Treatment with the allosteric cardiac myosin inhibitor mavacamten in severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) allows for the deferral of invasive septal reduction therapy (SRT) for nearly 2.5 years, as shown in the end-of-trial results of VALOR-HCM presented at AHA 2024.

All patients were referred for consideration of SRT at baseline. Of these, 15.7 percent met the efficacy endpoint at 128 weeks, defined as a composite of a decision to proceed with SRT or to remain guideline-eligible for SRT. Unevaluable SRT status at week 128 (8.3 percent), classified as SRT-eligible per protocol, contributed to most of the endpoint events. Only 6.5 percent of patients eventually underwent SRT and 0.9 percent remained guideline-eligible for SRT by 128 weeks. [AHA 2024, abstract 4169095]

Together with the 56-week results, only one additional patient underwent SRT between weeks 56 and 128. At the end of treatment, 88 percent of patients chose to transition to commercial mavacamten. [JAMA Cardiol 2023;8:968-977; Circulation 2024;doi:10.1161/CIRCULATIONAHA.124.072445]

“At the end of the trial, mavacamten showed a sustained reduction in the need for invasive SRT at 128 weeks,” said principal investigator Professor Milind Desai, director of the Hypertrophic Cardiomyopathy Center at the Heart, Vascular & Thoracic Institute, Cleveland Clinic in Ohio, US. “The composite endpoint is driven by clinically relevant SRT guideline eligibility: how many patients need surgery or alcohol septal ablation, and nearly 9 out of 10 patients no longer needed that.”

On maximally tolerated medical therapy at baseline

Patients enrolled in VALOR-HCM had severe dyspnoea or chest pain despite maximally tolerated medical therapy, met guideline criteria for SRT, and were willing to undergo SRT. [J Am Coll Cardiol 2022;80:95-108]

In this highly symptomatic cohort (92.9 percent in New York Heart Association [NYHA] functional class III or higher), a sustained improvement in symptoms and quality of life was observed up to week 128 following mavacamten treatment. Improvements in NYHA functional class by ≥1 class and by ≥2 classes were demonstrated in 80.5 percent and 48.1 percent, respectively, of the total trial population (n=108). There was also a significant 14.2-point improvement from baseline in the mean Kansas City Cardiomyopathy Questionnaire 23-item clinical summary score by week 128.

Of note, 34.3 percent of patients at baseline were taking ≥2 background HCM therapies (among β-blockers, nondihydropyridine calcium channel blockers, and disopyramide), and by week 128, only 13 percent were still doing so in addition to mavacamten. Among those with available data, the use of two or three background HCM therapies was reduced by >50 percent.

Need for continued surveillance

The mechanism of action of mavacamten warrants careful monitoring of left ventricular (LV) systolic function during treatment. While a reduction in the LV ejection fraction (LVEF) was notable (mean ?4.8 percent), the mean LVEF remained within normal limits throughout 128 weeks.

Over the entire trial, a reduction in LVEF to <50 percent was observed in 13.9 percent of patients, with new events noted in 5.6 percent between weeks 56 and 128. The total exposure-adjusted incidence of LVEF decrease to 30?50 percent was 5.41 per 100 patient-years.

“The ongoing incidence of LVEF drop to <50 percent, observed in multiple long-term extensions of cardiac myosin inhibitor trials, supports the need for continued surveillance as currently mandated by the FDA Risk Evaluation and Mitigation Strategy programme,” said abstract discussant Dr Sharlene Day from the University of Pennsylvania, Philadelphia, Pennsylvania, US.

Still, all the adverse events reported at the end of the trial had been identified in earlier reports, allowing Desai to conclude that “all efficacy endpoints showed sustained beneficial effects without additional long-term safety signals.”