First-in-Human Single-Ascending-Dose Study of Iw-1973, a New Soluble Guanylate Cyclase Stimulator

Hanrahan, John P.; Profy, Albert T.; Lavins, Bernard J.; Ruff, Dennis; Poirier, Gabrielle; Wakefield, James; Wilson, Phebe; Hall, Michael; Currie, Mark G.

doi:10.1016/s0735-1097(16)31285-2

Cited by 4 publications

(6 citation statements)

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“…In this study, we explored the effects of the sGC stimulator IW‐1973 which is under clinical investigation for the treatment of heart failure with preserved ejection fraction but with the added complications of diabetes. IW‐1973 was selected because of its extensive tissue distribution, high oral bioavailability and long pharmacokinetic half‐life, which is consistent with once daily dosing in humans (Hanrahan et al ., ). Specifically, in this study, we explored the effects of IW‐1973 in an optimized murine model of NASH induced by the combination of a choline‐deficient l ‐amino acid‐defined diet with a high‐fat (CDAAH) diet (Matsumoto et al ., ).…”

Section: Introductionmentioning

confidence: 97%

The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

Flores‐Costa

Alcaraz‐Quiles

Titos

et al. 2018

British J Pharmacology

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Background and PurposeNon‐alcoholic steatohepatitis (NASH) is the hepatic manifestation of metabolic syndrome and is characterized by steatosis, inflammation and fibrosis. Soluble guanylate cyclase (sGC) stimulation reduces inflammation and fibrosis in experimental models of lung, kidney and heart disease. Here, we tested whether sGC stimulation is also effective in experimental NASH.Experimental ApproachNASH was induced in mice by feeding a choline‐deficient, l‐amino acid‐defined, high‐fat diet. These mice received either placebo or the sGC stimulator IW‐1973 at two different doses (1 and 3 mg·kg−1·day−1) for 9 weeks. IW‐1973 was also tested in high‐fat diet (HFD)‐induced obese mice. Steatosis, inflammation and fibrosis were assessed by Oil Red O, haematoxylin–eosin, Masson's trichrome, Sirius Red, F4/80 and α‐smooth muscle actin staining. mRNA expression was assessed by quantitative PCR. Levels of IW‐1973, cytokines and cGMP were determined by LC‐MS/MS, Luminex and enzyme immunoassay respectively.Key ResultsMice with NASH showed reduced cGMP levels and sGC expression, increased steatosis, inflammation, fibrosis, TNF‐α and MCP‐1 levels and up‐regulated collagen types I α1 and α2, MMP2, TGF‐β1 and tissue metallopeptidase inhibitor 1 expression. IW‐1973 restored hepatic cGMP levels and sGC expression resulting in a dose‐dependent reduction of hepatic inflammation and fibrosis. IW‐1973 levels were ≈40‐fold higher in liver tissue than in plasma. IW‐1973 also reduced hepatic steatosis and adipocyte hypertrophy secondary to enhanced autophagy in HFD‐induced obese mice.Conclusions and ImplicationsOur data indicate that sGC stimulation prevents hepatic steatosis, inflammation and fibrosis in experimental NASH. These findings warrant further evaluation of IW‐1973 in the clinical setting.

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Section: Introductionmentioning

confidence: 97%

The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

Flores‐Costa

Alcaraz‐Quiles

Titos

et al. 2018

British J Pharmacology

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“…Pharmacodynamic (PD) effects included dose‐related increases in heart rate and decreases in blood pressure, as well as dose‐related increases in plasma cGMP levels and plasma renin activity (PRA). No effect on platelet function was observed …”

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confidence: 94%

“…In a phase 1 first‐in‐human study in healthy subjects, single oral doses of praliciguat (3 to 100 mg) in a polyethylene glycol solution formulation were tested. Doses up to 35 mg were tolerated . The most common adverse events (AEs) in praliciguat‐treated subjects were headache, tachycardia, vomiting, dizziness/postural dizziness, hypotension, and nausea.…”

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confidence: 99%

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

Hanrahan

Wakefield

Wilson

et al. 2018

Clinical Pharm in Drug Dev

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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.

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“…Pharmacology of IW-1973, a Novel sGC Stimulator moderate clearance. Clinical studies suggest that predictions of once daily dosing from preclinical models translate to humans (Hanrahan et al, 2017). Mass balance studies performed in rats revealed that IW-1973 was primarily cleared by the liver (Zimmer et al, 2017).…”

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confidence: 99%

“…IW-1973 has high oral bioavailability and a long PK half-life, which translated into PK consistent with once daily dosing in humans. Indeed, in a phase 1 study in healthy volunteers, once daily dosing of IW-1973 elicited not only dose-related increases in plasma cGMP but also reductions in blood pressure that were sustained through 24 hours postdose (Hanrahan et al, 2017). Clinical studies will be required to determine whether the ability of IW-1973 to enhance NO-sGC-cGMP signaling offers the potential to treat diseases associated with impaired NO signaling as well as diseases involving inflammation and fibrosis.…”

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confidence: 99%

Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease

Tobin

Zimmer

Shea

et al. 2018

J Pharmacol Exp Ther

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Soluble guanylate cyclase (sGC), a key signal-transduction enzyme, increases the conversion of guanosine-5'-triphosphate to cGMP upon binding of nitric oxide (NO). Endothelial dysfunction and/or reduced NO signaling have been implicated in cardiovascular disease pathogenesis and complications of diabetes and have been associated with other disease states and aging. Soluble guanylate cyclase (sGC) stimulators are small-molecule drugs that bind sGC and enhance NO-mediated cGMP signaling. The pharmacological characterization of IW-1973 [1,1,1,3,3,3-hexafluoro-2-(((5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1-pyrazol-3-yl) pyrimidin-4-yl)amino)methyl)propan-2-ol], a novel clinical-stage sGC stimulator under clinical investigation for treatment of heart failure with preserved ejection fraction and diabetic nephropathy, is described. In the presence of NO, IW-1973 stimulated sGC in a human purified enzyme assay and a HEK-293 whole cell assay. sGC stimulation by IW-1973 in cells was associated with increased phosphorylation of vasodilator-stimulated phosphoprotein. IW-1973, at doses of 1-10 mg/kg, significantly lowered blood pressure in normotensive and spontaneously hypertensive rats. In a Dahl salt-sensitive hypertension model, IW-1973 significantly reduced blood pressure, inflammatory cytokine levels, and renal disease markers, including proteinuria and renal fibrotic gene expression. The results were affirmed in mouse lipopolysaccharide-induced inflammation and rat unilateral ureteral obstruction renal fibrosis models. A quantitative whole-body autoradiography study of IW-1973 revealed extensive tissue distribution and pharmacokinetic studies showed a large volume of distribution and a profile consistent with predicted once-a-day dosing in humans. In summary, IW-1973 is a potent, orally available sGC stimulator that exhibits renoprotective, anti-inflammatory, and antifibrotic effects in nonclinical models.

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First-in-Human Single-Ascending-Dose Study of Iw-1973, a New Soluble Guanylate Cyclase Stimulator

Cited by 4 publications

References 0 publications

The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

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

Pharmacological Characterization of IW-1973, a Novel Soluble Guanylate Cyclase Stimulator with Extensive Tissue Distribution, Antihypertensive, Anti-Inflammatory, and Antifibrotic Effects in Preclinical Models of Disease

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