praliciguat (IW-1973) / Cyclerion - LARVOL DELTA

A Study of Praliciguat in Participants With Focal Segmental Glomerulosclerosis (FSGS) (clinicaltrials.gov) - P2 | N=60 | Not yet recruiting | Sponsor: Akebia Therapeutics

New P2 trial • Focal Segmental Glomerulosclerosis • Glomerulonephritis

Analysis of research trends and development prospects of soluble guanylate cyclase stimulators/activators: using bibliometric methods. (PubMed, Front Pharmacol) - "The future research hotspots will focus on the following aspects based on the current research hotspots: the safety verification of riociguat, the clinical efficacy of vericiguat for other types of heart failure, the role of praliciguat in diabetes nephropathy, and the efficacy and safety of newly discovered drugs. Furthermore, actively exploring new therapeutic directions for sGC stimulators or activators may also be an important trend in the future development of this field."

Journal • Review • Cardiovascular • Congestive Heart Failure • Diabetes • Diabetic Nephropathy • Heart Failure • Metabolic Disorders • Renal Disease

Soluble guanylate cyclase stimulators for heart failure: a network meta-analysis and subgroup analyses of reduced and preserved ejection fraction. (PubMed, Egypt Heart J) - "Vericiguat 10 mg was effective in reducing the composite CVS mortality and HF hospitalization, with an acceptable safety profile. This was only observed in HFrEF patients, but not in HFpEF patients. However, our data regarding other agents (riociguat and praliciguat) and HFpEF can be underpowered, warranting further RCTs to clarify vericiguat 10 mg place in HFrEF management guidelines and to investigate sGC stimulators for HFpEF in large-scale trials."

Journal • Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure

Soluble guanylate cyclase in heart failure: A network meta-analysis and subgroup analyses of reduced and preserved ejection fraction. (ESC 2023) - "Therefore, our data regarding other agents (riociguat and praliciguat) and HFpEF can be underpowered. This warrants further RCTs to clarify vericiguat 10 mg place in HFrEF management guidelines and to investigate sGC stimulators for HFpEF in large-scale adequately designed trials."

Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure

Recent developments in targets for ischemic foot disease. (PubMed, Diabetes Metab Res Rev) - "Similarly, administration of soluble guanylate cyclase stimulators riociguat or praliciguat or 3-ketoacyl-CoA thiolase inhibitor trimetazidine promoted blood flow recovery. In conclusion, an ever-expanding list of potential targets for medical revascularisation is being identified. It is hoped that through ongoing research and further larger clinical trials, these will translate into new broadly applicable therapies to improve outcomes."

Journal • Review • Cardiovascular • Diabetes • Metabolic Disorders • Oncology • Pain • Peripheral Arterial Disease • CD34 • HGF

The 10th International Conference on cGMP 2022: recent trends in cGMP research and development-meeting report. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "The biannual international cGMP conference, launched nearly 20 years ago, brings all these aspects together as an established and important forum for all topics from basic science to clinical research and pivotal clinical trials. This review summarizes the contributions to the "10th cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications," which was held in Augsburg in 2022 but will also provide an overview of recent key achievements and activities in the field of cGMP research."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Congestive Heart Failure • Coronary Artery Disease • Dementia • Erectile Dysfunction • Gastrointestinal Disorder • Genetic Disorders • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Soluble Guanylate Cyclase Activators and Stimulators in Patients with Heart Failure. (PubMed, Curr Cardiol Rep) - "Cinaciguat and praliciguat have shown no clear clinical benefit in patients with heart failure in clinical trials. To date, only vericiguat reduces the composite of death from cardiovascular causes or first hospitalization for heart failure in patients with heart failure with reduced ejection fraction and riociguat might improve clinical symptoms and quality of life in patients with heart failure, both heart failure with reduced and preserved ejection fraction. We need more exploration about soluble guanylate cyclase activators and stimulators in patients with heart failure."

Journal • Review • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases

Praliciguat and Soluble Guanylate Cyclase Stimulators for Peripheral Artery Disease. (PubMed, Circ Res) - No abstract available

Journal • Cardiovascular • Peripheral Arterial Disease

Praliciguat Promotes Ischemic Leg Reperfusion on Leptin Receptor-Deficient Mice. (PubMed, Circ Res) - "Our results demonstrated that praliciguat promotes blood flow recovery in the ischemic muscle of mice with type 2 diabetes, at least in part by increasing arteriole diameter and by downregulating ICAM1 expression."

Journal • Preclinical • Cardiovascular • Diabetes • Metabolic Disorders • Peripheral Arterial Disease • Type 2 Diabetes Mellitus • CXCL12 • ICAM1 • LEP • LEPR

Current updates in the pharmacotherapy of heart failure with a preserved ejection fraction. (PubMed, Cardiovasc Hematol Disord Drug Targets) - "EMPEROR-PRESERVED (Empagliflozin) and PRESERVED-HF (Dapagliflozin) results in the management of HFpEF look promising irrespective of diabetes status. Sacubitril-valsartan and Empagliflozon are the only medications approved for its management as per the PARAGON-HF and EMPEROR-PRESERVED studies respectively."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Coronary Artery Disease • Diabetes • Heart Failure • Hypertension • Metabolic Disorders

Soluble Guanylate Cyclase Stimulator Praliciguat Promotes Ischemic Leg Reperfusion in db/db Mice (ADA 2022) - "These results suggest that praliciguat restored perfusion and function in the ischemic muscle of db/db mice by increasing arteriolar diameter and decreasing ICAM-1 expression in endothelial cells via downregulation of Cxcl12 in myocytes."

Preclinical • Diabetes • Metabolic Disorders • CXCL12 • ICAM1

Sotatercept Analog RAP-011 Is More Effective Than Praliciguat in Improving Pulmonary Hypertension and Reducing Right Ventricular Hypertrophy in a ZSF1 Rat Model of Heart Failure with Preserved Ejection Fraction (ATS 2022) - " PH was induced in adult male obese ZSF1 rats by a single subcutaneous injection of SU5416 (100 mg/kg). Therapeutic treatment with the sotatercept analog RAP-011 exerted beneficial cardiopulmonary effects in a ZSF1 rat model of PH-HFpEF that were significantly greater than those produced by praliciguat, almost completely suppressing PH development and fully normalizing RV hypertrophy. These findings support evaluation of sotatercept in patients with PH-HFpEF (Group 2 PH)."

Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypertension • Obesity • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A

Beneficial Metabolic Effects of Praliciguat, a Soluble Guanylate Cyclase Stimulator, in a Mouse Diet-Induced Obesity Model. (PubMed, Front Pharmacol) - "In conclusion, praliciguat-treated DIO mice had increased energy utilization, improved insulin sensitivity, and lower plasma triglycerides. These results illustrate metabolic effects associated with praliciguat treatment in DIO mice."

Journal • Preclinical • Fibrosis • Genetic Disorders • Metabolic Disorders • Obesity • LPL

SGLT2 inhibition potentiates the cardiovascular, renal and metabolic effects of sGC stimulation in hypertensive rats with prolonged exposure to high fat diet. (PubMed, Am J Physiol Heart Circ Physiol) - "Simultaneous administration of PRALICIGUAT and EMPAGLIFLOZIN (n=10) accelerated the decrease in AP, improved glucose tolerance, reduced (P<0.05) incremental body weight gain, and decreased (P<0.05) insulin resistance index, RVR and the infiltration of T-CD3 lymphocytes in renal cortex and renal medulla. In summary, the combined administration of PRALICIGUAT and EMPAGLIFLOZIN leads to a greater improvement of the cardiovascular, renal and metabolic dysfunction secondary to prolonged exposure to HFD in hypertensive rats with ARDev than the treatment with either PRALICIGUAT or EMPAGLIFLOZIN alone."

Journal • Preclinical • Cardiovascular • Genetic Disorders • Hypertension • Metabolic Disorders • Obesity • LEP

Novel Therapies for Kidney Disease in People with Diabetes. (PubMed, J Clin Endocrinol Metab) - "Trials have yielded promising results in the search for new therapies to manage DKD. Sodium-glucose cotransporter-2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid-receptor antagonists are another class of agents with increasing evidence of benefits."

Journal • Cardiovascular • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Ophthalmology • Renal Disease • Type 1 Diabetes Mellitus • Type 2 Diabetes Mellitus

[VIRTUAL] SAFETY AND EFFICACY OF SOLUBLE GUANYLATE CYCLASE STIMULATORS IN PATIENTS WITH HEART FAILURE (ACC 2021) - "Background: The merits of novel oral soluble guanylate cyclase (sGC) stimulators (vericiguat, riociguat and praliciguat) in patients with reduced or preserved ejection fraction heart failure (HFrEF/HFpEF) remains controversial. Digital databases were queried to identify relevant RCT. The use of sGC stimulators in conjunction with the standard HF therapy might decrease the overall incidence of heart failure-related hospitalization with no overall increase in the net adverse events."

Clinical • Anemia • Cardiovascular • Congestive Heart Failure • Heart Failure • Hematological Disorders • Hypotension • sGC HDA+

An exploratory, randomised, placebo-controlled, 14 day trial of the soluble guanylate cyclase stimulator praliciguat in participants with type 2 diabetes and hypertension. (PubMed, Diabetologia) - P2 | "In participants with type 2 diabetes and hypertension on standard therapies, over 14 days praliciguat was well tolerated, except for a single SAE, and showed positive trends in metabolic and BP variables. These results support further clinical investigation of praliciguat."

Clinical • Journal • Diabetes • Gastrointestinal Disorder • Hypertension • Metabolic Disorders • Type 2 Diabetes Mellitus • sGC HDA+

[VIRTUAL] 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 (HFSA 2020) - "In a population selected to enrich for the metabolic/NO-deficient profile of HFpEF, PRL was well tolerated but did not affect pVO 2 , 6MWD, VE/VCO 2 slope, proportion of pVO 2 responders or KCCQ scores over 12 weeks compared to placebo."

Clinical • P2 data • Cardiomyopathy • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hypertension • Hypotension • Metabolic Disorders • Obesity • Pain • sGC HDA+

Soluble guanylate cyclase stimulators and their potential use: a patent review. (PubMed, Expert Opin Ther Pat) - "After the first generation of sGC stimulators like riociguat or lificiguat, new compound classes with different physicochemical and kinetic profiles were identified, like the sGC stimulators vericiguat or praliciguat...Expert Opinion: With the recent advancements reported in the patent literature, sGC stimulators might be differentiated due to tissue selectivity or route of application although exhibiting the same molecular mode of action. The indication space of these compounds is potentially very broad and multiple indications in cardiovascular diseases and beyond are under investigation."

Journal • Review • Cardiovascular • sGC HDA+

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease: A Randomized Placebo-Controlled Clinical Trial. (PubMed, Clin J Am Soc Nephrol) - P2 | "Praliciguat treatment for 12 weeks did not significantly reduce albuminuria compared with placebo in the primary efficacy analysis. Nonetheless, the observed changes in urine albumin-creatinine ratio, BP, and metabolic variables may support further investigation of praliciguat in diabetic kidney disease."

Clinical • Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Hypertension • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction: The CAPACITY HFpEF Randomized Clinical Trial. (PubMed, JAMA) - P2 | "These findings do not support the use of praliciguat in patients with HFpEF. ClinicalTrials.gov Identifier: NCT03254485."

Clinical • Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hypertension • Hypotension • Metabolic Disorders • Obesity • Pain

Stimulation of soluble guanylate cyclase exerts antiinflammatory actions in the liver through a VASP/NF-κB/NLRP3 inflammasome circuit. (PubMed, Proc Natl Acad Sci U S A) - "Here, we investigated the mechanisms underlying the antiinflammatory effect of the sGC stimulator praliciguat (PRL) in the liver...PRL also reduced active cleaved-caspase-1 levels independent of pannexin-1 activity. These data indicate that sGC stimulation with PRL exerts antiinflammatory actions in the liver through mechanisms related to a PKG/VASP/NF-κB/NLRP3 inflammasome circuit."

Journal • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Steatohepatitis • IL1B • sGC HDA+

[VIRTUAL] Effect of Praliciguat, a Once-Daily, Oral Soluble Guanylate Cyclase Stimulator, on Albuminuria in Patients with Diabetic Kidney Disease: A Randomized, Double-Blind, Phase 2 Trial (KIDNEY WEEK 2020) - "PRL did not significantly reduce UACR in the primary ITT analysis, but favorable trends in UACR, BP, and metabolic variables warrant further clinical study of PRL in DKD. Funding: Commercial Support"

Clinical • P2 data • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus • sGC HDA+

Praliciguat inhibits progression of diabetic nephropathy in ZSF1 rats and suppresses inflammation and apoptosis in human renal proximal tubular cells. (PubMed, Am J Physiol Renal Physiol) - "In this study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy (DN). Praliciguat treatment also attenuated transforming growth factor β-mediated apoptosis, changes to a mesenchymal-like cellular phenotype, and phosphorylation of SMAD3 in RPTC. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of DN, and its actions in human RPTC suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health."

Journal • Preclinical • Diabetic Nephropathy • Fibrosis • Immunology • Obesity • Renal Disease • CCL2 • sGC HDA+ • TNFA

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. (PubMed, Clin Pharmacol Drug Dev) - "Repeated once-daily dosing showed sustained decreases in BP. Results support evaluation of praliciguat for the treatment of conditions associated with deficient NO signaling."

Clinical • Journal • PK/PD data • Immunology