Mavacamten triumphs in pivotal trial for obstructive hypertrophic cardiomyopathy
Mavacamten, a first-in-class myosin inhibitor, may be the first targeted therapy to address the underlying cause of obstructive hypertrophic cardiomyopathy (OHCM), the EXPLORER-HCM trial has shown.
Symptoms of HCM (eg, shortness of breath, decreased exercise capabilities) may impair quality of life and increase the likelihood of serious comorbidities (eg, atrial fibrillation, heart failure, stroke, and sudden cardiac death).
“By targeting the underlying pathophysiology of HCM … excess contractility and myocardial energetics [may be improved. Our study] promises targeted medical therapy [for] OHCM for the first time … which treats the cause instead of just managing symptoms,” said principal investigator Professor Iacopo Olivotto from the Careggi University Hospital in Florence, Italy, who presented the findings at ESC 2020.
Participants (n=251; mean age 58 years, 41 percent female) were randomized 1:1 to receive mavacamten 5 mg QD (titrating at weeks 8 and 14) or placebo for 30 weeks. Background therapy was allowed. [ESC 2020, Hot Line session 2]
At treatment end, more mavacamten vs placebo recipients achieved the primary endpoint* (37 percent vs 17 percent) and had both ≥3-mL/kg/min increase in pVO2 and ≥1 NYHA** class improvement (20 percent vs 8 percent; p=0.0005 for both).
Compared with placebo, mavacamten use also led to greater reduction in post-exercise LVOT*** gradient (–47 vs –10 mm Hg; p<0.0001), greater increase in peak oxygen consumption (pVO2; 1.40 vs –0.05 mL/kg/min; p=0.0006), more patients achieving ≥1 NYHA class improvement (65 percent vs 31 percent; p<0.0001), and marked improvements in patient-reported outcomes (13.6 vs 4.2; p<0.0001 [KCCQ-CSS#] and –2.8 vs –0.9; p<0.0001 [HCMSQ-SoB## subscore]).
Mavacamten also led to dramatic, sustained reductions in both resting and Valsalva LVOT gradients. “At any given time during treatment, these gradients fell below the threshold for invasive septal reduction therapies. Importantly, most patients (56 percent) went well below the 30-mm Hg threshold … [Therefore,] they had complete relief of obstruction at rest and during Valsalva,” explained Olivotto.
Marked, sustained reductions were also seen in NT-proBNP (–80 percent) and troponin (–41 percent) with mavacamten, indicating improvement in left ventricular (LV) wall stress and myocardial damage.
Mavacamten was well-tolerated, with a very high completion rate (97 percent). Adverse event (AE) rates were comparable between mavacamten and placebo (88 percent vs 79 percent [treatment-emergent AEs], 8 percent vs 9 percent [serious AEs], and 3 percent in both arms [serious cardiac AEs]).
Three mavacamten recipients temporarily ceased treatment due to a drop (<50 percent) in LV ejection fraction (LVEF) during treatment. Four other patients on mavacamten had drops in LVEF at treatment end; however, systolic function reverted to baseline in three patients after the 8-week washout period, while the fourth patient partially recovered to an LVEF of 50 percent. All patients resumed treatment and successfully completed the trial.
Filling the gap
While there are drugs### currently used for OHCM, these focus on symptomatic relief, are mostly ineffective, and/or have side effects. “These are old drugs which are not designed to address the molecular defects of OHCM [and] do not modify the natural history of the disease,” said Olivotto.
Invasive treatment options (eg, septal myectomy, alcohol septal ablation), albeit more effective, are limited by their inherent operative risks. The expertise required to perform these surgeries is also not universally available, he added.
“Therefore, OHCM is a disease orphan of targeted medical options … Developing an effective pharmacological therapy for OHCM represents a major unmet medical need in cardiovascular medicine,” Olivotto underscored. “This landmark study is therefore on track to fill the gap of a disease-specific treatment for OHCM patients … [B]ased on these results, the promise of a dedicated pharmacological treatment for [OHCM] patients may now be fulfilled.”
The FDA has granted a breakthrough therapy designation for mavacamten owing to its innovative approach in targeting OHCM, as well as the gravity of the disease, noted Olivotto. “We hope this will help improve the lives of many patients with OHCM.”
Less striking, but promising
However, the composite primary endpoint findings were “less striking”, according to discussant Professor Franco Cecchi from the University of Florence in Italy. “VO2 max was calculated even in patients who took beta-blockers. This probably affected the results,” he said. Also, the drops in LVEF – despite reverting to normal following drug discontinuation – highlight the importance of LVEF evaluation and dose titration, he added.
“[Nonetheless,] mavacamten is a promising drug for symptom relief and functional class improvement associated with LVOT gradient reduction in selected patients with OHCM … [Mavacamten] might be the first choice of drug in the elderly, with careful dose titration,” he said.
Cecchi called for longer follow-up to reinforce the findings, and further exploration to identify optimal individual dosing and patient selection criteria. Future trials should also probe deeper into the potential of mavacamten for young patients with high proBNP and troponin values, given the favourable results seen in a phase II trial evaluating mavacamten for nonobstructive HCM. [J Am Coll Cardiol 2020;75:2649-2660]