Cardurion Pharmaceuticals Reports Positive Phase 2a Results for Heart Failure PDE9 Inhibitor

Cardurion Pharmaceuticals, Inc., a clinical-stage biotechnology firm, has presented promising results from its CARDINAL-HF Phase 2 clinical trial at the Annual Congress of the Heart Failure Association of the European Society of Cardiology in Lisbon, Portugal. The trial assessed the efficacy and safety of CRD-740, a phosphodiesterase-9 (PDE9) inhibitor, in patients with heart failure with reduced ejection fraction (HFrEF).

The CARDINAL-HF Phase 2a trial, the first proof-of-concept study for a PDE9 inhibitor in heart failure patients, demonstrated that CRD-740 met its primary endpoint by showing a statistically significant increase in plasma cyclic guanosine monophosphate (cGMP) levels after four weeks of treatment. The elevation in cGMP levels is a crucial indicator of the activation of the myocardial natriuretic peptide (NP) signaling pathway, a pathway known for its beneficial effects in heart failure patients. CRD-740 was also well tolerated among participants.

James Udelson, MD, Chief of Cardiology at Tufts Medical Center and Principal Investigator of the trial, emphasized the significance of these findings. He noted that the robust inhibition of PDE9, the ensuing elevation of cGMP in both plasma and urine, and the favorable safety profile support further clinical trials. Dr. Scott D. Solomon from Harvard Medical School echoed these sentiments, highlighting the potential of PDE9 inhibition as a new mechanism for activating the NP signaling pathway, addressing significant unmet needs in heart failure treatment.

The presentation, titled "A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Tolerability and Pharmacodynamic Effects of CRD-740, a PDE9 Inhibitor, in Participants with Chronic Heart Failure," was delivered by Dr. Udelson during the "Late-Breaking Clinical Trials: Medical Therapy" session. Key findings included:
- CRD-740 was well-tolerated in patients with HFrEF.
- PDE9 inhibition by CRD-740 achieved significant median increases in plasma and urinary cGMP after four weeks compared to the placebo.
- The results indicated that CRD-740 prevents cGMP metabolism, enhancing NP signaling pathway activation.

These results were observed regardless of whether patients were concurrently treated with sacubitril/valsartan, suggesting the potential of CRD-740 both as a monotherapy and in combination with existing treatments. Following the promising Phase 2a trial results, Cardurion has initiated two further Phase 2 clinical studies involving 640 patients. These include a dose-ranging trial for HFrEF patients and a proof-of-concept trial for those with heart failure with preserved ejection fraction (HFpEF).

Cardurion’s CEO, Peter Lawrence, and Chief Medical and Scientific Officer, Dr. Howard Surks, expressed optimism about the future of PDE9 inhibition in heart failure treatment. They acknowledged the contributions of patients and investigators and affirmed the company's commitment to advancing this novel therapeutic approach.

The CARDINAL-HF trial, the first of its kind for a PDE9 inhibitor in heart failure, involved 60 chronic, stable HFrEF patients receiving guideline-directed medical therapy (GDMT). The trial focused on the safety and tolerability of CRD-740 and changes in plasma cGMP levels over four weeks. Other evaluated endpoints included changes in urinary cGMP, N-terminal pro b-type natriuretic peptide (NTpro-BNP), and the Kansas City Cardiomyopathy Questionnaire (KCCQ), which assesses symptoms and quality of life.

The trial's Executive Committee comprises renowned experts such as Dr. Udelson, Dr. Solomon, Dr. John McMurray from the University of Glasgow, and Dr. Eugene Braunwald of Harvard Medical School. These experts, along with the CARDINAL-HF Steering Committee, guide the development of Cardurion's clinical programs.

PDE9 inhibitors aim to inhibit the PDE9 enzyme, which degrades cGMP and diminishes the beneficial effects of the NP pathway in heart muscle cells. By preserving cGMP, PDE9 inhibitors enhance NP signaling, providing therapeutic benefits in heart failure.

Heart failure remains a significant health issue, affecting approximately 6.5 million individuals in the U.S., with high morbidity and mortality rates. Despite existing treatments, there remains substantial medical need, especially for innovative therapies like PDE9 inhibitors.

Cardurion Pharmaceuticals, based in Burlington, Massachusetts, and Shonan, Japan, focuses on developing next-generation cardiovascular therapies. Founded by leading physician-scientists, the company is dedicated to improving patient outcomes through groundbreaking research and clinical development.