Ji Xing completes Phase 1 study of aficamten, a potential next-generation cardiac myosin inhibitor, for patients with hypertrophic cardiomyopathy (HCM)
Ji Xing will conduct the China cohort of the global Phase 3 clinical trial evaluating aficamten in patients with obstructive HCM (oHCM), SEQUOIA-HCM, under its collaboration with Cytokinetics
Today, Ji Xing Pharmaceuticals Limited (Ji Xing) 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 Caucasian subjects in the US.
“There are close to 100 people who die every day from HCM in China. Based on the pre-clinical and clinical data, we believe aficamten can have a meaningful impact for HCM patients.” said Joseph Romanelli, CEO of Ji Xing. “We want to thank the participants and physicians who contributed to our Phase 1 study and we look forward to conducting the China cohort of the global Phase 3 clinical trial (SEQUOIA-HCM) under our collaboration agreement with Cytokinetics in 2022.”
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder. 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. Discovered by Cytokinetics, Incorporated (Cytokinetics), aficamten is an allosteric inhibitor of cardiac myosin designed to reduce cardiac hypercontractility which underlies the pathophysiology of HCM. Aficamten showed positive results in REDWOOD-HCM, Cytokinetics’ Phase 2 clinical trial in patients with oHCM.
About SEQUOIA-HCM study
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.
Following the successful completion of the China Phase 1 clinical study, Ji Xing will conduct the China cohort of SEQUOIA-HCM under its collaboration and license agreement with Cytokinetics. SEQUOIA-HCM is a global Phase 3 clinical trial of aficamten in patients with oHCM being sponsored by Ji Xing in China and by Cytokinetics in multiple other jurisdictions.
About REDWOOD-HCM study
The trial design of SEQUOIA-HCM is informed by the results of REDWOOD-HCM, a Phase 2, multi-center clinical trial conducted by Cytokinetics to evaluate aficamten in patients with symptomatic oHCM. The first two completed cohorts enrolled patients with symptomatic oHCM receiving standard of care medications in a randomized, placebo-controlled, double-blind fashion with the intent to conduct dose finding of aficamten. A third ongoing open-label cohort has enrolled patients in an open-label fashion to assess aficamten in addition to standard of care background therapy that includes disopyramide.
The primary objective of this trial is to determine the safety and tolerability of aficamten in patients with symptomatic oHCM. Overall, treatment with aficamten in REDWOOD-HCM was generally well tolerated. The incidence of adverse events was similar between treatment arms. There were no treatment emergent adverse events that resulted in treatment interruption or discontinuation, and no serious adverse events ascribed to aficamten by investigators.
The secondary objective of this trial is to describe the concentration-response relationship of aficamten on the resting and post-Valsalva LVOT-G on echocardiogram over 10 weeks of treatment. Treatment with aficamten resulted in statistically significant reductions from baseline compared to placebo in the average LVOT-G. The majority of patients treated with aficamten (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved the target goal of treatment, defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg at Week 10 compared to placebo (7.7%). Reductions in LVOT-G occurred within two weeks of initiating treatment with aficamten, were maximized within two to six weeks of the start of dose titration, and were sustained until the end of treatment at 10 weeks. The observed reductions in LVOT-G were dose dependent, with patients achieving greater reductions of LVOT-G with increasing doses of aficamten.
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%. HCM is life-threatening and seriously impairs the quality of life of patients.
At present, there are no approved drugs that are disease-specific for HCM in either the US or 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.
Fundamentally, aficamten reduces the number of active myosin force-producing cross bridges during each cardiac cycle by directly binding to the cardiac myosin motor domain and inhibiting the myosin ATPase, stabilizing the motor in a non-force producing state. This mechanism of action may be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM. Aficamten arose from an extensive chemical optimization program conducted with careful attention to therapeutic index and pharmacokinetic properties that may translate into next-in-class potential.
In July 2020, Ji Xing entered into a license and collaboration agreement with Cytokinetics, a late-stage biopharmaceutical company headquartered in California, pursuant to which Cytokinetics has granted to Ji Xing an exclusive license to develop and commercialize aficamten (formerly known as CK-274) in the Greater China territory. Ji Xing submitted an 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.
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