Phase 3 Trial Demonstrates Benefits to Mavacamten Treatment in Hypertrophic Cardiomyopathy


Sehnert emphasizes that mavacamten treatment benefits were present in both patients with sarcomere mutation positive HCM and sarcomere mutation negative HCM.

In an interview with Pharmacy Times, study author Amy Sehnert MD, vice president, global program lead of CV Transition Assets at Bristol Myers Squibb, discusses the significance of the EXPLORER-HCM phase 3 trial and the treatment benefit of mavacamten in patients with and without gene variants. Sehnert also highlights the importance of analyzing patients with and without sarcomere gene variants, because mavacamten acts within the sarcomere. The phase 3 trial will be discussed further at the American Heart Association conference in Philadelphia, Pennsylvania (November 11, 2023, to November 13, 2023).

Pharmacy Times: Why was it important to investigate treatment benefit of mavacamten in patients with and without sarcomere gene variants specifically?

Amy Sehnert: So, the EXPLORER-HCM trial was a randomized, placebo-controlled trial of 251 patients with obstructive symptomatic hypertrophic cardiomyopathy (HCM). HCM is a genetic disease—the most common cardiovascular genetic disease—and genetic testing was offered as an option for HCM genes, of which about 75% of the participants opted in for that. And of those [participants], about 25% of the patients did show a pathogenic or likely pathogenic mutation in an HCM gene. It was important to look at this analysis for patients with or without mutations or genetic changes in genes of the sarcomere, in part because mavacamten is a drug that acts within the sarcomere. It's a myosin actin inhibitor. And there was a question as to whether there would be any differential response to the drug based on genetic background.

Pharmacy Times: What did the phase 3 EXPLORER-HCM trial show regarding treatment benefit of mavacamten in patients with and without sarcomere gene variants?

Sehnert: So, the EXPLORER-HCM trial overall, met its primary and all secondary endpoints in the overall population, and when the subgroup analysis was performed, it was also seen that all patients had the benefit for the primary and secondary and several exploratory endpoints. And this was seen regardless of whether or not they were…SARC-positive or SARC-negative based on their genetic background. So, the findings did show benefit in both groups and the study was not powered. To look at this specifically, the numbers will be presented in the abstract at the American Heart Association [conference], and the confidence intervals are largely overlapping. But overall, the benefit was seen whether or not the sarcomere gene positive status was present.

Pharmacy Times: What are next steps following these study findings?

Sehnert: So, the EXPLORER-HCM trial was initially reported in 2020 and then there have been at least a dozen manuscripts published since the original publication as we continue to look at different aspects of the trial, results from the cardiopulmonary exercise testing, echocardiography, cardiac magnetic resonance imaging, and of course, from the long-term extension study. In our clinical program overall of clinical studies, we also had the VALOR-HCM trial in obstructive HCM and the ongoing phase 3 ODYSSEY-HCM trial in nonobstructive HCM, we do continue to collect data about genetic background and biomarkers in order to continue to understand any effects—if any—in terms of response to that treatment.

So, this is a continuing journey, as we look at that data. But the genetic results are also consistent with other subgroup analyses that we've done that have been presented, for example, in patients who have hypertension or not in analyses by gender, by age, and duration of disease, and these have most recently been reported at the American College of Cardiology last spring in 2023.

Pharmacy Times: What is the role of the pharmacist in identifying the appropriate treatment in this patient population?

Sehnert: So, the pharmacist plays a key role in [mavacamten] treatment in terms of the risk evaluation and mitigation strategies (REMS) program. So, the REMS program includes involvement of the the prescribing cardiologist, who's really the individual who would identify the right patient to treat, the patient themselves, and the pharmacist. The pharmacist’s role is really in helping to dispense the correct doses and along with the physician and patient, keep an eye on any other medications the patient is on to ensure the correct dosing of [mavacamten] as per the label.

Pharmacy Times: Closing thoughts?

Sehnert: I think just generally, it's important for anyone…I'm a pediatric cardiologist, but for any health care provider who care for patients and/or their family members with HCM, [should know] that it is a genetic disease, that there are tests and assays available in which to obtain that information about whether sarcomere or other HCM genetic mutation may be involved in. And it's important in the overall aspect of care, and as per the professional guidelines for the care of HCM, so, bringing it up in terms of an option in the care to undergo genetic testing to kind of really understand that to the individual and their family, I think is still an important message.

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