First-in-Human Study of SK-08, a Novel Soluble Guanylyl Cyclase Activator: Safety, Pharmacokinetics, Pharmacodynamics, and Therapeutic Potential for CKD

Background: The nitric oxide-soluble guanylyl cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling axis is a validated yet underexploited therapeutic target in CKD. Despite disease modification by current therapies (e.g., RAS inhibitors, SGLT2 inhibitors), residual renal risk remains. SK-08, a heme-independent next-generation sGC activator, is under development as a potential treatment for CKD. Methods: This phase 1 randomized, double-blind, placebo-controlled single ascending dose study (NCT07021157) evaluates SK-08 in healthy Chinese adults. Six escalating dose cohorts (5-60 mg) are assessed using a 3:1 (active:placebo) randomization scheme, with 48 participants planned in total. The study evaluates safety, tolerability, PK, and PD, including plasma cGMP levels as a key PD biomarker. Results: Initial data from the 5 mg and 10 mg cohorts showed dose-proportional PK (Cmax: 205.3 vs 436.8 ng/mL; AUC0-∞: 2323.8 vs 5315.2 h●ng/mL, respectively) and dose-dependent cGMP elevation (ΔcGMP: +24.8% vs +46.1% from baseline), with a Tmax of 2.5 hours (Figure A-B). A food effect substudy (10 mg) showed no clinically significant impact on PK parameters (Figure C) , and a preliminary PK-PD correlation trend was observed (R2=0.585; Figure D). SK-08 had a favorable safety profile with no serious adverse events or severe adverse events reported. Higher-dose evaluation is ongoing to further define the PK/PD and safety profile, and establish the therapeutic window of SK-08. Conclusion: SK-08 exhibits promising clinical potential, characterized by linear PK, dose-dependent PD responses, no significant safety signals across the evaluated doses, and negligible food effects observed. These preliminary phase 1 findings support further clinical development of SK-08 in CKD patients as a potential disease-modifying therapy. Funding: Commercial Support - Consun Pharmaceutical Group