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).