Effect Of Acoramidis On Outpatient Worsening Heart Failure In Transthyretin Amyloid Cardiomyopathy: Findings From ATTRibute-CM

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Author Block: Marianna Fontana¹, Francesco Cappelli², Pablo Garcia-Pavia³, Daniel P. Judge⁴, Laura Obici⁵, Ahmad Masri⁶, João R. Agostinho⁷, Carsten Tschöpe⁸, Kai Vogtländer⁹, Antonio Ciaccia¹⁰, Ana Zazula¹¹, Stefan Zeitler¹², Jean-François Tamby¹³, Julian Gillmore¹, Thibaud Damy¹⁴. ¹National Amyloidosis Centre, University College London, London, United Kingdom; ²Tuscan Referral Center for Amyloid Treatment, Careggi University Hospital, Florence, Italy; ³Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, CIBERCV, Madrid, Spain; ⁴Medical University of South Carolina, Charleston, SC; ⁵Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; ⁶Oregon Health and Science University School of Medicine, Portland, OR; ⁷Hospital Universitário de Santa Maria, Lisbon, Portugal; ⁸German Heart Center of the Charité (DHZC), Charité Universitätsmedizin, Berlin, Germany; ⁹Bayer AG, Wuppertal, Germany; ¹⁰Global Medical and Evidence, Bayer, Inc., Mississauga, ON, Canada; ¹¹Bayer, Sao Paulo, Brazil; ¹²Bayer Consumer Care AG, Basel, Switzerland; ¹³BridgeBio Pharma, Inc., San Franciso, CA; ¹⁴Department of Cardiology, Referral Center for Cardiac Amyloidosis, Hôpital Henri-Mondor, Creteil, France
Disclosure Block: M. Fontana: Advisory Panel; Pharmaceutical Company/Distributors; Alexion Pharmaceuticals, AstraZeneca, Alnylam Pharmaceuticals, Bridgbio, Attralus, Intellia Cardior, Lexeo Prothena, Mycardium., Intellia Therapeutics, Ionis Pharmaceuticals. Consultant; Pharmaceutical Company/Distributors; Janssen, Pfizer. Advisory Panel; Pharmaceutical Company/Distributors; Novo Nordisk. D.P. Judge: Consultant; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Attralus, BridgeBio, LEXEO Therapeutics, Novo Nordisk, Rocket Pharmaceuticals, Bayer AG, Alexion Pharmaceuticals. L. Obici: Speaker's Bureau; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Pfizer, Novartis, Akcea Therapeutics. A. Masri: Research Support; Pharmaceutical Company/Distributors; Pfizer, Ionis Pharmaceuticals. Consultant; Pharmaceutical Company/Distributors; AstraZeneca, Attralus, Bristol-Myers Squibb, Cytokinetics, Alnylam Pharmaceuticals. Consultant; Bio-Medical Startup; Tenaya Therapeutics. Consultant; Pharmaceutical Company/Distributors; Pfizer, Ionis Pharmaceuticals, Eidos Therapeutics. Advisory Panel; Bio-Medical Startup; Haya. Consultant; Pharmaceutical Company/Distributors; BioMarin, Lexicon Pharmaceuticals. Consultant; Bio-Medical Startup; Intellia Therapeutics, Akros. Consultant; Pharmaceutical Company/Distributors; Alexion Pharmaceuticals. Consultant; Bio-Medical Startup; Prothena, Edgewise. J. Gillmore: Advisory Panel; Pharmaceutical Company/Distributors; Alnylam Pharmaceuticals, Ionis Pharmaceuticals, Akcea Therapeutics, Intellia Therapeutics, Eidos Therapeutics, Pfizer, Lycia. T. Damy: None.

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by destabilization of transthyretin (TTR) and aggregation of amyloid fibrils in the heart. Outpatient worsening heart failure (HF) is prognostic for all-cause mortality (ACM) in ATTR-CM. Acoramidis, an oral TTR stabilizer that achieves near-complete (≥90%) TTR stabilization, significantly reduced the burden of cumulative cardiovascular-related mortality (CVM) and recurrent cardiovascular-related hospitalization (CVH) vs placebo over 30 months in the phase 3 ATTRibute-CM study (NCT03860935), with clinical effects seen as early as Month 1.
Hypothesis: Outpatient worsening HF has prognostic significance beyond ACM in participants with ATTR-CM; acoramidis reduces outpatient worsening HF, with early and persistent effects on clinical outcomes after adjusting for time-dependent outpatient worsening HF.
Methods: This post hoc analysis of the ATTRibute-CM modified intention-to-treat population (N=611) evaluated associations between outpatient worsening HF (defined as initiation or dose increase of loop diuretics post baseline) and clinical outcomes using a randomization factor-stratified Cox regression model with baseline 6-minute walk distance as a covariate. The impact of acoramidis on outpatient worsening HF and on other clinical outcomes after adjusting for first outpatient worsening HF as a time-dependent covariate was also assessed. Nominal p values are reported.
Results: Outpatient worsening HF occurred in 287 participants (47.0%) and was associated with an increased risk of ACM/recurrent CVH (hazard ratio [HR] 1.95; 95% CI 1.51-2.51), first CVH (HR 2.78; 95% CI 1.95-3.95), ACM (HR 1.64; 95% CI 1.14-2.36), and CVM (HR 1.63; 95% CI 1.08-2.46) through Month 30 (all p<0.05). A lower proportion of acoramidis recipients had outpatient worsening HF (167/409 [40.8%]) vs placebo (120/202 [59.4%]). Acoramidis reduced the risk of first outpatient worsening HF by 41% vs placebo (HR 0.59; 95% CI 0.46-0.75; p<0.0001); Kaplan-Meier curves separated early, by Day 30 (HR 0.562; 95% CI 0.317-0.998; p<0.05) (Figure). Acoramidis was associated with a reduced risk of ACM/recurrent CVH (HR 0.59; 95% CI 0.45-0.77; p=0.0001) and of first CVH (HR 0.63; 95% CI 0.45-0.88; p=0.0072) over 30 months vs placebo after adjusting for time-dependent first outpatient worsening HF.
Conclusions: Outpatient worsening HF was strongly prognostic of other clinical outcomes in participants with ATTR-CM. Acoramidis treatment led to an early and sustained reduction in the risk of outpatient worsening HF and was associated with a reduced risk of ACM/recurrent CVH and of first CVH vs placebo, even after adjusting for time-dependent outpatient worsening HF.