Highlights
The primary findings of the CARDINAL-HF trial underscore the therapeutic potential of PDE9 inhibition in heart failure management. Key takeaways include:
- CRD-740 significantly increased plasma cGMP levels compared to placebo, with a least squared mean difference of 26.5%.
- The pharmacodynamic effect was additive to standard-of-care treatments, including sacubitril/valsartan (ARNI therapy).
- Urinary cGMP levels also showed significant increases at multiple time points, suggesting systemic enhancement of the natriuretic peptide pathway.
- The drug demonstrated a favorable safety profile with no significant impact on systolic blood pressure or increased rates of hypotension.
Background: The Natriuretic Peptide Pathway in Heart Failure
Chronic heart failure with reduced ejection fraction (HFrEF) remains a leading cause of morbidity and mortality globally, despite the advent of foundational therapies like beta-blockers, SGLT2 inhibitors, and mineralocorticoid receptor antagonists. Central to the pathophysiology of heart failure is the impairment of the natriuretic peptide (NP) system. Under physiological conditions, NPs such as ANP and BNP bind to their receptors to stimulate the production of cyclic guanosine monophosphate (cGMP). This secondary messenger mediates critical cardioprotective effects, including vasodilation, natriuresis, and the inhibition of fibrosis and hypertrophy.
Current therapeutic strategies, most notably the use of angiotensin receptor-neprilysin inhibitors (ARNIs), focus on increasing NP levels by inhibiting their degradation by neprilysin. However, an alternative or complementary approach involves targeting the degradation of cGMP itself. While phosphodiesterase 5 (PDE5) inhibitors have been extensively studied, they primarily target cGMP generated via the nitric oxide (NO) pathway. In contrast, phosphodiesterase 9 (PDE9) has a high affinity for cGMP and is specifically upregulated in the failing human heart. Crucially, PDE9 appears to preferentially regulate the pool of cGMP generated by the natriuretic peptide pathway rather than the NO pathway. Therefore, inhibiting PDE9 with agents like CRD-740 offers a novel mechanism to amplify the beneficial effects of NPs.
Study Design and Methodology
The CARDINAL-HF study (Effectiveness of CRD-740 in Heart Failure) was a Phase 2, randomized, double-blind, placebo-controlled trial designed to evaluate the safety and pharmacodynamic activity of CRD-740. The trial enrolled 60 patients across multiple international sites.
Patient Population
Eligible participants were required to have a diagnosis of HFrEF for at least six months, classified as NYHA functional class II or III. Inclusion criteria specified a left ventricular ejection fraction (LVEF) of 40% or less and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, ensuring a population with high clinical need and active disease markers. Notably, the study allowed patients on stable doses of guideline-directed medical therapy, including those already receiving sacubitril/valsartan.
Intervention and Endpoints
Participants were randomized in a 2:1 ratio to receive either CRD-740 (n = 40) or a matching placebo (n = 20). The dosing regimen involved an initial phase of 10 mg twice daily for two weeks, followed by a titration to 25 mg twice daily for an additional ten weeks. The primary pharmacodynamic endpoint was the change in the area under the curve (AUC) for plasma cGMP from baseline to week 4. Secondary endpoints included changes in urinary cGMP, safety assessments, and hemodynamic monitoring.
Key Findings and Results
The results of the CARDINAL-HF trial provide robust evidence of the biochemical efficacy of CRD-740. The baseline characteristics were well-balanced between the two groups, with a mean LVEF of 28% and a high prevalence (73%) of background sacubitril/valsartan use.
Pharmacodynamic Impact on cGMP
At the 4-week mark, the CRD-740 group demonstrated a significant increase in plasma cGMP levels. Specifically, the placebo-corrected change in plasma cGMP AUC (0-6 hours) showed a 19.1% increase in the treatment group compared to an 8.8% decrease in the placebo group. The least squared mean difference was 26.5% (95% CI: 7.8-45.1; P = 0.003). This confirms that CRD-740 successfully inhibits the PDE9 enzyme, leading to a measurable accumulation of intracellular cGMP that spills over into the plasma.
Urinary Markers and Consistency
The increase in cGMP was not limited to the plasma. Significant elevations in urinary cGMP were observed as early as Day 1 (P = 0.012) and sustained through Week 2 (P = 0.014). Although the statistical significance at Week 4 was marginal (P = 0.09), the overall trend supported a consistent systemic effect on cGMP signaling. Importantly, subgroup analysis revealed no interaction between the efficacy of CRD-740 and the use of sacubitril/valsartan (P = 0.47), suggesting that PDE9 inhibition provides an incremental benefit regardless of whether neprilysin is being inhibited.
Safety and Tolerability
One of the primary concerns with new heart failure medications is the risk of hypotension, particularly when added to existing vasodilators. However, CRD-740 was well tolerated. There were no significant differences between the treatment and placebo groups regarding systolic blood pressure changes, clinical hypotension, or the incidence of serious adverse events. This safety profile is particularly encouraging for a Phase 2 study, suggesting that the drug can be safely integrated into complex multidrug regimens.
Expert Commentary and Clinical Implications
The CARDINAL-HF trial is a proof-of-concept success. By demonstrating that CRD-740 can elevate cGMP levels above and beyond what is achieved with ARNIs, the study opens a new door for combination therapy in HFrEF. The biological distinction between PDE5 and PDE9 is critical here; while PDE5 inhibition has largely disappointed in chronic heart failure trials, the PDE9-specific approach targets the natriuretic peptide pathway more directly and efficiently.
From a mechanistic perspective, the lack of blood pressure reduction is fascinating. It suggests that the cGMP pool regulated by PDE9 may be more closely tied to myocardial and renal cytoprotection than to acute systemic vasodilation. This could allow for higher dosing to maximize organ-protective effects without the dose-limiting side effect of hypotension that often plagues other HF therapies.
However, as a Phase 2 trial, there are limitations. The study was not powered to detect changes in hard clinical outcomes such as heart failure hospitalizations or mortality. Furthermore, the 12-week duration is insufficient to assess long-term remodeling effects. Future Phase 3 trials will need to confirm whether these biochemical increases in cGMP translate into meaningful improvements in functional capacity and survival.
Conclusion
The CARDINAL-HF trial successfully met its primary objective, showing that the PDE9 inhibitor CRD-740 significantly and safely increases cGMP levels in patients with HFrEF. By demonstrating that this effect is additive to standard care, including ARNI therapy, the study establishes PDE9 inhibition as a promising new frontier in heart failure treatment. As we move toward larger clinical trials, the medical community remains optimistic that CRD-740 could become a vital tool in the quest to further reduce the burden of heart failure.
Funding and ClinicalTrials.gov
This study was funded by Cardurion Pharmaceuticals. ClinicalTrials.gov Identifier: NCT05409183.
References
- Udelson JE, Bělohlávek J, Dukát A, et al. Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of CRD-740, a PDE9 Inhibitor, in Chronic Heart Failure. JACC Heart Fail. 2025; Epub ahead of print. PMID: 41171251.
- Mullens W, Martens P. PDE9 Inhibition: A New Avenue for Enhancing Natriuretic Peptide Signaling? JACC Heart Fail. 2025 (Editorial Comment).
- Lee DI, et al. Phosphodiesterase 9A controls RNA-protein complexes and cGMP signaling in the heart. Nature. 2015;519(7544):472-476.
