Cytokinetics, Incorporated (Cytokinetics) operates as a late-stage biopharmaceutical company. The company focuses on discovering, developing and commercializing first-in-class muscle activators and next-in-class muscle inhibitors as potential treatments for debilitating diseases in which muscle performance is compromised and/or declining.
The company has discovered and is developing muscle-directed investigational medicines that may potentially improve the healthspan of people with devastating...
Cytokinetics, Incorporated (Cytokinetics) operates as a late-stage biopharmaceutical company. The company focuses on discovering, developing and commercializing first-in-class muscle activators and next-in-class muscle inhibitors as potential treatments for debilitating diseases in which muscle performance is compromised and/or declining.
The company has discovered and is developing muscle-directed investigational medicines that may potentially improve the healthspan of people with devastating cardiovascular and neuromuscular diseases of impaired muscle function. Its research and development activities relating to the biology of muscle function have evolved from its knowledge and expertise regarding the cytoskeleton, a complex biological infrastructure that plays a fundamental role within every human cell. As a leader in muscle biology and the mechanics of muscle performance, the company is discovering and developing small molecule drug candidates specifically engineered to impact muscle function and contractility, with the objective to build a sustainable specialty biopharmaceutical business.
The company's research continues to drive innovation and leadership in muscle biology. All of its drug candidates have arisen from its cytoskeletal research activities. The company's focus on the biology of the cytoskeleton distinguishes it from other biopharmaceutical companies and potentially positions it to identify, discover, develop, and commercialize novel therapeutics that may be useful for the treatment of severe diseases and medical conditions. The company intends to leverage its experience in muscle contractility to expand its current pipeline and expects to identify additional potential drug candidates that may be suitable for clinical development and commercialization.
Strategy
As a leader in muscle biology and the mechanics of muscle performance, the company is developing small molecule drug candidates specifically engineered to impact muscle function and contractility. The key components of the company's five-year corporate strategy are to advance 2 product approvals across 3 indications and 10 novel molecular entities into its pipeline; achieve broad access and rapid use of its medicines in 15 countries throughout North America and Europe; reach 100,000 patients globally with its medicines; foster a patient-centric culture with emphasis on equitable access; extend leadership in muscle deploying multiple therapeutic modalities; and building a specialty cardiology franchise.
Research and Development Programs
The company's research and development activities related to muscle contractility include its cardiac muscle contractility programs and its skeletal muscle contractility programs. The company also conducts research and development on novel treatments for disorders involving muscle function beyond muscle contractility.
Specialty Cardiology Programs
The company's specialty cardiology program is focused on the cardiac sarcomere, the basic unit of muscle contraction in the heart. The cardiac sarcomere is a highly ordered cytoskeletal structure composed of cardiac myosin, actin, and a set of regulatory proteins. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell, and it is directly responsible for converting chemical energy into mechanical force, resulting in cardiac muscle contraction. The company's most advanced cardiac program is based on the hypothesis that inhibitors of cardiac myosin may attenuate the hyperdynamic contraction resulting from pathologic mutations in the sarcomere that lead to hypertrophic cardiomyopathies. A targeted oral therapy addressing this disease etiology may improve symptoms, function, exercise capacity, and potentially slow disease progression.
The company also has a late-stage program based on the hypothesis that activators of cardiac myosin may target the underlying deficit of cardiac contractility in heart failure with reduced ejection fraction and address certain adverse properties of existing positive inotropic agents. Its novel cardiac myosin activator works by a mechanism that directly stimulates the activity of the cardiac myosin motor protein, without increasing the intracellular calcium concentration. It accelerates the rate-limiting step of the myosin enzymatic cycle and shifts it in favor of the force-producing state. Rather than increasing the velocity of cardiac contraction, this mechanism instead lengthens the systolic ejection time, which results in increased cardiac function in a potentially more oxygen-efficient manner.
Aficamten
Aficamten is a novel, oral, small molecule cardiac myosin inhibitor that the company's scientists discovered for the treatment of HCM. Aficamten arose from an extensive chemical optimization program conducted with attention to therapeutic index and pharmacokinetic properties that may translate into next-in-class potential. Aficamten was designed to reduce the hypercontractility associated with HCM. In preclinical models, aficamten reduces myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state. Aficamten reduces the number of active actin-myosin cross bridges during each cardiac cycle and consequently reduces myocardial contractility. This mechanism of action may be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM. The preclinical pharmacokinetics of aficamten were characterized evaluated and optimized for potential rapid onset, ease of titration and rapid symptom relief.
FDA granted aficamten orphan drug designation for the treatment of symptomatic HCM.
The development program for aficamten assessed its potential as a treatment that improves exercise capacity and relieves symptoms in patients with oHCM, as well as its potential long-term effects on cardiac structure and function. Aficamten was evaluated in SEQUOIA-HCM, a positive pivotal Phase 3 clinical trial in patients with symptomatic oHCM.
The results from SEQUOIA-HCM met the company's high expectations for the trial, and are consistent with its target product profile that may enable aficamten to provide physicians and patients with an important alternative to currently available treatment options. The results from SEQUOIA-HCM showed that treatment with aficamten for 24 weeks significantly improved exercise capacity compared to placebo, increasing peak oxygen uptake (pVO2) by 1.8 ml/kg/min compared to baseline in patients treated with aficamten versus 0.0 ml/kg/min in patients treated with placebo (p=0.000002). This treatment effect was consistent across all pre-specified subgroups, including patients receiving beta blockers.
Following the positive results of SEQUOIA-HCM, the company submitted an NDA for the treatment of oHCM. The FDA accepted and filed the NDA and assigned the NDA a standard review with a PDUFA target action date of September 26, 2025. Additionally, the company submitted an MAA with the EMA which has validated the MAA for the treatment of oHCM. The MAA is now under review by the EMA's Committee for Medicinal Products for Human Use.
Aficamten is also 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. In addition, a Phase 1 study of aficamten in healthy Japanese patients is being conducted.
Collaboration for Commercialization of Aficamten in Greater China
The company is a party to a license and collaboration agreement, pursuant to which it granted Corxel an exclusive license to develop and commercialize aficamten in China and Taiwan. In the fourth quarter of 2024, Genzyme Corporation, an affiliate of Sanofi, acquired Corxel's rights to develop and commercialize aficamten in China and Taiwan.
Collaboration for Commercialization of Aficamten in Japan
On November 19, 2024, the company announced that it has entered into a collaboration and license agreement with Bayer Consumer Care AG, an affiliate of Bayer AG, for the exclusive development and commercialization of aficamten in Japan, subject to certain reserved development rights of Cytokinetics to continue conducting ACACIA-HCM and CEDAR-HCM in Japan.
Omecamtiv mecarbil
The company is developing omecamtiv mecarbil as a potential treatment across the continuum of care in heart failure both for use in the hospital setting and for use in the outpatient setting.
Omecamtiv mecarbil is a selective, small molecule cardiac myosin activator, the first of a novel class of myotropes designed to directly target the contractile mechanisms of the heart, binding to and recruiting more cardiac myosin heads to interact with actin during systole. Omecamtiv mecarbil is designed to increase the number of active actin-myosin cross bridges during each cardiac cycle and consequently augment the impaired contractility that is associated with heart failure with reduced ejection fraction, or HFrEF.
GALACTIC-HF
GALACTIC-HF was a Phase 3 cardiovascular outcomes clinical trial of omecamtiv mecarbil which was conducted by Amgen in collaboration with Cytokinetics. The primary objective of this double-blind, randomized, placebo-controlled multicenter clinical trial was to determine if treatment with omecamtiv mecarbil when added to standard of care is superior to standard of care plus placebo in reducing the risk of cardiovascular death or heart failure events in patients with high risk chronic heart failure and reduced ejection fraction.
COMET-HF Informed by Results from Patient Subgroup in GALACTIC-HF
Since its release of the primary results of GALACTIC-HF, the company has conducted and announced supplemental and subgroup analyses suggesting that certain biologically plausible subgroups of patients treated with omecamtiv mecarbil in GALACTIC-HF may have benefited more than the general patient population in the trial. Based on these and other promising subgroup analyses from GALACTIC-HF, as well as the high unmet need in patients with heart failure with severely reduced ejection fraction, the company decided to continue the development program for omecamtiv mecarbil and to conduct a confirmatory study in a patient population similar to the approximately 4,000 prespecified subgroup of patients with an LVEF <28% in GALACTIC-HF. Accordingly, in the fourth quarter of 2024, the company commenced patient enrollment in COMET-HF (Confirmation of Omecamtiv Mecarbil Efficacy Trial in Heart Failure), a Phase 3 multi-center, double-blind, randomized, placebo-controlled trial to assess the efficacy and safety of omecamtiv mecarbil in patients with symptomatic HFrEF 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. COMET-HF is expected to enroll approximately 1,800 patients randomized on a 1:1 basis to receive omecamtiv mecarbil or placebo for up to 48 weeks.
Collaboration for Commercialization of Omecamtiv Mecarbil in Greater China
The company was a party to a license and collaboration agreement under which it granted Corxel an exclusive license to develop and commercialize omecamtiv mecarbil in China and Taiwan. In the fourth quarter of 2024, the company terminated the license and collaboration agreement by mutual agreement with Corxel. Accordingly, all rights to develop and commercialize omecamtiv mecarbil in China and Taiwan have reverted to the company.
CK-586
CK-586 is a novel, selective, oral, small molecule cardiac myosin inhibitor designed to reduce the hypercontractility associated with heart failure with preserved ejection fraction, or HFpEF. Approximately half of the estimated 6.7 million patients in the United States with heart failure have HFpEF, and the prevalence of HFpEF is increasing. A subset of HFpEF patients with hypercontractility, ventricular hypertrophy, elevated biomarkers and symptoms of heart failure may benefit from treatment with a cardiac sarcomere inhibitor.
In preclinical models, CK-586 reduced cardiac hypercontractility by decreasing the number of active myosin cross-bridges during cardiac contraction thereby reducing the contractile force, without effect on calcium transients. CK-586 selectively inhibits the ATPase of intact cardiac myosin but does not inhibit the ATPase of subfragment-1 of myosin (S1) as does aficamten, a cardiac myosin inhibitor also developed by the company. Unlike aficamten, the inhibitory effect of CK-586 requires the presence of the regulatory light chain (RLC) of myosin in the context of the intact myosin dimer (heavy meromyosin or HMM). In preclinical models, CK-586 reduced cardiac hypercontractility by decreasing the number of active myosin cross-bridges during cardiac contraction thereby reducing the contractile force, without effect on calcium transients. In engineered human HCM heart tissues, CK-586 demonstrated a shallow force-concentration response and improved lusitropy. Lending support for investigating this mechanism of action in HFpEF, a subset of patients with HFpEF resemble patients with non-obstructive hypertrophic cardiomyopathy (HCM) in that those patients have higher ejection fractions, thickened walls of their heart, elevated biomarkers, and symptoms of heart failure. Data from a Phase 2 clinical trial of aficamten in patients with non-obstructive HCM show that aficamten was well tolerated, improved patient reported outcomes (Kansas City Cardiomyopathy Questionnaire (KCCQ) and New York Heart Association (NYHA) Functional Class) and biomarkers, measures that are also relevant to HFpEF.
Phase 1 Trial Results
The company conducted a Phase 1 double-blind randomized, placebo-controlled, multi-part single and multiple ascending dose clinical study with the goal of evaluating the safety, tolerability and PK of CK-586 when administered orally as single or multiple doses to healthy participants. The primary objective of this Phase 1 double-blind randomized, placebo-controlled, single and multiple ascending dose clinical study was to evaluate the safety, tolerability and PK of CK-586 when administered orally to healthy participants.
AMBER-HFpEF
In the fourth quarter of 2024, the company announced the design of AMBER-HFpEF (Assessment of CK-586 in a Multi-Center, Blinded Evaluation of Safety and Tolerability Results in HFpEF), a Phase 2 randomized, placebo-controlled, double-blind, multi-center, dose-finding clinical trial in patients with symptomatic HFpEF with left ventricular ejection fraction greater than or equal to 60%. The primary objective is to evaluate the safety and tolerability profile of CK-586 compared to placebo. The secondary objectives include assessing the effect of CK-586 on LVEF and NT-proBNP, its pharmacokinetics, and its pharmacokinetic/pharmacodynamic relationship. AMBER-HFpEF is currently enrolling patients.
Neuromuscular Program
The company's neuromuscular program focuses on the activation of the skeletal sarcomere, the basic unit of skeletal muscle contraction. The skeletal sarcomere is a highly ordered cytoskeletal structure composed of skeletal muscle myosin, actin, and a set of regulatory proteins, which include the troponins and tropomyosin. This program leverages the company's expertise developed in its ongoing discovery and development of cardiac sarcomere activators.
The clinical effects of muscle weakness and wasting, fatigue and loss of mobility can range from decreased quality of life to, in some instances, life-threatening complications. By directly improving skeletal muscle function, a small molecule activator of the skeletal sarcomere potentially could enhance functional performance and quality of life in patients suffering from diseases or medical conditions associated with skeletal muscle weakness or wasting.
In the fourth quarter of 2024, the company announced that the first participants have been dosed in a Phase 1 randomized, double-blind, placebo-controlled, multi-part, single and multiple ascending dose clinical study of CK-089 in healthy human participants. CK-089 is a fast skeletal muscle troponin activator with potential therapeutic applications for a specific type of muscular dystrophy and other conditions of impaired muscle function. The primary objective of this Phase 1 randomized, double-blind, placebo-controlled, multi-part single and multiple ascending dose clinical study is to evaluate the safety, tolerability, and pharmacokinetics of CK-089 when administered orally as single or multiple doses to healthy participants. The study design includes single ascending dose cohorts and multiple-dose ascending cohorts comprises 10 participants each. The company's clinical development program for CK-089 is subject to a partial clinical hold from the FDA that limits its ability to dose patients at doses anticipated to result in plasma exposures higher than certain levels, which may limit the ability of its Phase 1 trial to identify a therapeutic dose for CK-089.
Beyond Muscle Contractility
The company has developed preclinical expertise in the mechanics of skeletal, cardiac, and smooth muscle that extends from proteins to tissues to intact animal models. Its translational research in muscle contractility has enabled it to better understand the potential impact of small molecule compounds that increase cardiac or skeletal muscle contractility and to apply those findings to the further evaluation of its drug candidates in clinical populations. In addition to contractility, other major functions of muscle play a role in certain diseases that could benefit from novel mechanism treatments. Accordingly, the company's knowledge of muscle contractility may serve as an entry point to the discovery of novel treatments for disorders involving muscle functions other than muscle contractility. The company is leveraging its current understanding of muscle biology to investigate new ways of modulating these other aspects of muscle function for other potential therapeutic applications.
Commercial Readiness
The company began building its commercial capabilities in the U.S. prior to the potential FDA approval and launch of omecamtiv mecarbil, its cardiac myosin activator. Upon receipt of the complete response letter from the FDA in response to its NDA for omecamtiv mecarbil, the company maintained the infrastructure that had been built and further refined the team and activities in anticipation of what may now be its first commercial launch with aficamten, its cardiac myosin inhibitor, in the third quarter of 2025. The company plans to expand the team with customer-facing sales positions as it nears potential FDA approval in 2025. Additionally, it established its field-based medical affairs team, inclusive of medical directors, medical education and medical communications functions, as well as medical science liaisons in key geographies across the U.S. In Europe, the company filled key leadership positions in country leadership, medical affairs, and market access, and made meaningful progress in building the corporate infrastructure necessary to enable a commercial launch of aficamten as soon as 2026.
The company's go-to-market approach for aficamten includes three phases: learn, design, and build. Based on its market research, the company learned that the overall journey to diagnosis is complex and challenging due to unique symptoms present in each patient, along with limited disease awareness across the broader healthcare system, leading to confusion and complexity for patients and the healthcare professionals who treat them. HCM patients experience many complications, and in addition to the physical impact, patients experience profound psychological effects that impact social involvement and other aspects of everyday life.
Manufacturing Resources and Product Supply
For its portfolio of small molecules, the company continues to expand its network through well-established and reputable third-party contract manufacturers for its CMC and manufacturing needs that have good regulatory standing and suitable manufacturing capabilities and capacities. These third parties must comply with applicable regulatory requirements, including the FDA's cGMP, the E.U.'s Guidelines on Good Distribution Practice, as well as other stringent regulatory requirements enforced by the FDA or foreign regulatory agencies, as applicable, and are subject to routine inspections by such regulatory agencies. In addition, through its third-party contract manufacturers and data service providers, the company continues to provide serialized commercial products as required to comply with the Drug Supply Chain Security Act.
Intellectual Property Resources
As of December 31, 2024, the company owned, co-owned, or licensed 80 issued U.S. patents, over 600 issued patents in various foreign jurisdictions, and over 380 additional pending U.S. and foreign patent applications.
Aficamten
In Japan, aficamten is protected by an issued patent covering the composition of matter of aficamten that expires in 2039. In China, aficamten is protected by issued patents covering the composition of matter, polymorphic forms, and formulations of aficamten that expire between 2039 and 2040.
Omecamtiv Mecarbil
In Japan, omecamtiv mecarbil is protected by issued patents covering the composition of matter, the salt form and formulation of omecamtiv mecarbil that expire between 2025 and 2034. In China, omecamtiv mecarbil is protected by issued patents covering the salt form and formulation of omecamtiv mecarbil that expire in 2034.
Research and Development
The company’s research and development expenses included $339.4 million in 2024.
Compliance with Government Regulation
In addition, the company is subject to other state and federal laws, including, among others, anti-kickback laws, fraud and abuse, false claims laws, Sunshine Act, patient protection and affordable care, data privacy and security laws and regulations, and transparency laws that restrict certain business practices in the pharmaceutical industry. The company's manufacturing Contract Manufacturing Organizations (CMOs) are subject to periodic inspection by the U.S. Food and Drug Administration (FDA) and other foreign equivalents to ensure that they are operating in compliance with current Good Manufacturing Practice (cGMP) requirements.
History
Cytokinetics, Incorporated was founded in 1997. The company was incorporated in 1997.
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