ATLANTA — A investigative drug that uses a novel pathway to target cardiac metabolism was safe and well-tolerated and showed a signal to improve cardiac function in symptomatic patients with moderate nonobstructive hypertrophic cardiomyopathy (nHCM) in a phase 2 proof-of-concept trial.
The IMPROVE-HCM trial randomized 67 nHCM patients to the drug ninerafaxstat or placebo. Ninerafaxstat is a cardiac mitotrope, a class of drugs that influence myocardial energetics.
While the trial showed no significant improvement in cardiovascular outcomes between the two treatment arms overall, a post hoc analysis of patients with the worst symptoms demonstrated measurable improvement in heart failure symptoms and exercise capacity, the researchers reported.
The results were presented here on April 8 at the American College of Cardiology meeting and published online simultaneously in the Journal of the American College of Cardiology.
‘Greatest Unmet Need’
“There have been a number of therapies that have been advanced for obstructive HCM, but in the nonobstructive HCM population, comprising about a third of the total HCM population, very little to no treatment interventions have shown efficacy,” study leader Martin S. Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Lahey Medical Center, Burlington, Massachusetts, said in presenting the results. “Probably the greatest unmet need now in this disease is with the nonobstructive group.”
He added, “Treatment with ninerafaxstat was associated with significant improvement in exercise performance of about a 2.1 decrease in slope compared to placebo.” The trial used the ventilator efficiency slope to measure exercise capacity.
As a phase 2 trial, the study was designed to evaluate the safety of ninerafaxstat over 12 weeks. The study demonstrated comparable safety results in terms of treatment emergent adverse events — 11% and 6% for the treatment and placebo arms, respectively.
In the overall study population, the mean improvement in heart failure symptom burden from baseline, measured by a baseline Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCQQ-CSC), showed no appreciable difference between the arms.
The statistically significant difference in exercise capacity was demonstrated in a cohort of patients with worst symptoms, defined by a baseline KCCQ-CSS of ≤ 80, Maron said.
This cohort also showed a statistically significant improvement of 9.4 points in KCCQ-CSS for treatment vs placebo (P = .04), he added, noting that a 5-point change in KCCQ-CSS is considered clinically meaningful.
“These are patients that are, if you look at KCCQ-CSS of 80 to 60 for a score, frustrated but they’re not super sick,” Maron told theheart.org | Medscape Cardiology. “What we’re saying is, we’re trying to remove the asymptomatic to mildly symptomatic patient out of the trial because we’re not going to show benefit.”
Patients with KCCQ-CSS of ≤ 80 would be a suitable target for the phase 3 trial going forward, he said.
“The mitotropes are altering the utilization of energy to a more efficient form,” Maron said. He explained ninerafaxstat works by partially inhibiting mitochondrial fatty acid oxidation to shift cardiac metabolism toward glucose, which increases efficiency of adenosine triphosphate production to enhance cardiac function.
While the IMPROVE-HCM trial met its primary phase 2 endpoint of showing the drug was well tolerated, it also provided clues to how it influences cardiac function, noted Himabindu Vidula, MD, medical director of mechanical circulatory support at the University of Pennsylvania in Philadelphia.
“In patients randomized to the drug, there were favorable changes in functional capacity, which may have resulted in functional changes in diastolic function during exercise,” she said.
“The left atrial dimension which is a surrogate marker of diastolic function was also positively impacted,” she said. “It’s important to note that all of these changes occurred in a relatively short period of time of only 12 weeks of treatment, and this underscores the potential for enhancing outcomes with longer exposure to the drug.”
The results “strongly support further investigation,” Vidula added.
Imbria Pharmaceutical provided funding for the study. Maron disclosed financial relationships to Cytokinetics, Imbria and Edgewise. Vidula disclosed a financial relationship with Abbott Laboratories.
Richard Mark Kirkner is a medical journalist based in the Philadelphia area.
Source link : https://www.medscape.com/viewarticle/novel-drug-shows-signal-improve-nhcm-2024a100071b?src=rss
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Publish date : 2024-04-12 13:06:53
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