Adjunctive mavacamten averts need for invasive therapy in OHCM

Adding mavacamten – an allosteric modulator of cardiac myosin  – to maximal medical therapy slashes the need for septal reduction therapy (SRT) in patients with obstructive hypertrophic cardiomyopathy (OHCM) who are candidates for such intervention, the VALOR-HCM trial has shown.

“SRT is reserved for patients in NYHA* class III or IV heart failure, with a resting or provoked LVOT** gradient of at least 50 mm Hg,” said lead author Dr Milind Desai from the Cleveland Clinic Heart Vascular and Thoracic Institute, Cleveland, Ohio, US, at ACC.22.

In the VALOR-HCM trial, patients treated with adjunctive mavacamten were far less likely to still be eligible for SRT 16 weeks later. [ACC.22, abstract 402-0] This means their OHCM had improved enough with mavacamten that SRT could no longer be recommended as per current guidelines.

“Additionally, mavacamten improved symptoms, biomarker levels, and quality of life metrics vs placebo through 38 weeks,” Desai shared. “It is actually the first agent tested in prospective trials to appear as a viable treatment option for severe OHCM.”

A promising option

A previous trial of mavacamten, the EXPLORER-HCM, showed that it improved exercise capacity, LVOT obstruction, NYHA class, and health status through 30 weeks in patients with OHCM. [Lancet 2020;396:759-769]  

Based on these results, mavacamten was given the breakthrough therapy designation by the US Food and Drug Administration, which allowed for an expedited review by the agency.

“But unlike in EXPLORER-HCM, patients in the VALOR-HCM were maxed out on medical treatment and their backs were against the wall to a point where the next stop was surgery or interventional procedure,” Desai said.

“VALOR gives this group of highly symptomatic patients an alternative to SRT, and this could help change the lives of many of our patients,” he added.

VALOR-HCM population

Patients (mean age 60 years, 50 percent female) in the study were sick enough to qualify for an SRT. They had a maximum septal wall thickness of ≥15 mm or ≥13 mm on echocardiography, with family history, and remained symptomatic (92.9 percent in NYHA class III or higher) despite maximal medical therapy (46 percent were on beta-blockers; 20 percent were on disopyramide).

All had been referred for SRT (87 percent to myectomy). Fifty-six patients were started on mavacamten 5 mg once daily that was titrated up or down based on LVEF, LVOT at rest, and Valsalva status. Patients consented to be followed for 128 weeks.

After 16 weeks, only 17.9 percent of patients treated with mavacamten were still eligible to receive SRT vs 76.8 percent for placebo (p< 0.0001).

Additionally, each secondary endpoint (post-exercise LVOT, NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, NT-proBNP, and troponin levels) improved with mavacamten relative to placebo (all p<0.001). Sixty-three percent and 27 percent of patients had one and two improvements in NYHA classes, respectively, after treatment.

What was meaningful, Desai said, was that only 2 patients from each group opted to go for SRT. “The point is, given the choice, at least in the study, patients were more likely to go for medical therapy over an invasive procedure.”

Takeaways

An “incredibly impressive trial” was how Dr Michael Mack from Baylor Scott & White Heart Hospital, Plano, Texas, US, described the VALOR-HCM study. If mavacamten gets approved, could it be a background therapy option prior to SRT? he asked during a discussion that followed the presentation.

“Yes, but it has to be tested in a trial fashion,” said Desai. “It makes sense for patients to be offered medical therapy prior to an invasive therapy.”