Cardurion’s Phase 2 trials found NT-proBNP reductions with lower-dose tovinontrine in HFrEF, while 50 mg twice daily showed no biomarker benefit.
Written By: Kirti Kumbhar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
Cardurion Pharmaceuticals has reported Phase 2 results for tovinontrine (CRD-750), an investigational oral phosphodiesterase-9 (PDE9) inhibitor being developed as a potential treatment for chronic heart failure. Presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2026 in Phoenix, Arizona, the findings showed reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at two lower doses in patients with heart failure with reduced ejection fraction (HFrEF), while the highest dose showed no benefit on this biomarker.
Phase 2 Trial Shows Greater Biomarker Reductions at Lower Doses
The Cycle-1REF Phase 2 trial (NCT06215911) enrolled 529 participants with HFrEF who were randomized to one of three tovinontrine doses or placebo, alongside guideline-directed medical therapy (GDMT).
At 12 weeks, tovinontrine doses of 2.5 mg twice daily (BID) and 25 mg BID reduced NT-proBNP levels, with the greatest reduction observed at 2.5 mg BID. The reduction at 25 mg BID was slightly smaller, while the highest dose of 50 mg BID showed no NT-proBNP benefit.
The reductions emerged as early as Week 2 and persisted through the 12-week treatment period. Cardurion also reported reductions in B-type natriuretic peptide (BNP) and increases in plasma and urinary cyclic guanosine monophosphate (cGMP), findings that support biological activity and engagement of the targeted pathway.
PDE9 Inhibition and the Proposed Mechanism
Tovinontrine is designed to enhance natriuretic peptide signaling (NPS) in cardiomyocytes by inhibiting PDE9. This signaling pathway contributes to protective cardiac functions, while PDE9 activity is described by Cardurion as elevated in chronic heart failure, potentially weakening the pathway.
The absence of a biomarker benefit at 50 mg BID, despite reductions at lower doses, raises questions about the relationship between dose and downstream biological activity.
Cardurion has proposed that excessive intracellular cGMP may trigger counter-regulatory neurohormonal feedback, reducing the beneficial effects of NPS. The company also reported that further analysis of Cycle trial data found an association between plasma cGMP elevations beyond a threshold and attenuation of downstream NPS activity.
This explanation remains a hypothesis rather than an established clinical mechanism. Further investigation will be needed to clarify the relationship between cGMP levels, PDE9 inhibition and the observed dose-response pattern.
Biomarker Findings on Top of Standard Heart Failure Treatment
Participants in Cycle-1REF were receiving background GDMT, including high rates of treatment with sacubitril/valsartan (Entresto) and sodium-glucose cotransporter-2 (SGLT2) inhibitors.
Cardurion reported that NT-proBNP reductions were consistent among patients receiving or not receiving Entresto and other background therapies. These findings support further investigation of tovinontrine as a potential add-on treatment for patients already receiving established heart failure therapies.
HFpEF Trial Shows No Significant NT-proBNP Change
The Cycle-2PEF Phase 2 trial (NCT06215586) randomized 277 patients with heart failure with preserved ejection fraction (HFpEF) to tovinontrine 50 mg BID or placebo.
The trial showed no significant change in NT-proBNP at the tested dose. This finding is consistent with the absence of a biomarker benefit at 50 mg BID in Cycle-1REF.
Cardurion indicated that lower doses warrant further evaluation in HFpEF. Because the reported comparison evaluated the 50 mg BID dose, the results do not establish whether lower doses could produce a measurable biomarker response in this population.
Safety and Further Development
According to Cardurion, tovinontrine demonstrated a favorable safety and tolerability profile across the doses tested in both trials. Further studies will be needed to characterize its longer-term safety.
Cardurion plans to continue advancing tovinontrine as a potential first-in-class therapy that could complement existing heart failure treatments. Further studies will need to clarify dose selection, confirm the biomarker findings and determine whether the observed changes translate into meaningful clinical outcomes.
What the Results Mean for Tovinontrine’s Development
The Phase 2 findings identify dose selection as an important question for tovinontrine’s continued development. In HFrEF, the lower doses produced the clearest NT-proBNP response, while the highest dose showed no benefit in either HFrEF or HFpEF. This pattern raises the possibility that increasing the dose does not necessarily improve the drug’s biological effect. However, the available results do not establish why the response differed across doses, and Cardurion’s proposed cGMP-mediated feedback mechanism remains unconfirmed. The next stage of development will need to establish whether the lower-dose biomarker response is reproducible and whether it translates into clinical benefits, such as fewer heart failure hospitalizations or improved survival.
Reference
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.
Cycle-1REF clinical trial record: NCT06215911
Cycle-2PEF clinical trial record: NCT06215586
About the Writer
Kirti Kumbhar (LinkedIn) is an M.Pharm graduate with experience in Quality Assurance at Lupin Limited and a strong interest in clinical research, regulatory affairs, and Trial Master File (TMF) management. She has developed knowledge of regulatory documentation, quality systems, compliance, and healthcare research through her professional experience. Passionate about clinical development and continuous learning, Kirti is committed to supporting high-quality healthcare documentation, regulatory excellence, and research-driven healthcare advancements.