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Background: Praliciguat (IW-1973) is an sGC stimulator in clinical development as a potential treatment for diabetic kidney disease. In animal models, praliciguat distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed the metabolic effects of praliciguat in diabetic TALLYHO mice housed at thermoneutrality in order to minimize any confounding contribution of brown fat thermogenesis on metabolism, which is rare in humans but common in mice. Methods: Six- to eight-week-old male TALLYHO/JngJ mice were maintained on low-fat diet (10% kcal from fat, LFD). Due to incomplete penetrance of the diabetic phenotype in this model, diabetic mice were identified prior to study initiation using HbA1c and urinary glucose/creatinine ratio as criteria. At 10-12 weeks of age, a diabetic control group (n=6) was maintained on LFD, while another group (n=6) was switched to LFD formulated with praliciguat to achieve a Cmax drug exposure similar to a 20 mg oral clinical dose. Plasma was collected at baseline and after 4 weeks of treatment. Oral glucose tolerance tests (OGTT) and oral lipid tolerance tests (LTT) were performed after 5 and 6 weeks of treatment, respectively. Results: At week 4, praliciguat treatment attenuated the HbA1c increase in TALLYHO diabetic mice (+0.40 vs. +0.95%, in praliciguat and control groups, respectively P Conclusion: Praliciguat improved nutrient handling in diabetic TALLYHO mice. Disclosure C. Schwartzkopf: None. A. Carvalho: Stock/Shareholder; Self; Cyclerion Therapeutics. J. Hadcock: None. M. Currie: Employee; Self; Cyclerion Therapeutics. Stock/Shareholder; Self; Cyclerion Therapeutics. J.E. Jones: None.

Background: The soluble guanylate cyclase (sGC) stimulator praliciguat (PRL) lowers blood pressure and improves metabolism in preclinical models. PRL is under development for diabetic nephropathy and therefore combination with antidiabetic agents such as empagliflozin (EMPA), a sodium glucose cotransporter 2 (SGLT2) inhibitor, is of interest. Here, we assessed the metabolic effects of PRL, EMPA, and their combination in SD rats with programmed hypertension and early exposure to high fat diet (HT-HF), a model with several features of metabolic syndrome - hypertension, glucose intolerance and increased adiposity. Methods: Mean arterial pressure (MAP) and abdominal fat (AF) were determined at 12 weeks of age in 4 groups of HT-HF rats that were subsequently treated for 6 weeks with vehicle control (HT-HF), PRL (10 mg/kg/day), EMPA (7.5 mg/kg/day), or PRL+EMPA. A normotensive, non-disease group on normal diet was also included. At Week 6 of treatment, an intraperitoneal glucose tolerance test (GTT) was performed, and MAP, AF, plasma leptin, and adipocyte area (AA) were measured. Results: See table. Conclusion: The sGC stimulator praliciguat in combination with the SGLT2 inhibitor empagliflozin has additive pharmacological effects in a rat programmed hypertension model. Disclosure C. Schwartzkopf: None. V. Reverte Ribó: Research Support; Self; Cyclerion. F. Rodriguez: Research Support; Self; CYCLERION. L. Oltra: Research Support; Self; Cyclerion. J. Moreno Ayuso: Research Support; Self; Cyclerion. M. Llinás: Research Support; Self; Cyclerion. A.S. Nicolas: None. C. Shea: None. M. Currie: Employee; Self; Cyclerion Therapeutics. Stock/Shareholder; Self; Cyclerion Therapeutics. J.E. Jones: None. E.S. Buys: Employee; Self; Cyclerion. Stock/Shareholder; Self; Cyclerion. J. Masferrer: None. F. Salazar aparicio: Research Support; Self; Cyclerion.

Background: Praliciguat (IW-1973) is a soluble guanylate cyclase (sGC) stimulator under clinical investigation as a potential treatment for diabetic nephropathy. In animal models, praliciguat distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed the metabolic effects of praliciguat in a mouse diet-induced obesity (DIO) model when housed at thermoneutrality. Methods: Six week old male C57BL/6N mice were maintained on a low-fat diet (LFD, lean mice) or put on a 60% high-fat diet (HFD, obese mice). At 14 weeks of age, one group of obese mice was maintained on HFD (obese controls) while another group of obese mice was switched to HFD formulated with praliciguat to achieve a Cmax similar to a daily oral administration of 6 mg/kg (praliciguat treatment). A group of lean mice were also included (lean controls). Indirect calorimetry was performed on days 8, 9, 20, 21, 32 and 33. On day 35, an oral lipid tolerance test (LTT) was conducted. In a second study under the same dosing paradigm, overnight fasted blood and organs were collected on day 28. Results: Compared to obese controls, energy expenditure was higher in praliciguat-treated mice throughout a 24h recording period as assessed by AUC (Day 8: +13%, Day 20: +9%, Day 21: +7%, Day 32: +5%, P Conclusions: In a mouse DIO model housed at thermoneutrality, praliciguat increased energy utilization, improved triglycerides in response to an oral lipid challenge, improved insulin sensitivity, and lowered plasma triglycerides. Disclosure C. Schwartzkopf: Employee; Self; Ironwood Pharmaceuticals, Inc. J. Hadcock: Employee; Self; Ironwood Pharmaceuticals, Inc. J. Roux: None. G. Liu: None. C. Shea: Employee; Self; Ironwood Pharmaceuticals, Inc. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G. Milne: Employee; Spouse/Partner; Catabasis Pharmaceuticals. Employee; Self; Ironwood Pharmaceuticals, Inc. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc. J. Masferrer: Employee; Self; Ironwood Pharmaceuticals, Inc. J.E. Jones: None.

Background: Praliciguat (IW-1973) is a soluble guanylate cyclase (sGC) stimulator in clinical development. In animal models, praliciguat has broad tissue distribution and enhances nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling, which has been shown to elicit hemodynamic, anti-inflammatory, and anti-fibrotic effects. This study assessed the metabolic effects of praliciguat in a mouse DIO model. Methods: Male C57BL/6J mice (12 weeks old at the start of treatment) were either maintained on regular chow (lean mice) or switched to a 60% high fat diet (HFD) starting at age 6 weeks (obese mice). At the start of treatment, obese mice received either praliciguat (6 mg/kg) or vehicle in the HFD. The lean mice remained on regular chow. On day 28, an oral glucose tolerance test (OGTT) was performed after a 3-h fast. On day 29, organs and terminal blood were collected for analysis after a 3-h fast. Results: Praliciguat treatment lowered OGTT glucose area under the curve (-22%, P Conclusions: Praliciguat improved insulin sensitivity, glucose tolerance, and yielded lower circulating and liver triglycerides in a mouse diet-induced obesity model. Disclosure C.D. Schwartzkopf: None. J. Hadcock: None. J.E. Jones: None. M. Currie: Employee; Self; Ironwood Pharmaceuticals, Inc. G.T. Milne: Employee; Self; Ironwood Pharmaceuticals, Inc.. Stock/Shareholder; Self; Ironwood Pharmaceuticals, Inc.. Employee; Spouse/Partner; Catabasis Pharmaceuticals. Stock/Shareholder; Spouse/Partner; Catabasis Pharmaceuticals. J. Masferrer: Employee; Self; Ironwood Pharmaceuticals, Inc..

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.

This study was undertaken to compare the ability of two guanidine compounds (aminoguanidine and methylguanidine), with different in vitro effects on NO synthase activity and AGE formation, to inhibit diabetic vascular dysfunction developing early after the onset of diabetes. In rats with STZ-induced diabetes of 5-wk duration, regional vascular [125I]albumin permeation was increased about two- to threefold in ocular tissues, sciatic nerve, and aorta; in general, both guanidine compounds normalized albumin permeation in diabetic rats without affecting it in controls. Methylguanidine was only approximately 7% as effective as aminoguanidine as an inhibitor of AGE formation from L-lysine and G6P; both compounds were poor inhibitors of AR. Methylguanidine was approximately 1-5% as potent as aminoguanidine and L-NMMA as an inhibitor of the cytokine- and endotoxin-inducible isoform of NO synthase. In contrast, the potency of methylguanidine as an inhibitor of the constitutive isoform of NO synthase was comparable to that of aminoguanidine, and both guanidine compounds were much less effective than L-NMMA. These observations suggest a role for a relative or absolute increase in NO production in the pathogenesis of early diabetic vascular dysfunction and raise the possibility that inhibition of diabetic vascular functional changes by aminoguanidine may reflect inhibition of NO synthase activity rather than, or in addition to, prevention of AGE formation.