Dr Jay Edelberg: Mavacamten Is Producing Exciting Long-term Results in HCM

Patients with hypertrophic cardiomyopathy (HCM) had symptomatic, functional, and structural biomarker changes over the course of a little over 6 months. Mavacamten reduces the hypercontractile state of the heart by resetting the myosin heads back to a normal state, explained Jay Edelberg, MD, PhD, head of Heart Failure and Cardiomyopathy Development at Bristol Myers Squibb.

Data on mavacamten (Bristol Myers Squibb) from the EXPLORER-HCM trial were released earlier today during the session, “Health Status Benefits of Mavacamten In Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results from the EXPLORER-HCM Randomized Clinical Trial,” at ACC.21, the 70th Scientific Session from the American College of Cardiology.

Transcript

Can you briefly discuss the phase 3 EXPLORER-HCM data on mavacamten?

So we're really excited about what EXPLORER did for our patients. We enrolled patients who have the symptomatic form of obstructive hypertrophic cardiomyopathy, and we enrolled 251 patients who were randomized to receive mavacamten or placebo over the course of 30 weeks. What we saw was really exciting.

Our patients had symptomatic, functional, structural biomarker changes, all with mavacamten treatment, over the course of a little over 6 months. Their New York Heart Association class improved, their patient-reported outcomes improved, their exercise capacity as measured by peak VO2 and other measures improved. Their gradients were markedly reduced. Other important parameters improved. Their biomarkers of wall stress and injury all improved.

We're really excited about what this means for our patients.

How does the mechanism of mavacamten work to modulate cardiac myosin and regulate hypercontractility?

So with HCM, the heart is basically in a hypercontractile state for much. The engine of the heart, the sarcomere, has too many of its myosin heads engaged. It's basically working overtime all the time, and that leads to hypertrophy and ill effects for our patients. This is due to genetics for the most part. Too many of the myosin heads are engaged.

What mavacamten does is it helps to reset them back to a normal state so the heart can increase when it needs to but is back into that normal state of myosin head engagement. And this translates to our patients by being able to reduce that hypercontractility. Therefore, the dynamic gradient is reduced and our patients are feeling better, and they're functioning better.

Why is it important to treat the actual mechanism of obstructive HCM vs the symptoms?

So with HCM, especially with obstructive forms of the disease, what we see is this is a dynamic outflow tract obstruction. We can see this gradient and these symptoms exist at rest. And it can get worse when patients exercise. And so the mainstay of the therapy has really been about preventing the hearts from actually exercising in the first place, basically getting beta-blockers to limit the ability of the heart to increase its rate.

With mavacamten, what we're doing is we're targeting the cause of the disease with the sarcomeric state, which allows the heart to get back to a normal function. And so our patients are able to relieve their gradient and improve their symptoms and improve their function—basically resetting where the heart was. We're not trying to simply mask the symptoms by blunting the heart rate. We’re trying to treat the disease.

What have we learned about mavacamten since the phase 3 results were released last August?

Well, what we're reporting here at the American College of Cardiology is the continued benefit we're seeing in our patients here. We'd had good results in the PIONEER phase 2 study and the continuation of those are our open-label extension. With EXPLORER, we continued to treat all the patients—those who were both on drug as well as on placebo—in a long-term extension. We've seen that those results demonstrate that our patients continue to get benefit. The symptoms and the overall structural changes, the biomarkers, are all improved. The effects of mavacamten are durable when we continue to study them.

We're also seeing results of the expanded analysis of the patient-reported outcome, KCCQ [Kansas City Cardiomyopathy Questionnaire], showing all elements of the KCCQ. How patients are feeling have been improved, with some patients getting really dramatic improvements. They're demonstrating what we knew: that mavacamten is helping our patients to really feel better. And now we can see that it's actually doing it long term.