Fourteen-Day Study of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in Patients with Diabetes and Hypertension

Abstract

Background: Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, has been shown to augment nitric oxide (NO) signaling and reduce fasting plasma glucose and proteinuria in an animal model of diabetic nephropathy. In healthy adults, repeated oral doses of 15-40 mg were tolerated and lowered blood pressure (BP). Methods: This Phase 2a, double-blind, placebo (PBO)-controlled study assessed the effects of oral praliciguat in 26 patients with type 2 diabetes mellitus (T2DM) and hypertension on stable glycemic and BP-lowering therapy. Most (69%) were also on statins. Two praliciguat regimens were tested: (1) 40 mg QD for days 1-14 (N=10), and (2) 20 mg BID for days 1-7 then 40 mg QD for days 8-14 (N=10). Assessments included serum chemistry, fasting plasma glucose, BP and heart rate, platelet function, reactive hyperemia index (RHI), plasma biomarkers, and adverse events (AEs). Results: Results were similar for both praliciguat regimens and are here combined. After 14 days of treatment, praliciguat-treated patients had notable differences in least squares mean change from baseline (95% CI) relative to PBO in 24-hour mean arterial pressure [-4.7 mmHg (-10, 0.8)], heart rate [2.9 bpm (-0.7, 6.5)], fasting glucose [-13 mg/dL (-32, 7)], HOMA-IR [-26 (-58, 7)], total serum cholesterol [-26 mg/dL (-44, -7)], and LDL cholesterol [-20 mg/dL (-37, -3)]. Praliciguat had no effect on platelet function or RHI. Among the exploratory biomarkers tested, levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine were lower in praliciguat vs. PBO recipients. Both praliciguat dose regimens were generally well tolerated. Except for one serious AE of upper gastrointestinal hemorrhage, AEs in praliciguat-treated patients were mild. Conclusion: In this initial trial, praliciguat had beneficial effects on BP and metabolic parameters in T2DM patients with hypertension on standard therapies. Further clinical investigation of praliciguat in T2DM patients is warranted. 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. P. Miller: None. J. Chickering: None. L. Morrow: Stock/Shareholder; Self; ProSciento. Employee; Spouse/Partner; Eli Lilly and Company. 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.

Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model

“…We fed DIO mice HFD that was formulated with or without praliciguat. In both studies, the resulting blood exposure achieved with praliciguat-formulated HFD (0.4-0.9 nM; data not shown) was within the range of the concentrations measured in a clinical study in humans with type 2 diabetes and hypertension (Hanrahan et al, 2018;Hanrahan et al, 2020b).…”

sGC stimulator praliciguat suppresses stellate cell fibrotic transformation and inhibits fibrosis and inflammation in models of NASH

“…Thus, it may partially oppose the antiinflammatory and antifibrotic effects of praliciguat. Clinical doses of praliciguat resulted in exposures similar to those observed in groups receiving 1 and 3 mg/kg per day (25).…”

“…Similar effects in the DIO model were previously noted with a different sGC stimulator, Bay 41-8543 (30). In an exploratory phase 2 clinical study, subjects with type 2 diabetes and controlled hypertension who received daily praliciguat for 2 wk had lower levels of plasma LDL cholesterol and triglycerides than the subjects receiving placebo, suggesting that praliciguat can also affect metabolism in humans (25). Although, further studies will be needed to clarify the exact mechanism behind this metabolic modulation; our current findings suggest a role for AMPK, a pathway recently suggested to be the connection between nitrate–nitrite–NO signaling and decreased steatosis (31).…”

Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of praliciguat, a clinical‐stage soluble guanylate cyclase stimulator in rats

“…Clinically, oral administration of praliciguat in healthy volunteers was associated with elevation of cGMP and modest reductions in blood pressure, indicating target engagement and stimulation of the NO‐sGC‐cGMP pathway 8 . These hemodynamic effects were also observed in an exploratory clinical study in patients with type 2 diabetes and hypertension, along with additional positive trends on metabolic and lipid parameters 9 …”

“…In addition to the anti‐inflammatory, antifibrotic, renoprotective, and hepatoprotective effects of praliciguat demonstrated in preclinical models, 7,13,14 emerging preclinical and clinical data indicate that praliciguat may have favorable effects on metabolic parameters, including cholesterol and insulin resistance 9,15,16 . These effects are of particular interest since, to our knowledge, they have not been reported for other sGC stimulators in humans and could be accentuated by the extensive tissue distribution of praliciguat.…”