The soluble guanylate cyclase activator runcaciguat significantly improves albuminuria in patients with chronic kidney disease: a randomized placebo-controlled clinical trial

Abstract

Background and hypothesis: In chronic kidney disease (CKD) the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway is impaired. Runcaciguat, an sGC activator, activates heme-free sGC, restoring cGMP production. This phase 2a trial studied the efficacy, safety, and tolerability of runcaciguat in CKD patients with or without sodium-glucose co-transporter-2 inhibitor (SGLT2i).

Methods: Patients with CKD and established atherosclerotic cardiovascular disease or heart failure, plus type 2 diabetes (T2D) and/or hypertension, were enrolled. All were receiving stable maximum tolerated renin-angiotensin system inhibitors with or without SGLT2i. They were randomized 3:1 to runcaciguat once daily, titrated weekly (30-120 mg if tolerated), or placebo for 8 weeks. The primary efficacy endpoint was urine albumin-to-creatinine ratio (UACR) (average of post-randomization Days 22, 29, and 57 vs baseline). CONCORD was separately powered for CKD and T2D with stable SGLT2i comedication, CKD and T2D without SGLT2i, and non-diabetic CKD.

Results: Of 243 patients randomized, 229 were included in the full analysis set (FAS) and 170 in the per-protocol set (PPS). In the PPS, UACR decreased by -45.2% versus placebo with runcaciguat in patients with CKD without SGLT2i (P < 0.001) and by -48.1% versus placebo in patients with CKD taking SGLT2i (P = 0.02) In the FAS, the relative reductions were -46.9% (P < 0.001) and -44.8% (P = 0.01), respectively. No significant difference was observed between patients with or without SGLT2i. In non-diabetic CKD, UACR was reduced versus baseline with runcaciguat, but the change was not statistically significant (P = 0.10). Serious treatment-emergent adverse events were reported in 7% of patients receiving runcaciguat and 8% receiving placebo.

Conclusion: 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).

Keywords: albuminuria; chronic kidney disease; sodium-glucose co-transporter-2 inhibitors; soluble guanylate cyclase activator; type 2 diabetes.

Figure 1:

CONCORD study design. ^aDown-titration could be performed once because of tolerability issues or due to safety concerns. This dose was then maintained until the end of treatment. o.d.: once daily; R: randomization.

Figure 2:

CONSORT flow diagram. If a subject had more than one validity finding that excluded them from an analysis set, all the findings are displayed. ^aProhibited medication (mineralocorticosteroid): n = 1; conflict with treatment schedule: n = 1; rescreened but randomization not in time window: n = 1. ^bPatients had up to three reasons for exclusion. ACEi: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker; CKD: chronic kidney disease; FAS: full analysis set; PPS: per-protocol set; SAS: safety analysis set; SGLT2i: sodium-glucose co-transporter-2 inhibitor; UACR: urine albumin-to-creatinine ratio.

Figure 3:

Patient disposition.

Figure 4:

Mean change in UACR over time (95% CI, ANCOVA) (PPS). Estimated mean % change from baseline and 95% CI (ANCOVA) for (A) patients with diabetic CKD not on SGLT2i; (B) patients with diabetic CKD on SGLT2i; and (C) patients with non-diabetic CKD. Placebo upper limit for the diabetic CKD with SGLT2i stratum was 2.649 (165%) on Day 15, 2.318 (132%) on Day 22, 1.987 (98.7%) on Day 29, and 2.310 (131%) on Day 87 (follow-up). ANCOVA: analysis of covariance; CI: confidence interval; CKD: chronic kidney disease; NS: not significant; PPS: per-protocol set; SGLT2i: sodium-glucose co-transporter-2 inhibitor; UACR: urine albumin-to-creatinine ratio.

Figure 5:

Absolute change in (A) eGFR versus baseline^a, (B) SBP versus baseline^a, (C) DBP versus baseline^a, (D) heart rate versus baseline^a, and (E) HbA1c versus baseline^b. ^aEstimated mean absolute change from baseline and 95% CI (ANCOVA) of the PPS for the average across Days 22, 29, and 57. ^bEstimated mean absolute change from baseline and 95% CI (ANCOVA) of the PPS for Day 57. ANCOVA: analysis of covariance; CI: confidence interval; CKD: chronic kidney disease; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration; eGFR: estimated glomerular filtration rate (CKD-EPI equation); HbA1c: glycated hemoglobin; PPS: per-protocol set; SBP: systolic blood pressure; SGLT2i: sodium-glucose co-transporter-2 inhibitor.