About Cytokinetics
Cytokinetics, Incorporated operates as a late-stage biopharmaceutical company that focuses on discovering, developing and commercializing muscle activators and 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 health span of people with devastating cardiovascular and neuromuscular diseases of impaired muscle function. 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. Research and Development Programs The company segments its research and development activities related to muscle contractility by its cardiac muscle contractility program and its skeletal muscle contractility program. The company also conducts research and development on novel treatments for disorders involving muscle function beyond muscle contractility. Cardiac Muscle Program The company’s cardiac muscle contractility program is focused on the cardiac sarcomere, the basic unit of muscle contraction in the heart. The company’s most advanced cardiac program is based on the hypothesis that activators of cardiac myosin may address certain adverse properties of existing positive inotropic agents. Positive inotropic agents, such as beta-adrenergic receptor agonists or inhibitors of phosphodiesterase activity, increase the concentration of intracellular calcium, thereby increasing cardiac sarcomere contractility. The effect on calcium levels, however, also has been linked to potentially life-threatening side effects. In contrast, the company’s novel cardiac myosin activators work by a mechanism that directly stimulates the activity of the cardiac myosin motor protein, without increasing the intracellular calcium concentration. They accelerate the rate-limiting step of the myosin enzymatic cycle and shift 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. 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 (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure) is a Phase 3 cardiovascular outcomes clinical trial of omecamtiv mecarbil which was conducted by Amgen, in collaboration with the company. The primary objective of this double-blind, randomized, placebo-controlled multicenter clinical trial is 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. GALACTIC-HF was conducted under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). GALACTIC-HF: Primary Results The results of GALACTIC-HF show that after a median duration of follow-up of 21.8 months, the trial demonstrated a statistically significant effect of treatment with omecamtiv mecarbil to reduce risk of the primary composite endpoint of CV 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. The overall safety profile of omecamtiv mecarbil in GALACTIC-HF appeared to be consistent with data from previous trials. GALACTIC-HF: Further Analyses Since its release of the primary results, the company has conducted and announced supplemental and subgroup analyses suggesting that certain subgroups of patients treated with omecamtiv mecarbil in GALACTIC-HF may benefit more than the general patient population in such trial. New Drug Application/Regulatory In February 2023, the company announced that it received a complete response letter (CRL) from the FDA’s Division of Cardiology and Nephrology regarding its new drug application (NDA) for omecamtiv mecarbil for the treatment of HFrEF. In addition, FDA stated that results from an additional clinical trial of omecamtiv mecarbil are required to establish substantial evidence of effectiveness for the treatment of HFrEF, with benefits that outweigh the risks. FDA’s decision to issue a CRL follows an FDA Cardiovascular and Renal Drugs Advisory Committee’s vote of 8 to 3 in December 2022 that the benefits of omecamtiv mecarbil do not outweigh its risks for the treatment of HFrEF. In December 2022, the European Medicines Agency (EMA) accepted for review the company’s marketing authorization application (MAA) seeking approval of omecamtiv mecarbil for the treatment of HFrEF in the European Union (E.U.) and the other states of the European Economic Area (EEA), and in November 2022, the company’s partner, Ji Xing (Ji Xing Pharmaceuticals Limited and/or its affiliates, including Ji Xing Pharmaceuticals Hong Kong Limited) announced that the Center for Drug Evaluation of the National Medical Products Administration of the People’s Republic of China had accepted the submission of the NDA for omecamtiv mecarbil for the treatment of HFrEF. Ji Xing Collaboration for Greater China In December 2021, the company entered into the Ji Xing OM License Agreement, pursuant to which it granted to Ji Xing an exclusive license to develop and commercialize omecamtiv mecarbil in China and Taiwan. Aficamten Aficamten is a novel, oral, small molecule cardiac myosin inhibitor that the company’s scientists discovered. 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 in clinical development. Aficamten was purposely designed to reduce the hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). The initial focus of the development program for aficamten will include an extensive characterization of its pharmacokinetics/pharmacodynamic (PK/PD) relationship as has been a hallmark of the company’s industry-leading development programs in muscle pharmacology. The overall development program will assess the potential of aficamten to improve exercise capacity and relieve symptoms in patients with hyperdynamic ventricular contraction due to HCM. FDA has granted aficamten orphan drug designation for the treatment of symptomatic HCM and Breakthrough Therapy Designation for aficamten for the treatment of obstructive HCM (oHCM). REDWOOD-HCM REDWOOD-HCM (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM) is a Phase 2, multi-center, randomized, placebo-controlled, double-blind, dose finding clinical trial of aficamten in patients with symptomatic HCM. In Cohorts 1 and 2 of REDWOOD-HCM, patients continued taking background medications exclusive of disopyramide. Cohort 3 of REDWOOD-HCM enrolled thirteen patients with symptomatic oHCM and a resting or post-Valsalva LVOT-G of =50 mmHg whose background therapy included disopyramide and, in the majority (11 out of 13 patients), a beta-adrenergic blocker. Cohort 3 of REDWOOD-HCM enrolled thirteen patients with symptomatic oHCM and a resting or post-Valsalva LVOT-G of =50 mmHg whose background therapy included disopyramide and, in the majority (11 out of 13 patients), a beta-adrenergic blocker. Cohort 4 of REDWOOD-HCM has completed enrollment. Cohort 4 enrolled, in an open label fashion, 30-40 patients with symptomatic non-obstructive HCM (nHCM) receiving background medical therapy. SEQUOIA-HCM SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) is a Phase 3 randomized, placebo-controlled, double-blind, multi-center clinical trial designed to evaluate aficamten in patients with symptomatic oHCM on background medical therapy for 24 weeks. SEQUOIA-HCM is open for enrollment. The company has enrolled more than two-thirds of the targeted 270 patients. In SEQUOIA-HCM, this trial is enrolling patients randomized on a 1:1 basis to receive aficamten or placebo in addition to standard-of-care treatment. The company expects to announce topline results from SEQUOIA-HCM in the fourth quarter of 2023. MAPLE-HCM The company is preparing for the second Phase 3 clinical trial of aficamten as monotherapy in patients with oHCM, MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Endpoints in HCM). The company expects to begin MAPLE-HCM in the first half of 2023. MAPLE-HCM is a Phase 3, multi-center, randomized, double-blind, active-comparator trial in patients with symptomatic oHCM and elevated left ventricular outflow tract (LVOT) gradient. FOREST-HCM In May 2021, the company announced that the first site had been activated to enroll patients in REDWOOD-HCM OLE (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM Open Label Extension), an open-label extension clinical study designed to assess the long-term safety and tolerability of aficamten in patients with symptomatic oHCM. In May 2022, the company announced positive data relating to 38 patients, including 30 patients treated for 12 weeks and 19 patients treated for 24 weeks. In September 2022, the company announced new data on the reduction and withdrawal of background standard of care medical therapy in patients treated with aficamten in FOREST-HCM. Patients in FOREST-HCM were classified as receiving standard of care therapy if they were being treated with at least a beta-blocker, nondihydropyridine calcium channel blocker, or disopyramide. In October 2022, the company announced new data on symptom improvement and quality of life related to treatment with aficamten in FOREST-HCM (Five-Year, Open-Label, Research Evaluation of Sustained Treatment with Aficamten in HCM). This new analysis evaluated patients’ self-reported health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and compared baseline values to those collected at Week 12 and Week 24. The KCCQ is a validated patient reported outcomes tool 1 used to evaluate heart failure symptoms and their impact on social and physical limitations, as well as quality of life. Higher scores indicate better health status. The company will be presenting the results from twelve months of treatment with aficamten in FOREST-HCM at the American College of Cardiology 72nd Annual Scientific Session in March, 2023. FOREST-HCM continues to enroll patients. Ji Xing Collaboration for Greater China In July 2020, the company entered into the Ji Xing Aficamten License Agreement, pursuant to which it granted to Ji Xing an exclusive license to develop and commercialize aficamten in China and Taiwan. In addition, Ji Xing will pay the company tiered royalties in the low-to-high teens range on the net sales of pharmaceutical products containing aficamten in China and Taiwan, subject to certain reductions for generic competition, patent expiration and payments for licenses to third party patents. CK-136 CK-136 is a novel, selective, oral, small molecule cardiac troponin activator. In preclinical models, CK-136 increases myocardial contractility by binding to cardiac troponin through an allosteric mechanism that sensitizes the cardiac sarcomere to calcium, facilitating more actin-myosin cross bridge formation during each cardiac cycle thereby resulting in increased myocardial contractility. Similar to cardiac myosin activation, preclinical research has shown that cardiac troponin activation does not change the calcium transient of cardiac myocytes. Dosing of patients in a Phase 1 clinical trial of CK-136 commenced in December 2022. The primary objective of this Phase 1 randomized, double-blind, placebo-controlled, single and multiple ascending dose trial is to assess the safety, tolerability and pharmacokinetics of CK-136 when administered orally as single or multiple doses to healthy participants. Skeletal Muscle Contractility Program The company’s skeletal muscle contractility program is focused 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. Reldesemtiv The company is developing reldesemtiv, a fast skeletal muscle troponin activator (FSTA), as a potential treatment for people living with debilitating diseases and conditions associated with muscular weakness, and/or muscle fatigue, including ALS. Reldesemtiv is an investigational drug candidate intended to slow the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers. Reldesemtiv has demonstrated pharmacological activity in preclinical models and evidence of potentially clinically relevant pharmacodynamic effects in humans. The FDA granted reldesemtiv orphan drug designation for the potential treatment of amyotrophic lateral sclerosis (also known as Lou Gehrig’s Disease) (ALS). The EMA granted reldesemtiv orphan medicinal product designation for the potential treatment of ALS. FORTITUDE-ALS Reldesemtiv was the subject of FORTITUDE-ALS (Functional Outcomes in a Randomized Trial of Investigational Treatment with CK-2127107 to Understand Decline in Endpoints – in ALS). This Phase 2 trial enrolled 458 eligible ALS patients. Post-hoc analyses from FORTITUDE-ALS demonstrated that, in the combined middle and faster progressing tertiles of patients, the decline in the ALS Functional Rating Scale – Revised (ALSFRS-R) total score from baseline to week 12 in patients who received any dose of reldesemtiv was significantly smaller than the decline on placebo, while no significant difference between reldesemtiv and placebo was observed in slower progressing patients. Additional post-hoc analyses from FORTITUDE-ALS evaluated how baseline patient characteristics impacted the effect of treatment with reldesemtiv versus placebo. A subgroup analyses of FORTITUDE-ALS showed that the effect of reldesemtiv on patients with ALS was similar whether or not patients were also receiving RADICAVA (edaravone) and/or RILUTEK (riluzole). COURAGE-ALS COURAGE-ALS (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS) is the Phase 3 clinical trial of reldesemtiv in patients with ALS, which is open for enrollment. COURAGE-ALS has enrolled over 450 patients or more than three-quarters of the company’s target patient enrollment with a goal to enroll approximately 555 patients with ALS. This Phase 3 clinical trial design builds on insights gained from FORTITUDE-ALS, further exploring the hypothesis that fast skeletal muscle activation with reldesemtiv may be an important therapeutic strategy in ALS. In October 2022, the company announced that the Data Monitoring Committee (DMC) for COURAGE-ALS, recently convened to conduct the first planned interim analysis of this ongoing Phase 3 clinical trial which assessed for the potential of futility. The first interim analysis was triggered twelve (12) weeks after approximately one-third or more of the intended number of patients were randomized to participate in COURAGE-ALS. A second interim analysis, which is anticipated to occur in the first half of next year, will also assess for potential futility and will also allow for a fixed increase in total enrollment, if deemed necessary, to augment the statistical power of the trial. COURAGE-ALS OLE COURAGE-ALS OLE is an open-label extension clinical study designed to assess the long-term safety and tolerability of reldesemtiv in people with ALS. Patients will be eligible for COURAGE-ALS OLE after completing their participation in COURAGE-ALS. COURAGE-ALS OLE is enrolling patients. Astellas Revenue Interest Reldesemtiv was developed as part of the company’s previous collaboration with Astellas. Under the company’s Fast Skeletal Regulatory Activator (FSRA) Agreement with Astellas, which it refer to as the Astellas FSRA Agreement, Astellas agreed to pay one-third of the out-of-pocket clinical development costs which may be incurred in connection with its Phase 3 clinical trial of reldesemtiv in ALS, Ongoing Research in Skeletal Muscle Activators The company is conducting translational research in preclinical models of disease and muscle function with FSTAs to explore the potential clinical applications of this novel mechanism in diseases or conditions associated with skeletal muscle dysfunction. Beyond Muscle Contractility The company developed preclinical expertise in the mechanics of skeletal, cardiac and smooth muscle that extends from proteins to tissues to intact animal models. The company’s translational research in muscle contractility has enabled it to better understand the potential impact of small molecule compounds that increase skeletal or cardiac 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 understandings of muscle biology to investigate new ways of modulating these other aspects of muscle function for other potential therapeutic applications. Strategy The key elements of the company's strategy are to achieve regulatory approvals for at least two drugs arising from its pipeline; build commercial capabilities to market and sell its medicines reflective of their innovation and value; generate sustainable and growing revenues from product sales; double its development pipeline to include ten therapeutic programs; and expand its discovery platform to muscle energetics, growth and metabolism. Research and Development The company’s research and development expenses were $240.8 million for 2022. Intellectual Property As of December 31, 2022, the company owned, co-owned or licensed 73 issued U.S. patents, over 650 issued patents in various foreign jurisdictions, and over 430 additional pending U.S. and foreign patent applications. With regard to the company’s drug candidates directed to muscle biology targets, it has a U.S. patent covering omecamtiv mecarbil, U.S. patents covering its skeletal muscle sarcomere activators, including, but not limited to reldesemtiv, and a U.S. patent covering aficamten, which expire in 2027, 2031 and 2039, respectively, unless extended or otherwise adjusted. The company also has issued patents in various foreign jurisdictions and additional U.S. and foreign patent applications pending for these drug candidates. Government Regulation Any drugs manufactured or distributed by the company or its partners pursuant to FDA approvals or their foreign counterparts are subject to continuing regulation by the applicable regulatory authority, including recordkeeping requirements and reporting of adverse experiences associated with the drug. Health care providers in the United States, including research institutions from which the company or its partners obtain patient information, are subject to privacy rules under the Health Insurance Portability and Accountability Act of 1996 and state and local privacy laws. In the E.U., these entities are subject to the Directive 95/46-EC of the European Parliament on the protection of individuals with regard to the processing of personal data and individual E.U. member states implementing additional legislation. History Cytokinetics, Incorporated was founded in 1997. The company was incorporated under the laws of the state of Delaware in 1997.
