High Doses of Experimental Heart Failure Drug Fail, Prompting a Lower-Dose Trial

Heart failure can limit exercise capacity and independence as adults age. Researchers are testing tovinontrine, an experimental drug that blocks the enzyme PDE9, to influence signaling involved in heart function. Two trials reported at the Heart Failure Society of America meeting found that the main dose did not meaningfully improve a blood marker of heart strain.

In CYCLE-1, 529 patients with reduced pumping function received different doses or placebo alongside standard treatment. Their average age was 69. At 12 weeks, 50 milligrams twice daily produced a nonsignificant 4.4% reduction in NT-proBNP relative to placebo. The 25 milligram dose produced a 10.8% reduction, with borderline statistical evidence. In CYCLE-2, involving preserved pumping function, the highest dose also failed; placebo showed a larger marker decrease.

Lower doses raised interest because changes from baseline appeared more favorable than changes at higher doses. However, those comparisons alone cannot establish superiority to placebo. Additional exploratory analyses linked smaller increases in the signaling molecule cGMP with more consistent reductions in heart strain. Researchers suspect that excessive signaling could activate compensatory processes, but this explanation remains unproven.

A planned phase IIb trial, CYCLE-3, will test lower doses in patients with reduced pumping function starting in 2027. Testing in preserved pumping function could follow if results are encouraging. For patients now, these findings do not justify changing established heart failure medication. Tovinontrine remains investigational, and reducing a laboratory marker would not itself prove better survival or physical function.

These results come from conference coverage rather than a complete trial publication. The supplied article ends mid-sentence and omits detailed safety findings and much of the second trial's design. CYCLE-1 enrolled mostly men and white patients, limiting generalizability. Confirming whether lower doses help requires prospectively designed trials measuring symptoms, hospitalizations, exercise capacity, and other outcomes that matter directly to patients.