baseline Characteristics in Participants of ATTRibute-CM by Genotypea.

Primary Efficacy and Clinical Outcome End Points

Figure 1. Forest Plots for Efficacy Outcomes by Transthyretin Amyloid Cardiomyopathy (ATTR-CM) Genotype.

Figure 2. Kaplan-Meier Curves for Time to All-Cause Mortality (ACM) or First Cardiovascular Hospitalization (CVH) in the Wild-Type Transthyretin Amyloid Cardiomyopathy (ATTRwt-CM) and Variant Transthyretin Amyloid Cardiomyopathy (ATTRv-CM) Subgroups.

Biomarkers, Functional Assessment, and Quality of Life

Figure 3. Change From Baseline to Month 30 in Biomarkers, Functional Assessments, and Quality of Life in Modified Intention-to-Treat Population.

Misclassification of ATTRv-CM Population

Efficacy in the p.Val142Ile Variant Subpopulation

Figure 4. Kaplan-Meier Curves of Modified Intention-to-Treat Population for Time to All-Cause Mortality (ACM) or First Cardiovascular Hospitalization (CVH) in Participants With p.Val142Ile Variant Transthyretin Amyloid Cardiomyopathy (ATTRv-CM).

Safety

Discussion

Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Table. Demographics and Baseline Characteristics in Participants of ATTRibute-CM by Genotype^a.