JIXING Announces the CTA Approval of China Cohort of ACACIA-HCM, a Pivotal Phase 3 Clinical Trial of Aficamten in Patients With nHCM

The development of aficamten has been accelerated to provide new treatment options for more patients with HCM

SHANGHAI, China, March 13, 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 that 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 ACACIA-HCM (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints In Adults with Non-Obstructive HCM), a Phase 3 clinical trial of aficamten in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (nHCM).

ACACIA-HCM is a Phase 3, multi-center, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the effect of aficamten compared to placebo on health-related quality of life in participants with symptomatic nHCM. ACACIA-HCM builds on the findings from Cohort 4 of REDWOOD-HCM, the Phase 2 clinical trial which demonstrated that treatment with aficamten resulted in statistically significant improvements in heart failure symptoms and cardiac biomarkers in patients with nHCM.

“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 ACACIA-HCM, Academician of the Chinese Academy of Sciences, Director of the Department of Cardiology, Zhongshan Hospital and Chairman of the National Cardiovascular Health Alliance. , "There is a significant unmet medical need for patients with nHCM who do not have access to targeted therapies because conventional treatments only alleviate symptoms and do not slow disease progression. The CTA approval of the China cohort of ACACIA-HCM demonstrates that the clinical development of aficamten for the treatment of symptomatic HCM in China is now fully underway. We look forward to assessing the impact of aficamten in patients with nHCM on symptoms and quality of life as well as on other measures of disease burden, including exercise capacity, functional class, cardiac structure and function and cardiovascular outcomes.”

"Aficamten has the potential to revolutionize the standard of care for HCM and is expected to bring tremendous clinical benefits to patients in China," said Yuan Li, MD, Chief Medical Officer of Cardiovascular at JIXING. " ACACIA-HCM is the fourth Phase 3 clinical trial of aficamten in China. We will explore the potential of aficamten to accelerate the introduction of new treatment options for patients with oHCM and nHCM in China."

About ACACIA-HCM

The primary endpoint of ACACIA-HCM is the change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score from baseline to Week 36. Secondary endpoints include the change from baseline to Week 36 in maximal exercise performance (peak VO2) and sub-maximal exercise performance (Ve/VCO2), the proportion of patients with ≥1 class improvement in New York Heart Association (NYHA) functional class, changes in left atrial volume index (LAVI) and NT-proBNP. After the primary analysis at 36 weeks, patients will continue treatment with aficamten or placebo for up to 72 weeks to evaluate additional secondary and exploratory analyses including the time to first cardiovascular event.

ACACIA-HCM patients are randomized on a 1:1 basis to receive aficamten or placebo. Randomization will be stratified by persistent atrial fibrillation and presence of intracavitary obstruction. At screening, patients enrolled in ACACIA-HCM must have a resting left ventricular outflow tract gradient (LVOT-G) < 30 mmHg and post-Valsalva LVOT-G < 50 mmHg in addition to left ventricular ejection fraction (LVEF) ≥60%, respiratory exchange ratio (RER) ≥ 1.00 and peak VO2 ≤ 90% predicted, NT-proBNP ≥ 300 pg/mL or ≥ 900 pg/mL if atrial fibrillation or atrial flutter are present at screening, NYHA functional class II or III and KCCQ Clinical Summary Score ≥ 30 and ≤ 85.

ACACIA-HCM will consist of two parts, with Part 1 comprising Day 1 to Week 36 and Part 2 comprising Week 36 to Week 72. All participants will complete Part 1. At the end of Part 1, participants will continue with Part 2 until the last randomized participant has completed Part 1. Each patient will receive up to four escalating doses of aficamten or placebo 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 20mg. Dose escalation will occur only if a patient has an LVEF ≥ 60%. Patients who do not meet escalation criteria will continue to receive their current dose or may be down-titrated if their LVEF is < 50%. Patients who complete ACACIA-HCM will be eligible to participate in an open-label extension clinical trial.

About Aficamten and the Broad Phase 3 Clinical Trials Program

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. 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. 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.

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. SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), was the pivotal Phase 3 clinical trial in patients with symptomatic obstructive hypertrophic cardiomyopathy (oHCM). The results from SEQUOIA-HCM show that treatment with aficamten significantly improved exercise capacity compared to placebo, increasing peak oxygen uptake (pVO2) measured by cardiopulmonary exercise testing (CPET) by a least square mean difference (95% CI) of 1.74 (1.04 - 2.44) mL/kg/min (p=0.000002). The treatment effect with aficamten was consistent across all prespecified subgroups reflective of patient baseline characteristics and treatment strategies, including patients receiving or not receiving background beta-blocker therapy. Statistically significant (p<0.0001) and clinically meaningful improvements were also observed in all 10 prespecified secondary endpoints. Aficamten was well-tolerated with an adverse event profile comparable to placebo. Treatment emergent serious adverse events occurred in 8 (5.6%) and 13 (9.3%) patients on aficamten and placebo, respectively. Core echocardiographic left ventricular ejection fraction (LVEF) was observed to be <50% in 5 patients (3.5%) on aficamten compared to 1 patient (0.7%) on placebo. There were no instances of worsening heart failure or treatment interruptions due to low LVEF. Aficamten is currently the subject of two Phase 3 clinical trials: MAPLE-HCM, a Phase 3 clinical trial evaluating aficamten as monotherapy compared to metoprolol as monotherapy in patients with oHCM, and ACACIA-HCM, a pivotal Phase 3 clinical trial in patients with symptomatic nHCM. Aficamten received Breakthrough Therapy Designation for the treatment of symptomatic oHCM from the U.S. Food & Drug Administration (FDA) as well as the National Medical Products Administration (NMPA) in China.

About Hypertrophic Cardiomyopathy (HCM)

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 ??-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.

About JIXING

JIXING is a biopharmaceutical company headquartered in Shanghai committed to bringing innovative science and medicines to underserved patients in China and around the world 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 and around the world.

JIXING’s cardiovascular portfolio includes 5 assets in late-stage clinical development (aficamten, Etripamil, omecamtiv mecarbil, JX09 and JX10). 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 .

About Cytokinetics

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. Cytokinetics is preparing for regulatory submissions for aficamten, its next-in-class cardiac myosin inhibitor, following positive results from SEQUOIA-HCM, the pivotal Phase 3 clinical trial in obstructive hypertrophic cardiomyopathy. Aficamten is also currently being evaluated in two ongoing Phase 3 clinical trials: 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-586, a cardiac myosin inhibitor with a mechanism of action distinct from aficamten for the potential treatment of HFpEF, and 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.

For additional information about Cytokinetics, visit www.cytokinetics.com and follow us on X, LinkedIn, Facebook and YouTube.

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