EXPLORER-HCM: Mavacamten Improves Exercise Capacity and Functional Class

In patients with hypertrophic cardiomyopathy (HCM), the first-in-class cardiac myosin inhibitor mavacamten (MyoKardia), on top of medical therapy, significantly improved hemodynamics, functional capacity, and symptoms when compared with patients who received placebo, according to results of the EXPLORER-HCM study.

Presented today as part of the Hot Line session during the virtual European Society of Cardiology Congress 2020, and published simultaneously in the Lancet, the study showed that 37% of patients who received mavacamten met the study’s primary endpoint, which was defined as either a ≥ 1.5 ml/kg per minute increase in peak VO2 and ≥ 1 NYHA class improvement (or a ≥ 3.0 ml/kg per minute increase in peak VO2 and no worsening NYHA class), compared with 17% of patients who received placebo (P = 0.0005).

“From this study, a new molecule has emerged with a promise of targeted medical therapy for obstructive hypertrophic cardiomyopathy for the first time since the original description of the disease almost 60 years ago,” said lead investigator Iacopo Olivotto, MD (Azienda Ospedaliera-Universitaria Careggi, Florence, Italy), during the hotline presentation.

The big question here is the long-term safety of the drug. Can we give it for decades in a safe manner? Iacopo Olivotto

The current treatment of HCM—a condition characterized by hypercontractility, diastolic abnormalities, and dynamic LVOT obstruction—focuses on symptom improvement using beta blockers, non-dihydropyridine calcium channel blockers, and disopyramide, “but these are old drugs that are not designed to address the molecular defects of HCM and do not modify the natural history of the disease,” said Olivotto. “For many patients, these are insufficient to adequately resolve the symptoms or they may have side effects.”

While more invasive procedures such as surgical septal myectomy and alcohol septal ablation can help, the expertise required to perform these procedures isn’t universal, and developing a pharmacological agent for HCM has been an unmet medical need for some time, he added. Mavacamten has been successful in smaller studies, including the phase 2 PIONEER-HCM study. As a selective allosteric inhibitor of cardiac myosin ATPase, the small molecule reduces actin-myosin crossbridge formation, which in turn reduces contractility and restores myocardial energetics.

Based on some the earliest studies, the US Food and Drug Administration designated mavacamten a breakthrough therapy in July 2020 for the treatment of symptomatic, obstructive HCM. 

Improved LVOT Gradients, Patient Symptoms

EXPLORER-HCM included 251 patients (mean age 58.5 years) with obstructive HCM randomly assigned to mavacamten or placebo for 30 weeks. Patients were started on a 5-mg daily dose of mavacamten, which was uptitrated at weeks 8 and 14. Most patients had NYHA class 2 symptoms at baseline and nearly all patients were on background medical therapy with beta blockers or a calcium channel antagonist.

In addition to meeting its primary endpoint, the study also demonstrated that more patients treated with mavacamten met the higher benchmark of peak exercise capacity, Olivotto reported, with 20% of patients achieving a ≥ 3.0 ml/kg per minute increase in peak VO2 and ≥ 1 NYHA class improvement, compared with just 8% of patients treated with placebo. As for secondary endpoints, mavacamten improved post-exercise LVOT gradient, peak VO2, and NYHA class from baseline to week 30. These improvements were statistically significant compared with changes in the placebo group.

“There was also a marked improvement in patient-reported outcomes,” said Olivotto, referring to changes in two validated HCM symptom scores. Additionally, patients treated with mavacamten had a “dramatic and sustained reduction” in resting and Valsalva LVOT gradients. “At any given time during treatment, these gradients fell below the 50-mmHg threshold for invasive septal reduction therapies,” said Olivotto. “Importantly, most of these patients fell well below the 30-mmHg threshold, which actually defines the obstruction. They had a complete relief of obstruction at rest and during Valsalva.”

Finally, Olivotto said LVOT gradients were reduced to less than 30 mmHg and NYHA class 1 was achieved in 27% of mavacamten-treated patients compared with 1% of placebo-treated patients. “This is comparable to a best-case scenario following successful invasive septal reduction therapy, such as surgical myectomy, for example,” he said.  

In terms of side effects, patients treated with the investigational agent generally tolerated the drug well, with study investigators reporting a safety profile comparable to placebo.

Franco Cecchi, MD (University of Florence, Italy), the discussant following the Hot Line session, said the benefit of mavacamten on peak VO2 and NYHA functional class—the study’s primary endpoint—was a little less impressive than the observed changes in LVOT gradients. The treatment effect was also more pronounced in patients not taking beta blockers at baseline, as well as in older patients, he said. As for side effects, a severe reduction in LVEF (to less than 50%) was seen in 7% of patients treated with mavacamten and in 2% of placebo-treated patients.

“This means that careful dose-titration with left ventricular ejection fraction evaluation is mandatory,” said Cecchi.

Nonetheless, based on EXPLORER-HCM, he believes mavacamten is a “promising drug” for symptom relief and functional class improvement associated with LVOT-gradient reductions in selected patients with obstructive HCM. “It might be the first-choice drug in the elderly,” he added, provided physicians carefully titrate the dose.

Long-Term Safety

Speaking after his presentation, Olivotto said EXPLORER-HCM has been extended and patients are being tracked for long-term safety. As part of that extension study, researchers are considering allowing physicians to withdraw beta blocker therapy in patients doing well on mavacamten. As to whether mavacamten will be a long-term treatment or a bridge to surgical myectomy, Olivotto believes it is more likely to be used in lieu of invasive procedures.  He noted that patients taking disopyramide and those with NYHA class 4 symptoms were excluded from the trial, but these patients will be studied in the upcoming VALOR-HCM. The aim of that trial is to determine if mavacamten can postpone or reduce the need for surgery.

“Of course, the big question here is the long-term safety of the drug,” said Olivotto. “Can we give it for decades in a safe manner?”

In an editorial accompanying the study, Michael Papadakis, MD, Joyee Basu, MD, and Sanjay Sharma, MD (all St. George’s University Hospitals NHS Foundation Trust, London, England), say that if mavacamten turns out to be safe and effective long term, it would “represent a much-anticipated development in the treatment of hypertrophic cardiomyopathy.” However, it needs to be tested in a more diverse patient population—93% of the patients who received the drug in EXPLORER-HCM were white—and in younger patients. “Were the drug to realize its potential as a disease-modifying therapy in younger individuals, it would represent a great milestone in the area of inherited cardiomyopathies,” they write.