IMPROVE-HCM: Promising results for ninerafaxstat in non-obstructive HCM

Ninerafaxstat demonstrated promising safety and trends supporting potential efficacy in patients with symptomatic non-obstructive hypertrophic cardiomyopathy (HCM) in the phase 2 IMPROVE-HCM trial.

Ninerafaxstat is a novel cardiac mitotrope designed to restore myocardial energy homeostasis by shifting cardiac energy metabolism from fatty acid oxidation to glucose oxidation. This innovative approach enhances cardiac efficiency, particularly in conditions of limited oxygen supply, potentially offering a novel therapeutic approach for patients with non-obstructive HCM.

In the phase 2 IMPROVE-HCM trial (NCT04826185), Prof. Martin Maron (Lahey Hospital & Medical Center, MA, USA) and colleagues evaluated the safety and efficacy of ninerafaxstat in patients with symptomatic non-obstructive HCM and objective evidence of exercise limitation [1]. Conducted across 12 academic centres, the trial enrolled 67 adult patients aged 18–80 years with a clinical diagnosis of non-obstructive HCM and exercise limitation, excluding those with specific contraindications. The participants were randomised to receive either ninerafaxstat, 200 mg twice daily, or a placebo and underwent comprehensive assessments before and after the 12-week treatment period.

At 12 weeks, ninerafaxstat demonstrated a safety profile comparable with placebo, with the primary endpoint of treatment-emergent adverse events (TEAEs) occurring in 70.6% of the participants, and serious adverse events (SAEs) in 11.8%. While overall improvement in a standardised heart failure symptom burden (assessed by Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]) was non-significant, an exploratory subgroup analysis of participants with baseline KCCQ-CSS ≤80 points showed significant improvement with ninerafaxstat (P=0.04). Ninerafaxstat significantly improved functional capacity measured by V_E/VCO₂ slope, an important prognostic variable in HCM, compared with placebo (P=0.005), particularly in participants with advanced symptoms (i.e. NYHA class III). Although not significant, NT-proBNP levels showed a trend towards lower levels in patients randomised to ninerafaxstat, suggesting potential cardioprotective effects. Left atrial size also appeared lower ninerafaxstat-treated patients, suggesting improved cardiac function.

These findings support investigation in larger phase 3 trials, underscoring the potential of ninerafaxstat to address the unmet needs of patients with non-obstructive HCM.

1. Maron MS, et al. Efficacy and safety of ninerafaxstat, a novel cardiac mitotrope, in patients with symptomatic nonobstructive hypertrophic cardiomyopathy: Results of IMPROVE-HCM. LB4, Session 411, ACC 2024 Scientific Session, 6–8 April, Atlanta, USA.

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Posted on 16 May 202413 June 2024