Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of CRD-740, a PDE9 Inhibitor, in Chronic Heart Failure

BACKGROUND: The beneficial effects of natriuretic peptide receptor activation are mediated by cyclic guanosine monophosphate (cGMP). Phosphodiesterase 9 (PDE9) hydrolyzes cGMP and therefore its inhibition has the potential to increase intracellular cGMP signaling. OBJECTIVES: The aim of this study is to assess the effects of the oral PDE9 inhibitor CRD-740 on plasma and urinary cGMP in patients with heart failure and reduced ejection fraction (HFrEF). METHODS: Patients with HFrEF of >6 months, NYHA functional class II/III, ejection fraction ≤40%, and elevated N-terminal pro-B-type natriuretic peptide were randomized 2:1 to CRD-740 (10 mg twice a day for 2 weeks, then 25 mg twice a day for 10 weeks) or placebo. The primary pharmacodynamic endpoint was the change in plasma cGMP to week 4. RESULTS: Sixty patients were randomized to CRD-740 (n = 40) or placebo (n = 20). Baseline characteristics included ejection fraction 28% ± 7%, with 73% of patients taking sacubitril/valsartan. The placebo-corrected change in plasma cGMP from baseline at week 4 increased with CRD-740, 19.1% ± 26.9% increase vs 8.8% (31.3%) decrease in area under the curve from 0 to 6 hours, respectively, for a least squared mean difference of 26.5% (95% CI: 7.8-45.1; P = 0.003). There was no interaction with the presence/absence of sacubitril/valsartan (P = 0.47). An increase in urinary cGMP was observed with CRD-740 at day 1 (P = 0.012), week 2 (P = 0.014), and week 4 (P = 0.09). No significant between-group differences in systolic blood pressure, hypotension, or serious adverse events were observed. CONCLUSIONS: In this initial phase 2 trial, PDE9 inhibition with CRD-740 was well tolerated and resulted in elevations of plasma and urinary cGMP on top of standard care, including sacubitril/valsartan, supporting the potential of PDE9 inhibition to enhance the beneficial effects of the natriuretic peptide receptor-cGMP pathway incremental to existing heart failure treatments. (Effectiveness of CRD-740 in Heart Failure [CARDINAL-HF]; NCT05409183).