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Mavacamten Shines in Phase 3 Trial; Could Be First Specific Treatment for Obstructive HCM


Results from the phase 3 EXPLORER-HCM trial show mavacamten may finally offer a therapeutic solution for patients with hypertrophic cardiomyopathy.

A treatment described as 60 years in the making could soon reach millions who have no specific drug to treat a condition called hypertrophic cardiopmyopathy (HCM), which can linger silently and then suddenly emerge, causing tiredness, shortness of breath, or even sudden death.

Results from a phase 3 study, EXPLORER-HCM, showed twice as many patients with obstructive HCM who took the experimental therapy, mavacamten, achieved a series of benchmarks involving symptoms and cardiac function as those taking placebo. The findings were presented today during the European Society of Cardiology 2020 Congress, being presented virtually due to the coronavirus disease 2019 pandemic. Findings were simultaneously published in The Lancet.

HCM is a chronic, progressive disease believed to have an underlying genetic cause that causes the heart muscle to contract more than normal and thicken, creating debilitating and dangerous symptoms. Medications developed for other conditions may address symptoms, but they do not treat HCM and bring serious side effects. In many cases, the only relief comes from surgery to the septum, which carries significant risk. HCM is associated with increased risk of heart failure, stroke, and atrial fibrillation, in addition to sudden cardiac arrest. The condition affects 1 in 500 people, but many are unaware.

In hypertrophic cardiomyopathy, said EXPLORER-HCM principal investigator Iacopo Olivotto, MD, “this hyper contractility which may seem like a good thing is actually too much of a good thing.”

Mavacamten is a first-in-class cardiac myosin inhibitor, which targets a protein causing the contraction that leads to the muscle thickening. By addressing the pathophysiology of HCM, the therapy restores the heart’s normal function. In earlier trials, including PIONEER-HCM, patients who took mavacamten experienced improvements in symptoms, physical function, exercise capacity, and quality of life. Clinicians were also able measure left ventricle outflow tract (LVOT) obstruction, a hallmark of obstructive HCM.

Excitement for mavacamten has been building for some time. A poster session on early results drew a standing-room only crowd during the final hour of the American Heart Association Scientific Sessions in Philadelphia in November 2019. Last month, MyoKardia, which is developing mavacamten, received FDA breakthrough therapy status for the therapy, based on topline results for EXPLORER-HCM. It is anticipated the company will file a new drug application in early 2021.

“The results of this pivotal trial support a role for disease-specific therapy for obstructive hypertrophic cardiomyopathy, which treats the cause instead of just managing symptoms,” said Olivotto, of Careggi University Hospital in Florence, Italy.“It is really hard to convey what this actually means for the scientific and clinical community that has spent over 60 years trying to understand and cure hypertrophic cardiomyopathy.”

Study details. For EXPLORER-HCM,investigators assessed 429 adults for eligibility and enrolled 251 who met criteria for obstructive HCM; patients were randomly assigned to mavacamten (123) or placebo (128). Extensive steps were taking to ensure study participants, clinicians, and pharmacists were blinded. Patients were started on a 5 mg dose and evaluated every 2-4 weeks for 30 weeks, receiving dose adjustments to achieve target mavacamten plasma and LVOT gradient levels. The study’s primary endpoint was:

  • a 1.5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least 1 NY Heart Association (NYHA) class reduction, OR
  • a 3.0 mL/kg per min or greater pVO2 increase without NYHA class worsening.

Secondary endpoints measured: post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score, and Hypertrophic Cardiomyopathy Symptom Shortness of Breath subscore.

Results. Among the 123 patients taking mavacamten, 45 (37%) met the primary endpoint, compared with 22 (17%) on placebo, for a difference of 19.4%, 95% CI (8.7%-30.1%, P = .0005). Other results included:

  • Patients on mavacamten had greater reductions in post-exercise LVOT gradient than those on placebo (-36 mmHg).
  • Patients taking mavacamten had a greater increase in pVO2 (+1.4 mL/kg per min)
  • 65% of the patients in the mavacamten group improved by at least 1 NYHA class or more, which was twice the placebo group.
  • In a finding that Olivotto said was important for a first-in-class therapy, safety and tolerability were similar across groups, and treatment related adverse events were mild.
  • 97% of patients finished the study.

During his presentation today, Olivotto explained that 27.4% of patients in the mavacamten group achieved the study's definition of a "complete response," defined as a complete deletion of all gradients. "This is comparable to a best case scenario," he said.

When asked if mavacamenten was a bridge to surgery, Olivotto said the hope is that the drug offers the exact opposite: a way for patients to avoid surgery and instead treat or even reverse their condition with therapy. Too few places in the world can offer the surgery needed to properly treat HCM. "Having a drug makes it more democratic," he explained.

Benefits were seen among patients with obesity, and those age 50 or older, especially those 65 years of age. Benefits were not as consistent among patients taking beta blockers, and this may have affected results. Younger patients (those under age 50) and non-white patients were underrepresented in the study.

According to the authors in The Lancet, an ongoing, long-term extension of the study will continue to collect evidence on clinical benefits of mavacamten over 5 years, as well as safety data.


Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. Published online August 29, 2020. https://doi.org/10.1016/ S0140-6736(20)31792-X

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