After 16 weeks on placebo, patients in the control group were invited to start mavacamten alongside the treatment group, explained Milind Desai, MD, MBA, director of the Hypertrophic Cardiomyopathy Center and vice chair of education at the Heart, Vascular & Thoracic Institute, Cleveland Clinic.
Milind Desai, MD, MBA, director of the Hypertrophic Cardiomyopathy Center and vice chair of education at the Heart, Vascular & Thoracic Institute, Cleveland Clinic, provides an overview of the VALOR-HCM trial and its findings at 56 weeks, which were presented at the European Society of Cardiology (ESC) 2023 Congress.
What was the primary objective of the VALOR-HCM trial, and how does it differ from EXPLORER-HCM?
The VALOR-HCM trial was conducted. It's a phase 3 randomized controlled trial in symptomatic hypertrophic obstructive cardiomyopathy [HCM] patients—patients with advanced symptoms who were on maximally tolerated medical therapy, background medical therapy, and referred for septal reduction therapies [SRTs], like alcohol septal ablation or myectomy.
So, how does it differ from the previous EXPLORER study? Patients had advanced symptoms, intractable symptoms. So 93% of patients were in NYHA [New York Heart Association] class III and they were on maximally tolerated combination therapy, including beta-blocker, calcium channel blocker, and disopyramide. And everyone was referred for surgery or alcohol ablation and were actively considering it within the 6-month timeframe.
Why did the trial include a placebo crossover group, and did their results differ at 56 weeks?
The first 16 weeks were placebo controlled randomized, so 56 patients in each arm, and the background characteristics were very similar. Notably, almost 50% were women. So the background characteristics were very similar. The idea was see what happens to SRT eligibility as a placebo controlled in the first 16 weeks. And that was what we presented as a late breaker a couple of years ago at ACC 2022, which showed that after 16 weeks, 82% of patients in the mavacamten group no longer met guideline criteria for SRT. But then, because this is a sicker population referred for SRT, we didn't want to be on a placebo; we met that primary objective. Then we wanted to see what happens when patients cross over? The placebo folks, once they start getting mavacamten, how do they behave?
Long story short, what we saw was in the original mavacamten group, the gradient, the symptoms, the need for SRT, biomarkers, and many echocardiography markers like diastolic function, etc, they significantly improved in the first 16 weeks compared to placebo. But then they demonstrated sustained improvement, meaning after a few weeks, it didn't get worse. We also found the placebo group did not demonstrate these changes in the first 16 weeks, but then they they started demonstrating the same exact changes as the original mavacamten group.
At 56 weeks, what we are showing is that the 2 groups—one group had 56-week exposure and the other one had 40-week exposure—they are basically tracking all in the right direction, demonstrating favorable impact of mavacamten. The reason—as I alluded to—we chose this design is we did not want to hold sick patients from having definitive therapy. We wanted to give them a chance. If they are not improving at 16 weeks, 32 weeks, 56 weeks, we gave everybody a chance to have SRT.
Was it a conscious effort to include such a high proportion of women in your study?
Absolutely. At this point of time, in 2023 and beyond, it is incumbent upon us as a scientific community to be inclusive—not just gender inclusivity but try our best to be ethnicity inclusive. Diversity and inclusion has to be in the conversation. Sometimes it may or may not work, but we have to give it a shot.