Two phase II trials of the PDE9 inhibitor tovinontrine failed to show a significant improvement in the heart failure biomarker NT-proBNP at week 12, according to results presented at the Heart Failure Society of America annual meeting. In the CYCLE-1 trial of patients with heart failure with reduced ejection fraction (HFrEF), the high dose (50 mg twice daily) produced a placebo-adjusted 4.4% reduction in NT-proBNP, which was not significant. In CYCLE-2, which enrolled patients with preserved ejection fraction (HFpEF), the same dose actually appeared worse than placebo, with a placebo-adjusted mean change of +9.4%.
However, the data suggested an inverse dose response. In CYCLE-1, the lowest tested dose (2.5 mg twice daily) was associated with a median NT-proBNP reduction of 16%, while higher doses produced smaller reductions. The investigators concluded the trials may have tested the wrong dose. A post hoc analysis found that patients with only modest increases in plasma cGMP had more consistent NT-proBNP reductions, supporting the idea that there is a ceiling beyond which further cGMP elevation is counterproductive.
Based on these findings, a new phase IIb trial, CYCLE-3, is planned to start in 2027, testing a lower tovinontrine dose in HFrEF. If successful, the program would then move to HFpEF. Safety data from the two trials showed mostly mild treatment-emergent adverse events, with transient and reversible renal changes. No PDE9 inhibitor is currently available in clinical practice.