Tovinontrine Failed to Improve Heart Failure Biomarkers
Two clinical trials showed that high doses of the experimental heart failure drug failed to meet primary reduction expectations.
Updated on Oct. 11, 2026 in Heart Disease
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Tovinontrine failed to improve NT-proBNP levels in two phase II heart failure trials, with researchers pointing to a possible dosing error. Patients receiving higher doses did not see the expected reduction in biomarkers compared to those on lower doses.
Why it matters
The unexpected results suggest a potential therapeutic ceiling where elevated myocardial cGMP levels may trigger compensatory mechanisms that prevent further biomarker reduction. This finding challenges current dosing strategies for heart failure treatments.
The CYCLE-1 trial enrolled 529 participants with HFrEF, while the CYCLE-2 trial included 277 patients with HFpEF. In CYCLE-1, the 50 mg BID dose resulted in a 4.4% reduction in NT-proBNP, while the 25 mg BID dose saw a 10.8% reduction.
The players
CYCLE-1
This clinical trial enrolled 529 participants to evaluate the efficacy of tovinontrine in patients with heart failure with reduced ejection fraction.
CYCLE-2
This clinical trial evaluated the drug in 277 participants diagnosed with heart failure with preserved ejection fraction.
The details
Researchers randomized patients to varying doses of tovinontrine or a placebo over a 12-week period to monitor changes in NT-proBNP and plasma cGMP. The CYCLE-1 study revealed an inverse dose response, suggesting the lowest tested dose of 2.5 mg BID was more effective than higher quantities.
Timeline
Week 4 marked the point where plasma cGMP levels increased from baseline.
Week 12 served as the primary outcome measurement period for NT-proBNP reduction.
2027 is the scheduled start year for the upcoming CYCLE-3 phase IIb study.
The Big Picture
This study updates a dosing figure previously established by the HFrEF clinical trial framework. By identifying an inverse dose response, the findings force a re-evaluation of standard high-dose protocols in heart failure research.
Patients currently involved in or considering heart failure trials should discuss these dosing findings with their clinical teams. Because the drug remains in the experimental phase, there is no immediate impact on standard over-the-counter or prescription treatment options.
The takeaway
These trial results highlight the importance of identifying therapeutic ceilings in drug development rather than assuming higher doses always yield better results. Future research will pivot toward testing lower doses to determine if optimal clinical efficacy can be achieved without adverse outcomes.
What happens next
The CYCLE-3 phase IIb study is scheduled to begin in 2027 and will specifically test the efficacy of lower doses of tovinontrine in HFrEF patients.
Further reading
Learn more about the latest research and clinical efforts to manage Heart Disease.
Source note: This article includes information reported by MedPage Today.
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