Soluble Guanylate Cyclase Stimulator Research Articles

Praliciguat inhibits progression of diabetic nephropathy in ZSF1 rats and suppresses inflammation and apoptosis in human renal proximal tubular cells.

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In the present study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy. Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury was lower in praliciguat-treated obese ZSF1 rats than in obese control rats; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacological effects on the kidneys, we studied the effects of praliciguat on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTCs). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein-1 in tumor necrosis factor-α-challenged RPTCs. Praliciguat treatment also attenuated transforming growth factor-β-mediated apoptosis, changes to a mesenchyme-like cellular phenotype, and phosphorylation of SMAD3 in RPTCs. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of diabetic nephropathy, and its actions in human RPTCs suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

A Surrogate Matrix-Based Approach Toward Multiplexed Quantitation of an sGC Stimulator and cGMP in Ocular Tissue and Plasma.

A liquid chromatography-tandem mass spectrometry assay was developed and qualified for the multiplexed quantitation of a small molecule stimulator of soluble guanylate cyclase (sGC) and its target engagement biomarker, 3',5'-cyclic guanosine monophosphate (cGMP), in ocular tissues and plasma from a single surrogate matrix calibration curve. A surrogate matrix approach was used in this assay due to the limited quantities of blank ocular matrices in a discovery research setting. After optimization, the assay showed high accuracy, precision, and recovery as well as parallelism between the surrogate matrix and the biological matrices (rabbit plasma, vitreous, and retina-choroid). This assay provided pharmacokinetic and target engagement data after intravitreal administration of the sGC stimulator. The nitric oxide-sGC-cGMP pathway is a potential target to address glaucoma. Increasing sGC-mediated production of cGMP could improve aqueous humor outflow and ocular blood flow. The sGC stimulator showed dose-dependent exposure in rabbit vitreous, retina-choroid, and plasma. The cGMP exhibited a delayed yet sustained increase in vitreous humor but not retina-choroid. Multiplexed measurement of both pharmacokinetic and target engagement analytes reduced animal usage and provided improved context for interpreting PK and PD relationships.

Management of Patients with Heart Failure: Focus on New Pharmaceutical and Device Options

Hospitalization rates and survival of patients with Heart Failure (HF) have improved. However, 5-year mortality rates remain high and the prevalence of the disease is rising likely due to aging of the population and advances in diagnosis and treatment of other acute and chronic cardiovascular diseases. Over the past three decades the therapeutic armamentarium of heart failure has improved substantially with development of medications targeting neuro-hormonal activation and devices preventing sudden cardiac death and improving cardiac synchrony. Recently, inhibition of angiotensin receptors and neprilysin as well as sinoatrial pacemaker modulating f-current, have been found safe and effective strategies that improve HF hospitalization rates and/or mortality. Antidiabetic agents inhibiting sodium-glucose co-transporters 2, result in natriuresis and osmotic diuresis and may further improve HF related outcomes. Furthermore, emerging therapies such as cardiac myosin activators, soluble guanylate cyclase stimulators and non-steroidal mineralocorticoid receptor antagonists are undergoing investigation in phase II and III studies of HF patients. Finally, rapid evolution of in the management of advanced HF has occurred with the application of second and third generation continuous flow left ventricular assist devices in clinical practice. Ongoing clinical studies will validate the safety and efficacy of emerging therapeutic strategies in HF population underrepresented in previous clinical trials.

Management of hospitalized patients with pulmonary arterial hypertension and COVID-19 infection.

Management of hospitalized patients with pulmonary arterial hypertension and COVID-19 infection.

Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies).

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg–maximum (N = 131 pretreated patients) and placebo (N = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: –8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.

1073-P: Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Soluble Guanylate Cyclase Stimulator Praliciguat in Patients with Diabetic Kidney Disease

Background: Impaired nitric oxide (NO) signaling has been implicated in the progression of diabetic kidney disease (DKD). Praliciguat (PRL) is a soluble guanylate cyclase stimulator that augments NO signaling in vitro and reduces proteinuria and fasting plasma glucose in the ZSF1 rat model of DKD. Methods: We evaluated the safety and efficacy of PRL in adults (25-75 y) with type 2 diabetes, eGFR 30-75 mL/min/1.73 m2, urine albumin creatinine ratio (UACR) 200-5000 mg/g, hemoglobin A1c (HbA1c) <12%, systolic blood pressure (BP) 110-160 mmHg, on stable glucose-lowering and renin angiotensin system-inhibition therapy. Participants were randomized 1:1:1 to placebo (PBO), PRL 20 mg, or PRL 40 mg daily for 12 weeks. Two first morning void specimens for UACR were collected at baseline and weeks 1, 4, 8, 12. Adverse events, 24 h BP and serum chemistry were also assessed. The primary efficacy endpoint was change from baseline (CFB) in UACR to weeks 8 and 12 analyzed by mixed-effect repeated measures model to compare pooled PRL vs. PBO. Results: A total of 156 participants enrolled and 140 completed treatment. Model estimates of mean UACR CFB [90% CI] [intent-to-treat (ITT)] were -28% [-36, -18] for pooled PRL and -15% [-27, 0] for PBO; PBO-adjusted UACR CFB was -15% [-31, 4] (p=0.17). Quality checks identified a site with data inconsistent with that from the overall study population. In a post-hoc sensitivity analysis excluding this site, PBO-adjusted UACR CFB for PRL was -20% [-33, 5], nominal p=0.03. PBO-adjusted CFB for other variables at week 12 (ITT) were 24 h systolic BP -4.2 mmHg [-7.5, -0.8], 24 h heart rate 3.4 bpm [1.6, 5.2], HbA1c -0.27% [-0.50, 0.03], and cholesterol 10.1 mg/dL [-19.2, -1.0]. Both praliciguat doses were well tolerated. Conclusion: PRL did not significantly reduce UACR in the primary ITT analysis, but positive trends in UACR, BP, and metabolic variables warrant further clinical study of PRL in DKD. Disclosure J.P. Hanrahan: Employee; Self; Cyclerion Therapeutics. I. de Boer: Advisory Panel; Self; Boehringer Ingelheim International GmbH. Consultant; Self; George Clinical, Goldfinch Bio, Ironwood Pharmaceuticals. G. Bakris: Consultant; Self; Alnylam, Merck & Co., Inc., Relypsa, Inc., Teijin Pharma Limited. Other Relationship; Self; Bayer AG, Novo Nordisk Inc., Vascular Dynamics. P. Wilson: Employee; Self; Cyclerion Therapeutics. J.D. Wakefield: Stock/Shareholder; Self; Cyclerion Therapeutics. J.P. Seferovic: Employee; Self; Cyclerion Therapeutics. J. Chickering: None. M. Cressman: Employee; Self; Covance, LabCorp. M. Currie: Employee; Self; Cyclerion Therapeutics. Stock/Shareholder; Self; Cyclerion Therapeutics. G.T. Milne: None. A.T. Profy: Employee; Self; Cyclerion Therapeutics, Ironwood Pharmaceuticals. Employee; Spouse/Partner; UpToDate. Stock/Shareholder; Self; Cyclerion Therapeutics, Ironwood Pharmaceuticals. Funding Cyclerion Therapeutics

1081-P: Metabolic Effects of Praliciguat, Empagliflozin, and Their Combination in Rats with Programmed Hypertension and Early Exposure to High-Fat Diet

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.

124-LB: Praliciguat, a Clinical-Stage Soluble Guanylate Cyclase (sGC) Stimulator, Improved Oral Glucose and Lipid Handling and Slowed Diabetic Weight Loss in TALLYHO Mice

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<0.05). At week 5, fasting glucose (561 ± 33 vs. 650 ± 46 mg/dl; -14%, P<0.01) and OGTT glucose AUC (-12%, P<0.01) were lower in praliciguat-treated mice than in untreated controls. At week 6, fasting plasma triglycerides (721 ± 97 vs. 1134 ± 190 mg/dl; -36%, P<0.05) and LTT triglyceride AUC (-23%, P<0.01) were lower in praliciguat-treated mice than in untreated controls. Body weight loss and food intake were lower in praliciguat-treated mice than in untreated mice. 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.

Metabolism and Pharmacokinetic Drug-Drug Interaction Profile of Vericiguat, A Soluble Guanylate Cyclase Stimulator: Results From Preclinical and Phase I Healthy Volunteer Studies.

BackgroundVericiguat is a stimulator of soluble guanylate cyclase currently under investigation as a first-in-class therapy for worsening chronic heart failure (NCT02861534). Patients with heart failure often require polypharmacy because of comorbidities. Hence, understanding the clearance mechanisms, elimination, and potential for pharmacokinetic drug–drug interactions of vericiguat is important for dose recommendations in this patient population.MethodsBiotransformation and perpetrator properties of vericiguat were characterized in vitro using human hepatocytes, liver microsomes, and recombinant enzymes. This was complemented by a human mass balance study and ten drug–drug interaction studies in healthy volunteers wherein vericiguat was co-administered orally with omeprazole, magnesium/aluminum hydroxide, ketoconazole, rifampicin, mefenamic acid, midazolam, warfarin, digoxin, sacubitril/valsartan, aspirin, or sildenafil.ResultsIn the human mass balance study, mean total radioactivity recovered was 98.3% of the dose administered (53.1% and 45.2% excreted via urine and feces, respectively). The main metabolic pathway of vericiguat is glucuronidation via uridine diphosphate-glucuronosyltransferase 1A9 and 1A1. In vitro studies revealed a low risk of vericiguat acting as a perpetrator by inhibiting cytochrome P450s, uridine diphosphate-glucuronosyltransferase isoforms, or major transport proteins, or by inducing cytochrome P450s. These observations were supported by phase I drug–drug interaction studies. Phase I studies that assessed the propensity of vericiguat as a victim drug showed changes in the range that did not warrant recommendations for dose adjustment in phase III.ConclusionsA low pharmacokinetic interaction potential of vericiguat was estimated from in vitro data and confirmed in vivo. Thus, vericiguat is suitable for a patient population with multiple comorbidities requiring polypharmacy.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00895-x) contains supplementary material, which is available to authorized users.

Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction

BackgroundThe effect of vericiguat, a novel oral soluble guanylate cyclase stimulator, in patients with heart failure and reduced ejection fraction who had recently been hospitalized or had received intravenous diuretic therapy is unclear.MethodsIn this phase 3, randomized, double-blind, placebo-controlled trial, we assigned 5050 patients with chronic heart failure (New York Heart Association class II, III, or IV) and an ejection fraction of less than 45% to receive vericiguat (target dose, 10 mg once daily) or placebo, in addition to guideline-based medical therapy. The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure.ResultsOver a median of 10.8 months, a primary-outcome event occurred in 897 of 2526 patients (35.5%) in the vericiguat group and in 972 of 2524 patients (38.5%) in the placebo group (hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.02). A total of 691 patients (27.4%) in the vericiguat group and 747 patients (29.6%) in the placebo group were hospitalized for heart failure (hazard ratio, 0.90; 95% CI, 0.81 to 1.00). Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). The composite of death from any cause or hospitalization for heart failure occurred in 957 patients (37.9%) in the vericiguat group and in 1032 patients (40.9%) in the placebo group (hazard ratio, 0.90; 95% CI, 0.83 to 0.98; P=0.02). Symptomatic hypotension occurred in 9.1% of the patients in the vericiguat group and in 7.9% of the patients in the placebo group (P=0.12), and syncope occurred in 4.0% of the patients in the vericiguat group and in 3.5% of the patients in the placebo group (P=0.30).ConclusionsAmong patients with high-risk heart failure, the incidence of death from cardiovascular causes or hospitalization for heart failure was lower among those who received vericiguat than among those who received placebo. (Funded by Merck Sharp & Dohme [a subsidiary of Merck] and Bayer; VICTORIA ClinicalTrials.gov number, NCT02861534.)

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry.

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.

SUN-662 Praliciguat, a Clinical-Stage Soluble Guanylate Cyclase Stimulator, Improves Lipid Handling and Insulin Sensitivity in Diet-Induced Obese Mice

Praliciguat (PRL) is a soluble guanylate cyclase (sGC) stimulator which in animal models distributes broadly to tissues and elicits hemodynamic, anti-inflammatory, anti-fibrotic, and metabolic effects. Here, we assessed metabolic effects of PRL in a mouse diet-induced obesity model.Six-week-old male C57BL/6N mice were maintained on a low-fat diet (LFD, lean mice) or placed on a 60% high-fat diet (HFD, obese mice). At age 14 weeks, one group of obese mice was maintained on HFD (obese controls) and one group of obese mice was switched to HFD formulated with PRL to achieve a Cmax similar to a 6-mg/kg oral dose (PRL-treated mice). After 38 days of treatment, an oral lipid tolerance test (LTT) was conducted. In a 2nd study under the same dosing paradigm, overnight fasted blood and organs were collected on day 28.As reported previously (1), compared to obese controls, PRL-treated mice had lower fasting insulin (-28%), HOMA-IR (-26%) and triglycerides (-16%) as well as lower plasma triglycerides AUC after LTT (-34%). Gene expression and phosphorylated proteins associated with insulin pathways were measured in liver, skeletal muscle and white adipose tissue. PRL treatment normalized expression of genes involved in lipid handling (liver Pnpla3, Slc27a1, Lpl; muscle Lipe; white adipose tissue Fdft1, Ppara). Expression of proinflammatory genes (liver Tnf; muscle Ccl2; white adipose tissue Akt1, Icam1) was lower in PRL-treated mice than in obese controls. Liver insulin signaling was assessed by determining pAKT (T308) and pAKT (S473), markers of PI3K pathway activity and pERK, a marker of MAPK pathway activity. Compared to lean mice, pAKT (T308) and pERK were lower in obese controls, whereas pAKT (S473) was similar; PRL-treated mice had higher pAKT (T308) and pAKT (S473) compared to obese controls while pERK was unchanged. In skeletal muscle and white adipose tissue, levels of pVASP, a key mediator of the sGC pathway, were higher in PRL-treated mice than in obese controls.In summary, PRL improved insulin sensitivity and lipids in diet-induced obese mice by affecting mechanisms of lipid handling, inflammation, and insulin signaling in key tissues associated with metabolism.1. Author information excluded, 1924-P: Praliciguat, a Clinical-Stage sGC Stimulator, Improves Insulin Sensitivity, Lipid Tolerance, and Energy Utilization in a Mouse Diet-Induced Obesity Model Housed at Thermoneutrality. Diabetes, 2019. 68(Supplement 1): p. 1924-P.

Soluble Guanylate Cyclase Stimulators for Chronic Thromboembolic Pulmonary Hypertension Patients Treatment: New Data

This narrative review describes and appraises some relatively new studies investigating the efficacy and safety profile of soluble guanylate cyclase stimulator riociguat in patients suffering from pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). It has been a while since the publication date of pivotal CHEST-1 trial in 2013. New studies available complement existing evidence, expound on specific questions and open new frontiers for CTEPH investigations going forward. In this paper authors attempted to present data from post-hocanalysis of the CHEST-1 study and real-world data on riociguat treatment, confirming the positive effect of the drug on hemodynamic parameters of the pulmonary circulation and the functional status of patients. This effect was shown previously in large randomized trials. The extremely important positive effect of riociguat demonstrated both in the group of inoperable patients with CTEPH and in patients with residual pulmonary hypertension after pulmonary thrombendarterectomy. Of great interest are the presented some authors results of reverse remodelling of the right heart chambers during riociguat therapy in CTEPH patients, including using unique imaging methods (magnetic resonance imaging and positron emission tomography) to evaluate targeted medicinal therapy in terms of right heart remodelling. The safety profile of the drug was analyzed in the long-term post-registration international, multicenter, prospective, observational study EXPERT (NCT02092818), which confirmed the good tolerability and safety of riociguat therapy in PAH and CTEPH patients.

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

The pharmacokinetics (PK), metabolism, excretion, mass balance, and tissue distribution of [14C]praliciguat were evaluated following oral administration of a 3‐mg/kg dose in Sprague‐Dawley rats and in a quantitative whole‐body autoradiography (QWBA) study conducted in male Long‐Evans rats. Plasma T max was 1 hour and the t 1/2 of total plasma radioactivity was 23.7 hours. Unchanged praliciguat accounted for 87.4%, and a minor metabolite (N‐dealkylated‐praliciguat) accounted for 7.6% of the total radioactivity in plasma through 48 hours (AUC0‐48). 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. Most of the [14C]praliciguat‐derived radioactivity was excreted within 48 hours after oral administration. Mean cumulative recovery of the administered radioactivity in urine and feces over 168 hours was 3.7% and 95.7%, respectively. Unchanged praliciguat was not quantifiable in urine or bile of cannulated rats; however, based on the total radioactivity in these fluids, a minimum of approximately 82% of the orally administered dose was absorbed. [14C]Praliciguat was metabolized via oxidative and glucuronidation pathways and the most abundant metabolites recovered in bile were praliciguat‐glucuronide and hydroxy‐praliciguat‐glucuronide. These results indicate that praliciguat had rapid absorption, high bioavailability, extensive tissue distribution, and elimination primarily via hepatic metabolism.

Stimulation of soluble guanylate cyclase improves donor organ function in rat heart transplantation

Heart transplantation remains the definitive therapy of end-stage heart failure. Ischemia-reperfusion injury occurring during transplantation is a primary determinant of long-term outcome of heart transplantation and primary graft insufficiency. Modification of the nitric oxide/soluble guanylate cyclase/cyclic guanosine monophosphate signaling pathway appears to be one of the most promising among the pharmacological interventional options. We aimed at characterizing the cardio-protective effects of the soluble guanylate cyclase stimulator riociguat in a rat model of heterotopic heart transplantation. Donor Lewis rats were treated orally with either riociguat or placebo for two days (n = 9) in each transplanted group and (n = 7) in donor groups. Following explantation, hearts were heterotopically transplanted. After one hour reperfusion, left ventricular pressure-volume relations and coronary blood flow were recorded. Molecular biological measurements and histological examination were also completed. Left ventricular contractility (systolic pressure: 117 ± 13 vs. 48 ± 5 mmHg, p < 0.001; dP/dtmax: 2963 ± 221 vs. 1653 ± 159 mmHg/s, p < 0.001), active relaxation (dP/dtmin: −2014 ± 305 vs. −1063 ± 177 mmHg/s, p = 0.02; all at 120 µl of left ventricular volume), and alteration of coronary blood flow standardized to heart weight (2.55 ± 0.32 vs. 1.67 ± 0.22 ml/min/g, p = 0.03) were markedly increased following preconditioning with riociguat. Myocardial apoptosis markers were also significantly reduced in the riociguat pretreated group as well as the antioxidant markers were elevated. Pharmacological preconditioning with riociguat decreases ischemia-reperfusion injury and improves donor organ function in our animal model of heart transplantation. Therefore, riociguat might be a potential cardioprotective agent.

Estrogen Receptor-α Non-Nuclear Signaling Confers Cardioprotection and Is Essential to cGMP-PDE5 Inhibition Efficacy

Using genetically engineered mice lacking estrogen receptor-α non-nuclear signaling, this study demonstrated that estrogen receptor-α non-nuclear signaling activated myocardial cyclic guanosine monophosphate-dependent protein kinase G and conferred protection against cardiac remodeling induced by pressure overload. This pathway was indispensable to the therapeutic efficacy of cyclic guanosine monophosphate-phosphodiesterase 5 inhibition but not to that of soluble guanylate cyclase stimulation. These results might partially explain the equivocal results of phosphodiesterase 5 inhibitor efficacy and also provide the molecular basis for the advantage of using a soluble guanylate cyclase simulator as a new therapeutic option in post-menopausal women. This study also highlighted the need for female-specific therapeutic strategies for heart failure.

Treatment of pulmonary hypertension with riociguat: a review of current evidence and future perspectives

ABSTRACT Introduction Pulmonary arterial hypertension (PAH) is still a chronic disorder characterized by high morbidity and mortality. Chronic thromboembolic pulmonary hypertension (CTEPH) is another form of pulmonary hypertension (PH) for which pulmonary endarterectomy (PEA) is the treatment of choice. However, not all patients are operable, while PH is often recurrent or persistent. Thus, for both disorders novel treatment options are urgently needed. Areas covered This review describes the mechanism of action of riociguat, a soluble guanylate cyclase (sGC) stimulator, with a dual mode of action. The most relevant publications are presented regarding the efficacy of riociguat in PAH and CTEPH, and also data regarding its potential effect on other forms of PH. Expert opinion Riociguat is a first-in-class drug approved for the treatment of PAH as a monotherapy or added to endothelin-receptor antagonists as a sequential combination therapy, and for the treatment of inoperable CTEPH or persistent/recurrent PH after PEA. As it can stimulate sGC independently of NO, it could be beneficial in PAH patients with inadequate response to phosphodiesterase 5 inhibitors (PDE5i). Future studies are needed to evaluate whether drug switching is beneficial in PAH and which baseline markers could guide the optimal initial treatment selection.

Multicentre randomised controlled trial of balloon pulmonary angioplasty and riociguat in patients with chronic thromboembolic pulmonary hypertension: protocol for the MR BPA study

IntroductionManagement of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remains a clinical challenge. Currently, medical treatment involving pulmonary vasodilators (such as soluble guanylate-cyclase stimulators) is recommended, primarily for ameliorating symptoms. More...

Rationale and design for a multicenter, randomized, double-blind, placebo-controlled, phase 2 study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator praliciguat over 12 weeks in patients with heart failure with preserved ejection fraction (CAPACITY HFpEF)

Heart failure with preserved ejection fraction (HFpEF) is a significant cause of morbidity and mortality worldwide. Exercise intolerance is the main symptom of HFpEF and is associated with a poor quality of life and increased mortality. Currently, there are no approved medications for the treatment of HFpEF. Praliciguat (IW-1973), a novel soluble guanylate cyclase stimulator that may help restore deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine 3',5'-monophosphate signaling, is being investigated for the treatment of patients with HFpEF. CAPACITY HFpEF is a phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial designed to evaluate the safety and efficacy of praliciguat over 12 weeks in approximately 184 patients with HFpEF. Eligible patients must have evidence supporting clinical HFpEF and at least 2 of the following 4 conditions associated with NO deficiency: diabetes/prediabetes, hypertension, obesity, and age >70 years. The primary efficacy end point is the change from baseline in peak VO2 by cardiopulmonary exercise test (CPET). Secondary end points include the change from baseline in 6-minute walk test distance and the change in ventilatory efficiency on CPET, as well as number of CPET responders. Other exploratory end points include changes in echocardiographic parameters, New York Heart Association functional classification, cardiac events, blood and urine biomarkers pathophysiologically relevant to heart failure, and patient-reported outcomes including Kansas City Cardiomyopathy Questionnaire. The CAPACITY HFpEF trial will provide data on short-term safety and efficacy of praliciguat on peak exercise capacity, as well as multiple secondary end points of submaximal functional capacity, patient-reported outcomes, and biomarkers.

EXPRESS: Switching to riociguat: A potential treatment strategy for the management of CTEPH and PAH.

Currently, five classes of drug are approved for the treatment of pulmonary arterial hypertension (PAH): phosphodiesterase 5 inhibitors (PDE5i); endothelin receptor antagonists; prostacyclin analogs; the IP receptor agonist selexipag; and the soluble guanylate cyclase (sGC) stimulator riociguat. For patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), riociguat is currently the only approved pharmacotherapy. Despite the development of evidence-based guidelines on appropriate use of specific drugs, in clinical practice patients are often prescribed PAH-targeted therapies off label or at inadequate doses.PDE5i are the most often prescribed class of drugs as initial therapy, either alone or in combination with other drug classes. However, a proportion of patients receiving PAH therapies do not reach or maintain treatment goals. As PDE5i and riociguat target different molecules in the nitric oxide-sGC-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway, for patients with PAH without an initial or sustained response to PDE5i, there is a biological rationale for switching to riociguat. However, robust data from randomized controlled trials on the safety and efficacy of switching are lacking, as is formal guidance for clinicians. Here we review studies of sequential combination therapy, and trial data and case studies that have investigated switching between PAH-approved therapies, particularly from PDE5i to riociguat in patients with PAH with an insufficient response to PDE5i, and in patients with CTEPH who were receiving off-label treatment. These studies summarize the current evidence and practical real-life experience on the concept of switching treatments.