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Novel Tx Turns in Favorable Performance in Obstructive HCM

— Mavacamten tackles underlying pathophysiology of hypertrophic cardiomyopathy

Ƶ MedicalToday

People with symptomatic obstructive hypertrophic cardiomyopathy (HCM) gained functional capacity, and had left ventricular outflow tract (LVOT) gradients reduced, when treated with a cardiac myosin inhibitor, the EXPLORER-HCM trial showed.

Mavacamten treatment led 37% of patients to enjoy a 1.5 mL/kg/min or greater increase in peak oxygen consumption (pVO2) and at least one New York Heart Association (NYHA) class reduction (or a 3.0 mL/kg/min or greater pVO2 increase without NYHA class worsening), compared with 17% of peers assigned to placebo instead (P=0.0005).

The novel drug was associated with other benefits over 30 weeks of treatment, according to Iacopo Olivotto, MD, of Careggi University Hospital in Florence, Italy:

  • Greater reductions in post-exercise LVOT gradient: -47 vs -10 mmHg with placebo (P<0.0001)
  • Greater increase in pVO2: +1.4 vs -0.1 mL/kg/min (P=0.0006)
  • More patients improving by at least one NYHA class: 65% vs 31% (P<0.0001)
  • Significantly better symptoms according to the Kansas City Cardiomyopathy Questionnaire-Clinical Symptom Score and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath instruments
  • Better odds of a complete response (defined as NYHA class I and LVOT peak gradients less than 30 mmHg): 27% vs 1% (difference 26.6%, 95% CI 18.3-34.8)
  • Greater relief from LVOT obstruction (post-exercise gradient <30 mmHg): 57% vs 7% (difference 49.6%, 95% CI 39.3-59.9)
  • Gradients more likely reduced to <50 mm Hg: 74% vs 21% (difference 53.5%, 95% CI 42.0-65.0)

Olivotto reported the EXPLORER-HCM results during a late-breaking trial session at the European Society of Cardiology (ESC) virtual meeting. The findings were simultaneously published online in the .

"Mavacamten treatment was effective in reducing LVOT gradients and improving symptoms, exercise performance, and health status in a patient population representative of that encountered in real-world clinical practice," the investigators concluded.

By reducing contractility and improving myocardial energetics, mavacamten acts like a "finely tuned handbrake" to fix the cardiac muscle hypercontractility of HCM, Olivotto explained during an ESC press conference.

Safety and tolerability were similar between mavacamten and placebo in the trial.

"The safety of the drug revolves around dosing. Because it is so effective in lessening the force of myocardial contraction, excess drug causes undue -- but reversible -- depression of left ventricular ejection fraction," commented Michael Fifer, MD, of Massachusetts General Hospital and Harvard Medical School in Boston.

Although mavacamten doesn't appear to have off-target toxicity, "close monitoring of outflow tract gradient and ejection fraction will be essential to the safe administration of mavacamten," said Fifer, who was not involved with the study.

Symptom relief is the focus of current treatments for obstructive HCM, which include beta blockers, non-dihydropyridine calcium channel blockers, and disopyramide, the authors noted.

"However, these non-specific agents are often inadequate or poorly tolerated, do not address the underlying molecular mechanisms of hypertrophic cardiomyopathy, and do not modify its natural history," they explained.

Pharmacological treatments aside, invasive therapies do exist but carry inherent risks.

The ongoing VALOR-HCM study is expected to show whether mavacamten reduces a person's need for surgery or alcohol septal ablation. The drug may allow earlier and broader treatment of HCM patients who do not have an immediate indication for surgery, according to Olivotto (73% of EXPLORER-HCM participants were in NYHA class II).

The present phase III trial was conducted in 13 countries. Participants were 251 patients with HCM, an LVOT gradient ≥50 mm Hg, and NYHA class II-III symptoms.

Patients were randomized to mavacamten (titrated starting at 5 mg) or placebo for 30 weeks; 97% completed their assigned treatments.

Average age of the cohort was 58.5. The mavacamten group had fewer men, fewer patients with a history of atrial fibrillation, and higher baseline NT-proBNP concentrations.

Background beta blocker or calcium channel blocker therapy was noted in 92% of patients.

"Benefit from mavacamten extended across most prespecified subgroups. Not unexpectedly, patients receiving concomitant β blockers displayed less of an effect on the composite primary endpoint, which includes pVO2, compared with those not on β blockers," Olivotto and colleagues reported.

"We do not believe that the use of β blockers attenuates the primary mechanism by which mavacamten works, as is evident by the extent of gradient reduction and other improvements observed. Rather, the observed effect on the primary endpoint might be related to the well established heart rate limitations on CPET [cardiopulmonary exercise testing] performance," they argued.

Future investigation will probe the benefit of mavacamten on people on background beta blockers, they said.

An extension study is underway assessing the safety and efficacy of mavacamten in participants of the EXPLORER-HCM and MAVERICK-HCM studies.

EXPLORER-HCM should be interpreted with caution given that non-white and younger patients were underrepresented in the study, according to an by Michael Papadakis, MD, of University of London and St. George's University Hospitals NHS Foundation Trust, and colleagues.

"In addition, the study provides no information relating to the concomitant use of disopyramide, which was included in the exclusion criteria, but is commonly used as a second-line therapy and can also prolong QT interval," they added.

"Should mavacamten prove to be clinically effective and safe following long-term therapy in a larger and more diverse population, it would represent a much anticipated development in the treatment of HCM. Were the drug to realise its potential as a disease modifying therapy in younger individuals, it would represent a great milestone in the area of inherited cardiomyopathies," according to Papadakis' group.

Mavacamten was granted in July 2020.

If approved, the drug "will give physicians the ability to treat the underlying pathophysiology of HCM for the first time," said EXPLORER-HCM co-author Anjali Owens, MD, of the Hospital of the University of Pennsylvania in Philadelphia.

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    Nicole Lou is a reporter for Ƶ, where she covers cardiology news and other developments in medicine.

Disclosures

The study was funded by MyoKardia.

Olivotto disclosed support from, and/or relevant relationships with, MyoKardia, Sanofi-Genzyme, Shire, and Bayer.

Fifer disclosed being a site principal investigator in the VALOR-HCM study and a member of the steering committee for the study of a drug that is in the same class as mavacamten that is funded by Cytokinetics.

Papadakis disclosed support from Cardiac Risk in the Young.

Owens disclosed relevant relationships with MyoKardia and Cytokinetics.

Primary Source

The Lancet

Olivotto I, et al "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial" Lancet 2020; DOI: 10.1016/S0140-6736(20)31792-X.

Secondary Source

The Lancet

Papadakis M, et al "Mavacamten: treatment aspirations in hypertrophic cardiomyopathy" Lancet; DOI: 10.1016/S0140-6736(20)31793-1.