Ninerafaxstat, a novel cardiac mitotrope that targets energy metabolism, is safe and effective in the treatment of nonobstructive hypertrophic cardiomyopathy (HCM), according to the Phase 2 IMPROVE-HCM study, presented during a Late-Breaking Clinical Trial session at ACC.24 and simultaneously published in JACC.

The double-blind study, performed between June 2021 and October 2023 at 12 academic centers in North America and the U.K., randomized 67 participants to either ninerafaxstat 200 mg BID or placebo for 12 weeks. All patients had a clinical diagnosis of nonobstructive HCM with peak VO2 <80% predicted for age and sex, end-diastolic left ventricular (LV) wall thickness ≥15 mm (or ≥13 mm plus family history of HCM or positive for pathogenic sarcomere gene mutation), peak LV outflow gradient <30 mm Hg and ejection fraction ≥50%. Assessments included the Kansas City Cardiomyopathy Questionnaire (KCCQ-23), CPET, echocardiography, CMR and biomarkers.

The average age of the study participants was 57 years, 55% were women, 83.6% White and 6% Black. Maximal LV wall thickness was 18.8 mm and ejection fraction was 65.4%; 59% were in NYHA class II and 35% in NYHA class III. Exercise capacity with peak VO2 was 19.2 mL/kg/minute, 60.5% predicted at baseline.

Results showed that at 12 weeks, the primary endpoint of treatment emergent serious adverse events (TEAE) occurred in 11.8% of patients in the ninerafaxstat group (four patients with diverticulitis, pyelonephritis, CABG and COVID pneumonia) and 6.1% of the placebo group (two patients with septic shock and acute hypoxic event). Overall, 70.6% of the ninerafaxstat group and 60.6% of the placebo group experienced one or more TEAE. No significant between-group difference was seen for change in ejection fraction, blood pressure or heart rate.

Additionally, researchers found significantly better ventilatory efficiency (VE/VCO2 slope), a secondary endpoint, with ninerafaxstat compared to placebo, with a between-group least square (LS) mean difference of –2.1 (p=0.006) and no significant difference in peak VO2 (p=0.9). They also found that ninerafaxstat vs. placebo was associated with a directional but not significant improvement in KCCQ-CCS (LS mean, 3.2; p=0.2). However, a post hoc analysis revealed a significant improvement with the novel agent vs. placebo among 35 patients with a baseline KCCQ-CSS score ≤80 (LS mean, 9.4; p=0.04).

“Favorable changes of a magnitude considered clinically meaningful were observed,” in patients randomized to ninerafaxstat, wrote authors Martin S. Maron, MD, et al., including functional capacity and health status. Left atrial dimension, a surrogate marker of diastolic function, was also “positively impacted.” “Abnormal myocardial energetics are an important disease mechanism resulting in morbidity in HCM and is a potential therapeutic target,” wrote the authors, adding the present “findings support assessing ninerafaxstat in a Phase 3 study.” 

Maron added, “Our findings provide enthusiasm that a novel drug therapy with ninerafaxstat may provide nonobstructive HCM patients an opportunity to achieve a better quality of life by decreasing symptom burden and improving exercise capacity.”