Background: Impaired nitric oxide (NO) signaling has been implicated in the progression of diabetic kidney disease (DKD). Praliciguat (PRL) is a soluble guanylate cyclase stimulator that augments NO signaling in vitro and reduces proteinuria and fasting plasma glucose in the ZSF1 rat model of DKD.
Methods: We evaluated the safety and efficacy of PRL in adults (25-75 y) with type 2 diabetes, eGFR 30-75 mL/min/1.73 m2, urine albumin creatinine ratio (UACR) 200-5000 mg/g, hemoglobin A1c (HbA1c) <12%, systolic blood pressure (BP) 110-160 mmHg, on stable glucose-lowering and renin angiotensin system-inhibition therapy. Participants were randomized 1:1:1 to placebo (PBO), PRL 20 mg, or PRL 40 mg daily for 12 weeks. Two first morning void specimens for UACR were collected at baseline and weeks 1, 4, 8, 12. Adverse events, 24 h BP and serum chemistry were also assessed. The primary efficacy endpoint was change from baseline (CFB) in UACR to weeks 8 and 12 analyzed by mixed-effect repeated measures model to compare pooled PRL vs. PBO.
Results: A total of 156 participants enrolled and 140 completed treatment. Model estimates of mean UACR CFB [90% CI] [intent-to-treat (ITT)] were -28% [-36, -18] for pooled PRL and -15% [-27, 0] for PBO; PBO-adjusted UACR CFB was -15% [-31, 4] (p=0.17). Quality checks identified a site with data inconsistent with that from the overall study population. In a post-hoc sensitivity analysis excluding this site, PBO-adjusted UACR CFB for PRL was -20% [-33, 5], nominal p=0.03. PBO-adjusted CFB for other variables at week 12 (ITT) were 24 h systolic BP -4.2 mmHg [-7.5, -0.8], 24 h heart rate 3.4 bpm [1.6, 5.2], HbA1c -0.27% [-0.50, 0.03], and cholesterol 10.1 mg/dL [-19.2, -1.0]. Both praliciguat doses were well tolerated.
Conclusion: PRL did not significantly reduce UACR in the primary ITT analysis, but positive trends in UACR, BP, and metabolic variables warrant further clinical study of PRL in DKD.
J.P. Hanrahan: Employee; Self; Cyclerion Therapeutics. I. de Boer: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Consultant; Self; George Clinical, Goldfinch Bio, Ironwood Pharmaceuticals. G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. P. Wilson: Employee; Self; Cyclerion Therapeutics. J.D. Wakefield: Stock/Shareholder; Self; Cyclerion Therapeutics. J.P. Seferovic: Employee; Self; Cyclerion Therapeutics. J. Chickering: None. M. Cressman: Employee; Self; Covance, LabCorp. M. Currie: Employee; Self; Cyclerion Therapeutics. Stock/Shareholder; Self; Cyclerion Therapeutics. G.T. Milne: None. A.T. Profy: Employee; Self; Cyclerion Therapeutics, Ironwood Pharmaceuticals. Employee; Spouse/Partner; UpToDate. Stock/Shareholder; Self; Cyclerion Therapeutics, Ironwood Pharmaceuticals.