Cytokinetics, Incorporated announced that the baseline characteristics of patients randomized in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM), the pivotal Phase 3 clinical trial of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM), were presented at the HCM Society Scientific Sessions in Cleveland, Ohio by Martin S. Maron, M.D., Director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital and Medical Center. SEQUOIA-HCM was designed to evaluate aficamten in patients with symptomatic obstructive HCM on background medical therapy over a 24-week period. Patients enrolled in SEQUOIA-HCM were required to have severe left ventricular outflow tract (LVOT) obstruction as evidenced by a resting LVOT-G =30 mmHg, a post-Valsalva peak LVOT-G =50 mmHg, NYHA functional class II or III, and a peak VO2 =90% predicted.
SEQUOIA-HCM enrolled a total of 282 patients, with one third from the United States, one half from Europe and Israel, and the remainder from China. Patients were on average 59.1 years of age, 40.4% female, and 21% were non-white. Background medical therapy consisted of beta-blockers (61%), calcium channel blockers (26.6%), and disopyramide (12.8%); combination background therapy was permitted.
At baseline, 75.9% of patients were NYHA functional class II, 23.8% were functional class III, and 0.4% were functional class IV. One quarter of patients were guideline-eligible for septal reduction therapy at the time of enrollment. The pooled mean (SD) for baseline peak VO2 was 18.5 (4.5) mL/kg/min or 56.9% (11.8) of age- and sex-predicted peak VO2, and for the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) was 74.7 (18.0).
The geometric mean (Q1, Q3) high-sensitivity cardiac troponin I was 12.1 (7.7, 27.3) ng/L. (Table 1). Key baseline characteristics that remain blinded include left ventricular ejection fraction (LVEF), resting and Valsalva LVOT-G, and NT-proBNP. 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 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.
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