NMPA granted Breakthrough Therapy Designation for the treatment of symptomatic obstructive hypertrophic cardiomyopathy based on results of REDWOOD-HCM and China Phase I study
SHANGHAI, Feb. 16, 2022 /PRNewswire/ -- 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, today announced that the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA) of the PRC has granted Breakthrough Therapy Designation for aficamten (CK-3773274) for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in China. Aficamten, discovered by Cytokinetics, Incorporated (Cytokinetics), is a next-generation cardiac myosin inhibitor in development for the potential treatment of HCM. Earlier, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for aficamten to Cytokinetics for the treatment of symptomatic oHCM.
Breakthrough Therapy Designation was granted for aficamten by the NMPA to recognize its potential impact on patients with oHCM and to support the development and review of aficamten in China. Based on clinical trial results for aficamten, especially Cohorts 1 and 2 of REDWOOD-HCM, the global Phase 2 clinical trial, this Breakthrough Therapy Designation by CDE was granted for aficamten for the treatment of symptomatic oHCM, a severe and life-threatening disease. Currently, disease-specific therapies for symptomatic oHCM are limited. Aficamten may be a potential option in light of existing treatments. The CDE will prioritize resources for drugs included in the Breakthrough Therapy Designation program and provide intensive guidance. A drug that receives Breakthrough Therapy Designation by the CDE is eligible for a priority review in the New Drug Application (NDA) process to further shorten the review time and accelerate approval.
"We are grateful to the NMPA for granting Breakthrough Therapy Designation for aficamten. This important regulatory classification (BTD) allows us to potentially accelerate the clinical development of aficamten which may benefit patients who suffer from oHCM. We look forward to continuing our strong collaboration with the NMPA as we conduct the China cohort of the global Phase 3 clinical trial, SEQUOIA-HCM, under our collaboration with Cytokinetics," said Joseph Romanelli, CEO of JIXING. "As a company, our goal is to bring disruptive science to help improve upon the standard of care for patients in China, and this Breakthrough Therapy Designation is another great milestone in that quest."
In December 2021, JIXING announced the completion of its Phase 1 study of aficamten in China. The study was a Phase 1, double-blind, randomized, placebo-controlled study to evaluate the safety, tolerability, and PK profile of aficamten in healthy Chinese participants. A total of 28 subjects were randomized and completed the study. Overall, the results showed a safety and tolerability profile comparable to placebo and dose-proportional pharmacokinetics, similar to the results observed in the Phase 1 study of aficamten in healthy, mostly Caucasian subjects in the US.
Aficamten is an investigational selective, small molecule cardiac myosin inhibitor 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. 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 long-term effects on cardiac structure and function.
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 (formerly known as CK-274) in the Greater China territory. JIXING submitted an Investigational New Drug (IND) application for aficamten for the treatment of obstructive HCM, or oHCM, in September 2020 to the National Medical Products Administration (NMPA) and received the IND approval in December 2020.
About hypertrophic cardiomyopathy (HCM)
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder. The prevalence is 80/100000 in China and it is estimated that there are more than 1.5 million HCM patients in China. HCM may result in exertional dyspnea, fatigue, chest pain, syncope/presyncope and limited exercise capacity. Disease-related mortality is most often attributable to sudden cardiac death, heart failure, and embolic stroke. HCM is one of the main reasons of death in teenagers and athletes. 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-age patients and stroke due to HCM related atrial fibrillation is common in old patients. The annual mortality rate for HCM patients in tertiary care centers 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, are originally intended to treat other conditions, 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. These available treatments do not address the underlying pathology of HCM (hypercontractility) either.
The Breakthrough Therapy Designation for aficamten was mainly based on results from Cohorts 1 and 2 of REDWOOD-HCM (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM), the Phase 2 clinical trial of aficamten in patients with symptomatic oHCM, which were presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting in September 2021. The results showed that treatment with aficamten for 10 weeks resulted in statistically significant reductions from baseline compared to placebo in the average resting left ventricular outflow tract pressure gradient (LVOT-G) and the average post-Valsalva LVOT-G. A large majority of patients treated with aficamten achieved the target goal of treatment, defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg at Week 10, compared to placebo. Patients treated with aficamten also saw improvements in heart failure symptoms and reductions in NT-proBNP, a biomarker of cardiac wall stress. Treatment with aficamten in REDWOOD-HCM was generally well tolerated and the incidence of adverse events on aficamten was similar to that of placebo. No serious adverse events were attributed to aficamten, and no treatment interruptions occurred on aficamten.
SEQUOIA-HCM is a Phase 3, randomized, placebo-controlled, double-blind, multi-center trial in patients with symptomatic oHCM. Approximately 270 eligible patients will be randomized in a 1:1 ratio to receive aficamten or placebo for 24 weeks. Doses of 5, 10, 15, or 20 mg or matching placebo will be administered in an escalating manner using echocardiography to guide dose titration. SEQUOIA-HCM is planned to titrate patients with a flexible dosing scheme to personalize and maximize the potential treatment effect for patients.
The primary objective is to assess the effect of aficamten on change in peak oxygen uptake (pVO2) measured by cardiopulmonary exercise testing (CPET) from baseline to week 24. Secondary objectives include change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to week 12 and week 24, the proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) functional class from baseline to week 12 and week 24, change in post-Valsalva left ventricular outflow tract gradient (LVOT-G) to week 12 and week 24, the proportion of patients with post-Valsalva LVOT-G <30 mmHg, and change in total workload during cardiopulmonary exercise testing (CPET) to week 24. SEQUOIA-HCM is expected to start enrolling patients in early 2022.
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 Greater China.
Ji Xing Pharmaceuticals
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