Ninerafaxstat Shows Promise in Phase 2 IMPROVE-HCM Trial for Nonobstructive HCM


Martin Maron, MD, discusses the results of the IMPROVE-HCM trial and how it informs the community on the potential of ninerafaxstat.

Data from the phase 2 IMPROVE-HCM trial suggest ninerafaxstat, a novel cardiac mitotrope, was well-tolerated and improved symptom burden among patients with nonobstructive hypertrophic cardiomyopathy (HCM).

The data, which were presented at the American College of Cardiology 2024 (ACC.24) Annual Scientific Sessions, indicate use of the agent was associated with greater ventilatory efficiency than placebo therapy at 12 weeks, with no drug-related serious adverse events reported in the trial.

“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,” said lead investigator Martin S. Maron, MD, a cardiologist and director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital and Medical Center. “The safety and tolerability of the drug in this phase 2 trial was excellent. These data strongly support moving on to phase 3 development.”

Conducted at 12 centers in the US and UK, IMPROVE-HCM was a multicenter, randomized, placebo-controlled, double-blind, study launched in 2021 with the intent of assessing the safety and tolerability of ninerafaxstat in patients with symptomatic nonobstructive HCM. The trial randomized patients in a 1:1 ratio to 200 mg ninerafaxstat modified-release tablets or placebo therapy twice daily for 12 weeks. Additional inclusion criteria consisted of a rest and/or provocable left ventricular outflow gradient less than 30 mmHg, NYHA Class II or greater with LVEF greater than or at 50%, and a peak VO2 less than 80% of predicted.

The primary outcome of interest for the trial was safety and tolerability of the agent, with efficacy outcomes, such as effects on maximal and submaximal exercise capacity, O2 uptake recovery kinetics, and KCCQs, were assessed as secondary outcomes of interest.

The trial included 67 patients, with 34 randomized to ninerafaxstat and 33 randomized to placebo. This cohort had a mean age of 56.9 (Standard Deviation, 11.8) years and 55% were female. Investigators noted this cohort had a maximal LV wall thickness of 18.8 (SD, 4.4) mm, a mean ejection fraction of 65.4% (SD, 5.2%), and an exercise capacity with peak VO2 of 19.2 (SD, 3.9) mL/kg/min, which is 60.5% (SD, 10.1) of predicted.

Safety analyses revealed 4 of the 34 patients (11.8%) in the ninerafaxstat group experienced a treatment emergent serious adverse events compared to 2 of the 33 patients receiving placebo. Of note, the 4 adverse events among the ninerafaxstat group were diverticulitis, pyelonephritis, CABG, and COVID-19 pneumonia. Investigators pointed out 70.6% of the ninerafaxstat group experienced 1 or more treatment-emergent adverse events compared to 60.6% of the placebo group

Analysis of efficacy outcomes indicated use of ninerafaxstat was associated with a non-significant LS mean difference of 3.1 between the groups (p=0.2) for change in KCCQ-CSS from baseline to the end of the treatment period, with a greater proportion of patients receiving ninerafaxstat achieving an improvement in KCCQ-CSS of 5 or more, 10 or more, or 20 or more points. Additionally, results revealed a VE/VCO2 slope improvement from 31.2(SD, 4.3) to 30.9 (SD, 3.7) in the ninerafaxstat group and changed from 32.7 (SD, 5.1) to 34.3 (SD, 5.7) in placebo, which correlates to a LS mean difference between the groups of -2.1 (95% Confidence Interval [CI], -3.5 to -0.6; P= .005).

“There’s little question that the greatest unmet treatment need for HCM is in the nonobstructive patients who experience limiting symptoms. They’re very frustrated by the impact of symptoms on their quality of life with no approved medical therapies,” Maron said.

Check out our full interview with Maron for more insight into the trial:

Relevant disclosures for Maron include Imbria, Cytokinetics, Edgewise, and iRhythm.


  1. Maron MS, Mahmod Masliza, Abd Samat AH, et al. Kulac I, et al. Safety and Efficacy of Metabolic Modulation with Ninerafaxstat in Nonobstructive Hypertrophic Cardiomyopathy: Phase 2 Study. Presented at: American College of Cardiology (ACC.24) Annual Scientific Session. April 6 – 8, 2024. Atlanta, GA.
  2. American College of Cardiology. Ninerafaxstat well-tolerated and safe for nonobstructive hypertrophic cardiomyopathy. American College of Cardiology. April 8, 2024. Accessed April 8, 2024.
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