Soluble Guanylate Cyclase Stimulator Research Articles

Clinical Significance of Guanylate Cyclase Stimulator, Riociguat, on Right Ventricular Functional Improvement in Patients with Pulmonary Hypertension

Background: Riociguat is a soluble guanylate cyclase stimulator that improves hemodynamics in patients with pulmonary hypertension (PH). Accumulating evidence implicates the additional effect of riociguat on the increase in cardiac output. However, its mechanisms have not been fully understood. This study aimed to investigate whether riociguat could ameliorate right ventricular (RV) contraction as well as hemodynamics. Methods: We studied 45 patients with pulmonary arterial hypertension (14) or chronic thromboembolic pulmonary hypertension (31) and evaluated hemodynamics, using right-sided heart catheterization, before and after the administration of riociguat. RV function was assessed by echocardiography, including speckle-tracking echocardiography. Results: Riociguat significantly improved the WHO functional class and reduced the mean pulmonary arterial pressure and vascular resistance. In addition, the cardiac index increased. RV remodeling was ameliorated after riociguat administration as assessed by the echocardiographic parameters, such as RV diameter and RV area index. RV function, including RV fractional area change and RV global longitudinal strain, also significantly improved, and their improvement was even observed in patients with mild PH after pulmonary endarterectomy or balloon pulmonary angioplasty. Furthermore, covariance analysis revealed that RV global longitudinal strain and RV fractional area change improved after riociguat administration, even with the same mean pulmonary arterial pressure, implicating the improvement of RV contractile function by riociguat, regardless of RV loading. Conclusions: Riociguat not only improved the hemodynamics of patients with PH but also ameliorated the echocardiographic parameters with RV function. RV strain could detect the subtle improvement in mild PH, and riociguat may have a benefit even after intervention, as assessed by speckle-tracking echocardiography.

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

ObjectiveThe soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice. MethodsEXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms. ResultsIn total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial [CHEST-2]). ConclusionData from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.

Stimulation of soluble guanylate cyclase diminishes intrauterine growth restriction in a rat model of placental ischemia.

Placental ischemia in preeclampsia (PE) results in hypertension and intrauterine growth restriction (IUGR). Stimulation of soluble guanylate cyclase (sGC) reduces blood pressure in the clinically relevant reduced uterine perfusion pressure (RUPP) rat model of PE, implicating involvement in RUPP-induced hypertension. However, the contribution of sGC in the development of IUGR in PE is not known. Thus, this study demonstrated the efficacy of Riociguat, an sGC stimulator, in IUGR reversion in the RUPP rat model of PE, and tested the hypothesis that improvement in fetal weight occurs in association with improvement in placental perfusion, placental morphology, and placental nutrient transport protein expression. Sham or RUPP surgery was performed at gestational day 14 (G14) with administration of vehicle (Sham or RUPP) or the sGC stimulator (Riociguat, 10 mg/kg/day sc; sGC-treated) until G20. Fetal weight was reduced (P = 0.004) at G20 in RUPP but not in sGC-treated RUPP compared with Sham, the control group. At G20, uterine artery resistance index (UARI) was increased (P = 0.010) in RUPP, indicating poor placental perfusion; proportional junctional zone surface area was elevated (P = 0.035), indicating impaired placental development. These effects were ameliorated in sGC-treated RUPP. Placental protein expression of nutrient transporter heart fatty acid-binding protein (hFABP) was increased (P = 0.008) in RUPP but not in sGC-treated RUPP, suggesting a compensatory mechanism to maintain normal neurodevelopment. Yet, UARI (P < 0.001), proportional junctional zone surface area (P = 0.013), and placental hFABP protein expression (P = 0.008) were increased in sGC-treated Sham, suggesting a potential adverse effect of Riociguat. Collectively, these results suggest sGC contributes to IUGR in PE.

Physiologically-based pharmacokinetic (PBPK) exploration of extrinsic factors influencing vericiguat pharmacokinetics

Abstract Introduction Vericiguat is a once daily, novel oral stimulator of soluble guanylate cyclase (sGC) that showed clinical benefit in the Phase III VICTORIA study in heart failure patients with reduced ejection fraction (HFrEF, NCT02861534). Nonclinical and clinical studies demonstrated that the primary route of elimination of vericiguat was glucuronidation to an inactive metabolite M-1 (N-glucuronide). This glucuronidation was catalyzed by uridine 5'-diphospho-glucuronosyltransferases (UGT)1A9 as well as UGT1A1, thus vericiguat may have a potential for victim drug-drug interaction (DDI) when co-administered with potent UGT inhibitors. Purpose In a clinical DDI study with mefenamic acid as an UGT1A9 inhibitor no clinically relevant increase in vericiguat exposure in healthy subjects was observed (EudraCT 2014–000764–17). This analysis aims to prospectively investigate as extrinsic factors the DDI potential with atazanavir as a selective UGT1A1 inhibitor via full dynamic physiologically-based pharmacokinetic (PBPK) modelling. Methods A PBPK model for vericiguat and M-1 in healthy adults was built with PK-Sim (PBPK platform as part of the Open Systems Pharmacology Suite) by integrating physicochemical, in vitro metabolism and transporter data as well as PK data from clinical pharmacology studies in order to assess the victim DDI potential of vericiguat when co-administered with UGT inhibitors. First, PBPK models for mefenamic acid and atazanavir were separately developed and verified using published literature data. The PBPK model for vericiguat was then verified with regard to its fraction of metabolism by UGTs by comparing simulated and observed data of the clinical mefenamic acid DDI study. Finally, the UGT1A1 DDI potential of vericiguat was prospectively predicted by simulating an in silico study between the UGT1A1 inhibitor atazanavir and vericiguat. Results In line with the results of the clinical DDI study with mefenamic acid, an increase in total vericiguat exposure by 14% (area under the concentration time curve ratio (AUCR) of 1.14 (geoCV 5.3%; 90% population interval: 1.06 to 1.25) and peak exposure increase by 6% (CmaxR of 1.06; geoCV 5.9%; 90% population interval: 1.01 to 1.20) was simulated using the PBPK model. A prospective prediction of a virtual DDI trial between the UGT1A1 inhibitor atazanavir yielded an AUCR of 1.12 (geoCV 2.9%; 90% population interval: 1.07 to 1.17) and a CmaxR of 1.04 (geoCV 1.1%; 90% population interval: 1.03 to 1.06). The proposed population intervals for AUCR and CmaxR for both DDI studies lie within the default no-effect boundary of 0.80 to 1.25 according to the to January 2020 FDA DDI guideline. Conclusion(s) Results of UGT1A9-DDI simulations were consistent with those of the clinical study-The prospective UGT1A1-DDI simulation results suggest a low potential for vericiguat to be subject to DDI when co-administered with UGT1A1 inhibitors. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Funding for this research was provided by Bayer and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA

Safety and efficacy of soluble guanylate cyclase stimulators in patients with heart failure: A systematic review and meta-analysis.

BACKGROUNDThe utility of novel oral soluble guanylate cyclase (sGC) stimulators (vericiguat and riociguat), in patients with reduced or preserved ejection fraction heart failure (HFrEF/HFpEF) is currently unclear.AIMTo determine the efficacy and safety of sGC stimulators in HF patients.METHODSMultiple databases were searched to identify relevant randomized controlled trials (RCTs). Data on the safety and efficacy of sGC stimulators were compared using relative risk ratio (RR) on a random effect model.RESULTSSix RCTs, comprising 5604 patients (2801 in sGC stimulator group and 2803 placebo group) were included. The primary endpoint (a composite of cardiovascular mortality and first HF-related hospitalization) was significantly reduced in patients receiving sGC stimulators compared to placebo [RR 0.92, 95% confidence interval (CI): 0.85-0.99, P = 0.02]. The incidence of total HF-related hospitalizations were also lower in sGC group (RR 0.91, 95%CI: 0.86-0.96, P = 0.0009), however, sGC stimulators had no impact on all-cause mortality (RR 0.96, 95%CI: 0.86-1.07, P = 0.45) or cardiovascular mortality (RR 0.94, 95%CI: 0.83-1.06, P = 0.29). The overall safety endpoint (a composite of hypotension and syncope) was also similar between the two groups (RR 1.50, 95%CI: 0.93-2.42, P = 0.10). By contrast, a stratified subgroup analysis adjusted by type of sGC stimulator and HF (vericiguat vs riociguat and HFrEF vs HFpEF) showed near identical rates for all safety and efficacy endpoints between the two groups at a mean follow-up of 19 wk. For the primary composite endpoint, the number needed to treat was 35, the number needed to harm was 44.CONCLUSIONThe use of vericiguat and riociguat in conjunction with standard HF therapy, shows no benefit in terms of decreasing HF-related hospitalizations or mortality.

Overview of Riociguat and Its Role in the Treatment of Pulmonary Hypertension

Pulmonary hypertension (PH), which includes pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), is a progressive condition with significant morbidity and mortality due to right heart failure if left untreated. Riociguat is a soluble guanylate cyclase (sGC) stimulator and is the only treatment approved for both PAH and CTEPH. The objectives of this review are to describe the epidemiology and pathophysiology of PAH and CTEPH; synthesize the pharmacology, efficacy, safety, and utilization of riociguat; and discuss the role of the pharmacist in managing patients with these conditions. Data presented in this review is supported by peer reviewed literature, using PubMed and key words including pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and riociguat. The review draws on key studies and review articles that discuss the pathophysiology of PAH and CTEPH, as well as articles discussing the safety and efficacy of riociguat. The overall goal in the treatment of PAH and CTEPH is to improve long-term survival. Treatment planning depends on the type of PH, treatment goals, comorbidities, and risk profiles. Pharmacists serve a valuable role as part of the multidisciplinary team in the care of patients with PH, many of whom may have comorbidities that contribute to high costs and resource utilization. Riociguat is a first-in-class medication and the only approved treatment for both PAH and CTEPH. In clinical trials, riociguat has demonstrated favorable efficacy and tolerability. Riociguat is a valuable addition to the armamentarium of options for treating patients with PH.

Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is often characterized by nitric oxide deficiency. To evaluate the efficacy and adverse effects of praliciguat, an oral soluble guanylate cyclase stimulator, in patients with HFpEF. CAPACITY HFpEF was a randomized, double-blind, placebo-controlled, phase 2 trial. Fifty-nine sites enrolled 196 patients with heart failure and an ejection fraction of at least 40%, impaired peak rate of oxygen consumption (peak V̇o2), and at least 2 conditions associated with nitric oxide deficiency (diabetes, hypertension, obesity, or advanced age). The trial randomized patients to 1 of 3 praliciguat dose groups or a placebo group, but was refocused early to a comparison of the 40-mg praliciguat dose vs placebo. Participants were enrolled from November 15, 2017, to April 30, 2019, with final follow-up on August 19, 2019. Patients were randomized to receive 12 weeks of treatment with 40 mg of praliciguat daily (n = 91) or placebo (n = 90). The primary efficacy end point was the change from baseline in peak V̇o2 in patients who completed at least 8 weeks of assigned dosing. Secondary end points included the change from baseline in 6-minute walk test distance and in ventilatory efficiency (ventilation/carbon dioxide production slope). The primary adverse event end point was the incidence of treatment-emergent adverse events (TEAEs). Among 181 patients (mean [SD] age, 70 [9] years; 75 [41%] women), 155 (86%) completed the trial. In the placebo (n = 78) and praliciguat (n = 65) groups, changes in peak V̇o2 were 0.04 mL/kg/min (95% CI, -0.49 to 0.56) and -0.26 mL/kg/min (95% CI, -0.83 to 0.31), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -0.30 mL/kg/min ([95% CI, -0.95 to 0.35]; P = .37). None of the 3 prespecified secondary end points were statistically significant. In the placebo and praliciguat groups, changes in 6-minute walk test distance were 58.1 m (95% CI, 26.1-90.1) and 41.4 m (95% CI, 8.2-74.5), respectively; the placebo-adjusted least-squares between-group difference in mean change from baseline was -16.7 m (95% CI, -47.4 to 13.9). In the placebo and praliciguat groups, the placebo-adjusted least-squares between-group difference in mean change in ventilation/carbon dioxide production slope was -0.3 (95% CI, -1.6 to 1.0). There were more dizziness (9.9% vs 1.1%), hypotension (8.8% vs 0%), and headache (11% vs 6.7%) TEAEs with praliciguat compared with placebo. The frequency of serious TEAEs was similar between the groups (10% in the praliciguat group and 11% in the placebo group). Among patients with HFpEF, the soluble guanylate cyclase stimulator praliciguat, compared with placebo, did not significantly improve peak V̇o2 from baseline to week 12. These findings do not support the use of praliciguat in patients with HFpEF. ClinicalTrials.gov Identifier: NCT03254485.

Effect of Vericiguat vs Placebo on Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction

Patients with heart failure and preserved ejection fraction (HFpEF) are at high risk of mortality, hospitalizations, and reduced functional capacity and quality of life. To assess the efficacy of the oral soluble guanylate cyclase stimulator vericiguat on the physical limitation score (PLS) of the Kansas City Cardiomyopathy Questionnaire (KCCQ). Phase 2b randomized, double-blind, placebo-controlled, multicenter trial of 789 patients with chronic HFpEF and left ventricular ejection fraction 45% or higher with New York Heart Association class II-III symptoms, within 6 months of a recent decompensation (HF hospitalization or intravenous diuretics for HF without hospitalization), and with elevated natriuretic peptides, enrolled at 167 sites in 21 countries from June 15, 2018, through March 27, 2019; follow-up was completed on November 4, 2019. Patients were randomized to receive vericiguat, up-titrated to 15-mg (n = 264) or 10-mg (n = 263) daily oral dosages, compared with placebo (n = 262) and randomized 1:1:1. The primary outcome was change in the KCCQ PLS (range, 0-100; higher values indicate better functioning) after 24 weeks of treatment. The secondary outcome was 6-minute walking distance from baseline to 24 weeks. Among 789 randomized patients, the mean age was 72.7 (SD, 9.4) years; 385 (49%) were female; mean EF was 56%; and median N-terminal pro-brain natriuretic peptide level was 1403 pg/mL; 761 (96.5%) completed the trial. The baseline and 24-week KCCQ PLS means for the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 60.0 and 68.3, 57.3 and 69.0, and 59.0 and 67.1, respectively, and the least-squares mean changes were 5.5, 6.4, and 6.9, respectively. The least-squares mean difference in scores between the 15-mg/d vericiguat and placebo groups was -1.5 (95% CI, -5.5 to 2.5; P = .47) and between the 10-mg/d vericiguat and placebo groups was -0.5 (95% CI, -4.6 to 3.5; P = .80). The baseline and 24-week 6-minute walking distance mean scores in the 15-mg/d vericiguat, 10-mg/d vericiguat, and placebo groups were 295.0 m and 311.8m , 292.1 m and 318.3 m, and 295.8 m and 311.4 m, and the least-squares mean changes were 5.0 m, 8.7 m, and 10.5 m, respectively. The least-squares mean difference between the 15-mg/d vericiguat and placebo groups was -5.5 m (95% CI, -19.7 m to 8.8 m; P = .45) and between the 10-mg/d vericiguat and placebo groups was -1.8 m (95% CI, -16.2 m to 12.6 m; P = .81), respectively. The proportions of patients who experienced symptomatic hypotension were 6.4% in the 15-mg/d vericiguat group, 4.2% in the 10-mg/d vericiguat group, and 3.4% in the placebo group; those with syncope were 1.5%, 0.8%, and 0.4%, respectively. Among patients with HFpEF and recent decompensation, 24-week treatment with vericiguat at either 15-mg/d or 10-mg/d dosages compared with placebo did not improve the physical limitation score of the KCCQ. ClinicalTrials.gov Identifier: NCT03547583.

Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation.

Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study, we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)-mediated signaling. Cyclic GMP (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.

Emerging therapies for right ventricular dysfunction and failure.

Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited. Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular- and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA- and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support.

SWITCHING TO RIOCIGUAT IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION NOT AT TREATMENT GOAL WITH PHOSPHODIESTERASE TYPE-5 INHIBITORS: SUBGROUP ANALYSIS RESULTS OF THE REPLACE STUDY

SWITCHING TO RIOCIGUAT IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION NOT AT TREATMENT GOAL WITH PHOSPHODIESTERASE TYPE-5 INHIBITORS: SUBGROUP ANALYSIS RESULTS OF THE REPLACE STUDY

Safety and Efficacy of Soluble Guanylate Cyclase Stimulators in Patients with Heart Failure: A Systematic Review and Meta-analysis

Background The utility of novel oral soluble guanylate cyclase (sGC) stimulators (vericiguat and riociguat), in patients with reduced or preserved ejection fraction heart failure (HFrEF/HFpEF) is currently unclear. Methods ultiple databases were searched to identify relevant randomized controlled trials (RCTs). Data on the safety and efficacy of sGC stimulators were compared using relative risk ratio (RR) on a random effect model. Results Six RCTs, comprising 5604 patients (2801 in sGC stimulator group and 2803 placebo group) were included. The primary endpoint (a composite of cardiovascular mortality and first HF-related hospitalization) was significantly reduced in patients receiving sGC stimulators compared to placebo [RR 0.92, 95% confidence interval (CI) 0.85-0.99, p=0.02]. The incidence of total HF-related hospitalizations were also lower in sGC group (RR 0.91, 95% CI 0.86-0.96, p=0.0009), however, sGC stimulators had no impact on all-cause mortality (RR 0.96, 95% CI 0.86-1.07, p=0.45) or cardiovascular mortality (RR 0.94, 95% CI 0.83-1.06, p=0.29). The overall safety endpoint (a composite of hypotension and syncope) was also similar between the two groups (RR 1.50, 95% CI 0.93-2.42, p=0.10). (Figure) By contrast, a stratified subgroup analysis adjusted by type of sGC stimulator and heart failure (vericiguat vs. riociguat and HFrEF vs. HFpEF) showed near-identical rates for all safety and efficacy endpoints between the two groups at a mean follow-up of 19 weeks. For the primary composite endpoint, the number needed to treat was 35, the number needed to harm was 44. Conclusion The use of vericiguat and riociguat in conjunction with standard heart failure therapy shows no benefit in terms of decreasing HF-related hospitalizations or mortality.

Safety And Effect on Mortality of Soluble Guanylate Cyclase Stimulators In Heart Failure Patients- A Systemic Review And Meta-analysis

Background Soluble guanylate cyclase stimulators (sGCS) have been studied in patients with congestive heart failure (CHF). Several randomized controlled trials (RCTs) were conducted to determine their efficacy in CHF patients. To date, no definite recommendations exist for their use in CHF patients. We performed a systematic review and meta-analysis to study the effectiveness and safety of sGCS of this novel class of medications in CHF patients. Objective To study the efficacy and safety of soluble guanylate cyclase stimulators (GCS) in patients with congestive heart failure (CHF). Methods and Results We searched PubMed, MEDLINE, EMBASE, and Cochrane databases from inception until April 25th, 2020, for RCTs comparing sGCS to placebo for CHF treatment. We included seven RCTs comprising a total of 5,754 patients (2,902 in sGCS arm and 2,856 in the placebo arm). We used RevMan Version 5.3 Copenhagen to calculate relative risk (RR) of dichotomous data using a random-effects model for our review and analysis. The sensitivity analysis was performed for significant heterogeneity (I2) > 50%. Our primary outcome was mortality from any and cardiovascular causes. We performed a subgroup analysis of heart failure with reduced (HFrEF Conclusion Like earlier RCTs, our meta-analysis of sGCS failed to show any significant mortality benefit in addition to standard of care CHF treatment. There were significantly more episodes of hypotension with the use of sGCS. This raises concern about their safety in CHF patients who take several classes of medications with mortality benefit and blood pressure reducing property.

Safety and Efficacy of the Soluble Guanylate Cyclase Stimulator Praliciguat in Patients with Heart Failure with Preserved Ejection Fraction (Capacity HFpEF): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial

Introduction Heart failure with preserved ejection fraction (HFpEF) is associated with poor quality of life and increased mortality with exercise intolerance being the main symptom. Hypothesis The soluble guanylate cyclase (sGC) stimulator praliciguat (PRL) may help restore deficient NO-sGC-cGMP signaling and improve exercise capacity. Methods CAPACITY HFpEF was a phase 2, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of PRL over 12 weeks in patients with HFpEF and at least 2 of 4 conditions potentially associated with NO deficiency (diabetes, hypertension, obesity, age >70 years). Patients were randomized to PRL or placebo. The primary endpoints were change from baseline to week 12 in peak oxygen consumption (pVO2) by cardiopulmonary exercise testing and treatment-emergent adverse events (TEAEs). Secondary endpoints included the change in 6-minute walk distance (6MWD), ventilatory efficiency (VE/VCO2 slope), and the proportion of pVO2 responders (change ≥1.5 mL/kg/min). Health status was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Results Among 196 patients randomized (mean age 70.3 years, 57% men), 169 completed. For the evaluable population (completed 8 weeks of dosing with no dose reduction), mean baseline pVO2 was 13.3 and 12.8 mL O2/kg/min in PRL 40 mg (N=65) and placebo (N=78) groups, respectively. Placebo-adjusted least squares mean changes from baseline to week 12 [95% CI] were pVO2 (-0.30 mL O2/kg/min [-0.95, 0.35] p=0.37), 6MWD (-16.7 m [-47.4, 13.9]) and VE/VCO2 slope (-0.30 [-1.59, 1.00]). The odds ratio for pVO2 response [95% CI] was 0.91 [0.40, 2.1]. KCCQ overall and domain scores did not improve in the PRL group versus the placebo group. PRL was generally well tolerated; headache, dizziness, and hypotension TEAEs were reported more frequently in the PRL group. The frequency of serious TEAEs was similar between groups. Conclusion In a population selected to enrich for the metabolic/NO-deficient profile of HFpEF, PRL was well tolerated but did not affect pVO2, 6MWD, VE/VCO2 slope, proportion of pVO2 responders or KCCQ scores over 12 weeks compared to placebo.

Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.

The place of riociguat in the treatment of patients with pulmonary arterial hypertension associated with systemic connective tissue diseases

Pulmonary hypertension (PH) can develop in different systemic autoimmune rheumatic diseases (SARD), such as systemic scleroderma (SSD), systemic lupus erythematosus, rheumatoid arthritis, and mixed connective tissue disease In most cases, patients with SARD develop WHO group I PH (pulmonary arterial hypertension associated with systemic connective tissue diseases, PAH-SCTD). General prevalence of this pathology reaches 15 cases per million adults. Most cases of PAH-SCTD are induced by SSD. Survival of PAH-SCTD patients is generally lower than survival of patients with other forms of LAH. Treatment of any SARD, including in LAH, implies a complex approach using glucocorticoids, disease-modifying anti-rheumatic drugs (cyclophosphamide, methotrexate, azathioprine, and others), and genetically engineered biologics. Specific targeted therapy is indicated for most patients with PAH-SCTD. The representative of a new class (soluble guanylate cyclase (sGC) stimulators), riociguat, has been approved for the treatment of PAH. This drug has a unique double mechanism of action: (i) sGC sensibilization to endogenous nitric oxide (NO) by stabilizing the NO-sGC bond; and (ii) direct, NO-independent sGC stimulation. For patients with PAH-SCTD, riociguat is the major alternative to phosphodiesterase-5 inhibitors both as monotherapy and combination therapy.

Discovery of Novel Pyrazolo[3,4-b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension.

Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.

The soluble guanylate cyclase stimulator riociguat is the first-line therapy for chronic thromboembolic pulmonary hypertension patients

Chronic thromboembolic pulmonary hypertension (CTEPH) is a precapillary type of pulmonary hypertension with chronic obstruction of large and medium branches of pulmonary arteries along with secondary alterations in pulmonary microcirculation, which cause progressive increases in pulmonary vascular resistance and pulmonary arterial pressure and ensuing severe right heart dysfunction and heart failure. Pulmonary thromboendarterectomy (PTE) is the treatment of choice for CTEPH; however, this procedure is available not for all patients. Although the surgery performed in the conditions of centers with advanced experience generally shows good results, up to 40% of patients are technically inoperable or PTE is associated with a high risk of complications. At present, riociguat, the only officially approved drug from the class of soluble guanylate cyclase stimulators, is considered as a first-line treatment for inoperable and residual forms of STEPH. Introduction of riociguat to clinical practice can be called a real breakthrough in the treatment of patients with STEPH who cannot undergo PTE or those with relapse or persistent STEPH after the surgery.

Nitric oxide activates AMPK by modulating PDE3A in human pulmonary artery smooth muscle cells.

Phosphodiesterase 3 (PDE3), of which there are two isoforms, PDE3A and PDE3B, hydrolyzes cAMP and cGMP—cyclic nucleotides important in the regulation of pulmonary vascular tone. PDE3 has been implicated in pulmonary hypertension unresponsive to nitric oxide (NO); however, contributions of the two isoforms are not known. Furthermore, adenosine monophosphate‐activated protein kinase (AMPK), a critical regulator of cellular energy homeostasis, has been shown to be modulated by PDE3 in varying cell types. While AMPK has recently been implicated in pulmonary hypertension pathogenesis, its role and regulation in the pulmonary vasculature remain to be elucidated. Therefore, we utilized human pulmonary artery smooth muscle cells (hPASMC) to test the hypothesis that NO increases PDE3 expression in an isoform‐specific manner, thereby activating AMPK and inhibiting hPASMC proliferation. We found that in hPASMC, NO treatment increased PDE3A protein expression and PDE3 activity with a concomitant decrease in cAMP concentrations and increase in AMPK phosphorylation. Knockdown of PDE3A using siRNA transfection blunted the NO‐induced AMPK activation, indicating that PDE3A plays an important role in AMPK regulation in hPASMC. Treatment with a soluble guanylate cyclase (sGC) stimulator increased PDE3A expression and AMPK activation similar to that seen with NO treatment, whereas treatment with a sGC inhibitor blunted the NO‐induced increase in PDE3A and AMPK activation. These results suggest that NO increases PDE3A expression, decreases cAMP, and activates AMPK via the sGC‐cGMP pathway. We speculate that NO‐induced increases in PDE3A and AMPK may have implications in the pathogenesis and the response to therapies in pulmonary hypertensive disorders.

The effect of Riociguat on cardiovascular function and efficiency in healthy, juvenile pigs.

IntroductionRiociguat is a soluble guanylate cyclase stimulator approved for the treatment of pulmonary hypertension. Its effect on cardiometabolic efficiency is unknown. A potential cardiac energy sparing effect of this drug could imply a positive prognostic effect, particularly in patients with right heart failure from pulmonary hypertension.MethodWe infused Riociguat in six healthy juvenile pigs and measured the integrated cardiovascular effect and myocardial oxygen consumption. To assess the interplay with NO‐blockade on cardiac function and efficiency we also administered the NO‐blocker L‐ NAME to the animals after Riociguat.Results and DiscussionInfusion of 100 µg/kg Riociguat gave modest systemic vasodilatation seen as a drop in coronary and systemic vascular resistance of 36% and 26%, respectively. Right and left ventriculoarterial coupling index (Ees/Ea), stroke work efficiency (SWeff), and the relationship between left ventricular myocardial oxygen consumption (MVO2) and total mechanical work (pressure–volume area; PVA) were unaffected by Riociguat. In contrast, systemic and pulmonary vasoconstriction induced by L‐NAME (15 mg/kg) shifted the Ees/Ea ratio toward reduced SWeff in both systemic and pulmonary circulation. However, there was no surplus oxygen consumption, that was measured by the MVO2/PVA relationship after L‐NAME in Riociguat‐treated pigs. This suggests that Riociguat can reduce the NO‐related cardiometabolic inefficiency previously observed by blocking the NO pathway.