In a big step towards better hypertrophic cardiomyopathy treatments, two separate studies presented at ESC suggest cardiac myosin inhibitors’ efficacy depends critically on whether patients have the obstructive or nonobstructive form of the disease.
- Cardiac myosin inhibitors like aficamten (Cytokinetics) and mavacamten (Bristol-Myers Squibb) treat HCM by reducing hypercontractility.
- Current guidelines recommend adding these medications after beta-blockers or calcium channel blockers fail, but beta-blocker efficacy in HCM has been limited despite decades of use.
- There are two forms of HCM: obstructive which leads to thickened heart muscle that blocks blood flow out of the heart, and nonobstructive which leads to muscle thickening without impairing blood flow.
Two similar but different trials presented contrasting outcomes at ESC 2025, with MAPLE-HCM testing aficamten versus metoprolol in obstructive HCM patients, and ODYSSEY-HCM testing mavacamten versus placebo in nonobstructive HCM.
- On one hand, MAPLE-HCM found Cytokinetics’ aficamten led to a 2.3 mL/kg/min improvement in peak oxygen uptake, plus better outcomes in NYHA class, quality of life scores, and LVOT gradients compared to metoprolol.
- On the other hand, ODYSSEY-HCM found that BMS’ mavacamten led to non-significant improvements in peak oxygen uptake (0.47 mL/kg/min difference) and QoL compared to placebo.
Safety profiles across the two studies were quite different, with aficamten showing comparable adverse events in MAPLE-HCM (8% vs 7%), while mavacamten saw more treatment interruptions (14.6% vs 5.2%) and LVEF reductions in 21.5% of treated patients in ODYSSEY-HCM.
Even with mavacamten’s nonobstructive setback, cardiac myosin inhibitors might finally help shift HCM treatment paradigms, with MAPLE-HCM potentially supporting the drug’s use as a first-line monotherapy in obstructive disease.
With the clear obstructive versus nonobstructive divide, the future of cardiac myosin inhibitors may depend on precision medicine approaches and drug-specific advantages.
- For example, aficamten offers potential advantages over mavacamten including shorter half-life for easier monitoring, though its FDA approval is still pending.
- With how complex nonobstructive HCM is, treating it with cardiac myosin inhibitors may require identifying specific physiological subgroups to be more effective.
The Takeaway
These pivotal trials suggest cardiac myosin inhibitors could be the future first-line therapy for obstructive HCM while highlighting the complexity of the disease’s nonobstructive form. That said, the data seems to already support replacing decades-old beta-blocker therapy as a first line treatment.
