Praliciguat, a Clinical-Stage sGC Stimulator, Improved Glucose Tolerance and Insulin Sensitivity and Lowered Triglycerides in a Mouse Diet-Induced Obesity Model

Schwartzkopf, Chad D.; Hadcock, John R.; Jones, Juli E.; Currie, Mark G.; Milne, G. Todd; Masferrer, Jaime L.

doi:10.2337/db18-1886-p

Cited by 4 publications

(5 citation statements)

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“…In this study, praliciguat treatment was also associated with modest reductions in certain metabolic measures, including HbA1c and total and LDL cholesterol levels. This is consistent with clinical data on praliciguat in people with type 2 diabetes and hypertension (36), as well as findings from nonclinical studies (36,45,46). Possible mechanisms of Intent-to-treat population.…”

Section: Discussionsupporting

confidence: 90%

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease

Hanrahan¹,

Bakris²,

Wilson³

et al. 2020

CJASN

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Background and objectivesImpaired nitric oxide signaling through soluble guanylate cyclase has been implicated in the pathophysiology of diabetic kidney disease. Praliciguat, a soluble guanylate cyclase stimulator that amplifies nitric oxide signaling, inhibited kidney inflammation and fibrosis in animal models.Design, setting, participants, & measurementsIn a phase 2 trial, 156 adults with type 2 diabetes, eGFR 30–75 ml/min per 1.73 m2, and urine albumin-creatinine ratio 200–5000 mg/g treated with renin-angiotensin system inhibitors were randomly allocated 1:1:1 to placebo, 20 mg praliciguat, or 40 mg praliciguat daily for 12 weeks. The primary efficacy and safety outcomes were change from baseline to weeks 8 and 12 in urine albumin-creatinine ratio and treatment-emergent adverse events, respectively. Other outcomes assessed were 24-hour ambulatory BP and metabolic parameters.ResultsOf 156 participants randomized, 140 (90%) completed the study. The primary efficacy analysis demonstrated a mean change from baseline in urine albumin-creatinine ratio of −28% (90% confidence interval, −36 to −18) in the pooled praliciguat group and −15% (−28 to 0.4) in the placebo group (difference −15%; −31 to 4; P=0.17). Between-group decreases from baseline to week 12 for praliciguat versus placebo were seen in mean 24-hour systolic BP (−4 mm Hg; −8 to −1), hemoglobin A1c (−0.3%; −0.5 to −0.03), and serum cholesterol (−10 mg/dl; −19 to −1). The incidence of treatment-emergent adverse events was similar in the pooled praliciguat and placebo groups (42% and 44%, respectively). Serious adverse events, events leading to study drug discontinuation, and events potentially related to BP lowering were reported at higher frequency in the 40-mg group but were similar in 20-mg and placebo groups.ConclusionsPraliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease.Clinical Trial registry name and registration number:A Study to Evaluate the Soluble Guanylate Cyclase (sGC) Stimulator IW-1973 in Diabetic Nephropathy/Diabetic Kidney Disease as Measured by Albuminuria, NCT03217591

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Section: Discussionsupporting

confidence: 90%

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease

Hanrahan¹,

Bakris²,

Wilson³

et al. 2020

CJASN

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“…The pharmacokinetic profile of praliciguat in individuals with diabetes and hypertension was found to be consistent with that observed in healthy volunteers, including rapid absorption, a high volume of distribution suggesting extensive dispersal into tissues, and a t ½ supportive of once daily dosing [10]. The large volume of distribution is consistent with high tissue-to-plasma concentration ratios observed in animal studies of praliciguat [8,9]. High local drug concentrations can produce sustained pharmacological effects [32] and supports investigation in conditions associated with impaired tissue NO-sGC-cGMP signalling.…”

Section: Resultssupporting

confidence: 72%

“…Praliciguat (IW-1973), an investigational sGC stimulator, decreased BP and protected against end-organ damage in nonclinical disease models relevant to diabetes and hypertension [8]. In addition, it demonstrated positive metabolic effects in a diet-induced obesity mouse model [9] and reduced proteinuria and fasting blood glucose in the ZSF1 rat model of diabetic nephropathy [6]. In healthy adults, plasma cGMP increased and haemodynamic effects were observed when praliciguat 15-40 mg was administered daily for up to 21 days [10].…”

Section: Introductionmentioning

confidence: 99%

An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension

et al. 2019

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Aims/hypothesis Praliciguat (IW-1973), a soluble guanylate cyclase stimulator, amplifies nitric oxide signalling. This exploratory trial investigated the safety, tolerability, pharmacokinetic profile and pharmacodynamic effects of praliciguat in individuals with type 2 diabetes and hypertension. Methods This Phase IIA, double-blind, placebo-controlled trial investigated praliciguat in 26 participants with type 2 diabetes and hypertension on stable glucose-and BP-lowering therapies. Participants were randomly allocated in a 3:5:5 ratio to three groups: placebo (n = 6), praliciguat 40 mg once daily for days 1-14 (n = 10), or praliciguat 20 mg twice daily for days 1-7 then 40 mg once daily for days 8-14 (n = 10). Assessments were made in clinic and included treatment-emergent adverse events, pharmacokinetics, metabolic variables, 24 h BP and heart rate, platelet function, reactive hyperaemia index (RHI) and plasma biomarkers. Participants, the sponsor, the investigator and clinic study staff (except designated pharmacy personnel) were blinded to group assignment. Results Participants treated for 14 days with praliciguat had least-square mean change-from-baseline differences vs placebo (95% CI) of −0.7 (−1.8, 0.4) mmol/l for fasting plasma glucose, −0.7 (−1.1, −0.2) mmol/l for total cholesterol, −0.5 (−1.0, −0.1) mmol/l for LDL-cholesterol, −23 (−56, 9) for HOMA-IR in those not being treated with insulin, and −5 (−10, 1) mmHg and 3 (−1, 6) beats/min for average 24 h mean arterial pressure and heart rate, respectively. Apart from one serious adverse event (SAE; upper gastrointestinal haemorrhage), praliciguat was well tolerated. Praliciguat did not affect platelet function or RHI. Among exploratory biomarkers, plasma levels of asymmetric dimethylarginine decreased in praliciguat vs placebo recipients. Conclusions/interpretation In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat. Trial registration ClinicalTrials.gov NCT03091920. Funding This trial was funded by Cyclerion Therapeutics.

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“…Treatment with the sGC stimulator BAY 41-8543 improved metabolic measures (weight gain, fat mass, diabetic phenotype) in a mouse diet-induced obesity (DIO) model (Hoffmann et al 2015). In a similar DIO model, treatment with the sGC stimulator praliciguat improved glucose tolerance and insulin sensitivity and lower triglycerides (Schwartzkopf et al 2018) Furthermore, olinciguat and praliciguat reduced fasting glucose in the ZSF1 model of diabetic nephropathy (Profy et al 2017;Masferrer et al 2016), and the sGC stimulator praliciguat reduced hepatic steatosis in an experimental NASH model (Flores-Costa et al 2017). The promising metabolic effects suggest evaluation of sGC stimulators in individuals with metabolic diseases including obesity, diabetes, hyperlipidemia, and metabolic syndrome, and NASH may be warranted.…”

Section: Metabolic Diseasementioning

confidence: 99%

Soluble Guanylate Cyclase Stimulators and Activators

Sandner

Zimmer

Milne

et al. 2018

Handbook of Experimental Pharmacology

131

149

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When Furchgott, Murad, and Ignarro were honored with the Nobel prize for the identification of nitric oxide (NO) in 1998, the therapeutic implications of this discovery could not be fully anticipated. This was due to the fact that available therapeutics like NO donors did not allow a constant and long-lasting cyclic guanylyl monophosphate (cGMP) stimulation and had a narrow therapeutic window. Now, 20 years later, the stimulator of soluble guanylate cyclase (sGC), riociguat, is on the market and is the only drug approved for the treatment of two forms of pulmonary hypertension (PAH/CTEPH), and a variety of other sGC stimulators and sGC activators are in preclinical and clinical development for additional indications. The discovery of sGC stimulators and sGC activators is a milestone in the field of NO/sGC/cGMP pharmacology. The sGC stimulators and sGC activators bind directly to reduced, heme-containing and oxidized, heme-free sGC, respectively, which results in an increase in cGMP production. The action of sGC stimulators at the heme-containing enzyme is independent of NO but is enhanced in the presence of NO whereas the sGC activators interact with the heme-free form of sGC. These highly innovative pharmacological principles of sGC stimulation and activation seem to have a very broad therapeutic potential. Therefore, in both academia and industry, intensive research and development efforts have been undertaken to fully exploit the therapeutic benefit of these new compound classes. Here we summarize the discovery of sGC stimulators and sGC activators and the current developments in both compound classes, including the mode of action, the chemical structures, and the genesis of the terminology and nomenclature. In addition, preclinical studies exploring multiple aspects of their in vitro, ex vivo, and in vivo pharmacology are reviewed, providing an overview of multiple potential applications. Finally, the clinical developments, investigating the treatment potential of these compounds in various diseases like heart failure, diabetic kidney disease, fibrotic diseases, and hypertension, are reported. In summary, sGC stimulators and sGC activators have a unique mode of action with a broad treatment potential in cardiovascular diseases and beyond.

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Praliciguat, a Clinical-Stage sGC Stimulator, Improved Glucose Tolerance and Insulin Sensitivity and Lowered Triglycerides in a Mouse Diet-Induced Obesity Model

Cited by 4 publications

References 0 publications

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease

An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension

Soluble Guanylate Cyclase Stimulators and Activators

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