Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

Background: A primary goal in treating obstructive hypertrophic cardiomyopathy (oHCM) is to improve patients' health status: their symptoms, function, and quality of life. The health status benefits of aficamten, a novel cardiac myosin inhibitor, have not been comprehensively described.
Objectives: This study sought to determine the effect of aficamten on patient-reported health status, including symptoms of fatigue, shortness of breath, chest pain, physical and social limitations, and quality of life.
Methods: SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) randomized symptomatic adults with oHCM to 24 weeks of aficamten (n = 142) or placebo (n = 140), followed by a 4-week washout. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and Seattle Angina Questionnaire 7-item (SAQ7) were serially administered. Changes in mean KCCQ-Overall Summary Score (KCCQ-OSS) and SAQ7-Summary Score (SAQ7-SS) from baseline to 24 weeks and following treatment withdrawal were compared using linear regression adjusted for baseline scores and randomization strata. Proportions of patients with clinically important changes were compared.
Results: Among 282 participants, the mean age was 59 ± 13 years, 115 (41%) were female, and 223 (79%) were White. Baseline KCCQ-OSS (69.3 ± 20.1 vs 67.3 ± 18.8) and SAQ7-SS (72.0 ± 21.0 vs 72.4 ± 18.3) were similar between aficamten and placebo groups. Treatment with aficamten, compared with placebo, improved both the mean KCCQ-OSS (13.3 ± 16.3 vs 6.1 ± 12.6; mean difference: 7.9; 95% CI: 4.8-11.0; P < 0.001) and SAQ7-SS (11.6 ± 17.4 vs 3.8 ± 14.4; mean difference: 7.8; 95% CI: 4.7-11.0; P < 0.001) at 24 weeks, with benefits emerging within 4 weeks. No heterogeneity in treatment effect was found across subgroups. A much larger proportion of participants experienced a very large health status improvement (≥20 points) with aficamten vs placebo (KCCQ-OSS: 29.7% vs 12.4%, number needed to treat: 5.8; SAQ7-SS: 31.2% vs 13.9%, number needed to treat: 5.8). Participants' health status worsened significantly more after withdrawal from aficamten than placebo (KCCQ-OSS: -16.2 ± 19.0 vs -3.0 ± 9.6; P < 0.001; SAQ7-SS: -17.4 ± 21.4 vs -2.5 ± 13.3), further confirming a causal effect of aficamten.
Conclusions: In patients with symptomatic oHCM, treatment with aficamten resulted in markedly improved health status, including significant improvement in chest pain-related health status, than placebo. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).
Competing Interests: Funding Support and Author Disclosures The SEQUOIA-HCM study was funded by Cytokinetics, Incorporated. Study design and data analysis were supported by the funder and aided by coauthors. Manuscript drafting was completed independently but reviewed by the funder. Dr Sherrod has received support from the National Heart, Lung, and Blood Institute (award number T32HL110837). Dr Saberi has received consultant/advisor fees from Bristol Myers Squibb; and has received research grants from Bristol Myers Squibb, Cytokinetics, Novartis, and Actelion Pharmaceuticals. Dr Nassif has received research and grant support from AstraZeneca and Cytokinetics; and has received consulting/advisory fees from Vifor and Cytokinetics. Dr Coats has received speaker fees from Alnylam and Pfizer; and has received advisory fees from Cytokinetics and Roche Diagnostics. Dr Garcia-Pavia has received speaker fees from Pfizer, AstraZeneca, Novo Nordisk, Ionis, BridgeBio, Bristol Myers Squibb, Intellia, and Alnylam; has received consultant/advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neuroimmune, Intellia, Ionis, BridgeBio, Lexeo, Rocket, Attralus, and AstraZeneca; and has received research/educational grants to his institution from Pfizer, AstraZeneca, Novo Nordisk, BridgeBio, and Alnylam. Dr Januzzi has received funding from the Hutter Family Professorship; has served as a board member for Imbria Pharmaceuticals; has served as a Director at Jana Care; has received grant support from Abbott, Applied Therapeutics, HeartFlow, Innolife, and Roche Diagnostics; has received consulting income from Abbott, Beckman, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Novartis, Pfizer, Merck, Roche Diagnostics, and Siemens; and has participated in clinical endpoint committees/Data Safety Monitoring Boards for Abbott, AbbVie, CVRx, Intercept, and Takeda. Dr Lewis has received research funding from the National Institutes of Health (R01-HL 151841, R01-HL131029, and R01-HL159514), American Heart Association (15GPSGC-24800006), Amgen, Cytokinetics, Applied Therapeutics, AstraZeneca, and SoniVie; has received honoraria for Advisory Boards from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen; and has received royalties from UpToDate for scientific content authorship related to exercise physiology. Dr Maron has received consultant/advisor fees from Imbria, Edgewise, and BioMarin; and has received Steering Committee fees for SEQUIOA-HCM from Cytokinetics, Incorporated. Dr Olivotto has received Speakers Bureau fees from Bristol Myers Squibb, Amicus, and Genzyme; has received consultant/advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma, and Lexeo; and has received research grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi, and Boston Scientific. Drs Butzner, Jacoby, Heitner, Kupfer, Malik, and Meng, and Ms Wohltman are employees of Cytokinetics Incorporated; and hold stock in Cytokinetics Incorporated. Dr Spertus has provided consultative services on patient-reported outcomes and evidence evaluation to Alnylam, AstraZeneca, Bayer, Merck, Janssen, Bristol Myers Squibb, 4DT Medical, Terumo, Cytokinetics, Imbria, and United Healthcare; holds research grants from Bristol Myers Squibb, and Janssen; owns the copyrights to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire, and Peripheral Artery Questionnaire; and has served on the Board of Directors for Blue Cross Blue Shield of Kansas City. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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