A second-generation cardiac myosin inhibitor showed promise for the treatment of obstructive hypertrophic cardiomyopathy (HCM) in the phase II REDWOOD-HCM trial.
In the dose-finding study, 10 weeks of treatment with aficamten brought resting left ventricular outflow tract (LVOT) gradients down significantly compared with placebo before a 2-week washout period returned gradients to baseline, reported Martin Maron, MD, of Tufts Medical Center in Boston, and Morristown Medical Center in New Jersey.
Similarly, aficamten reduced LVOT gradients following provocation with the Valsalva maneuver, with a subsequent washout-period reversing this effect, Maron reported at a late-breaking trial session at the Heart Failure Society of America meeting held both virtually and in Denver.
REDWOOD-HCM had five doses of aficamten tested in two cohorts: one with lower doses starting from 5 mg (n=14) and the other with higher doses starting from 10 mg (n=14). A combined placebo arm served as control (n=13).
Reductions in LVOT gradients, resting or Valsalva, were observed with both low and high doses of aficamten. In the end, however, it was the higher-dose cohort of patients that was more likely to meet criteria for a complete LVOT gradient response at 10 weeks (resting LVOT gradient <30 mmHg and Valsalva LVOT gradient <50 mmHg).
Aficamten's improvements in hemodynamics were mirrored by reductions in NT-proBNP, Maron reported.
As for safety, there were no serious adverse event attributed to the drug. One person on aficamten had exacerbation of preexisting back pain; another had left ventricular ejection fraction (LVEF) dip below 50% on aficamten 20 mg and got a dose reduction that allowed LVEF to bounce back.
Overall, the REDWOOD-HCM results support a phase III study that is planned to start later this year, Maron said.
A first-generation cardiac myosin inhibitor, mavacamten had already flexed its hemodynamic and clinical benefits for obstructive HCM in the phase III EXPLORER-HCM trial reported in 2020. Setting aficamten apart from mavacamten, Maron said, is aficamten's 3.4-day half life and wide therapeutic window allowing for individual dose adjustment.
He noted that many patients with HCM with outflow obstruction remain symptomatic despite available therapies. By targeting the mechanism of hypercontractility in HCM, aficamten is supposed to decrease LVOT gradients and improve heart failure symptoms.
Just under two-thirds of REDWOOD-HCM participants taking higher doses of aficamten were able to improve their New York Heart Association (NYHA) classification compared with 31% of the placebo group and 43% of the lower-dose cohort.
The small enrolled a cohort that was age 57 on average, with roughly half of participants being women. All were individuals with left ventricular wall thickness 15 mm or more and LVEFs at least 60% on stable background medical therapy (e.g., beta-blockers and calcium channel blockers). Most people were classified as NYHA class II at baseline.
Maron acknowledged that his group was unable to draw conclusions about aficamten's effects on arrhythmias.
That will require a larger study, he said, adding that investigators are incorporating a flexible dose-changing strategy and MRI substudy in the upcoming phase III study of aficamten.
Other therapies under investigation for obstructive HCM include alcohol ablation and percutaneous intramyocardial septal radiofrequency ablation.
Disclosures
REDWOOD-HCM was supported by Cytokinetics.
Maron disclosed no relationships with industry.
Primary Source
Heart Failure Society of America
Maron M "REDWOOD-HCM: randomized evaluation of dosing with aficamten in obstructive outflow disease - HCM" HFSA 2021.