Mavacamten improves outcomes in obstructive hypertrophic cardiomyopathy: EXPLORER-HCM
Click Here to Manage Email Alerts
Treatment with mavacamten — a first-in-class cardiac myosin inhibitor — improved symptoms, quality of life and functional status compared with placebo in patients with symptomatic, obstructive hypertrophic cardiomyopathy.
“EXPLORER-HCM is a landmark study promising to deliver the first targeted treatment for patients with hypertrophic cardiomyopathy,” Iacopo Olivotto, MD, staff physician at Careggi University Hospital in Florence, Italy, said during a press conference at the European Society of Cardiology Congress. “It is really hard to convey what this actually means for a scientific and clinical community that has spent over 60 years trying to understand and cure hypertrophic cardiomyopathy.”
Mavacamten (MyoKardia) is a novel, oral, allosteric modulator of cardiac myosin. This therapy was specifically developed to target the underlying cause of hypertrophic cardiomyopathy, Olivotto said.
“The drug interacts directly with the heart machinery, working as a highly selective handbrake, which can be fine-tuned to normalized contraction,” he said.
In July, the FDA granted a breakthrough therapy designation to mavacamten for the treatment of patients with symptomatic, obstructive hypertrophic cardiomyopathy.
Efficacy, safety endpoints met
The phase 3, randomized, double-blind, placebo-controlled trial enrolled patients who had hypertrophic cardiomyopathy with a left ventricular outflow tract gradient of 50 mm Hg or greater and NYHA class II to III symptoms. The mean age was 58 years, the majority were white, three-quarters had NYHA class II symptoms at baseline and nearly all were receiving background beta-blocker or calcium channel blocker therapy at baseline.
Patients were randomly assigned to mavacamten at a starting dose of 5 mg (n = 123; 54% men) or placebo (n = 128; 65% men) for 30 weeks.
“Mavacamten treatment led to a highly statistically significant improvement in all the study endpoints as compared to placebo,” Olivotto said during the presentation.
The trial’s primary endpoint was a 1.5 mL/kg/min or greater increase in peak oxygen consumption (VO2) and at least one NYHA class reduction, or a 3 mL/kg/min or greater peak VO2 increase without worsening of NYHA class. The primary endpoint was met in 36.6% of patients assigned mavacamten vs. 17.2% assigned placebo (difference, 19.4%; 95% CI, 8.7-30.1; P = .0005).
Treatment with mavacamten significantly improved all secondary endpoints, compared with placebo, from baseline to 30 weeks, including:
- mean post-exercise LV outflow tract gradient (–47 mm Hg vs. –10 mm Hg; difference, –35.6; 95% CI, –43.2 to –28.1; P < .0001);
- mean peak VO2 (1.4 mL/kg/min vs. –0.05 for placebo; difference, 1.4; 95% CI, 0.6-2.1; P = .0006);
- improvement in at least one NYHA class (65% vs. 31%; difference, 34%; 95% CI, 22-45; P < .0001);
- mean change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (13.6 vs. 4.2; difference, 9.1; 95% CI, 5.5-12.7; P < .0001); and
- mean change in Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath sub score (–2.8 vs. –0.9; difference, –1.8; 95% CI, –2.4 to –1.2; P < .0001).
“Importantly, analysis of the secondary endpoints showed that patients on mavacamten exercise more, were less symptomatic, had greater relief of obstruction and felt better, as shown by the score results assessing patient-reported outcome,” Olivotto said.
The researchers also reported rapid and sustained decreases in cardiac biomarkers. At 30 weeks, the reduction in N-terminal pro-B type natriuretic peptide was 80% greater in the mavacamten group vs. placebo and the reduction in high-sensitivity cardiac troponin was 41% greater in the mavacamten group. Olivotto and colleagues noted that similar reductions in cardiac biomarkers occurred in the MAVERICK-HCM study of patients with nonobstructive disease.
Safety and tolerability of mavacamten was similar to that of placebo, according to the researchers. Treatment-emergent adverse events were generally mild; at least one treatment-emergent adverse event occurred in 88% of the mavacamten group vs. 79% of the placebo group. There were 11 serious adverse events in the mavacamten group vs. 20 with placebo. In the placebo group, one patient died of sudden death.
Challenge of obstructive hypertrophic cardiomyopathy
Management of patients with symptomatic, obstructive hypertrophic cardiomyopathy remains a challenge, as current medical management does not address the underlying cause of disease and available options may be inadequate or poorly tolerated, Olivotto said during the press conference.
“The positive results from EXPLORER-HCM represents a major achievement toward improving the lives of patients with obstructive hypertrophic cardiomyopathy and support a role for targeted medical treatment of hypertrophic cardiomyopathy,” he said.
Following presentation of the results, discussant Franco Cecchi, MD, associate professor of cardiology at the University of Florence, Italy, said, on the basis of these data, mavacamten might become “the first-choice drug in the elderly, with careful dose titration.
“I can say that from these results, mavacamten is a promising drug for symptom relief and functional class improvement associated with output tract gradient reduction in patients with obstructive hypertrophic cardiomyopathy,” he said.
Further, Cecchi said, “we can hypothesize that mavacamten may also be beneficial in younger patients with high NT-proBNP and troponin values; however, further clinical studies are clearly needed.”
A long-term extension of this trial is ongoing and will provide further evidence of the clinical benefit and safety of mavacamten over 5 years, according to the researchers.
Reference:
Perspective
Back to Top
Athena Poppas, MD, FACC
Patients with symptomatic, obstructive hypertrophic cardiomyopathy are particularly challenging to manage. The population is relatively small, but their symptoms can be difficult and variable, and none of the available medications work predictably well. What’s exciting about mavacamten is that it reduces the actin-myosin cross-bridge formation to target the underlying pathophysiology of hypertrophic cardiomyopathy. This therapy works in a completely different manner than the other medications; it works directly on the sarcomeres.
The EXPLORER-HCM study design was very important. Combining NYHA class with an objective measure of VO2 max was powerful, and it is striking that there was a 19% difference in the primary endpoint of this trial. The reduction in NT-proBNP was also impressive. One caveat is that four patients in the mavacamten group had LVEF reduction to less than 50% at 30 weeks. When the medication was discontinued, LVEF recovered. Careful monitoring and postmarketing surveillance will be crucial to ascertain if this observation is a true side effect.
It will be interesting to see how we can apply this to the nonobstructive hypertrophic cardiomyopathy subtype. Will we see the same effects if patients don’t have a significant level of obstructive either at rest or with exertion? Overall, I think these findings will and should change practice in patients with symptomatic, obstructive hypertrophic cardiomyopathy.
Collapse
Olivotto I. Hot Line: EXPLORER-HCM. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
Click Here to Manage Email Alerts