Tovinontrine 50 mg Improves cGMP With Minimal Effect on NT-proBNP in HFpEF

Despite raising plasma cGMP, tovinontrine failed to lower NT-proBNP in patients with heart failure with preserved ejection fraction (HFpEF) at the highest dose.1

These data from the Cycle-2-PEF trial were presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026 in Phoenix, Arizona, by James Udelson, MD, the chief of the division of cardiology at Tufts Medical Center.1

“We know that PDE9 is upregulated in heart failure, and in prior human biopsy studies and preclinical models, it’s actually more highly upregulated in HFpEF patients than it is in HFrEF patients,” Udelson told HCPLive in an exclusive interview. “We also know that, in PDE9 inhibitor studies in preclinical models, it helped regress hypertrophy. There were a lot of lines of evidence to suggest that this might be useful in HFpEF.”

Structuring Cycle-2-PEF

Cycle-2-PEF was a phase 2, randomized, double-blind, placebo-controlled study assessing tovinontrine in patients with chronic HFpEF. Like its companion study Cycle-1-REF, this trial enrolled patients with a diagnosis of clinical HF syndrome at New York Heart Association functional class 2 or 3. Patients were also required to have an ejection fraction (EF) >40% and <60% with left atrial enlargement, along with NT-proBNP levels ≥300 pg/mL at screening, among other criteria.2,3

The primary endpoint of the study was the percent change from baseline in plasma NT-proBNP by week 12. A dose of 50 mg was specifically selected to achieve levels of PDE9 inhibition that maximally increased plasma cGMP. The secondary efficacy endpoint was an assessment of change in plasma cGMP between the treatment and placebo arms, while the safety endpoint was an assessment of treatment-emergent adverse events in both arms.1,3

A total of 277 patients were randomized into the trial – of these, 267 completed the study. 140 patients were assigned to receive 50 mg of tovinontrine, while the remaining 137 received placebo. Mean age was 72 +/- 10 years, and mean ejection fraction was 50% +/- 6%. Median NT-proBNP at baseline was 833 pg/mL, and 42% of patients had NYHA class 3 HFpEF. Additionally, 85% of patients were already receiving sacubitril/valsartan or RASi therapy, 73% were on SGLT2 inhibitors, and 54% were on MRAs.1

Mixed Results

Consistent with the lack of NT-proBNP effects at the highest dose in Cycle-1-REF, Udelson and colleagues found that the treatment arm in Cycle-2-PEF saw no significant change in NT-proBNP. The patients receiving tovinontrine saw a mean reduction in NT-proBNP of -1.7% (95% CI, -9.7 to 7), while the placebo arm saw a reduction of -10.1% (95% CI, -17.5 to -2). The tovinontrine arm did, however, see significant change in plasma cGMP, reaching a median 40% increase by week 12.1

Ultimately, Udelson and colleagues concluded that higher doses of tovinontrine appear to provide diminishing benefits for patients with HFpEF, similarly to HF with reduced ejection fraction (HFrEF) in the Cycle-1-REF trial. This further supports the inverse dose-response hypothesis, which will be further tested as the drug progresses into Cycle-3, a phase 2b study in patients with HFrEF planned to begin in 2027.1

“I think the strategy for moving forward is going to be based on a lot of practical reasoning,” Udelson said. “The idea was to start with HFrEF, lower doses, get what we think should be a good signal, and then move on to HFpEF.”

Editors’ Note: Udelson reports disclosures with Abiomed, Alleviant, Cardurion, Cytokinetics, Medtronic, Merck, and others.

References

1. Udelson J, Agladze R, Atkins B, et al. A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Assess the Safety and Effectiveness of Tovinontrine in Patients With Chronic Heart Failure With Preserved Ejection Fraction: The Cycle-2-PEF Trial. Presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026, Phoenix, AZ. October 9-12, 2026.

2. Cardurion Pharmaceuticals. Cardurion Pharmaceuticals Presents Phase 2 Results for Tovinontrine (CRD-750), a PDE9 Inhibitor, as a Novel Treatment for Heart Failure. October 11, 2026. Accessed October 12, 2026. https://cardurion.com/cardurion-pharmaceuticals-presents-phase-2-results-for-tovinontrine-crd-750-a-pde9-inhibitor-as-a-novel-treatment-for-heart-failure/

3. Cardurion Pharmaceuticals. Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Preserved Ejection Fraction (Cycle-2-PEF) (Cycle-2-PEF). ClinicalTrials.gov Identifier: NCT06215586. Updated September 1, 2026. Accessed October 12, 2026. https://clinicaltrials.gov/study/NCT06215586?term=NCT06215586&rank=1