Effect of Avenciguat on Albuminuria in Patients with CKD

Key Points Despite new treatments for CKD, kidney failure risk remains high, particularly where albuminuria remains. We report a prespecified pooled analysis of two randomized controlled trials assessing a soluble guanylate cyclase activator for CKD. Avenciguat led to improvements in albuminuria in patients with CKD with/without type 2 diabetes mellitus, with acceptable safety. Background Avenciguat is a novel, potent soluble guanylate cyclase activator in development for CKD. Two trials investigated avenciguat in diabetic (NCT04750577) and non-diabetic (NCT04736628) CKD. Methods A prespecified pooled analysis of two randomized, double-blind, placebo-controlled trials of identical design. Adults with CKD (eGFR ≥20 and <90 ml/min per 1.73 m 2 , urine albumin–creatinine ratio [UACR] ≥200 and <3500 mg/g) were randomized to 20 weeks of placebo or avenciguat 1, 2, or 3 mg three times daily (TID), adjunctive to angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The primary end point was change from baseline in UACR in 10-hour urine at week 20, analyzed per protocol. The secondary end point was UACR change from baseline in first morning void urine at week 20. Safety was monitored throughout. Results Overall, 500 patients (mean age 62 years [SD 13]; mean eGFR 44 ml/min per 1.73 m 2 [SD 18] and median 10-hour UACR 719 [interquartile range, 379–1285] mg/g) received placebo ( n =122) or avenciguat 1 mg ( n =125), 2 mg ( n =126), or 3 mg ( n =127) TID. All 243 patients in study one and 27 of 261 patients in study two had diabetes mellitus. Avenciguat 1, 2, and 3 mg TID reduced UACR in 10-hour and first morning void urine versus placebo throughout the treatment period. At week 20, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UACR in 10-hour urine with avenciguat 1, 2, and 3 mg TID were −15.5% (−26.4 to −3.0), −13.2% (−24.6 to −0.1), and −21.5% (−31.7 to −9.8), respectively, analyzed per protocol. Corresponding changes in first morning void urine were −19.4% (−30.0 to −7.3), −15.5% (−26.9 to −2.5), and −23.4% (−33.5 to −11.8), respectively. Avenciguat was well tolerated; the overall frequency of adverse events was low and similar to placebo. The number of patients who discontinued the study drug because of adverse events with avenciguat 1, 2, and 3 mg TID were five (4%), 11 (9%), and 11 (9%), respectively, compared with four (3%) in the placebo group. Conclusions Avenciguat lowered albuminuria and was well tolerated in patients with CKD. Clinical Trial registry name and registration number: A Study to Test the Effect of Different Doses of BI 685509 on Kidney Function in People With Diabetic Kidney Disease, NCT04750577 and A Study to Test the Effect of Different Doses of Avenciguat (BI 685509) on Kidney Function in People With Chronic Kidney Disease, NCT04736628.