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
Bibliographic record
Abstract
Abstract Background Natriuretic peptide (NP) receptor activation has a beneficial role in the treatment of heart failure (HF). The enzyme phosphodiesterase (PDE) 9 breaks down cGMP, the second messenger stimulated by natriuretic peptides. PDE9 inhibition may increase intracellular cGMP signaling and, potentially, have beneficial effects in HF. We examined the effects of the selective PDE9 inhibitor CRD-740 on the NP signaling pathway in HF. Purpose The objectives of this early phase 2 trial were to assess the tolerability of CRD-740 and its effects on plasma and urinary cGMP (markers of potential clinical effiacy) in patients with HFrEF, including those receving background treatment with sacubitril/valsartan. Methods Key inclusion criteria were patients with a history of HFrEF of > 6 mos, NYHA II or III, EF < 40% and NT-proBNP ≥600 pg/ml at screening (≥1000 pg/mL if in atrial fibrillation), on treatment with stable guideline-directed therapy for a minimum of 4 weeks. Patients were randomized 2:1 double-blind to CRD-740 (10mg twice daily for 2 weeks, then 25mg twice daily for 10 weeks) or placebo. Tolerability and safety were assessed. The primary pharmacodynamic endpoint was the between-group change from baseline in plasma cGMP at Week 4. Exploratory endpoints included urine cGMP levels, KCCQ and biomarkers. Results 60 patients were randomized to CRD-740 (n=40) or placebo (n=20). Baseline characteristics included age 67+13 yrs, 85% men, EF 28+7%, BMI 30+10, with 73% of patients taking sacubitril/valsartan, and 47% on SGLT2 inhibitors. The primary endpoint was positive, with placebo-corrected change in plasma cGMP significantly increased at all time points at week 4 in those treated with CRD-740 (see Table). cGMP levels were also increased on day 1 (Table) and week 2. A significant increase in urinary cGMP also was observed with CRD-740 vs placebo (Figure) in 6-hour collections at day 1 (p=0.012) and week 2 (p=0.014). In this small study, not powered for exploratory endpoints, directionally favorable placebo-corrected, baseline-adjusted changes also were seen in the KCCQ Clinical (+7.1 [95%CI, -1.6, +15.7], p=0.11) and Overall Summary Scores (+7.4 [-0.8, +15.5], p=0.075) for patients on CRD-740. No significant changes in NT-proBNP were observed between treatment groups. Adverse events (AEs) were observed in 62% and 50% of CRD-740 and placebo-treated patients, with discontinuation in 5% and 10% respectively, with no between-group difference in change in BP. There were no hypotension AEs, and no treatment-related serious adverse events. Conclusions In this early phase 2 trial, PDE9 inhibition with CRD-740 was well-tolerated and resulted in substantial elevations of plasma and urinary cGMP on top of standard care, including sacubitril/valsartan. These results support the potential of PDE9 inhibition to further activate the beneficial effects of the NP receptor-cGMP pathway incrementally to that achieved by existing HF treatments.Changes in Plasma cGMP over Time (ng/mL)Changes in Urinary cGMP over Time
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.009 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".