Rapid Dose Escalation Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension

Abstract

Background: Impaired nitric oxide (NO) signaling through soluble guanylate cyclase (sGC) has been associated with microvascular complications of diabetes. Praliciguat (IW-1973), an sGC stimulator that enhances NO signaling, reduced fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In a Phase 1 clinical study in healthy adults, doses of 15-40 mg were tolerated and lowered blood pressure (BP). Methods: This Phase 2a open-label in-clinic study assessed the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of oral praliciguat in 11 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP therapy. Patients received sequential 3-day dosing cycles escalating through placebo (PBO), 10, 20, 30, 40 and 50 mg praliciguat QD. Assessments included adverse events (AEs), blood chemistry, ambulatory BP and heart rate, platelet function, and reactive hyperemia index (RHI). Results: The escalating dose regimen was generally well tolerated; there were no serious or severe AEs. Escalation in 2 patients was stopped due to asymptomatic BP lowering. Overall PK showed a median Tmax of 1-3 h, low to moderate variability, and ∼2-fold accumulation supporting QD dosing. Average 12-h daytime mean arterial BP decreased by 2 to 9 mmHg relative to time-matched PBO baseline across praliciguat dose levels, while heart rate increased 4 to 7 bpm. Notable changes from PBO baseline [mean (95% CI)] at the end of treatment were seen for fasting serum glucose [-26.5 mg/dL (-43.4, -9.5], HbA1c [-0.4% (-0.8, -0.04)], cholesterol [-43 mg/dL (-67, -20)], and body weight [-3.5 kg (-4.9, -2.0)]. Praliciguat had no effect on RHI or platelet function. Conclusion: T2DM patients with hypertension on standard therapy showed improvements in hemodynamics and metabolic parameters in this small in-clinic study. These results support further evaluation of praliciguat in T2DM patients including those with complications. Disclosure J.P. Hanrahan: Employee; Self; Ironwood. J.D. Wakefield: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. P.J. Wilson: None. D.P. Zimmer: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. M. Mihova: None. J. Chickering: None. D. Ruff: None. M.L. Hall: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. A.T. Profy: Other Relationship; Self; Ironwood Pharmaceuticals.