Aficamten and Cardiopulmonary Exercise Test Performance
Authors: Lee Matthew M. Y. , Masri Ahmad , Nassif Michael E. , Barriales-Villa Roberto , Abraham Theodore P. , Claggett Brian L. , Coats Caroline J. , Gimeno Juan Ramón , Kulac Ian J. , Landsteiner Isabela , Ma Changsheng , Maron Martin S. , Olivotto Iacopo , Owens Anjali T. , Solomon Scott D. , Veselka Josef , Jacoby Daniel L. , Heitner Stephen B. , Kupfer Stuart , Malik Fady I. , Meng Lisa , Wohltman Amy , Lewis Gregory D. ,   SEQUOIA-HCM Investigators, Wang Andrew , Sherrid Mark V , Kelly Jacob P , Marian Ali J , Owens Anjali Tiku , Wever-Pinzon Omar , Owens David , Wheeler Matthew T , Nagueh Sherif F , Rader Florian , McGrew Frank A , Wong Timothy , O'Neill Thomas , Bach Richard G , Martinez Matthew , Lakdawala Neal K , Collado Elias , Turer Aslan , Desai Y Milind , Hussain Zainal , Tower-Rader Albree F , Hannawi Bashar , Geske Jeffrey , Saberi Sara , Phelan Dermot , Kramer Christopher , Sarswat Nitasha , Ahmad Ferhaan , Choudhury Lubna , Markowitz Jeremy S , Sen Sounok , Bering Patrick , Maron Martin S , Jani Sandeep , Brinkley Douglas , Naidu Srihari , Maurer Mathew S , Moss Noah , Bilen Ozlem , Silva Enciso Jorge , Fraser Robert , Akinboboye Olakunle , Asher Craig , Emani Sitaramesh , Sharma Abhinav , Fermin David , Lyle Melissa , Raymer David , Darlington Andrew , Resnic Frederic , Nielsen Christopher D , Metra Marco , Musumeci Beatrice , Emdin Michele , Targetti Mattia , Canepa Marco , Michels Michelle , Knackstedt Christian , Amin Ahmad S. , Barriales Villa Roberto , Garcia Pavia Pablo , Gimeno Blanes Juan Ramon , Hidalgo Urbano Rafael Jesus , Rincon Diaz Luis Miguel , Ripoll Vera Tomas Vicente V , Garcia Alvarez Ana , Zemanek David , Jensen MortenK , Mogensen Jens , Thune Jens J , Bundgaard Henning , Charron Philippe , Trochu Jean-Noel , Habib Gilbert , Lhermusier Thibault , Reant Patricia , Hagege Albert A , Logeart Damien , Mitrovic Veselin , Edelmann Frank , Seidler Tim , Meder Benjamin , Schulze Paul Christian , Stoerk Stefan , Bekfani Tarek , Rassaf Tienush , Merkely Bela , Arad Michael , Halabi Majdi , Zwas Donna , Piltz Xavier , Paz Offir , Habib Manhal , Dudek Dariusz , Oreziak Artur , Wojakowski Wojciech , Toste Batista Alexandra M , Mesquita Bastos Jose Adelino , Elliott Perry M , Mahmod Masliza , Coats Caroline , Cooper Robert , Bradlow William , Pantazis Antonios , Tome Esteban Maria Teresa , McGinnis Shaina , Campain Joseph , Cocca-Spofford Diane , Giverts Ilya , Griskowitz Catherine , Newlands Chloe , Moreno Fabely Moreno 
Published: September 2024

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 &amp;lt;.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 &amp;lt;.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 &amp;lt;.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