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SEQUOIA-HCM trial meets primary endpoint in obstructive hypertrophic cardiomyopathy

SEQUOIA-HCM trial presented in a late breaking science session today at Heart Failure 2024

Heart Failure

Lisbon, Portugal – 13 May 2024:  Even though mortality and hospitalisation rates have improved, the quality of life for those living with hypertrophic cardiomyopathy (HCM) can be compromised with limiting symptoms such as exertional dyspnoea and decreased exercise capacity. A major cause of this in HCM patients is left ventricular outflow tract (LVOT) obstruction, which results in elevated intracardiac pressures. This study demonstrated that aficamten enhanced HCM patients’ exercise capacity with significant improvement in peak oxygen uptake (pVO2), improvement in limiting symptoms, and decreases in LVOT pressure gradients. The late breaking research presented today at Heart Failure 2024, a scientific congress of the European Society of Cardiology (ESC).1

“The SEQUOIA-HCM trial demonstrated that aficamten can reliably and safely eliminate LVOT obstruction in patients with obstructive HCM using a simple and stepwise dosing regimen, and was associated with substantial improvements in clinically relevant endpoints such as exercise capacity and symptoms,” said principal investigator Professor Martin Maron of the Lahey Hospital and Medical Center, Burlington, Massachusetts, US. “HCM patients are often on multiple medications, which frequently provide suboptimal benefit, while aficamten was highly effective at providing clinical improvement as combination therapy, but also as monotherapy.”

HCM occurs in approximately one in 200 to 500 individuals, with 70% of patients having obstructive disease.2 The condition causes the walls of the left ventricle to become thick and stiff, which can also result in obstruction to blood flow out of the heart and increased intracardiac pressures.

Aficamten is a cardiac myosin inhibitor that was previously shown to reduce LVOT gradients in a phase 2 trial.3 The phase 3 SEQUOIA-HCM trial evaluated the efficacy and safety of aficamten versus placebo in adults with symptomatic obstructive HCM. The primary endpoint was the change in pVO2, assessed using cardiopulmonary exercise testing, from baseline to week 24. Secondary endpoints at 24 weeks included the change in KCCQ score; the proportion of patients with ≥1 class improvement in New York Heart Association (NYHA); change in Valsalva LVOT gradient; the proportion of patients with Valsalva LVOT gradient <30 mmHg; and eligibility for invasive septal reduction.

SEQUOIA-HCM included 282 patients from 101 sites in 14 countries in North America, Asia, and Europe, making it the largest-ever obstructive HCM trial. All participants had reduced exercise capacity due to obstructive HCM. Patients were randomised 1:1 to aficamten or placebo on top of their background medical therapy. The starting dose of aficamten was 5 mg once daily with opportunities at weeks 2, 4, and 6 to increase the dose in 5 mg increments to a maximum dose of 20 mg. Dose adjustments were made according to left ventricular ejection fraction and LVOT gradients assessed using echocardiography.

The mean increase in pVO2 from baseline to 24 weeks was 1.8 ml/kg/min with aficamten compared to 0.0 ml/kg/min with placebo (least-squares mean difference between groups, 1.7 ml/kg/min; 95% confidence interval [CI] 1.0, 2.4; p<0.001). Regarding secondary endpoints at 24 weeks, aficamten resulted in a least-squares mean difference of 7 points in KCCQ score relative to placebo (95% CI 5, 10; p<0.0001). A ≥1 NYHA class improvement was observed in 58.5% of patients on aficamten and 24.3% of patients on placebo (p<0.0001). Aficamten led to a 50 mmHg greater reduction in Valsalva LVOT gradient versus placebo (95% CI -57, -44; p<0.0001). Some 49.3% of patients on aficamten achieved a Valsalva LVOT gradient <30 mmHg versus 3.6% of patients on placebo (p<0.0001). The aficamten group had 78 fewer days eligible for invasive septal reduction compared with the placebo group (p<0.0001).

Professor Maron said: “It was impressive to see that the beneficial effects of aficamten occurred rapidly and consistently over the treatment period and that the doses could be adjusted effectively and safely using only site read echocardiographic measures. It was also reassuring to see that in the very small number of patients found to have an ejection fraction below 50% on aficamten, there was no associated heart failure or the need for dose interruption, and that the effect on ejection fraction was reversible with treatment discontinuation.”


Notes to editor

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Funding: Cytokinetics Inc. provided the funding for this study


Disclosures: Martin S. Maron has received Consultant/Advisor fees from Imbria, Edgewise, Biomarin and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. Ahmad Masri has received Consultant/Advisor fees from Tenaya, Attralus, Cytokinetics, Bristol Myers Squibb, and Ionis, and Research Grants from Ionis, Akcea, Pfizer, Ultromics, and Wheeler Foundation. Michael E. Nassif has received Research and grant support from Astra Zeneca and Cytokinetics, Consultant/Advisor fees from Vifor, and Cytokinetics. Roberto Barriales-Villa has received Consultant/Advisor fees from MyoKardia/Bristol Myers Squibb. Michael Arad reports consultant and lecture fees from Bristol Myers Squibb. Nuno Cardim has received Consultant/Advisor fees from Cytokinetics, Bristol Myers Squibb, Pfizer, Menarini, Boehinger-Ingelheim, Bial. Caroline J. Coats has received speaker fees from Alnylam and Roche, and advisory fees from Cytokinetics. Hans-Dirk Düngen reports grants from Novartis, CSL Behring, and Cytokinetics. Pablo Garcia-Pavia has received Speakers’ Bureau fees from Pfizer, AstraZeneca, Novo Nordisk, Ionis, Bridgebio, BMS, Intelllia and Alnylam, Consultant/Advisor fees from Pfizer, Alnylam, MyoKardia/Bristol Myers Squibb, Cytokinetics, Neuroimmune, Intellia, Ionis, Bridgebio, Lexeo, Rocket, Attralus, and AstraZeneca, Research/Educational Grants to his institution from Pfizer, AstraZeneca, Novo Nordisk, BridgeBio, and Alnylam.  Albert A. Hagège has received Consultant/Advisor fees from Alnylam, Amicus Therapeutics, Bayer, MyoKardia/Bristol Myers Squibb, Pfizer, Sanofi Genzyme, and Steering Committee fees for SEQUOIA-HCM from Cytokinetics, Incorporated. James L. Januzzi is funded in part by the Hutter Family Professorship; is a Trustee of the American College of Cardiology; 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 end point committees/data safety monitoring boards for Abbott, AbbVie, CVRx, Intercept, and Takeda. Matthew M.Y. Lee has received Research Grants through his institution from AstraZeneca, Boehringer Ingelheim, and Roche Diagnostics, and is a member of a Clinical Endpoints Committee for Bayer, and a Trial Steering Committee for Cytokinetics. Gregory D. 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, honoraria for advisory boards from Pfizer, Merck, Boehringer Ingelheim, Novartis, American Regent, Cyclerion, Cytokinetics, and Amgen, and royalties from UpToDate for scientific content authorship related to exercise physiology. Michelle Michels has received Consultant/ Advisor fees from Bristol Myers Squibb, Cytokinetics, Pfizer and Research Grant funding from Bristol Myers Squibb. Iacopo Olivotto has received Speakers’ Bureau fees from Bristol Myers Squibb, Amicus, Sanofi Genzyme, Consultant/Advisor fees from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Tenaya, Rocket Pharma and Lexeo, and Research Grant funding from Bristol Myers Squibb, Cytokinetics, Sanofi Genzyme, Amicus, Bayer, Menarini International, Chiesi and Boston Scientific. Artur Oreziak has received investigator fees from Cytokinetics and MyoKardia/Bristol Myers Squibb. Anjali T. Owens has received Consultant/Advisor fees from Cytokinetics, Bristol Myers Squibb/MyoKardia, and Pfizer. John A. Spertus is the PI of grants from the NIH, Abbott Vascular, and the American College of Cardiology Foundation; is a consultant for Janssen, Novartis, Amgen, Myokardia, AstraZeneca, Bayer, and Merck; serves on the Scientific Advisory Board of United Healthcare and the Board of Directors for Blue Cross Blue Shield of Kansas City; owns the copyright to the KCCQ, SAQ, and PAQ; and has an equity interest in Health Outcomes Sciences. Scott D. Solomon has received Consultant/Advisor fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, MyoKardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health, and Research Grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI. Jacob Tfelt-Hansen is a consultant for Leo Pharma, MicroPort, and Johnson and Johnson. Marion van Sinttruije is a patient advisory committee member and a SEQUOIA-HCM Steering Committee member for Cytokinetics Incorporated. Hugh C. Watkins has received Consultant/Advisor fees from Cytokinetics, BioMarin, and BridgeBio. Daniel L. Jacoby, Stephen B. Heitner, Stuart Kupfer, Fady I. Malik, Lisa Meng, and Amy Wohltman are employees of Cytokinetics Incorporated and hold stock in Cytokinetics Incorporated. Lubna Choudhury, Brian Claggett, Chang-Sheng Ma, Josef Veselka, and Theodore P. Abraham have no disclosures to report.


References and notes

1The ‘SEQUOIA-HCM’ trial will be presented during the session ‘Late Breaking Clinical trials: LVAD, HFpEF and hypertrophic cardiomyopathy’ which takes place on 13 May 2024 at 13:45 WEST in Room 1.

2Maron MS, Olivotto I, Zenovich AG, et al. Hypertrophic cardiomyopathy is predominantly a disease of left ventricular outflow tract obstruction. Circulation. 2006;114:2232–2239.

3Maron MS, Masri A, Choudhury L, et al. Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol. 2023;81:34–45.


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