Heart doctors testing a daily pill called CRD-740 have found it safely ramps up a vital body signal in patients with weakened hearts. This phase 2 study published in the JACC: Heart Failure targeted patients with heart failure and reduced ejection fraction, or HFrEF, lasting over six months. Patients had NYHA class II or III symptoms, pump strength at 40% or less, and high levels of a heart stress marker.
The team randomized 60 patients two-to-one to CRD-740 or placebo—40 got the drug starting at 10 mg twice daily for two weeks, then 25 mg for 10 more; 20 took dummy pills. Their main check was blood levels of cyclic guanosine monophosphate, or cGMP, at week four. This molecule drives good effects from natriuretic peptides, but an enzyme called PDE9 breaks it down fast.
Steady Climb in the Key Signal
Baseline stats showed average ejection fraction at 28%, with 73% already on sacubitril/valsartan. CRD-740 pushed up blood cGMP over placebo by a corrected 26.5% rise—19.1% gain versus 8.8% drop in the first six hours. Urine cGMP jumped too, significant at day one, week two, and nearly at week four. The drug worked the same whether patients took sacubitril/valsartan or not.
Safe Add-On with No Blood Pressure Dip
No big shifts showed in systolic blood pressure, low pressure spells, or serious side effects between groups.
Path to Stronger Heart Treatments
PDE9 inhibition blocks cGMP breakdown, amplifying natriuretic peptide benefits like less strain and fluid buildup.
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Key highlights
- CRD-740 increases placebo-corrected plasma cGMP by 26.5% (95% CI 7.8-45.1, P=0.003) at week 4 in HFrEF patients.
- Urinary cGMP rises significantly with CRD-740 at day 1 (P=0.012), week 2 (P=0.014), and trends higher at week 4 (P=0.09).
- Effects hold regardless of sacubitril/valsartan use, with no interaction (P=0.47).
- No differences occur in systolic blood pressure, hypotension, or serious adverse events versus placebo.
- PDE9 inhibition enhances natriuretic peptide-cGMP pathway safely on top of standard HFrEF therapies.
Source
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. 2026 Jan;14(1):102706. doi: https://doi.org/10.1016/j.jchf.2025.102706
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Phase 2 trial shows oral PDE9 inhibitor CRD-740 raises plasma cGMP by 26.5% in 60 HFrEF patients, even with sacubitril/valsartan, hinting at add-on heart failure therapy.
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