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News
A promising heart failure drug hits a snag. Two phase II trials of tovinontrine, a PDE9 inhibitor, failed to show meaningful improvement in a key heart failure biomarker — but researchers suspect they simply tested too high a dose. A new trial using lower doses is planned for 2027, keeping hopes alive for this novel drug class.
Two phase II trials of tovinontrine — a PDE9 inhibitor being developed for heart failure — came up short, but the story isn't over yet. Presented at the Heart Failure Society of America (HFSA) annual meeting, the CYCLE-1 (HFrEF) and CYCLE-2 (HFpEF) trials both failed to show a significant reduction in NT-proBNP, a key biomarker of heart failure severity, at 12 weeks using the high dose (50 mg BID). Researchers now believe they picked the wrong dose.
Here's the twist: the data actually showed an inverse dose-response relationship. Lower doses of tovinontrine performed better — the 2.5 mg BID dose produced a 16% median drop in NT-proBNP, while the highest dose barely moved the needle. This suggests there may be a ceiling effect on how much the heart's cGMP signaling pathway can be boosted before the benefits plateau or reverse.
A new phase IIb trial, CYCLE-3, is set to launch in 2027 to test lower tovinontrine doses in HFrEF, with HFpEF testing to follow if results are promising.
By the Numbers
Why it matters: No PDE9 inhibitor currently exists in clinical practice, and heart failure — especially HFpEF — remains an area of significant unmet need. If lower doses prove effective in CYCLE-3, tovinontrine could open a new therapeutic avenue for millions of heart failure patients.
