The tovinontrine HFrEF Phase 2 results are a study of two halves. Cardurion Pharmaceuticals reported on 11 October 2026 that its oral PDE9 inhibitor tovinontrine reduced the heart failure biomarker NT-proBNP in patients with reduced ejection fraction (HFrEF) at the two lower doses tested, but not at the highest dose. A second trial in heart failure with preserved ejection fraction (HFpEF) showed no significant change at the single dose studied.
The company calls the HFrEF finding positive. It is encouraging for a biomarker, but the announcement gives no numbers for the size of the effect, and it says nothing yet about whether patients feel better or live longer. This report sets out what was tested, what was found, and what remains unproven.
Key facts from the tovinontrine HFrEF Phase 2 trial
- Presented at: the Heart Failure Society of America annual meeting in Phoenix, as a late-breaking plenary.
- HFrEF study (Cycle-1REF): 529 participants randomised to three tovinontrine doses or placebo, on top of guideline-directed therapy.
- Doses: 2.5 mg, 25 mg and 50 mg twice daily.
- Primary endpoint: change in NT-proBNP from baseline at 12 weeks.
- Result: reductions were greatest at 2.5 mg and slightly smaller at 25 mg. No benefit was seen at 50 mg.
- HFpEF study (Cycle-2PEF): 277 patients, 50 mg twice daily against placebo, with no significant NT-proBNP change.
- Not disclosed: the size of the NT-proBNP reductions, p-values, arm sizes, specific adverse events and any Phase 3 plan.
What the tovinontrine HFrEF Phase 2 trial tested
Tovinontrine blocks PDE9, an enzyme that breaks down cGMP, a signalling molecule thought to protect the heart under stress. The idea is that preserving cGMP could ease the strain on a failing heart. Cardurion says it is the first company to bring a PDE9 inhibitor into chronic heart failure development, which is the company’s own claim. NT-proBNP is a blood marker that rises when the heart is stretched, and doctors use it to track heart failure. The National Heart, Lung, and Blood Institute and the American Heart Association explain the condition for general readers.
HFrEF, where the heart pumps out too little blood with each beat, and HFpEF, where the heart is stiff but the ejection fraction looks normal, are treated as different diseases, and drugs often work in one but not the other. That is why the two Cardurion trials matter separately.
Results of the tovinontrine HFrEF Phase 2 trial
According to the company, NT-proBNP fell as early as week 2 and stayed lower through week 12 at the effective doses. BNP, a related marker, also fell, and plasma and urinary cGMP rose, which the company says shows the drug engaged its target. The reductions were consistent in patients who were and were not taking Entresto or other background therapies, the company says. The release says high proportions of patients were on Entresto and SGLT2 inhibitors, without giving figures.
The most unusual finding is that the highest dose did not work. Cardurion describes an inverse dose-response, with smaller doses producing more benefit than larger ones. The company’s explanation is a counter-regulatory neurohormonal feedback mechanism, triggered when cGMP in the heart muscle becomes very high. It cites published studies and its own analysis, but this is a hypothesis, not a confirmed mechanism. In our assessment, an inverted dose-response is a flag for caution, because it can arise from biology, from chance or from differences between groups. Larger trials at the lower doses would be needed to tell which.
The HFpEF result next to the tovinontrine HFrEF Phase 2
In the 277-patient HFpEF trial, tovinontrine 50 mg twice daily did not produce a significant NT-proBNP change. Given that 50 mg also failed in HFrEF, the company argues that lower doses are worth testing in HFpEF, stating that additional evaluation at lower doses in this group is warranted. That is a reasonable next question. But the HFpEF study did not test lower doses, so the announcement cannot tell us whether they would work. Treating the HFpEF result as consistent with the HFrEF finding would go beyond the data.
How strong is the tovinontrine HFrEF Phase 2 evidence?
Several limits apply. First, the release is the main source, and no peer-reviewed paper or full dataset has been cited. Second, the reductions are described as substantial or meaningful but not quantified, with no percentages, confidence intervals or placebo-adjusted figures. Third, NT-proBNP is a surrogate marker. Changes in it do not always translate into fewer hospital admissions or deaths, and the trial did not report such outcomes. Fourth, the company reports a favourable safety and tolerability profile at all doses in both trials, but gave no data on adverse events, discontinuations or serious events.
The principal investigator, Dr James Udelson of Tufts Medical Center, was quoted on the reductions at the two lower doses in HFrEF. Chief medical and scientific officer Dr Howard Surks attributed the inverse dose-response to a feedback mechanism. Both statements are in the company’s release. Coverage of the data has varied, with some reports leading on the biomarker reductions and others on the failure at the highest dose, which reflects how mixed the picture is.
What the tovinontrine HFrEF Phase 2 results leave unanswered
- How large the NT-proBNP reductions were, and how they compare with placebo.
- Which dose Cardurion will carry forward, and whether it will run a Phase 3 trial. The company says only that it plans to continue advancing the drug.
- Safety data, including low blood pressure and discontinuations.
- Whether lower doses work in HFpEF.
- Whether biomarker reductions translate into better symptoms, fewer hospitalisations or longer survival.
For related cardiovascular and kidney coverage, see our report on the FDA acceptance of the Bayer KERENDIA application for chronic kidney disease without diabetes, or browse more pharmaceutical news. The Heart Failure Society of America has information on the meeting where the data were shown.
Frequently asked questions
What did the tovinontrine HFrEF Phase 2 trial show?
Lower doses of tovinontrine reduced NT-proBNP at 12 weeks in 529 HFrEF patients. The highest dose, 50 mg twice daily, showed no benefit.
Did tovinontrine work in HFpEF after the tovinontrine HFrEF Phase 2?
Not at the dose tested. The 277-patient study found no significant NT-proBNP change at 50 mg twice daily.
Is the tovinontrine HFrEF Phase 2 result a proven benefit to patients?
No. NT-proBNP is a biomarker, and the trial did not report clinical outcomes.
What is tovinontrine in the tovinontrine HFrEF Phase 2?
An oral PDE9 inhibitor from Cardurion that aims to raise cGMP in heart failure.
Will there be a Phase 3 trial after the tovinontrine HFrEF Phase 2?
The company says it plans to continue advancing tovinontrine but has not announced a Phase 3 design.
How we reported this: we relied on the company’s announcement of 11 October 2026 and coverage of the same data. Results and mechanism are the company’s. Last updated: 13 October 2026. This article is news reporting and not medical advice.
