Efficacy and Cardiovascular Safety of Pegmolesatide in Patients with Anemia of Chronic Kidney Disease: Post Hoc Analysis of Two Phase 3 Randomized Trials

Introduction: Pegmolesatide selectively binds to the erythropoietin receptor homodimer with higher binding stability and prolonged residency than erythropoietin, potentially offering an improved therapeutic profile for anemia management in chronic kidney disease (CKD) patients. This post hoc analysis of two randomized phase 3 trials compared pegmolesatide with epoetin alfa to further evaluate pegmolesatide's potential benefits. Methods: This analysis included a total of 545 patients: 372 with dialysis-dependent (DD)-CKD (248 pegmolesatide, 124 epoetin alfa) and 173 with non-dialysis-dependent (NDD)-CKD (115 pegmolesatide, 58 epoetin alfa). The proportion of patients maintaining mean hemoglobin (Hb) levels ≥ 10 g/dL and intraindividual hemoglobin variability (Hb-Var) were analyzed. Cardiovascular (CV) safety was assessed using five-point major adverse cardiovascular events (MACE), expanded cardiovascular events and three-point MACE. Results: During the efficacy evaluation period (weeks 17 - 24), pegmolesatide showed numerically higher proportions of patients who maintained mean Hb levels ≥ 10 g/dL versus epoetin alfa in both DD-CKD (91.8% vs. 88.6%; difference: 7.1% [95% confidence interval (CI): 0.1, 14.2]; P = 0.2802) and NDD-CKD (87.0% vs. 85.4%; difference: 3.3% [95% CI: -8.1, 14.6]; P = 0.6091) patients. From efficacy evaluation period to extended period (weeks 17 - 52), patients receiving pegmolesatide exhibited lower Hb-Var compared with those receiving epoetin alfa as measured by within-patient residual standard deviation (DD-CKD: 0.678 g/dL vs. 0.730 g/dL, P = 0.0061; NDD-CKD: 0.647 g/dL vs. 0.677 g/dL, P = 0.3158). The incidences of five-point MACE (DD-CKD: 3.7% vs. 6.5%, hazard ratio [HR] = 0.54 [95% CI: 0.21, 1.39]; NDD-CKD: 0.9% vs. 6.9%, HR = 0.14 [95% CI: 0.02, 1.28]), expanded CV events (DD-CKD: 9.8% vs. 11.3%, HR = 0.83 [95% CI: 0.43, 1.61]; NDD-CKD: 5.2% vs. 12.1%, HR = 0.49 [95% CI: 0.16, 1.45]) and three-point MACE (DD-CKD: 2.0% vs. 3.2%, HR = 0.60 [95% CI: 0.16, 2.23]; NDD-CKD: 0 vs. 1.7%, HR not estimable) were consistently lower in the pegmolesatide group across both patient populations. Conclusion: Pegmolesatide showed effectiveness in Hb management for both NDD-CKD and DD-CKD populations, with overall numerically favorable cardiovascular safety outcomes compared to epoetin alfa.