Results from the phase 2 MAVERICK-HCM clinical trial, presented at the American College of Cardiology/World Congress of Cardiology’s virtual scientific sessions (ACC.20/WCC Virtual) suggest that the use of mavacamten (MyoKardia) for the treatment of non-obstructive hypertrophic cardiomyopathy (nHCM) may be beneficial with longer-term treatment.
Findings from the multicentre, double-blind, placebo-controlled, dose ranging trial were presented by Carolyn Y Ho (Brigham and Women’s Hospital, Boston, USA). During her presentation, Ho said that, to date, no pharmalogic therapy has demonstrated clinical benefit for patients with symptomatic nHCM. “In constrast to obstructive HCM, where surgical myectomy or alcohol septal ablation can reliably improve symptoms, for patients with non-obstructive HCM, who develop symptoms refractory to medical therapy, cardiac transplant may be the only option,” Ho said. “Thus, there is a great need for effective medical therapy for these patients.”
Ho noted that by altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with nHCM. Ho described mavacamten as a novel drug developed to treat obstructive HCM, adding that it is a selective allosteric inhibitor of cardiac myosin, which reduces the number of myosin-actin cross-bridges, thus decreasing excessive contractility characteristic of HCM. She added that there is also evidence that the drug may help improve myocardial relaxation and energetics, two other hallmarks of HCM pathophysiology, that may be particularly relevant to patients without obstruction. “Therefore it [mavacampten] may be beneficial for patients with non-obstructive HCM,” she posited.
The MAVERICK-HCM trial aimed to assess the safety and tolerability of the drug, and to explore efficacy endpoints, including changes in N-terminal pro b-type natriuretic peptide (NT-proBNP) and cardiac troponin (cTn) levels. These are seen as biomarkers of elevated left ventricular filling pressure and myocardial injury, and were assessed due to their association with adverse outcomes in nHCM.
The study involved 59 adults with symptomatic nHCM (New York Heart Association Class II/III), left ventricular ejection fraction (LVEF) ≥55%, and NT-proBNP ≥300 pg/mL. Participants were randomised 1:1:1 to receive a PK-adjusted dose for a target mavacamten concentration of 200ng/mL (n=19), 500ng/mL (n=21), or placebo (PBO) (n=19) for 16-week treatment and an eight-week washout. Initial dose was 5mg daily with a dose titration at week six. The study cohort had a mean age of 54 years, and 58% were female.
According to Ho, the results showed that there was a 53% decrease in the NT-proBNP geometric mean (pooled mava group; baseline: 713 pg/mL) versus a 1% decrease in the PBO group (baseline: 967 pg/mL, p=0.0005). There was a 34% decrease in cardiac troponin-I geometric mean in the pooled mavacamten group versus a 4% increase in PBO (p=0.009). In the mavacamten-treated patients, change in NT-proBNP at week four correlated with change in cTnI at week 16 (rho=0.45, p=0.006).
On the decreases in NT-proBNP levels, Ho said: “These promising results are the first demonstration of medical therapy improving NT-proBNP levels in patients with non-obstructive HCM, and suggests physiologic benefit from mavacamten, potentially improving cardiac wall stress.”
And, on the reduction in cTnI, she commented: “There was a statistically significant decrease in troponin levels for participants receiving mavacampten, but not in those receiving placebo. These results were also notable because troponin levels have additionally been correlated with the prognosis of myocardial fibrosis and hypertrophic cardiomyopathy.”
Ninety per cent of participants on mavacamten versus 68% on PBO experienced an adverse event (AE), of which the majority were mild or moderate, self-limiting, and assessed by the investigator to be unrelated to treatment, Ho said. Serious AEs occurred in 10% (mavacamten) and 21% (PBO). Five participants on mavacamten had reversible reductions in LVEF to <45% at week 11–12 and met prespecified criteria for treatment discontinuation.
Summarising the key findings from the study, Ho said: “In this phase 2, dose ranging study in patients with symptomatic, non-obstructive HCM, mavacampten was generally tolerated by most participants. Reduction in LVEF can occur, and administration will be guided by clinical parameters, including LVEF, and suitable biomarkers. This was the first study to show an improvement in serum biomarkers of haemodynamic stress and myocardial injury in patients with non-obstructive HCM. There is also a suggestion that patients with more severe disease may benefit the most from mavacampten.”
She concluded: “These results are supporting further study to better characterise the use of mavacampten in non-obstructive HCM, and potentially in heart failure with preserved ejection fraction in general.”