NO- and Heme-Independent sGC Activators, Runcaciguat and Nurandociguat, as New Treatment Options for CKD: From Bench to Bedside

Background: Despite recent progress in the treatment of chronic kidney disease (CKD), there is still a substantial medical need for patients with cardiorenal diseases.Enhancing cGMP signaling by novel sGC activators which can activate the NO-sGC-cGMP signaling under conditions of oxidative stress could represent an effective treatment option for CKD. Methods: Firstly, the discovery, the mode of action and optimization of sGC activators in vitro and ex vivo in biochemical, cellular and organ bath assay systems will be described. In addition, results with sGC activators from a broad spectrum of in vivo animal disease models with hypertensive (AngII infused, Renin transgenic rats), diabetic and metabolic etiology (ZDF, ZSF1 rats) will be presented. Finally, first clinical results with sGC activators in patients with CKD which were treated with and without SGLT2 inhibitors will be summarized. Results: The sGC activators runcaciguat and nurandociguat exhibit a unique mode of action and can enhance cGMP formation in an NO- and heme-independent manner under conditions of oxidative stress in which Nitric Oxide can no longer activate the signaling cascade. These sGC activators could dose-dependently reduce kidney damage in different animal models of CKD and prevented progressive proteinuria by different mechanisms. Clinically, runcaciguat reduced proteinuria in CKD patients. Conclusion: These non-clinical and first clinical data strongly suggest that sGC activators could become an effective treatment option for CKD patients which can significantly reduce the residual risk of patients on top of optimized current therapies. Currently, nurandociguat is investigated clinically a phase 2 program in CKD patients (NCT06522997). Funding: Commercial Support - Bayer AG, Pharmaceuticals