#3000 EFFICACY AND SAFETY OF COTADUTIDE, A DUAL GLP1-GLUCAGON RECEPTOR AGONIST, IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND T2DM

Abstract

Background and Aims: Cotadutide is a dual GLP1-glucagon receptor agonist under development for NASH and CKD with T2DM. Incretin-based therapies have been shown to promote improvements in albuminuria while the addition of glucagon has been suggested to provide hepatic benefits; the renal benefits of dual GLP1-glucagon receptor agonism are unknown but kidney and liver are the organs with highest expression of glucagon receptor.We sought to evaluate the efficacy and safety of cotadutide in patients with CKD and T2DM. Method: In this randomised, double-blind, phase 2b study, patients with T2DM and CKD on insulin and/or oral therapy including ≥ 40% treated with SGLT-2i (HbA1c ≥ 6.5 and ≤ 10.5%), eGFR ≥ 20 and < 90 ml/min/1.73m2 and BMI≥ 25 (23 in Japan) kg/m2 were treated for 26 weeks. Participants were randomised (n=45 per arm) to receive once-daily SC cotadutide titrated up to 100, 300 or 600 μg, or placebo. The primary endpoint was percentage change in UACR (log-transformed) at 14 weeks. Secondary endpoints evaluated urinary albumin creatinine ratio (UACR) at 26 weeks, safety and tolerability. Changes in renal function was evaluated as an exploratory endpoint. Results: Atotal of 248 Participants were randomised.Approximately 47%were on SGLT-2i and 97% were on ACE inhibitors or ARBs at baseline. The primary endpoint was met. Dose dependent reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 μg of cotadutide, -39.9% (95% CI -52,5, - 23.9) and -46.0% (95% CI -57.1, -32.1) vs placebo (P <0.001). In patients on background SGLT2i therapy, similar reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 μg of cotadutide, - 31.2% (95% CI - 51.9, -1.5) and - 48.7% (95% CI -64.1, - 26.6) vs placebo (P=0.01 and <0.001 respectively). There was no observed change in eGFR early in dosing. At 26 weeks, an increase in eGFR (+5.5 ml/min/1.73m2) was observed with 600 μg of cotadutide (p = 0.028). A statistically significant, modest reduction in serum uric acid was observed as an exploratory endpoint at 26 weeks in the 100 and 600 μg arms (- 0.54 mg/dL, p = 0.03 and 0.76 mg/dL, p = 0.001 respectively) but not the 300 μg arm(- 0.32 mg/dL, p = 0.17). No significant changes in urine KIM-1 were observed. A significant increase in pulse rate was observed (+4.8 bpm), alongside a numerical reduction in systolic BP (- 8.3 mmHg) at 600 μg on office-based measures. SAEs were balanced across all arms and there were fewer AE-related discontinuations at 100 and 300 ug versus placebo, but more discontinuations at 600 μg. Conclusion: In patients with CKD with T2DM, cotadutide promoted clinically important effects on UACR on top of standard of care with an acceptable tolerability profile. The results suggest cotadutide has potential to provide benefit to patients with CKD and T2DM. Larger studies will be required to evaluate this.