Key Points:
- Despite the high symptomatic burden, very few effective treatments exits for symptomatic, non-obstructive HCM.
- In IMPROVE-HCM, a novel cardiac mitotrope (ninerafaxstat) was compared to placebo in non-obstructive HCM. The primary efficacy endpoint was change in KCCQ score from baseline. Safety and tolerability were also assessed.
- In the primary intention-to-treat analysis, ninerafaxstat did not improve symptoms; however, when restricting the population to patients with baseline limitation by KCCQ (or NYHA III), treatment resulted in a significant improvement in HF symptoms. Ninerafaxstat also improved exercise capacity on CPET in the total sample.
While many treatments have emerged for symptomatic relief in obstructive HCM, there are very limited options for non-obstructive HCM. In non-obstructive HCM, symptomatic diastolic dysfunction is contributed to by impaired LV relaxation and distensibility. Thus, the cardiac mitotrope (ninerafaxstat) was developed to influence myocardial energetics and improve diastolic function. In a breaking presentation at the 2024 ACC conference today, Dr. Martin Maron and his team presented their study: “IMPROVE-HCM: A Study to Evaluate the Safety, Tolerability, and Efficacy of IMB-1018972 in Patients With Non-obstructive Hypertrophic Cardiomyopathy Trial.”
The IMPROVE-HCM study (NCT04826185) was a randomized, double-blinded prospective phase-2 trial examining the safety and efficacy of 200mg oral ninerafaxstat vs placebo in symptomatic, non-obstructive HCM. Participants were required to have HCM with a LV wall thickness ≥ 1.5cm and evidence of reduced exercise capacity (peak VO2 ≤80% predicted) on CPET. Key exclusions were LVOT gradient ≥ 30mm Hg at rest or with exercise or a reduced ejection fraction. The primary efficacy outcome was change in heart failure symptom burden by KCCQ-CSS score from baseline, and the primary safety endpoint was the number of adverse events over the study period. Key secondary outcomes included change in baseline echocardiographic features (including LA size and E/e’), peak VO2, and NT-proBNP from baseline.
A total of 67 patients were 1:1 randomized to either ninerafaxstat or placebo. Both arms were treated for 12 weeks, and participants were assessed at baseline as well as weeks 6, 12, and 14. Echocardiograms were performed at the time of screening as well as at weeks 6 and 12, and CPETs were performed at screening and week 12. The mean age was 57 with 55% women; the baseline mean LVEF was 65% and % predicted peak VO2 was 60%. Additionally, most patients (60%) had baseline NYHA II symptoms.
Ninerafaxstat was well tolerated, with 4 (11.8%) vs 2 (6.1%) adverse events relative to placebo. Adverse events in the treatment arm included COVID, CABG, pyelonephritis, and abdominal abscess. There was no association between treatment and change in LVEF, BP, or HR at week 12. Using an intention-to-treat analysis, ninerafaxstat did not result in a significant reduction in HF symptom burden at 12 weeks (mean difference 3.2, 95% CI [-2.9-9.2]; p=0.2); however, when limiting the analysis to the 35 participants with limitation at baseline (ie, KCCQ-CCS ≤80), ninerafaxstat resulted in a statistically significant and clinically meaningful reduction in KCCQ (mean difference 9.4, 95% CI [0.3-18.5]; p=0.04) by 12 weeks. This finding was recapitulated when restricting the sample to the 23 participants with NYHA III symptoms at baseline (mean difference 13.6, 95% CI [1.4-25.9]; p=0.03). In the total ITT population, ninerafaxstat also meaningfully improved exercise capacity as measured by VE/VCO2 (mean difference -2.1 units, 95% CI [-3.6,-0.6]; p=0.005). Left atrial size was also reduced in the treatment group (mean reduction from baseline 0.20, 95% CI [-0.35, -0.05]; p=0.01).
When discussing the clinical implications of the study at the ACC conference, Dr. Maron stated: “In this Phase 2 proof-of-concept study, ninerafaxstat, a novel investigational cardiac mitotrope, was safe and well tolerated in nonobstructive HCM…in those nonobstructive HCM patients limited at baseline, ninerafaxstat significantly improved limiting symptoms with favorable change in KCCQ-CCS score…these results support progression to larger Phase 3 study in symptomatic nonobstructive HCM to investigate if targeted therapy at optimizing cardiac energetics may fulfill an important unmet treatment need in this disease.”