Ji Xing Pharmaceuticals Announces Aficamten Granted Breakthrough Therapy Designation in China for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Shanghai, China – February 16, 2022 – CORXEL (hereinafter referred to as “CORXEL”), a clinical-stage biopharmaceutical company dedicated to providing innovative medicines to Chinese patients suffering from serious and life-threatening diseases, today announced that the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation to aficamten (CK-3773274 tablets) for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM).Aficamten, developed by CORXEL’s licensing partner Cytokinetics, is a potential next-generation cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy (HCM). The U.S. Food and Drug Administration (FDA) has previously granted Breakthrough Therapy Designation to aficamten for the treatment of symptomatic obstructive HCM (oHCM).

The Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation to aficamten, recognizing the drug’s potential value for Chinese patients with obstructive hypertrophic cardiomyopathy (oHCM) and supporting its accelerated development and review in China. Based on clinical trial results, particularly those from Cohorts 1 and 2 of the global Phase 2 REDWOOD-HCM trial evaluating aficamten in patients with symptomatic oHCM, the CDE awarded this designation for the treatment of symptomatic oHCM, a serious and life-threatening condition. Currently, therapeutic options for symptomatic oHCM are very limited, and aficamten may offer a potential alternative beyond existing treatments. Drugs included in the Breakthrough Therapy Program receive prioritized resources for communication and consultation, along with enhanced guidance to facilitate drug development. Furthermore, drugs granted Breakthrough Therapy Designation are eligible for priority review and approval during the New Drug Application (NDA) process, further shortening the review timeline and accelerating market access.

“We appreciate the National Medical Products Administration granting Breakthrough Therapy Designation to aficamten. This important regulatory decision (Breakthrough Therapy Designation) enables us to accelerate the clinical development of aficamten, bringing benefit to patients with obstructive hypertrophic cardiomyopathy (oHCM) who suffer from this disease. We look forward to continuing our close collaboration with the National Medical Products Administration as we conduct the China cohort of the global Phase 3 SEQUOIA-HCM clinical trial in partnership with Cytokinetics,” said Joseph Romanelli, CEO of CORXEL. “As a company, our goal is to help raise the standard of care for patients in China through breakthrough innovation. This Breakthrough Therapy Designation represents another significant milestone in our ongoing journey.”

In December 2021, CORXEL announced the successful completion of a Phase I clinical trial in China for aficamten, a potential next-generation cardiac myosin inhibitor for the treatment of hypertrophic cardiomyopathy (HCM). This double-blind, randomized, placebo-controlled Phase I study evaluated the safety, tolerability, and pharmacokinetic parameters of aficamten in healthy Chinese subjects. A total of 28 subjects were randomized and all completed the study. The results demonstrated good tolerability of aficamten comparable to that of placebo, as well as dose-proportional pharmacokinetic properties, consistent with findings from previous Phase I studies conducted primarily in healthy Caucasian subjects in the United States.

Aficamten is an investigational selective small-molecule cardiac myosin inhibitor that, through comprehensive chemical optimization to improve the therapeutic index and pharmacokinetic profile, has the potential to become a next-generation cardiac myosin inhibitor. Aficamten reduces the number of force-generating myosin cross-bridges per cardiac cycle, thereby inhibiting the myocardial hypercontractility associated with hypertrophic cardiomyopathy (HCM). In preclinical models, aficamten reduces myocardial contractility by binding directly to cardiac myosin at a unique and selective allosteric site, preventing myosin from entering the contractile state. The new drug development program for aficamten aims to evaluate its therapeutic potential in improving exercise capacity, alleviating disease symptoms, and assessing the long-term effects on cardiac structure and function in patients with HCM.

In July 2020, CORXEL entered into a licensing and collaboration agreement with Cytokinetics, Incorporated, a late-stage biopharmaceutical company headquartered in California, USA. Under the agreement, Cytokinetics granted CORXEL an exclusive license to develop and commercialize aficamten (formerly known as CK-274) in the Greater China region. In September 2020, CORXEL submitted an Investigational New Drug (IND) application to the National Medical Products Administration for aficamten in the treatment of obstructive hypertrophic cardiomyopathy (oHCM), which was approved in December 2020.

Hypertrophic Cardiomyopathy (HCM) is the most common inherited cardiovascular disease, with a prevalence of 80 per 100,000 in China, where an estimated more than 1.5 million individuals are affected. HCM can lead to exertional dyspnea, fatigue, chest pain, syncope or presyncope, and limited exercise capacity. Disease-related mortality is largely attributable to sudden cardiac death, heart failure, and embolic stroke. HCM is one of the leading causes of sudden death in adolescents and athletes. Sudden cardiac death commonly occurs in young patients aged 10–35 years, deaths due to heart failure predominantly affect middle-aged patients, while strokes associated with HCM-related atrial fibrillation are more frequent in elderly patients. The annual mortality rate among HCM patients seen at tertiary medical centers is 2%–4%.

Currently, there are no approved drugs in China specifically targeting hypertrophic cardiomyopathy (HCM). Pharmacological therapies recommended by guidelines are based on empirical evidence and primarily include beta-blockers, verapamil, diltiazem, and disopyramide. However, these agents were originally developed for other indications and do not target the fundamental pathophysiological mechanism of HCM—namely, myocardial hypercontractility. They generally fail to halt disease progression and are associated with significant adverse effects; furthermore, disopyramide has not yet been marketed in China. For patients with obstructive HCM (oHCM) who exhibit severe symptoms refractory to medical therapy and have a left ventricular outflow tract gradient (LVOT-G) ≥ 50 mmHg at rest or during provocation, septal reduction therapies (surgical septal myectomy and percutaneous alcohol septal ablation) may be effective. Nevertheless, these procedures are not widely accessible and carry risks, including mortality. In summary, currently available treatment modalities do not directly address the underlying cause of the disease, which is myocardial hypercontractility.

The Breakthrough Therapy Designation for aficamten was primarily based on the results from Cohorts 1 and 2 of the REDWOOD-HCM study (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM), a Phase 2 clinical trial evaluating aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). The study results were presented at the 2021 Annual Scientific Meeting of the Heart Failure Society of America (HFSA) in September 2021. The results demonstrated that, compared with placebo, treatment with aficamten for 10 weeks led to significant reductions from baseline in both the mean resting left ventricular outflow tract pressure gradient (LVOT-G) and the mean LVOT-G after the Valsalva maneuver. Compared with placebo, the vast majority of patients treated with aficamten achieved the therapeutic goal, defined as a resting gradient <30 mmHg and a post-Valsalva gradient <50 mmHg at Week 10. Patients receiving aficamten also exhibited improvements in heart failure symptoms and reductions in NT-proBNP (a biomarker of ventricular wall stress). Overall, aficamten was well tolerated in the REDWOOD-HCM study, with an incidence of adverse events similar to that of placebo. No serious adverse events or treatment discontinuations related to aficamten occurred.

SEQUOIA-HCM is a randomized, placebo-controlled, multicenter, double-blind Phase 3 study conducted in patients with symptomatic obstructive hypertrophic cardiomyopathy. Approximately 270 eligible patients will be randomized in a 1:1 ratio to receive either aficamten or placebo for 24 weeks. Dose titration will be guided by echocardiography, with aficamten or matched placebo administered in an escalating manner at doses of 5, 10, 15, or 20 mg. SEQUOIA-HCM plans to employ a flexible dosing regimen for dose adjustments, thereby personalizing treatment and maximizing the therapeutic effect of aficamten.

The primary objective of the SEQUOIA-HCM study is to evaluate the effect of aficamten on exercise capacity in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM), as measured by the change in peak oxygen consumption (pVO2) determined by cardiopulmonary exercise testing (CPET) from baseline to Week 24. Secondary endpoints include changes in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) from baseline to Weeks 12 and 24, the proportion of patients with an improvement of ≥1 class in New York Heart Association (NYHA) functional class, changes in left ventricular outflow tract pressure gradient (LVOT-G) after the Valsalva maneuver, the proportion of patients with LVOT-G <30 mmHg after the Valsalva maneuver, and changes in total work load during CPET. The SEQUOIA-HCM study is expected to initiate in early 2022.

CORXEL is a biopharmaceutical company headquartered in Shanghai, China, dedicated to bringing innovative science and medicines to Chinese patients suffering from serious, life-threatening diseases. Founded in 2019 with investment from RTW Investments, LP, CORXEL collaborates with multiple global biotechnology companies to address unmet medical needs in therapeutic areas such as cardiovascular and ophthalmic diseases through the development and commercialization of unique, innovative treatments. With a robust and growing product pipeline, an experienced management team, and a patient-centric philosophy, CORXEL is poised to deliver lasting and profound impact to patient communities across Greater China.

References

1. Heart Failure Professional Committee of the Chinese Medical Doctor Association, Editorial Board of the Chinese Journal of Heart Failure and Cardiomyopathy. Guidelines for the Management of Hypertrophic Cardiomyopathy in China (2017). Chinese Journal of Heart Failure and Cardiomyopathy. 2017; 1(2): 65-86.

2. Writing Group for the Chinese Guidelines for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy in Adults, Chinese Society of Cardiology; Editorial Board of the Chinese Journal of Cardiology. Chinese Guidelines for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy in Adults. Chin J Cardiol. 2017;45(12):1015-1031.

3.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.

4. Cytokinetics Official Website.