Effect of Avenciguat on Albuminuria in Patients with CKD: Two Randomized Placebo-Controlled Trials

Abstract

Key Points:

1. Despite new treatments for CKD, kidney failure risk remains high, particularly where albuminuria remains.

2. We report a prespecified pooled analysis of two randomized controlled trials assessing a soluble guanylate cyclase activator for CKD.

3. 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 m², 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 m² [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.

Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_06_27_ASN0000000000000418.mp3

Keywords: CKD; albuminuria; chronic diabetic complications; chronic kidney failure; chronic renal disease; clinical trial; creatinine; diabetes mellitus; diabetic kidney disease; randomized controlled trials.

Graphical abstract

Figure 1

CONSORT flow diagram. A total of n=33 patients in the randomized set were excluded from the full analysis set (N=471 at baseline) owing to not having any UACR data after week 6 for the efficacy analysis: Four of these patients did not receive any randomized intervention, 14 patients discontinued treatment during the 4-week uptitration phase, another 14 patients discontinued treatment after week 4, and one patient completed the planned treatment period. In the full analysis set (N=471), six patients had UACR data missing at week 6 but were included in the full analysis set because they had at least one UACR measurement at week 12, 18, 19, or 20 (N=465+6=471). *Four patients changed SGLT2 inhibitor use during the trial (two patients in the avenciguat 1 mg TID dose group and two patients in the avenciguat 3 mg TID dose group). Patient data were included in the main analysis until the change in SGLT2 inhibitor use and were excluded from the MMRM after the intercurrent event. MMRM, mixed-effect model for repeated measures; SGLT2, sodium-glucose cotransporter 2; TID, three times daily; UACR, urine albumin–creatinine ratio.

Figure 2

Change from baseline in UACR over the study treatment period. (A) Adjusted geometric mean (95% CI) change from baseline in 10-hour UACR in the pooled population. (B) The DKD trial. (C) The non-DKD trial. (D) Adjusted geometric mean (95% CI) change from baseline in first morning void UACR in the pooled population. (E) Proportions of patients achieving ≥20% decrease in 10-hour UACR in the pooled population. (F) Proportions of patients achieving ≥20% decrease in first morning void UACR in the pooled population. (A–D) Four patients changed SGLT2 inhibitor use during the trial (two patients in the avenciguat 1 mg TID dose group and two patients in the avenciguat 3 mg TID dose group). Patient data were included in the main analysis until the change in SGLT2 inhibitor use. CI, confidence interval; DKD, diabetic kidney disease; FUp, follow-up.

Figure 3

Subgroup analysis of change from baseline in 10-hour UACR at week 20. Data shown are for avenciguat 3 mg versus placebo in the pooled population. BMI, body mass index.

Figure 4

Change from baseline in systolic and diastolic BP, and eGFR over the study treatment period and during washout. (A) Mean (95% CI) change from baseline in systolic BP and (B) diastolic BP over the study period and (C) from predose until 2 hours post-dose for systolic BP and (D) diastolic BP and (E) mean change from baseline in eGFR. Data shown are for the pooled population.