A Randomized, Placebo‐Controlled, Multiple‐Ascending‐Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Soluble Guanylate Cyclase Stimulator Praliciguat in Healthy Subjects

Abstract

Nitric oxide (NO)‐soluble guanylate cyclase (sGC)‐cyclic guanosine monophosphate (cGMP) signaling is central to the regulation of several physiological processes, including blood flow and inflammation. Deficient NO signaling is implicated in multiple diseases. sGC stimulators are small molecules that enhance sGC activity, particularly in combination with NO. In a randomized, placebo‐controlled phase 1 study, the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the sGC stimulator praliciguat were assessed in 44 healthy adults. Four cohorts of 11 subjects (8 praliciguat, 3 placebo) received once‐daily praliciguat for 14 days before up‐titrating for 7 days (treatment sequences: 15/30 mg, 20/40 mg, 30/40 mg, and weight‐based). All doses were tolerated. No serious or severe adverse events (AEs) were reported. The most common AEs in praliciguat recipients were headache and symptoms consistent with blood pressure (BP) lowering/vasodilation. There were no laboratory, vital sign, electrocardiographic, or platelet function findings indicative of a safety concern. Pharmacokinetics were dose proportional, with an effective half‐life of 24–37 hours, supporting once‐daily dosing. Praliciguat produced dose‐related increases in plasma cGMP consistent with stimulation of sGC. Repeated once‐daily dosing showed sustained decreases in BP. Results support evaluation of praliciguat for the treatment of conditions associated with deficient NO signaling.

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

“…The QWBA study revealed that praliciguat was widely distributed, which is consistent with the large volume of distribution found for praliciguat in pharmacological studies in the rat ( V ss 10.5 L/kg, 7 and with the apparent volume of distribution in the humans ( V z / F 3100‐3610 L, 8). Tissues with the highest exposure ratios relative to plasma were liver, intestines, adrenal gland, and adipose, and those with the lowest values were seminal vesicle, blood, CNS tissues, lens of the eye, and bone, there was no specific association with melanin in the skin or eye.…”

“…In conclusion, praliciguat is extensively distributed to tissues and is eliminated by phase 1 and phase 2 metabolic pathways. Given the minor contribution of renal elimination, which was confirmed in the clinic, 8 praliciguat exposure is not expected to be altered in patients with impaired renal function. The extensive tissue distribution of praliciguat is unique among clinical‐stage sGC stimulators, and may make praliciguat particularly well suited for the treatment of cardiometabolic diseases with multiorgan involvement.…”

“…Praliciguat has a large volume of distribution in both preclinical and clinical studies, consistent with extensive distribution to tissues 7,8 . Higher levels of drug in tissues than in the bloodstream could enhance sGC pharmacology in target organs while minimizing effects on systemic blood pressure.…”

“…In addition, praliciguat treatment in a lipopolysaccharide‐induced inflammation study in mice demonstrated significant reductions in the pro‐inflammatory cytokines IL‐6 and TNF‐α 7 . 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 …”

Soluble Guanylate Cyclase Stimulators and Activators

“…Praliciguat is an sGC stimulator with a long half-life in preclinical species, extensive tissue distribution, and mainly hepatic clearance (Tobin et al 2018). Its pharmacokinetic half-life in humans is consistent with QD dosing (Hanrahan et al 2018). Praliciguat has completed Phase 1 studies in healthy subjects and Phase 2a exploratory studies in patients with type 2 diabetes and a history of hypertension (NCT02906579, NCT03091920) Praliciguat is currently under investigation for treatment of diabetic nephropathy (NCT03217591) and heart failure with preserved ejection fraction (NCT03254485).…”