runcaciguat (BAY 1101042) / Bayer - LARVOL DELTA

Neuroprotective Effect of a Novel Soluble Guanylate Cyclase Activator (sGCa) Runcaciguat in Diabetes and Ischemic Retinopathy. (PubMed, Diabetes) - "In the STZ-induced diabetic rat model, runcaciguat significantly improved neuroretinal function and improved inner plexiform layer thickness. These studies suggest that sGC signaling is involved in neuroretinal function and vision and that diabetes negatively affects this pathway, supporting restoring sGC activation as a novel therapy for early DR."

Journal • Cardiovascular • CNS Disorders • Diabetes • Diabetic Retinopathy • Metabolic Disorders • Reperfusion Injury • Retinal Disorders

Discovery of the first isoform-specific sGC activator: selective activation of GC-1 by runcaciguat. (PubMed, Eur J Pharmacol) - "Drug research and development programmes targeting soluble guanylyl cyclase (sGC) have been highly successful, leading to the launch of the sGC stimulators riociguat for pulmonary hypertension (2014) and vericiguat for chronic heart failure (2021). Notably, runcaciguat is the first sGC activator identified to selectively target GC-1 at therapeutic concentrations. This selective targeting of isoforms not only opens avenues for new therapeutic strategies but also provides an alternative to knockout animal models for investigating isoform-specific functions."

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

NEON-NPDR study to investigate the efficacy and safety of the sGC-activator runcaciguat (RC) in patients with non-proliferative diabetic retinopathy (ARVO 2025) - "Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Clinical • Diabetic Retinopathy • Ophthalmology • Retinal Disorders

Potential New Treatments for Chronic Kidney Diseases: A Concise Review. (PubMed, Curr Pharm Des) - "This concise review will shed light on the clinical trials of runcaciguat, cotadutide, osocimab, and Endothelin Receptor Antagonists (ERAs) in patients with CKD and/or ESKD. These drugs were retrieved following surveying the Clinical Trial database as well as the Pubmed database, both maintained by the US National Library of Medicine."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Transplantation

Runcaciguat activates soluble guanylyl cyclase via the histidine essential for heme binding and nitric oxide activation. (PubMed, Biochem Pharmacol) - "We confirm that the first generation of sGC activators cinaciguat and BAY 60-2770 activate the α1/β1H105F and α1/β1H105A mutants. The histidine-dependency of some of the sGC activators provides a compelling rationale for a re-evaluation of previous research and drug development programs based on sGC histidine mutants. Whether the classification of sGC activators based on the activation mechanism also makes a therapeutic difference needs to be clarified in the future."

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

The soluble guanylate cyclase activator runcaciguat significantly improves albuminuria in patients with chronic kidney disease: a randomized placebo-controlled clinical trial. (PubMed, Nephrol Dial Transplant) - P2 | "Runcaciguat improved albuminuria in patients with CKD, irrespective of concomitant SGLT2i. Runcaciguat was well tolerated. sGC activation may represent a novel kidney-protective treatment in CKD patients (funded by Bayer AG; ClinicalTrials.gov number, NCT04507061)."

Clinical • Journal • Atherosclerosis • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Heart Failure • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

NEON-NPDR: Non-proliferative Diabetic Retinopathy Treated With Runcaciguat (clinicaltrials.gov) - P2 | N=104 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Trial completion • Diabetic Retinopathy • Retinal Disorders

The sGC Activator Runcaciguat Has Kidney Protective Effects and Prevents a Decline of Kidney Function in ZSF1 Rats. (PubMed, Int J Mol Sci) - P2 | "In summary, the sGC activator runcaciguat significantly prevented a decline in kidney function in a DKD rat model that mimics common comorbidities and conditions of oxidative stress of CKD patients. Thus, runcaciguat represents a promising treatment option for CKD patients, which is in line with recent phase 2 clinical study data, where runcaciguat showed promising efficacy in CKD patients (NCT04507061)."

Journal • Preclinical • Cardiovascular • Chronic Kidney Disease • Diabetes • Fibrosis • Genetic Disorders • Hypertension • Immunology • Inflammation • Nephrology • Obesity • Renal Disease

THE SGC ACTIVATOR RUNCACIGUAT IS ASSOCIATED WITH A STRONG REDUCTION IN UACR AND GOOD TOLERABILITY IN CKD PATIENTS WITH OR WITHOUT AN SGLT2 INHIBITOR (ERA-EDTA 2023) - No abstract available

Clinical • Late-breaking abstract

NEON-NPDR: Non-proliferative Diabetic Retinopathy Treated With Runcaciguat (clinicaltrials.gov) - P2 | N=104 | Active, not recruiting | Sponsor: Bayer | Recruiting ➔ Active, not recruiting | Trial primary completion date: Nov 2023 ➔ May 2024

Enrollment closed • Trial primary completion date • Diabetic Retinopathy • Retinal Disorders

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

Runcaciguat, a Novel Soluble Guanylate Cyclase (sGC) Activator, Shows Kidney Protection in Models of CKD (KIDNEY WEEK 2022) - P2 | "Data are mean ± SEM. Statistics determined by one-way ANOVA followed by Tuckey’s multiple comparison test."

Fibrosis • Glomerulonephritis • Immunology • Obesity • Renal Disease

Responses in Blood Pressure and Kidney Function to Soluble Guanylyl Cyclase Stimulation or Activation in Normal and Diabetic Rats. (PubMed, Nephron) - "sGC agonists impact kidney function directly and because they reduce MAP. The direct tendency to increase GFR is most apparent for MAP reductions <10%. The direct effect is otherwise subtle and overridden when MAP declines more. Effects of sGC agonists on tubular reabsorption are dominated by the effects on MAP."

Journal • Preclinical • Cardiovascular • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

CONCORD: Study on the Safety of the Drug Runcaciguat and How Well it Works When Given at the Highest Dose as Tolerated by Individual Patient Whose Kidneys Are Not Working Properly and Suffering at the Same Time From High Blood Sugar and/or High Blood Pressure and a Disease of the Heart and the Blood Vessels. (clinicaltrials.gov) - P2 | N=243 | Completed | Sponsor: Bayer | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease

The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms. (PubMed, Sci Rep) - "In vivo only runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

NEON-NPDR: Non-proliferative Diabetic Retinopathy Treated With Runcaciguat (clinicaltrials.gov) - P2 | N=98 | Recruiting | Sponsor: Bayer | N=290 ➔ 98 | Trial completion date: Jan 2026 ➔ Mar 2024 | Trial primary completion date: Oct 2022 ➔ Aug 2023

Enrollment change • Trial completion date • Trial primary completion date • Diabetic Retinopathy • Retinal Disorders

CONCORD: Study on the Safety of the Drug Runcaciguat and How Well it Works When Given at the Highest Dose as Tolerated by Individual Patient Whose Kidneys Are Not Working Properly and Suffering at the Same Time From High Blood Sugar and/or High Blood Pressure and a Disease of the Heart and the Blood Vessels. (clinicaltrials.gov) - P2 | N=216 | Active, not recruiting | Sponsor: Bayer | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease

Age Impairs Soluble Guanylyl Cyclase Function in Mouse Mesenteric Arteries. (PubMed, Int J Mol Sci) - "Endothelium-independent vasorelaxation by the NO donor sodium nitroprusside (SNP) was similar in both groups; however, SNP bolus application (10 mol L) as well as soluble guanylyl cyclase (sGC) activation by runcaciguat (10 mol L) caused faster responses in juvenile vessels. This was accompanied by higher cGMP concentrations and a stronger response to the PDE5 inhibitor sildenafil in juvenile vessels...In conclusion, vasorelaxation is compromised at an early age in mice even in the absence of histopathological alterations. Vascular smooth muscle sGC is a key element in aged vessel dysfunction."

Journal • Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia

[VIRTUAL] The Renoprotective Effects of the Soluble Guanylate Cyclase (sGC) Activator Runcaciguat Are Associated with Distinct Changes in Renal Gene Expression Profiles (KIDNEY WEEK 2021) - "These changes could contribute to the renoprotective effect of runcaciguat. Runcaciguat is currently evaluated in a Ph2a clinical trial (CONCORD) for CKD."

Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Obesity • Renal Disease • LCN2

Soluble guanylate cyclase stimulators and activators: Past, present and future. (PubMed, Br J Pharmacol) - "The first in class sGC stimulator riociguat was approved for pulmonary hypertension in 2013 and vericiguat very recently for heart failure...Substantial research efforts ameliorated the first-generation sGC activators such as cinaciguat, culminating in the discovery of runcaciguat, currently in clinical phase II for chronic kidney disease and diabetic retinopathy. Here we highlight the discovery and development of sGC stimulators and sGC activators, their unique modes of action, their preclinical characteristics and the clinical studies. In future, we expect to see more sGC agonists in new indications, reflecting their unique therapeutic potential."

Journal • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetic Retinopathy • Heart Failure • Hypertension • Nephrology • Pulmonary Arterial Hypertension • Pulmonary Disease • Renal Disease • Respiratory Diseases • Retinal Disorders

Runcaciguat, a novel soluble guanylate cyclase activator, shows renoprotection in hypertensive, diabetic, and metabolic preclinical models of chronic kidney disease. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "These data demonstrate that the sGC activator runcaciguat exhibits cardio-renal protection at doses which did not reduce blood pressure and was effective in hypertensive as well as diabetic and metabolic CKD models. These data, therefore, suggest that runcaciguat, with its specific mode of action, represents an efficient treatment approach for CKD and associated CV diseases."

Journal • Preclinical • Chronic Kidney Disease • Nephrology • Renal Disease

Study of the Influence of Liver Function on Blood Concentrations of Runcaciguat in Participants With Different Degrees of Liver Impairment (clinicaltrials.gov) - P1; N=5; Terminated; Sponsor: Bayer; N=24 ➔ 5; Trial completion date: Mar 2022 ➔ Jul 2021; Recruiting ➔ Terminated; Trial primary completion date: Jan 2022 ➔ Jul 2021; This study is prematurely terminated due to changes in sponsor's overall development strategy. The decision of termination is not related to any safety concern of the compound.

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Chronic Kidney Disease • Hepatology • Nephrology • Renal Disease

Novel sGC activators increase glomerular cGMP, induce vasodilation, and improve blood flow in the murine kidney. (PubMed, Br J Pharmacol) - "sGC activators increase glomerular cGMP, dilate glomerular arterioles, and improve RBF under disease-relevant oxidative stress conditions. Therefore, sGC activators represent a promising class of drugs for CKD treatment."

Journal • Preclinical • Chronic Kidney Disease • Nephrology • Renal Disease • sGC HDA+

CONCORD: Study on the Safety of the Drug Runcaciguat and How Well it Works When Given at the Highest Dose as Tolerated by Individual Patient Whose Kidneys Are Not Working Properly and Suffering at the Same Time From High Blood Sugar and/or High Blood Pressure and a Disease of the Heart and the Blood Vessels. (clinicaltrials.gov) - P2; N=216; Recruiting; Sponsor: Bayer; Trial completion date: Sep 2021 ➔ Jan 2022; Trial primary completion date: Aug 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease

Discovery of the Soluble Guanylate Cyclase Activator Runcaciguat (BAY 1101042). (PubMed, J Med Chem) - "The first generation of sGC activators like cinaciguat or ataciguat exhibited limitations and were discontinued. This program resulted in the discovery of the oral sGC activator runcaciguat (compound 45, BAY 1101042). Runcaciguat is currently investigated in clinical phase 2 studies for the treatment of patients with chronic kidney disease and nonproliferative diabetic retinopathy."

Journal • Chronic Kidney Disease • Diabetic Retinopathy • Nephrology • Renal Disease • Retinal Disorders • sGC HDA+