Cytokinetics Announces Start of COMET-HF, a Confirmatory Phase 3 Clinical Trial of Omecamtiv Mecarbil in Patients with Symptomatic Heart Failure with Severely Reduced Ejection Fraction
Cytokinetics (CYTK) announced the start of COMET-HF, a confirmatory Phase 3 clinical trial evaluating omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction. The trial, conducted with Duke Clinical Research Institute, will enroll approximately 1,800 patients randomized 1:1 to receive omecamtiv mecarbil or placebo. The primary endpoint is time to first event in a composite of cardiovascular death, first heart failure event, LVAD implantation, cardiac transplantation, or stroke. Eligible patients must have ejection fraction <30%, NT-proBNP ≥1,000 pg/mL, and a heart failure event within six months. The study includes a two-week run-in period and two-week washout period before randomization.
Cytokinetics (CYTK) ha annunciato l'inizio di COMET-HF, uno studio clinico di fase 3 confermativo che valuta omecamtiv mecarbil in pazienti con insufficienza cardiaca sintomatica e frazione di eiezione severamente ridotta. Lo studio, condotto con il Duke Clinical Research Institute, arruolerà circa 1.800 pazienti randomizzati 1:1 per ricevere omecamtiv mecarbil o placebo. L'endpoint primario è il tempo fino al primo evento in un composito di morte cardiovascolare, primo evento di insufficienza cardiaca, impianto di LVAD, trapianto cardiaco o ictus. I pazienti idonei devono avere una frazione di eiezione <30%, NT-proBNP ≥1.000 pg/mL e un evento di insufficienza cardiaca negli ultimi sei mesi. Lo studio prevede un periodo di pre-trattamento di due settimane e un periodo di washout di due settimane prima della randomizzazione.
Cytokinetics (CYTK) anunció el inicio de COMET-HF, un ensayo clínico de fase 3 confirmatorio que evalúa omecamtiv mecarbil en pacientes con insuficiencia cardíaca sintomática y fracción de eyección severamente reducida. El ensayo, llevado a cabo con el Duke Clinical Research Institute, inscribirá aproximadamente 1,800 pacientes asignados al azar 1:1 para recibir omecamtiv mecarbil o placebo. El objetivo principal es el tiempo hasta el primer evento en un compuesto de muerte cardiovascular, primer evento de insuficiencia cardíaca, implantación de LVAD, trasplante cardíaco o accidente cerebrovascular. Los pacientes elegibles deben tener una fracción de eyección <30%, NT-proBNP ≥1,000 pg/mL y un evento de insuficiencia cardíaca dentro de los seis meses. El estudio incluye un período de adaptación de dos semanas y un período de lavado de dos semanas antes de la randomización.
사이토키네틱스 (CYTK)는 증상이 있는 심부전 환자를 대상으로 심각하게 감소한 박출률을 가진 OMECAMTIV MECARBIL의 확인적인 3상 임상시험 COMET-HF의 시작을 발표했습니다. 듀크 임상 연구소와 함께 진행되는 이 시험은 약 1,800명의 환자를 무작위로 1:1 비율로 OMECAMTIV MECARBIL 또는 위약을 받도록 등록합니다. 주요 평가 기준은 심혈관 사망, 첫 번째 심부전 사건, LVAD 이식, 심장 이식 또는 뇌졸중의 복합체에서 첫 번째 사건까지의 시간입니다. 적격 환자는 박출률이 <30%, NT-proBNP ≥1,000 pg/mL이며, 최근 6개월 이내에 심부전 사건이 있어야 합니다. 연구는 무작위 배정 전에 2주 간의 선행 기간과 2주 간의 세척 기간이 포함됩니다.
Cytokinetics (CYTK) a annoncé le début de COMET-HF, un essai clinique de phase 3 de confirmation évaluant l'omécamtiv mécarbil chez des patients souffrant d'insuffisance cardiaque symptomatique avec une fraction d'éjection sévèrement réduite. L'essai, mené avec l'institut de recherche clinique de Duke, inscrira environ 1 800 patients randomisés 1:1 pour recevoir de l'omécamtiv mécarbil ou un placebo. Le critère principal est le temps jusqu'au premier événement dans une composition de décès cardiovasculaire, premier événement d'insuffisance cardiaque, implantation de LVAD, transplantation cardiaque ou AVC. Les patients éligibles doivent avoir une fraction d'éjection <30%, NT-proBNP ≥1 000 pg/mL et un événement d'insuffisance cardiaque survenu au cours des six derniers mois. L'étude comprend une période d'adaptation de deux semaines et une période de lavage de deux semaines avant la randomisation.
Cytokinetics (CYTK) gab den Beginn der COMET-HF bekannt, einer bestätigenden Phase-3-Studie zur Bewertung von Omecamtiv Mecarbil bei Patienten mit symptomatischer Herzinsuffizienz und stark reduzierter Ejektionsfraction. Die Studie, die in Zusammenarbeit mit dem Duke Clinical Research Institute durchgeführt wird, wird etwa 1.800 Patienten rekrutieren, die 1:1 randomisiert Omecamtiv Mecarbil oder ein Placebo erhalten. Endpunkt der Studie ist die Zeit bis zum ersten Ereignis in einer Kombination aus Herz-Kreislauf-Tod, erstem Herzinsuffizienzereignis, LVAD-Implantation, Herztransplantation oder Schlaganfall. Die geeigneten Patienten müssen eine Ejektionsfraktion von <30%, NT-proBNP ≥1.000 pg/mL und ein Herzinsuffizienzereignis innerhalb der letzten sechs Monate aufweisen. Die Studie umfasst eine zweiwöchige Einschleichphase und eine zweiwöchige Auswaschphase vor der Randomisierung.
- Phase 3 trial initiation represents significant milestone in drug development pipeline
- Large-scale trial with 1,800 patients strengthens potential statistical significance
- Collaboration with prestigious Duke Clinical Research Institute enhances trial credibility
- Extended trial timeline required to reach 850 primary composite endpoint events
- Complex trial design with run-in and washout periods may impact patient retention
- High patient qualification requirements may slow enrollment pace
Insights
The initiation of COMET-HF represents a significant milestone in omecamtiv mecarbil's development path. This Phase 3 trial targeting 1,800 patients is strategically designed with robust endpoints focusing on cardiovascular death and heart failure events. The trial's design shows notable improvements, including pragmatic features to enhance efficiency and reduce patient burden.
Key differentiators include the focus on severely reduced ejection fraction patients (<
The collaboration with Duke Clinical Research Institute adds credibility and expertise to the trial execution. The study's comprehensive endpoint structure, including LVAD implantation and cardiac transplantation, will provide valuable data for both regulatory approval and clinical practice guidance.
SOUTH SAN FRANCISCO, Calif., Dec. 03, 2024 (GLOBE NEWSWIRE) -- Cytokinetics, Incorporated (Nasdaq: CYTK) today announced that COMET-HF (Confirmation of Omecamtiv Mecarbil Efficacy Trial in Heart Failure), a confirmatory Phase 3 clinical trial of omecamtiv mecarbil in patients with symptomatic heart failure (HF) with severely reduced ejection fraction, is open to enrollment. Omecamtiv mecarbil is a novel investigational selective cardiac myosin activator in development for the potential treatment of heart failure with severely reduced ejection fraction. COMET-HF is being conducted in collaboration with Duke Clinical Research Institute (DCRI), a leading academic research organization.
“We are pleased to be starting COMET-HF to evaluate omecamtiv mecarbil in patients with severe heart failure who have limited treatment options and remain at high risk after failing guideline-directed medical therapy,” said Stuart Kupfer, M.D., Senior Vice President, Chief Medical Officer. “The design of COMET-HF is informed by encouraging data from GALACTIC-HF as well as extensive discussions with FDA and the heart failure community. This confirmatory trial has pragmatic features intended to improve the efficiency of study conduct and reduce patient burden. We hope to generate additional evidence of the potential treatment benefit of omecamtiv mecarbil among these heart failure patients with high unmet need.”
“Heart failure, and especially more severe forms of heart failure, is an area of major unmet need despite recent progress in developing more effective treatments,” said DCRI faculty member Michael Felker, M.D., M.H.S, Professor of Medicine and Cardiovascular Research Therapeutic Area Lead, and Principal Investigator for COMET-HF. “These patients are at high risk of heart failure hospitalization and death despite existing therapies, highlighting the critical need for new treatments. Through DCRI’s collaboration with Cytokinetics, we expect to leverage our decades of expertise in conducting cardiovascular clinical trials and advance our shared commitment to innovation in service of patients.”
COMET-HF is a Phase 3 multinational, multi-center, double-blind, randomized, placebo-controlled trial designed to assess the efficacy and safety of omecamtiv mecarbil in patients with symptomatic heart failure with severely reduced ejection fraction. The primary endpoint of COMET-HF is the time to first event in the primary composite endpoint of cardiovascular death, first heart failure event, left ventricular assist device (LVAD) implantation or cardiac transplantation, or stroke. Secondary endpoints will evaluate the risk of individual components, including heart failure hospitalization, cardiovascular death, and stroke, as well as the risk of irreversible morbidity/mortality based on the composite endpoint of cardiovascular death, LVAD or cardiac implantation, or stroke.
COMET-HF is expected to randomize approximately 1,800 patients on a 1:1 basis to receive omecamtiv mecarbil or placebo. At screening, patients enrolled in COMET-HF must have symptomatic heart failure with severely reduced ejection fraction defined as left ventricular ejection fraction <
Eligible patients will enter a two-week run-in period. Patients who are intolerant to omecamtiv mecarbil, are non-adherent, or have either undetectable or excessive plasma concentrations of omecamtiv mecarbil will not be eligible for randomization. Following the two-week run-in period, all patients will undergo a two-week washout period before being randomized to receive omecamtiv mecarbil, up to a maximum dose of 50 mg twice daily based on the plasma concentration of omecamtiv mecarbil during the run-in period, or placebo. Patients will continue to receive omecamtiv mecarbil or placebo twice daily until at least 850 primary composite endpoint events have occurred in the trial.
About Omecamtiv Mecarbil
Omecamtiv mecarbil is an investigational, selective, small molecule cardiac myosin activator, the first of a novel class of myotropes1 designed to directly target the contractile mechanisms of the heart, binding to and recruiting more cardiac myosin heads to interact with actin during systole. In doing so, omecamtiv mecarbil augments the impaired contractility that is associated with heart failure with reduced ejection fraction (HFrEF). Preclinical research has shown that omecamtiv mecarbil increases cardiac contractility without increasing intracellular myocyte calcium concentrations or myocardial oxygen consumption.2-4
The development program for omecamtiv mecarbil assessed its potential for the treatment of HFrEF. Positive results from GALACTIC-HF, the first Phase 3 clinical trial of omecamtiv mecarbil, demonstrated a statistically significant effect of treatment with omecamtiv mecarbil to reduce risk of the primary composite endpoint of cardiovascular death or heart failure events (heart failure hospitalization and other urgent treatment for heart failure) compared to placebo in patients treated with standard of care. No reduction in the secondary endpoint of time to cardiovascular death was observed. In general, the overall rates of myocardial ischemia, ventricular arrhythmias, and death were similar between treatment and placebo groups. Adverse events and treatment discontinuation of study drug were balanced between treatment arms.5 The magnitude of the treatment effect in a pre-specified subgroup of more than 4,500 patients with heart failure with severely reduced ejection fraction (<
About Heart Failure with Severely Reduced Ejection Fraction
Heart failure is a grievous condition that affects more than 64 million people worldwide5, about half of whom have reduced left ventricular function.8,9 HF is the leading cause of hospitalization and readmission in people age 65 and older.10,11 By 2029, is it estimated that 2.8 million people in the U.S. will have heart failure with severely reduced ejection fraction12, characterized as heart failure with reduced ejection fraction (HFrEF) <
About Cytokinetics
Cytokinetics is a late-stage, specialty cardiovascular biopharmaceutical company focused on discovering, developing and commercializing muscle biology-directed drug candidates as potential treatments for debilitating diseases in which cardiac muscle performance is compromised. As a leader in muscle biology and the mechanics of muscle performance, the company is developing small molecule drug candidates specifically engineered to impact myocardial muscle function and contractility. Following positive results from SEQUOIA-HCM, the pivotal Phase 3 clinical trial evaluating aficamten, a next-in-class cardiac myosin inhibitor, in obstructive hypertrophic cardiomyopathy (HCM), Cytokinetics is progressing regulatory submissions for aficamten for the treatment of obstructive HCM in the US, Europe, and China. Aficamten is also currently being evaluated in MAPLE-HCM, a Phase 3 clinical trial of aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM, ACACIA-HCM, a Phase 3 clinical trial of aficamten in patients with non-obstructive HCM, CEDAR-HCM, a clinical trial of aficamten in a pediatric population with obstructive HCM, and FOREST-HCM, an open-label extension clinical study of aficamten in patients with HCM. Cytokinetics is also developing omecamtiv mecarbil, a cardiac muscle activator, in patients with heart failure with severely reduced ejection fraction (HFrEF), CK-586, a cardiac myosin inhibitor with a mechanism of action distinct from aficamten for the potential treatment of heart failure with preserved ejection fraction (HFpEF), and CK-089, a fast skeletal muscle troponin activator (FSTA) for the potential treatment of a specific type of muscular dystrophy.
For additional information about Cytokinetics, visit www.cytokinetics.com and follow us on X, LinkedIn, Facebook and YouTube.
About the Duke Clinical Research Institute
The DCRI, part of the Duke University School of Medicine, is the largest academic clinical research organization in the world. Our mission is to develop, share, and implement knowledge that improves global health through innovative clinical research. The institute conducts multinational clinical trials, manages major national patient registries, and performs landmark outcomes research. The DCRI is a pioneer in cardiovascular and pediatric clinical research and conducts groundbreaking clinical research across multiple other therapeutic areas, including infectious disease, neuroscience, respiratory medicine, and nephrology.
For additional information about DCRI, visit dcri.org and follow us on X, LinkedIn, and YouTube.
Forward-Looking Statements
This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the "Act"). Cytokinetics disclaims any intent or obligation to update these forward-looking statements and claims the protection of the Act's Safe Harbor for forward-looking statements. Examples of such statements include, but are not limited to, statements, express or implied, relating to the Company’s development plans for omecamtiv mecarbil in the United States, including its ability to full enroll COMET-HF by any particular date, if at all. Such statements are based on management's current expectations, but actual results may differ materially due to various risks and uncertainties, including, but not limited to, potential difficulties or delays in the development, testing, regulatory approvals for trial commencement, progression or product sale or manufacturing, or production of Cytokinetics' drug candidates that could slow or prevent clinical development or product approval; Cytokinetics' drug candidates may have adverse side effects or inadequate therapeutic efficacy; the FDA or foreign regulatory agencies may delay or limit Cytokinetics' ability to conduct clinical trials; Cytokinetics may be unable to obtain or maintain patent or trade secret protection for its intellectual property; standards of care may change, rendering Cytokinetics' drug candidates obsolete; and competitive products or alternative therapies may be developed by others for the treatment of indications Cytokinetics' drug candidates and potential drug candidates may target. For further information regarding these and other risks related to Cytokinetics' business, investors should consult Cytokinetics' filings with the Securities and Exchange Commission.
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References:
- Psotka MA, Gottlieb SS, Francis GS et al. Cardiac Calcitropes, Myotropes, and Mitotropes. JACC. 2019; 73:2345-53.
- Planelles-Herrero VJ, Hartman JJ, Robert-Paganin J. et al. Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil. Nat Commun. 2017;8:190.
- Shen YT, Malik FI, Zhao X, et al. Improvement of cardiac function by a cardiac myosin activator in conscious dogs with systolic heart failure. Circ Heart Fail. 2010; 3: 522-27.
- Malik FI, Hartman JJ, Elias KA, Morgan BP, Rodriguez H, Brejc K, Anderson RL, Sueoka SH, Lee KH, Finer JT, Sakowicz R. Cardiac myosin activation: a potential therapeutic approach for systolic heart failure. Science. 2011 Mar 18;331(6023):1439-43.
- Teerlink JR, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. NEJM. 2021;384:105–16.
- Teerlink JR, et al. Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALACTIC-HF. Journal of the American College of Cardiology. 2021;78:97–108
- James et al. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Lancet 2018; 392: 1789–858.
- Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240-e327.
- Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129–2200.
- Roger VL. Epidemiology of Heart Failure. Circulation Research. 2013;113:646-659, originally published August 29, 2013. doi: 10.1161/CIRCRESAHA.113.300268.
- Kilgore M, Patel HK, Kielhorn A, et al. Economic burden of hospitalizations of Medicare beneficiaries with heart failure. Risk Manag Healthc Policy. 2017; 10: 63-70.
- Taylor C J, Ordóñez-Mena J M, Roalfe A K, et al. Trends in survival after a diagnosis of heart failure in the United Kingdom 2000-2017: population based cohort study. BMJ 2019; 364:l223 doi:10.1136/bmj.l223
- Greene SJ, Bauersachs J, Brugts JJ, et al. Worsening Heart Failure: Nomenclature, Epidemiology, and Future Directions: JACC Review Topic of the Week. JACC. 2023 Jan 31;81(4):413-424. doi:10.1016/j.jacc.2022.11.023. PMID: 36697141.
- Extrapolated from Desai NR, Butler J, Binder G, et al. Prevalence and Excess Risk of Hospitalization in Heart Failure with Reduced Ejection Fraction. Poster presented at: Heart Failure Society of America (HFSA) Annual Scientific Meeting; 2022 Sep 30-Oct 3; Washington, DC.
- Carnicelli AP, Clare RM, Hofmann P, et al. Clinical trajectory of patients with a worsening heart failure event and reduced ventricular ejection fraction. Am Heart J. 2022 Mar; 245:110-116. doi: 10.1016/j.ahj.2021.12.003. Epub 2021 Dec 18. PMID: 34932997.
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