Phase 2 results for cardiac mitotrope in patients with nonobstructive HCM


ACC.24 – In IMPROVE-HCM, treatment with the novel cardiac mitotrope ninerafaxstat for 12 weeks was safe and well tolerated in patients with nonobstructive hypertrophic cardiomyopathy (HCM).

This summary is based on the presentation of Martin Maron, MD (Burlington, MA, US) at the ACC.24 Scientific Session - Efficacy and Safety of Ninerafaxstat, a Novel Cardiac Mitotrope, in Patients with Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results of IMPROVE-HCM.

Introduction and methods

There is a unmet treatment need in nonobstructive hypertrophic cardiomyopathy (HCM), which comprises approximately one third of the total HCM patient population. Nonobstructive HCM is characterized by diastolic dysfunction, which is a highly energy dependent process.

Ninerafaxstat is a novel cardiac mitotrope that partially inhibits mitochondrial fatty acid oxidation, which leads to a shift towards glucose metabolism, increased ATP production and enhanced cardiac function. The goal of the IMPROVE-HCM trial was to evaluate the safety and efficacy of ninerafaxstat versus placebo in patients with nonobstructive HCM and exertional limitation.

IMPROVE-HCM was a blinded, prospective, randomized, 12 week, phase 2 trial in which 67 patients (18-80 year old) with nonobstructive HCM, baseline LVEF ≥50% and exertional limitation (pVO2≤80%; RER ≥1.05) were randomized to oral ninerafaxstat 200 mg twice daily (n=34) or placebo (n=33).

The primary endpoint was safety and tolerability. Secondary efficacy outcomes related to functional capacity and health status were also assessed.

Main results

  • Ninerafaxstat was well tolerated. Treatment-emergent serious adverse events occurred in 4 patients (11%) in the ninerafaxstat group compared with 2 patients (6%) in the placebo group. These events were COVID, pneumonia, CABG, pyelonephritis and abdominal abscess in the ninerafaxstat group and sepsis and hypoxia (post CPET) in the placebo group.
  • The proportion of patients experiencing ≥1 treatment-emergent adverse event was 71% in the ninerafaxstat group and 61% in the placebo group. Most of these adverse events were mild to moderate.
  • In the intention-to-treat population, treatment with ninerafaxstat versus placebo was associated with clinically meaningful improvements in exercise capacity as assessed with VE/VCO2 (LS mean difference: -2.1; 95%CI: -3.6 to -0.6; P=0.005).
  • In the intention-to-treat population, treatment with ninerafaxstat versus placebo did not alter KCCQ-CSS (LS mean difference: 3.2; 95%CI: -2.9 to 9.2; P=0.2).
  • In a post hoc analysis, ninerafaxstat versus placebo improved KCCQ-CSS in patients with a ≤80 KCCQ-CSS at baseline (LS mean difference: 9.4; 95%CI: 0.3 to 18.5; P=0.04), and in patients with NYHA Class III at baseline (LS mean difference: 13.6; 95%CI: 1.4 to 25.9; P=0.03).


In IMPROVE-HCM, treatment with ninerafaxstat was safe and well tolerated in patients with nonobstructive HCM. Treatment with ninerafaxstat was associated with improvements in functional capacity, and in patients who were most limited at baseline also improvements in HF symptom burden.

Martin Maron concludes his presentation by saying that these data “do support further investigation with a phase 3 study in a larger population of symptomatic nonobstructive HCM to better understand whether optimizing cardiac energetics can in fact fulfill an important unmet treatment need in this disease”.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -

The findings of this study were simultaneously published in J Am Coll Cardiol.

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