James Udelson, MD, is the chief of the division of cardiology at Tufts Medical Center.

James Udelson, MD

Despite raising plasma cGMP, tovinontrine failed to lower NT-proBNP in patients with 

heart failure with preserved ejection fraction (HFpEF)

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

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.

“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 

 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.”

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.

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.

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.

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.

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.

“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.

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.

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/

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

Videos

James Udelson, MD, discusses the Cycle-2-PEF trial, which ultimately supports the inverse dose-response hypothesis from companion trial Cycle-1-REF.

Tovinontrine, an investigative oral phosphodiesterase 9 (PDE9) inhibitor, has successfully reduced NT-proBNP in patients with 

heart failure with reduced ejection fraction (HFrEF)

, based on results from the phase 2 Cycle-1-REF trial.

Tovinontrine Reduces NT-proBNP in HFrEF, May Have Greater Benefit at Smaller Doses

 in Phoenix, Arizona, by James Udelson, MD, chief of the division of cardiology at Tufts Medical Center. At the meeting, Udelson met with 

 to discuss the trial, its findings, and the implications for this highly treated patient population.

“In contemporary practice, whether it’s the development of drugs or devices, you really have to show that your new drug or new device does something good on top of well-treated patients,” Udelson said. “If people are poorly treated and you show that a new drug helps them in some way, this community, and I myself, would be skeptical of that.”

Cycle-1-REF was a phase 2, randomized, double-blind, placebo-controlled, dose-finding study aiming to assess tovinontrine’s efficacy in patients with chronic HFrEF. Patients were eligible for enrollment if they had evidence supporting a diagnosis of clinical HF with New York Heart Association (NYHA) functional class 2 or 3, and an ejection fraction (EF) ≤40%, among other criteria. Patients with EF >40%, evidence of recent HF exacerbation, or major cardiovascular surgery within 60 days of screening, among other criteria, were excluded.

Patients were randomly assigned to a low (2.5 mg), medium (25 mg), or high (50 mg) dose of tovinontrine or placebo, all of which were administered orally and on top of guideline-directed medical therapy. The primary endpoint was the percent change in plasma NT-proBNP from baseline to week 12. Secondary outcomes included change in urine and plasma cGMP from baseline, the ratio between the percent change in urine and plasma cGMP versus NT-proBNP, and the change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CCS).

A total of 529 patients were included in the Cycle-1-REF trial, with 53 assigned to the low dose, 159 to the medium dose, 159 to the high dose, and 158 to placebo. These patients had a mean age of 69 +/- 10 years and a mean EF of 32% +/- 6%. Median NT-proBNP was 1473 at baseline, and 44% of patients had NYHA class 3 HF. Of the included patients, 93 were on sacubitril/valsartan or RASi at baseline, while 79 were on SGLT2 inhibitors or MRAs.

At 12 weeks, the patients receiving 2.5 mg of tovinontrine saw a mean change of -14.1% in NT-proBNP (95% CI, -27.2 to 1.3; 

 = .07), while the 25 mg arm saw a mean reduction of -10.8% (95% CI, -20.6 to 0.1; 

 = .05) and the 50 mg arm had a reduction of -4.4 (95% CI, -14.9 to 7.5; 

 = .45). Mean percent change in plasma cGMP was 6% in the 2.5 mg arm, 7% in the 25 mg arm, 6% in the 50 mg arm, and -9% in the placebo arm. These results led Udelson and colleagues to hypothesize that a threshold of myocardial cGMP elevation exists above which counter-regulatory mechanisms could limit downstream signaling.

In a post-hoc analysis, Udelson and colleagues segmented patients by cGMP increase – those with increases <20% generally had a greater placebo-adjusted geometric mean percent change in NT-proBNP by week 12. This was consistent across all 3 treatment arms, suggesting that smaller increases in cGMP corresponded with reductions in NT-proBNP across all dosing levels. Additionally, similar results were obtained using thresholds of 15% and 10% increase in plasma cGMP.

“No matter what we find, it generates a hypothesis, and we’re using that,” Udelson said. “We will test that hypothesis in the next trial, and there are already plans being made to do this trial and to study a lower dose range based on this finding. So, the next step is testing the hypothesis.”

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

Cardurion Pharmaceuticals. A Study to Assess Safety & Effectiveness of Tovinontrine in Chronic Heart Failure With Reduced Ejection Fraction (Cycle-1-REF) (Cycle-1-REF). ClinicalTrials.gov Identifier: NCT06215911. Updated September 1, 2026. Accessed October 12, 2026. 

https://clinicaltrials.gov/study/NCT06215911

James Udelson, MD, discusses the results of the Cycle-1-REF study, presented at HFSA 2026, that could support an inverse dose-response relationship with this PDE9 inhibitor.

James Udelson, MD

Articles