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Kidney Week

Abstract: PO1027

Effect of Praliciguat, a Once-Daily, Oral Soluble Guanylate Cyclase Stimulator, on Albuminuria in Patients with Diabetic Kidney Disease: A Randomized, Double-Blind, Phase 2 Trial

Session Information

Category: Diabetic Kidney Disease

  • 602 Diabetic Kidney Disease: Clinical

Authors

  • Hanrahan, John Patrick, Cyclerion Therapeutics, Cambridge, Massachusetts, United States
  • de Boer, Ian H., The University of Washington, Seattle, Washington, United States
  • Bakris, George L., The University of Chicago Medical Center Comprehensive Hypertension Center, Chicago, Illinois, United States
  • Wilson, Phebe, Cyclerion Therapeutics, Cambridge, Massachusetts, United States
  • Wakefield, James D., Cyclerion Therapeutics, Cambridge, Massachusetts, United States
  • Seferovic, Jelena P., Cyclerion Therapeutics, Cambridge, Massachusetts, United States
  • Chickering, Jennifer, Cyclerion Therapeutics, Cambridge, Massachusetts, United States
  • Cressman, Michael, Covance Inc, Princeton, New Jersey, United States
  • Currie, Mark, Cyclerion Therapeutics, Cambridge, Massachusetts, United States
  • Milne, George Todd, Cyclerion Therapeutics, Cambridge, Massachusetts, United States
  • Profy, Albert T., Cyclerion Therapeutics, Cambridge, Massachusetts, United States
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 amplifies 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-effects repeated measures model to compare pooled PRL vs PBO.

Results

A total of 156 participants enrolled and 140 completed treatment. Of the 156, 66% were men, 71% were White, 24% Black, and 54% Latino. 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]. Mediation analyses indicated that ~75% of the UACR decline was independent of SBP decrease. Both praliciguat doses were well tolerated.

Conclusion

PRL did not significantly reduce UACR in the primary ITT analysis, but favorable trends in UACR, BP, and metabolic variables warrant further clinical study of PRL in DKD.

Funding

  • Commercial Support