Background and Aims: Soluble guanylate cyclase (sGC) is a key enzyme in the nitric oxide–cyclic guanosine monophosphate (NO-cGMP) pathway. Oxidative stress impairs NO binding to sGC, preventing the formation of cGMP, contributing to CKD progression and accelerating cardiovascular (CV) disease in patients with CKD. Runcaciguat, a novel sGC activator, potently and selectively activates the hem-free form of sGC under oxidative stress, independently of NO. Activated sGC increases cGMP synthesis, restoring the impaired NO-pathway and potentially preventing CKD progression. This study assessed the efficacy, safety and tolerability of runcaciguat in CKD patients.
Method: The multicentre, randomized, double-blind, placebo-controlled, parallel-group, individual- titration, phase II trial (CONCORD, NCT04507061) enrolled patients aged ≥45 years with CKD (eGFR 25–60 ml/min/1.73 m2, UACR 30–3000 mg/g), ≥3 months stable, maximum tolerated ACEi/ARB treatment and type 2 diabetes and/or hypertension. Patients also had atherosclerotic CV disease and/or heart failure (NYHA class I–II). At 4 weeks after screening, patients were randomized 3:1 to receive runcaciguat od or matching placebo. During the 4-week titration phase, patients were up-titrated weekly from 30 mg to 120 mg, with down-titration acceptable if there were safety issues. Patients received the maximum tolerated dose for ≥4 weeks in the maintenance phase before entering a 30-day safety follow- up. The primary efficacy endpoint was the reduction in UACR from baseline to the average of days 22, 29 and 57 according to a per-protocol analysis for phase 2 studies. The study was separately poweredfor 3 strata: CKD patients with diabetes and SGLT2i co-medication for ≥3 months, CKD patients with diabetes without SGLT2i co-medication, and CKD patients without diabetes.
Results: From September 2020–April 2022, 395 patients from 82 study centres in 13 countries were enrolled and 243 were randomized. In the per protocol set (N=170), 80% were male with a mean ageof 70 years, BMI 30.5 kg/m2, eGFR 41.8 ml/min/1.73 m2 and UACR 220.1 mg/g. Baseline characteristics were largely well balanced between treatment arms and strata, although differences in BMI were observed between the non-diabetic and diabetic strata. An average reduction in UACR of 44% from baseline was observed from day 22 until end of treatment (day 57) in the runcaciguattreatment arm in all strata combined according to a mixed model Bayesian analysis (median 0.565; 10th–90th percentile, 0.526–0.607; >99.9 posterior probability). In contrast, an average UACR reductionof 16% was seen in the placebo arm in all strata combined, but there was no reduction in either diabetic group. Statistically significant reductions in UACR with runcaciguat vs placebo were observed in bothdiabetic strata (>99% posterior probability with 47% and 45% reduction vs placebo), with no significant difference between the strata of patients with diabetes prescribed an SGLT2i or not (p=0.41). Areduction in UACR vs baseline was observed in the runcaciguat arm in all strata combined from day 8 (30 mg od for 7 days). The UACR decreased further during the remainder of the 4-week titration phaseand remained stable at a low level throughout the maintenance phase. After treatment cessation, UACR returned to baseline at the follow-up visit. Up-titration to the highest dose was achieved in ~80% of runcaciguat-treated patients and ~86% of placebo-treated patients. Most treatment-emergent adverse events (TEAEs) were mild or moderate and occurred in 69% and 53% of patients receiving runcaciguat and placebo, respectively. The most common TEAE was peripheral edema in runcaciguat-treated patients (12%) vs nausea in placebo-treated patients (8.5%). Dizziness was the second most frequent TEAE in both groups.
Conclusion: The novel sGC activator runcaciguat significantly reduced UACR vs baseline in patients with CKD on top of ACEi/ARB, with or without concomitant SGLT2i treatment. Runcaciguat was well tolerated with no safety concerns. The results of the CONCORD study suggest that sGC activation may represent a promising approach for the management of patients with CKD with or without type 2 diabetes.
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