Ninerafaxstat improves symptoms, quality of life in nonobstructive HCM
Key takeaways:
- Few therapies have improved symptoms for patients with nonobstructive hypertrophic cardiomyopathy.
- In a small trial, ninerafaxstat safely improved heart failure symptoms and was well tolerated.
ATLANTA — For patients with nonobstructive hypertrophic cardiomyopathy, ninerafaxstat, a novel cardiac mitotrope, safely improved HF symptoms during a 12-week period vs. placebo, a speaker reported.
The results of the small phase 2 randomized controlled IMPROVE-HCM trial were presented at the American College of Cardiology Scientific Session and simultaneously published in the Journal of the American College of Cardiology.
“There have been a lot of therapies that have been advanced for obstructive HCM. There are lots of treatment options to improve how those patients can feel and do. For the nonobstructive HCM population, composing about one-third of the total HCM population, there are very little to no therapeutic interventions that have shown any efficacy,” Martin S. Maron, MD, a cardiologist and director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital and Medical Center in Burlington, Massachusetts, said during a press conference. “The IMPROVE-HCM study was evaluating a novel drug called ninerafaxstat, which is a cardiac mitotrope, which is a drug class that alters cardiac energetics.”
Maron said the heart utilizes two types of energy, glucose and fatty acids, and that ninerafaxstat (Imbria) is a partial inhibitor of the oxidation of fatty acids. That then shifts the utilization of energy toward glucose, which provides a greater amount of ATP per molecule of O2 to the heart.
Therefore, “By making the heart more energy-efficient ... you can potentially improve what is really the driver to why nonobstructive patients are limited, which is diastolic dysfunction,” Maron said.
For the present study, 67 patients with nonobstructive HCM were randomly assigned to oral ninerafaxstat 200 mg twice daily or placebo for 12 weeks. Nearly half of participants were men and the mean age was 56 years in the placebo group and 58 years in the ninerafaxstat group.
Patients were aged 18 to 80 years; had left ventricular wall thickness of 15 mm or more; had LV outflow tract gradient of more than 30 mm at rest and with exercise; had baseline LV ejection fraction of 50% or more; had peak oxygen uptake (VO2) of 80% or less than predicted for their age; and had a respiratory exchange ratio of more than 1.05.
Maron and colleagues evaluated any change in cardiopulmonary exercise test measures, Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score, echocardiographic measures and N-terminal pro-B-type natriuretic peptide compared with placebo at 12 weeks and the safety and tolerability of ninerafaxstat at 14 weeks.
Maron reported that ninerafaxstat was well tolerated, with mild to moderate treatment-emergent adverse events comparable with the placebo group.
There was no significant change in LVEF, BP or heart rate from baseline to week 12 among patients assigned to ninerafaxstat.
In the overall cohort, HF symptom burden as assessed by the KCCQ clinical summary score was numerically but not significantly better in the ninerafaxstat group than in the placebo group (least squares [LS] mean difference, 3.2; 95% CI, –2.9 to 9.2; P = .2). However, researchers observed significant improvement in nonobstructive HCM symptom burden in patients with a KCCQ clinical summary score of 80 or less (LS mean difference, 9.4; 95% CI, 0.3-19.5; P = .04) and those with NYHA class III symptoms at baseline (LS mean difference, 13.6; 95% CI, 1.4-25.9; P = .03).
In addition, ninerafaxstat was associated with significant improvement in ventilation-to-CO2 output (LS mean difference, 2.1; 95% CI, 3.6 to 0.6; P = .005), including for patients with a KCCQ score of 80 or less (LS mean difference, 2.1; 95% CI, 3.8 to 0.3; P = .02) and those with NYHA class III symptoms at baseline (LS mean difference, 3; 95% CI, 4.9 to 1; P = .004).
Moreover, ninerafaxstat reduced left atrial size from baseline compared with placebo (change from baseline, 0.09 mm vs. 0.1 mm; LS mean difference, 0.2; 95% CI, 0.35 to 0.05; P = .01).
The difference in NT-proBNP between ninerafaxstat and placebo groups was not significant (P = .85).
“In this phase 2 proof-of-concept study with ninerafaxstat, it was very well tolerated in nonobstructive HCM population. [Ninerafaxstat] was associated with significant improvement in functional capacity as measured by ventilatory efficiency, which is an important and prognostic submax [cardiopulmonary exercise testing] measurement in HCM,” Maron said during the press conference. “In those that were most limited at baseline, [ninerafaxstat was associated with] a significantly improved in how patients felt as assessed by KCCQ. Putting this together from phase 2, these data ... do support investigation with a phase 3 study in a larger population of symptomatic nonobstructive HCM to better understand whether optimizing cardiac energetics can fulfill an important unmet treatment need in this disease.”
After the presentation, Himabindu Vidula, MD, MS, FACC, director of the VAD program at the Hospital of the University of Pennsylvania and incoming chair of the ACC Board of Governors, discussed the improvement of HF symptoms during a short 12-week period and added her support for a larger ninerafaxstat trial in the nonobstructive HCM population.
“From a clinical perspective, in nonobstructive hypertrophic cardiomyopathy, there are no approved medical therapy and impaired myocardial energetics is a potential cause of symptoms and exercise limitations that these patients experience,” Vidula said. “The drug was well tolerated and, importantly, the adverse event profile was similar to placebo. In patients randomized to the drug, there were favorable changes in functional capacity, which may have results from beneficial changes in diastolic function during exercise. There were also directionally favorable changed in health status and quality of life ... which was significant in those with self-reported impaired health status at baseline. And finally, the left atrial dimension, which is a surrogate marker of diastolic function, was also positively impacted.
“I think it’s important to note that all of these changes occurred over a relatively short period of time of only 12 weeks of treatment. This really underscores the potential for enhancing the outcomes with a longer exposure time to the drug,” Vidula said. “Overall, these results strongly support further investigation of this therapy in a larger nonobstructive HCM trial.”
References:
- Maron MS. J Am Coll Cardiol. 2024;doi:10.1016/j.jacc.2024.03.387.
- Ninerafaxstat well-tolerated and safe for nonobstructive hypertrophic cardiomyopathy. https://www.acc.org/About-ACC/Press-Releases/2024/04/08/13/40/ninerafaxstat-well-tolerated-and-safe-for-nonobstructive-hypertrophic-cardiomyopathy. Published April 8, 2024. Accessed April 24, 2024.
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Mahmod M, et al. Joint American College of Cardiology/Journal of the American Medical Association late-breaking clinical trials IV. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.