JIXING Announces National Medical Products Administration Approval of the Clinical Trial Application for the China Cohort of MAPLE-HCM, the Phase 3 Clinical Trial of Aficamten Compared to Metoprolol in Patients with Symptomatic Obstructive Hypertrophic
First clinical trial directly comparing a cardiac myosin inhibitor to what is considered the standard of care therapy in patients with HCM
SHANGHAI, China, October 18, 2023 –Ji Xing Pharmaceuticals Limited (JIXING), a clinical-stage biopharmaceutical company committed to bringing innovative medicines to underserved Chinese patients with serious and life-threatening diseases, announces the Center for Drug Evaluation (CDE) of the National Medical Products Administration of the PRC (NMPA) has approved the Clinical Trial Application (CTA) for the China cohort of MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), an international, multi-center Phase 3 clinical trial,comparing aficamten (CK-3773274) as monotherapy to metoprolol as monotherapy in adult patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Ji Xing will start patient enrollment for the Chinese cohort of MAPLE-HCM.
As an investigational, selective, small molecule cardiac myosin inhibitor with next-in-class potential, aficamten was designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). Aficamten received Breakthrough Therapy Designation for the treatment of oHCM from the U.S. Food & Drug Administration (FDA) as well as the NMPA in China.
“HCM is a common inherited cardiovascular disorder. The current HCM treatment is based on clinical experience but does not target the underlying pathology which is hypercontractility,” said Professor Junbo Ge, Principal Investigator of the China cohort of MAPLE-HCM, Academician of the Chinese Academy of Sciences, Director of the Department of Cardiology, Zhongshan Hospital and Chairman of the National Cardiovascular Health Alliance. “MAPLE-HCM is, to date, the first and only clinical trial directly comparing a cardiac myosin inhibitor to what is considered the standard of care therapy in patients with HCM. As part of the global multi-center trial, we hope that MAPLE-HCM will generate evidence showing that treatment with aficamten as first-line monotherapy is superior to monotherapy with metoprolol and bring clinical benefits to Chinese HCM patients.”
“MAPLE-HCM is the third Phase 3 clinical trial of aficamten in China. We are very honored to cooperate with leading clinical centers to enable Chinese research data to support the global development of potential next-generation therapies for HCM patients. ”said Yuan Li, MD, Chief Medical Officer of Cardiovascular at JIXING. “We are actively advancing clinical development programs for aficamten in China. The Chinese cohort of SEQUOIA-HCM, the pivotal Phase 3 clinical trial of aficamten in patients with oHCM, has completed patient recruitment as scheduled and topline results are expected by the end of this year. In addition, a CTA for a Phase 3 Open Label Extension trial was approved by CDE earlier this year and first patient enrollment will start soon.”
MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), is a Phase 3, multi-center, randomized, double-blind active-comparator clinical trial of aficamten compared to metoprolol in patients with symptomatic obstructive HCM. The primary endpoint is the change in peak oxygen uptake (pVO2) from baseline to Week 24 measured by cardiopulmonary exercise testing (CPET). Secondary endpoints include the change from baseline to Week 24 in Kansas City Cardiomyopathy Questionnaire (KCCQ) score, the proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) functional class, and changes in left ventricular mass index (LVMI), left atrial volume index (LAVI), post-Valsalva left ventricular outflow tract gradient (LVOT-G) and NT-proBNP.
MAPLE-HCM is expected to enroll 170 patients, randomized on a 1:1 basis to receive aficamten or metoprolol. Randomization will be stratified by CPET exercise modality (treadmill or bicycle) and recently diagnosed versus chronic obstructive HCM. At screening, patients enrolled in MAPLE-HCM must have a resting LVOT-G ≥30 mmHg and/or post-Valsalva LVOT-G ≥50 mmHg in addition to left ventricular ejection fraction (LVEF) ≥ 60%, respiratory exchange ratio (RER) ≥ 1.05 and pVO2 <100% predicted, NYHA functional class II or III and a KCCQ Clinical Summary Score (KCCQ-CSS) score ≥ 35 and ≤ 90. Following the initial screening visit, all participants on standard of care (SOC) therapy will undergo a washout period of up to 14 days of weaning from SOC therapy, followed by an additional 7 days with no SOC therapy prior to the second screening visit. Each patient will receive up to four escalating doses of aficamten or metoprolol based on echocardiographic guidance. Patients receiving aficamten will begin with 5 mg dosed once daily. At weeks 2, 4 and 6 patients will receive an echocardiogram to determine if they will be up-titrated to escalating doses of 10, 15 or 20 mg. Patients receiving metoprolol will begin with 50 mg dosed once daily. At weeks 2, 4 and 6 patients will receive an echocardiogram to determine if they will be up-titrated to escalating doses of 100, 150 or 200 mg.
Aficamten, discovered by Cytokinetics, Incorporated (Cytokinetics), is an investigational selective, small molecule cardiac myosin inhibitor for the potential treatment of hypertrophic cardiomyopathy (HCM), discovered following an extensive chemical optimization program that was conducted with careful attention to therapeutic index and pharmacokinetic properties and as may translate into next-in-class potential in clinical development. In July 2020, JIXING entered into a license and collaboration agreement with Cytokinetics, a late-stage biopharmaceutical company headquartered in California, pursuant to which Cytokinetics has granted to JIXING an exclusive license to develop and commercialize aficamten in the Greater China territory.
Aficamten was designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently suppress the myocardial hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, aficamten reduced 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.
The development program for aficamten is assessing its potential as a treatment that improves exercise capacity and relieves symptoms in patients with HCM as well as its potential long-term effects on cardiac structure and function. Aficamten is currently the subject of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), a pivotal Phase 3 clinical trial in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), MAPLE-HCM (Metoprolol vs Aficamten in Patients with LVOT Obstruction on Exercise Capacity in HCM), a Phase 3 clinical trial evaluating aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM, and ACACIA-HCM (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints In Adults with Non-Obstructive HCM), a pivotal Phase 3 clinical trial in patients with symptomatic non-obstructive HCM. Results from SEQUOIA-HCM are expected by the end of 2023. Aficamten received Breakthrough Therapy Designation for the treatment of symptomatic obstructive HCM from the U.S. Food & Drug Administration (FDA) as well as the National Medical Products Administration (NMPA) in China.
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, and the prevalence is likely to be underestimated due to the limitations of early screening. The prevalence is currently estimated to be at least 1/200, with obstructive (either at rest or with provocation) HCM accounting for approximately 2/3 of cases and non-obstructive HCM for approximately 1/3 of cases in clinical practice. HCM may result in exertional dyspnea, fatigue, chest pain, syncope/presyncope and limited exercise capacity. HCM is one of the main reasons of death in teenagers and athletes. Disease-related fatal and disabling events are most often attributable to sudden cardiac death, heart failure, and embolic stroke. Sudden cardiac death is the common mode of death in young patients between 10 to 35 years old. Heart failure is the common mode of death in middle-aged patients and stroke due to HCM related atrial fibrillation is common in old patients. The annual mortality rate for HCM patients in hospitals is 2% to 4%.
At present, there are no approved drugs that are disease specific for HCM in China. Patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) are generally offered pharmacotherapy with 𝛽-blockers, verapamil, diltiazem and disopyramide based on experience; however, these medications often do not prevent progression of the disease, are associated with significant adverse effects, and do not target the underlying pathology (hypercontractility). Additionally, disopyramide is not available in China. For oHCM patients with a left ventricular outflow tract pressure gradient (LVOT-G) of ≥50 mm Hg either at rest or with provocation who also have severe symptoms refractory to medical therapy, septal reduction therapies (such as surgical myectomy or percutaneous alcohol septal ablation) can be effective, but these invasive procedures are not widely accessible in China and carry risk including death. Septal reduction therapies and their success depends on operator experience.
JIXING is a biopharmaceutical company headquartered in Shanghai committed to bringing innovative science and medicines to underserved patients in China with serious and life-threatening diseases. Backed by RTW Investments, LP, JIXING was founded in 2019 and partners with global biotechnology companies to develop and commercialize novel, innovative therapeutics to treat unmet medical needs in cardiovascular and ophthalmic diseases. With a strong and further developing asset pipeline, seasoned management team, and patient-centric focus, JIXING is dedicated to delivering a meaningful and lasting impact on patients in China.
JIXING’s cardiovascular portfolio includes 2 assets in late-stage clinical development (aficamten, etripamil) and 1 in pre-clinical stage (JX09). JIXING’s ophthalmology portfolio includes 4 assets in late-stage clinical development (varenicline solution nasal spray/US brand name TYRVAYA, OC-02 nasal spray, JX06/LNZ100, JX07/LNZ101) and 1 asset in pre-clinical stage (JX08). For further information about JIXING, please visit www.jixing.com.
Cytokinetics is a late-stage, specialty cardiovascular biopharmaceutical company focused on discovering, developing and commercializing first-in-class muscle activators and next-in-class muscle inhibitors 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. Aficamten is a next-in-class cardiac myosin inhibitor, currently the subject of three Phase 3 clinical trials: SEQUOIA-HCM, evaluating aficamten in patients with obstructive hypertrophic cardiomyopathy (HCM), MAPLE-HCM, evaluating aficamten as monotherapy compared to metoprolol as monotherapy in patients with obstructive HCM and ACACIA-HCM, evaluating aficamten in patients with non-obstructive HCM. Cytokinetics is also developing omecamtiv mecarbil, a cardiac muscle activator, in patients with heart failure. Additionally, Cytokinetics is developing CK-136, a cardiac troponin activator for the potential treatment HFrEF and other types of heart failure, such as right ventricular failure, resulting from impaired cardiac contractility, and CK-586, a cardiac myosin inhibitor with a mechanism of action distinct from aficamten for the potential treatment of HFpEF. In 2023, Cytokinetics is celebrating its 25-year history of pioneering innovation in muscle biology and related pharmacology focused to diseases of muscle dysfunction and conditions of muscle weakness.
For additional information about Cytokinetics, visit http://www.cytokinetics.com and follow us on X, LinkedIn, Facebook and YouTube.
- The Joint Committee of Cardiomyopathy Specialty Alliance, National Center for Cardiovascular Diseases/Cardiovascular Precision Medicine Branch of China International Exchange and Promotive Association for Medical and Health Care. 2023 Guideline for Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy. Chinese Circulation Journal, 2023, 38: 1.
- Chinese Heart Failure Association of Chinese Medical Doctor Association, National Heart Failure Committee, Editorial Board of Chinese Journal of Heart Failure and Cardiomyopathy. 2022 Chinese guideline on hypertrophic cardiomyopathy. Chin J Heart Fail & Cardiomyopathy, 2022, 6(2): 80-103
- Heart failure committee of Chinese medical association, Editorial board of the Chinese journal of heart failure and cardiomyopathy. 2017 Guidelines of hypertrophic cardiomyopathy management in China. Chin J Heart Fail & Cardiomyopathy. 2017; 1(2): 65-86.
- Ommen SR et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy. Circulation. 2020 Dec 22;142(25): e533-e557.
- Cytokinetics website.