Aficamten and Cardiopulmonary Exercise Test Performance
Matthew M.Y. Lee, Ahmad Masri, Michael E. Nassif, Roberto Barriales‐Villa, Theodore P. Abraham, Brian Claggett, Caroline Coats, Juan R. Gimeno, Ian J. Kulac, Isabela Landsteiner, Changsheng Ma, Martin S. Maron, Iacopo Olivotto, Anjali Owens, Scott D. Solomon, Josef Veselka, Daniel Jacoby, Stephen B. Heitner, Stuart Kupfer, Fady I. Malik, Lisa Meng, Amy Wohltman, Gregory D. Lewis, SEQUOIA-HCM Investigators, Andrew Wang, Mark V. Sherrid, Jacob P. Kelly, Ali J. Marian, Anjali Owens, Omar Wever‐Pinzon, David S. Owens, Matthew T. Wheeler, Sherif F. Nagueh, Florian Rader, Frank McGrew, Timothy C. Wong, Thomas O’Neill, Richard G. Bach, Matthew N. Martinez, Neal K. Lakdawala, Elias Collado, Aslan T. Turer, Milind Desai Y, Zainal Hussain, Albree Tower‐Rader, Bashar Hannawi, Jeffrey B. Geske, Sara Saberi, Dermot Phelan, Christopher M. Kramer, Nitasha Sarswat, Ferhaan Ahmad, Lubna Choudhury, Jeremy Markowitz, Sounok Sen, Patrick Bering, Martin S. Maron, Sandeep M. Jani, D. Marshall Brinkley, Srihari S. Naidu, Matthew J. Maurer, Noah Moss, Ozlem Bilen, Jorge Silva Enciso, Robert Fraser, Olakunle Akinboboye, Craig R. Asher, Sitaramesh Emani, Abhinav Sharma, David Fermin, Melissa Lyle, David Raymer, Andrew Darlington, Frederic S. Resnic, Christopher D. Nielsen, Marco Metra, Beatrice Musumeci, Michele Emdin, Mattia Targetti, Marco Canepa, Michelle Michels, Christian Knackstedt, Ahmad S. Amin, Roberto Barriales‐Villa, Pablo García Pavía, Juan R. Gimeno, Rafael Jesus Hidalgo Urbano, Luis Miguel Rincon Diaz, Tomas Vicente V Ripoll Vera, Ana García Álvarez, David Zemánek, M. Britt Jensen, Jens Mogensen, Jens Jakob Thune, Henning Bundgaard, Philippe Charron, Jean‐Noël Trochu, Gilbert Habib, Thibault Lhermusier, Patricia Réant
Abstract
Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. Trial Registration: ClinicalTrials.gov Identifier: NCT05186818.