Ninerafaxstat shows early promise for treating nonobstructive hypertrophic cardiomyopathy

medwireNews: The cardiac mitotrope ninerafaxstat is well tolerated by patients with nonobstructive hypertrophic cardiomyopathy (nHCM), with early signs of improvements in exercise capacity and health status, a phase 2 trial suggests. “This study provides support for a larger phase 3 study in symptomatic [n]HCM patients to further clarify the potential of this novel investigational therapy targeted at optimizing cardiac energetics, underscoring the possibility to fulfill an important unmet treatment need in patients with [n]HCM,” write Martin Maron (Lahey Hospital, Burlington, Massachusetts, USA) and colleagues in the Journal of the American College of Cardiology. The IMPROVE-HCM study, whose results were simultaneously presented at the American College of Cardiology Scientific Sessions 2024 in Atlanta, Georgia, USA, enrolled patients aged 18–80 years with nHCM and objective evidence of exercise limitation including a peak volume of O2 of up to 80% of that predicted for their age and sex. The patients were assigned to receive either oral ninerafaxstat 200 mg (n=34) or placebo (n=33) twice daily and their clinical status was measured once at baseline and again after 12 weeks of treatment. The participants were aged an average of 56.9 years, 55.2% were women, and 83.6% were White. The mean maximal left ventricular wall thickness and ejection fraction at baseline were 18.8 mm and 65.4%, respectively, and a total of 58.2% of the patients took beta-blocker medications and 32.8% took calcium channel blockers. At baseline, 59.7% of patients had heart failure symptoms corresponding to class II on the New York Heart Association (NYHA) classification, which ranges from class I (no symptoms) to class IV (severe limitations), while 35.8% of patients had symptoms corresponding to class III. Maron and colleagues found that a total of 70.6% of those taking ninerafaxstat experienced one or more adverse event (AE) related to the treatment compared with 60.6% of those in the placebo group, and these were generally mild to moderate in severity. The most common AEs were ventricular tachycardia (11.8 vs 18.2%), nausea (11.8 vs 3.0%), and headache (11.8 vs 3.0%). Treatment-emergent serious AEs occurred in 11.8% of the patients receiving ninerafaxstat compared with 6.1% of those taking placebo, including one case each of diverticulitis, pyelonephritis, COVID-19, and angina or coronary artery disease requiring coronary artery bypass graft among those taking ninerafaxstat, and one case each of septic shock, acute hypoxia, and death among those taking placebo. At 12 weeks, the patients given ninerafaxstat reported greater, albeit not significant, improvements in heart failure symptoms than those given placebo. Their scores on the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), a measure ranging from 0 to 100 points where higher scores indicate better health status, increased from a mean 67.60 points at baseline to 72.85 points, compared with an improvement from 73.51 to 74.48 points with placebo. This corresponded to a least squares (LS) mean difference of 3.18 in favor of ninerafaxstat, although the treatment effect was not significant. The researchers report that patients given ninerafaxstat were more likely than those given placebo to report KCCQ-CSS improvements from baseline of at least 5 points (41 vs 36%), at least 10 points (24 vs 18%), and at least 20 points (12 vs 3%). The team highlights that in a post-hoc analysis of a subgroup of 35 patients with the most limiting heart failure symptoms (baseline KCCQ-CSS of 80 points or less), those given ninerafaxstat had a significant improvement in their KCCQ-CSS scores by week 12, increasing from a mean 52.39 points at baseline to 63.79 points, compared with an improvement from 59.13 points to 60.54 points among those given placebo, with a LS mean difference of 9.30 points. Maron and colleagues say that “the magnitude of change observed with ninerafaxstat in [n]HCM patients who have impaired health status at baseline represents a change in symptom burden and health status that can likely be considered clinically meaningful to patients and health care providers.” The researchers also found that patients given ninerafaxstat had a significantly better exercise performance, as assessed by the slope of ventilation/carbon dioxide production (VE/VCO2) in cardiopulmonary exercise testing. The ninerafaxstat treatment group’s VE/VCO2 slope decreased, indicating improvement, from a mean 31.2 at baseline to 30.9 at week 12, compared with an increase in the placebo group from a mean 32.7 to 34.3, giving a significant LS mean difference in favor of ninerafaxstat of 2.1. This was also the case in the post-hoc analyses of patients with a KCCQ-CSS of 80 points or less and the 24 patients with more advanced symptoms (NYHA class III) at baseline, with significant LS mean differences of 2.0 and 2.9, respectively. Maron et al say that this finding suggests “a potential benefit of ninerafaxstat in those nHCM patients who are limited by heart failure symptoms, an important subgroup of patients for whom currently there are no proven therapies to relieve symptom burden, other than high-risk heart transplantation.” The authors also point out that “these changes occurred over a relatively short treatment period of 12 weeks, underscoring the potential for enhancing outcome with longer exposure time to ninerafaxstat.” medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group J Am Coll Cardiol 2024; doi:10.1016/j.jacc.2024.03.387 ACC 2024; Atlanta, Georgia, USA: 6–8 April

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