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

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.¹

These data were presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026 in Phoenix, Arizona, by James Udelson, MD, chief of the division of cardiology at Tufts Medical Center. At the meeting, Udelson met with HCPLive to discuss the trial, its findings, and the implications for this highly treated patient population.¹

“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.^2,3

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).³

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.¹

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; P = .07), while the 25 mg arm saw a mean reduction of -10.8% (95% CI, -20.6 to 0.1; P = .05) and the 50 mg arm had a reduction of -4.4 (95% CI, -14.9 to 7.5; P = .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.¹

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.¹

“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.”

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, 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.

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. 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