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Clinical Trial
. 2024 Nov 1;9(11):990-1000.
doi: 10.1001/jamacardio.2024.2781.

Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial

Matthew M Y Lee  1 , Ahmad Masri  2 , Michael E Nassif  3 , Roberto Barriales-Villa  4 , Theodore P Abraham  5 , Brian L Claggett  6 , Caroline J Coats  1 , Juan Ramón Gimeno  7 , Ian J Kulac  6 , Isabela Landsteiner  8 , Changsheng Ma  9 , Martin S Maron  10 , Iacopo Olivotto  11 , Anjali T Owens  12 , Scott D Solomon  6 , Josef Veselka  13 , Daniel L Jacoby  14 , Stephen B Heitner  14 , Stuart Kupfer  14 , Fady I Malik  14 , Lisa Meng  14 , Amy Wohltman  14 , Gregory D Lewis  8 ; SEQUOIA-HCM Investigators
Collaborators, Affiliations
Clinical Trial

Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial

Matthew M Y Lee et al. JAMA Cardiol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Lee reported serving on the steering committee of the Cytokinetics Trial; receiving grants from AstraZeneca, Boehringer Ingelheim, and Roche Diagnostics; and serving on the Bayer Clinical Events Committee outside the submitted work. Dr Masri reported receiving grants from Pfizer, Ionis, Attralus, and Cytokinetics and personal fees from Cytokinetics, BMS, Eidos, Pfizer, Ionis, Lexicon, Attralus, Haya, BioMarin, Prothena, Alexion, AstraZeneca, and Tenaya outside the submitted work. Dr Nassif reported receiving institutional research support from Cytokinetics and BMS outside the submitted work. Dr Barriales-Villa reported receiving advisory board fees from Pfizer, Bristol Myer Squibb, Cytokinetics, Sanofi, Chiesi and Alnylam and grants from Health in Code outside the submitted work. Dr Abraham reported receiving UCSF Clinical trial funds during the conduct of the study. Dr Claggett reported receiving consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, Rocket, CVRX, and BMS outside the submitted work. Dr Coats reported receiving personal fees from Cytokinetics, Alnylam, and Pfizer and grants from Roche outside the submitted work. Dr Maron reported serving on the steering committee for Cytokinetics and receiving data safety monitoring board and/or consultant fees from Imbria, Edgewise, and Cytokinetics outside the submitted work. Dr Olivotto reported receiving personal fees from Cytokinetics, BMS, Tenaya, Lexeo, Rocket Pharma, Edgewise, and Sanofi Genzyme and grants from Menarini International, Amicus, and Chiesi during the conduct of the study. Dr Owens reported receiving consulting and/or advisory board fees from BMS, Cytokinetics, Alexion, Edgewise, Tenaya, Biomarin, Stealth, Pfizer, Imbria, Lexeo, and Corvista during the conduct of the study. Dr Solomon reported receiving grants from Cytokinetics, Alexion, Alnylam, Applied Therapeutics, AstraZeneca, Bellerophon, Bayer, BMS, Boston Scientific, Cytokinetics, Edgewise, Eidos/BridgeBio, Gossamer, GSK, Ionis, Lilly, the National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Tenaya, Theracos, and US2.AI and consulting fees from Abbott, Action, Akros, Alexion, Alnylam, Amgen, Arena, AstraZeneca, Bayer, BMS, Cardior, Cardurion, Corvia, Cytokinetics, GSK, Lilly, Novartis, Roche, Theracos, Quantum Genomics, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo outside the submitted work. Dr Veselka reported receiving steering committee fees from Cytokinetics outside the submitted work. Dr Jacoby reported being employed by and stockholder in Cytokinetics during the conduct of the study and having 2 patents pending, 20240091203 and 20240115554. Drs Heitner, Kupfer, Malik, Meng, and Wohltman reported being employed by and stockholders in Cytokinetics during the conduct of the study. Dr Lewis reported receiving grants from Cytokinetics, Amgen, Applied Therapeutics, Pfizer, AstraZeneca, Rivus, the National Institutes of Health, and Pharmacosmos, and consulting fees from Edwards and American Regent outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Baseline and Week 24 Values and Changes in Integrated Exercise Performance and Its Component Variables
Baseline and week 24 values, connected by vertical lines, are shown for individual patients receiving aficamten (left) and placebo (right) for z score values (A), peak oxygen uptake (pVO2) values (C), and ventilatory efficiency values (E). Integrated exercise performance and its component variables (standardized 2-component z score of pVO2 and VE as measured by minute ventilation [VE]/carbon dioxide output [VCO2] slope throughout all of exercise). The z score was derived by reversing the directionality of VE/VCO2 slope values such that increases in both z score components indicate benefit; equal weights were used for each component. Changes in values (median and IQR) from baseline to week 24 are shown in panels B, D, and F. Box edges indicate the IQRs; the horizontal lines in between the edges indicate the median values. Whiskers extend to the upper and lower adjacent values, and dots represent outside values.
Figure 2.
Figure 2.. Responder Analyses of Categorical Change in Peak Oxygen Uptake (pVO2) With Aficamten vs Placebo at 24 Weeks
Data represented as proportion of patients experiencing small (0 to <1.5), moderate (≥1.5 to <3), or large (≥3.0) deteriorations or improvements in pVO2 (in milliliters per kilogram per minute) per treatment group.
Figure 3.
Figure 3.. Cubic Spline Graphs: Correlation Between Change in Peak Oxygen Uptake (pVO2) and Clinical Metrics
The panels display the change in pVO2 from baseline to 24 weeks for the following: Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) (A), New York Heart Association (NYHA) functional class (B), resting left ventricular outflow tract gradient (LVOT-G) (C), Valsalva LVOT-G (D), N-terminal pro–brain natriuretic peptide (NT-proBNP) (E), and high-sensitivity cardiac troponin I (hs-cTnI) (F). Graphs display linear regression with cubic terms. Analyses adjusted for baseline values of both parameters. Solid lines show the association correlate, and shaded areas show the 95% CIs. Histograms show the distribution of change in pVO2.
See this image and copyright information in PMC

References

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