Novel Cardiac Myosin Inhibitor Improves Exercise Capacity in HCM

The novel cardiac myosin inhibitor aficamten improved peak oxygen uptake in symptomatic obstructive hypertrophic cardiomyopathy (HCM), the pivotal SEQUOIA-HCM trial showed.

At 24 weeks, the mean change in the peak oxygen uptake was 1.8 mL/kg/min with the drug compared with no change in the placebo group (P<0.001), reported Martin S. Maron, MD, of Lahey Hospital and Medical Center in Burlington, Massachusetts, and colleagues in the New England Journal of Medicine.

The findings were also presented at the European Society of Cardiology Heart Failure meeting in Lisbon, Portugal.

All 10 secondary endpoints were significantly improved with aficamten, including quality of life, symptom class, left ventricular outflow tract (LVOT) gradient, continued need for septal reduction therapy, and cardiopulmonary exercise testing parameters.

The findings were consistent with trial results for the first cardiac myosin inhibitor, mavacamten (Camzyos), approved for the treatment of symptomatic obstructive HCM in 2022, noted Steve R. Ommen, MD, of the Mayo Clinic in Rochester, Minnesota, in an accompanying editorial.

This new class of negative inotropes home in on the cardiac hypercontractility seen in HCM from an excessive number of actin-myosin cross-bridges within the cardiac sarcomere that worsens dynamic obstruction of the LVOT.

However, “owing to the effects of cardiac myosin inhibitors on metabolic pathways (e.g., those of CYP2C19 and CYP3A4) and pharmacodynamics, along with the finding that approximately 10% of the patients in the trials of mavacamten had a decrease in the left ventricular ejection fraction, a complex strategy involving dose escalation, risk evaluation, and mitigation is mandated,” Ommen noted. “This patient safety strategy poses logistic burdens for patients and providers alike.”

There are possible reasons to think that aficamten might be a little better in that regard, given its faster pharmacodynamic effects (a plasma half-life that allows dose adjustments as often as every 2 weeks), lack of drug-drug interactions, and a less than 5% rate of severe left ventricular systolic suppression, he suggested. “Whether these findings will translate into an approval and safety surveillance mandate for aficamten that is different from that for mavacamten remains to be seen.”

“Longer-term trials will be needed to determine whether these drugs have disease- specific effects that are separate from reducing outflow-tract obstruction and whether they can bring about the same long-term benefits as those observed with invasive therapies involving septal reduction,” Ommen added. “Surgical myectomy and septal ablation, when performed by experienced surgeons, have success rates of 90 to 95% and 75 to 80%, respectively (as compared with the 60 to 70% associated with cardiac myosin inhibitors).”

As clinical experience with the cardiac myosin inhibitors builds, he wrote, “it seems prudent to continue to use widely available, easy-to-use, cost-effective agents, including beta-blockers and calcium-channel blockers, as first-line therapy in most patients. If patients remain symptomatic or have side effects from these drugs, then all options should be discussed, including treatment with disopyramide or cardiac myosin inhibitors and invasive septal reduction therapy.”

SEQUOIA-HCM was a phase III trial of 282 patients (mean age 59.1 years, 59.2% men) with symptomatic obstructive HCM who were randomized in a double-blind manner to aficamten (titrated up from 5 mg to a maximum 20 mg based on echocardiography results) or placebo, both atop standard drug therapy. Mean baseline resting LVOT gradient was 55.1 mm Hg, and mean baseline left ventricular ejection fraction (LVEF) was 74.8%.

The primary endpoint impact of aficamten on exercise capacity was similar across prespecified subgroups, including New York Heart Association (NYHA) class III or IV heart failure and those who were functionally limited with a peak oxygen uptake of 18 mL/kg/min or less at baseline.

“In contrast to the results that were observed with mavacamten in the EXPLORER-HCM trial, which suggested an attenuation of benefit among patients who were receiving beta-blockers, the treatment effects of aficamten appeared to be similar with or without background beta-blocker use and independent of the presence of a pathogenic sarcomere gene variant,” the researchers noted.

Among the secondary endpoints, aficamten led to significant benefits over placebo at week 24 in the following:

• Quality of life improvement on the Kansas City Cardiomyopathy Questionnaire (least squares mean difference 7 points, 95% CI 5-10)
• Gain of at least one NYHA class (58.5% vs 24.3%)
• LVOT gradient after the Valsalva maneuver (least squares mean difference -50 mm Hg, 95% CI -57 to -44)
• LVOT of less than 30 mm Hg after the Valsalva maneuver in 49.3% vs 3.6%
• Time eligible for septal reduction therapy under professional guidelines (least squares mean difference 78 fewer days, 95% CI -100 to -56)

Serious adverse events were numerically less common with aficamten (5.6% vs 9.3% with placebo). Adverse events more common with the drug were palpitations (7.0% vs 2.9%) and hypertension (7.7% vs 2.1%).

Aficamten also “modestly” lowered LVEF compared with placebo at week 24 (least squares mean difference -4.8 percentage points, 95% CI -6.3 to -3.2), but the difference disappeared after the 4-week washout period. Core lab-evaluated transient reduction of less than 50% in LVEF occurred in five aficamten-treated patients (3.5%) compared with one (0.7%) in the placebo group. Protocol-driven dose reduction occurred in seven (4.9%) aficamten patients. However, the researchers noted, “none of the patients in the aficamten group with a left ventricular ejection fraction of less than 50% had an interruption of treatment or an exacerbation of heart failure.”

They acknowledged the relatively short treatment period in the trial but noted that the improvement in exercise capacity with aficamten exceeded the minimal clinically important difference in peak oxygen uptake (1 ml/kg/min), “and previously reported improvements that were not as pronounced as those observed in this trial have been associated with enhanced survival among patients with heart failure without HCM.”

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