Synergistic Erythropoietic Effects and Safety Profile of Pegmolesatide Combined with Roxadustat in Preclinical Models of Chronic Kidney Disease-Associated Anemia

In China, chronic kidney disease (CKD)-associated anemia poses a significant clinical burden, with observational studies indicating suboptimal Hb target achievement rates despite guideline-directed therapies. To address persistent Hb maintenance challenges, clinicians increasingly adopt combination strategies pairing erythropoiesis-stimulating agents (ESAs) with hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). However, critical gaps exist in preclinical evidence supporting this practice. Pegmolesatide, a novel long-acting erythropoiesis-stimulating agent developed by Jiangsu Hansoh Pharmaceutical Group Co., Ltd., received regulatory approval in China in 2023 for anemia management in both dialysis and non-dialysis CKD patients. Its single-dose administration sustains erythropoietic activity for up to one month, coupled with favorable safety, positioning it as a promising therapeutic option. This study systematically evaluates the synergistic potential and safety of combining pegmolesatide — a breakthrough in sustained erythropoiesis — with roxadustat, a representative HIF-PHI, in translational rat models.

  Healthy Rats: 6-8-week-old SD males received pegmolesatide (0.06/0.6 mg/kg, single subcutaneous dose) ± roxadustat (10/20 mg/kg, oral thrice-weekly). Blood parameters (Hb, RBC, HCT) were analyzed on days 6/8/13;

ü  5/6 Nephrectomy Rats: Four weeks post-surgery, anemic models (Hb↓27 g/L, creatinine↑3× vs. sham) received pegmolesatide (0.1/1.0 mg/kg) ± roxadustat (20 mg/kg) under identical regimens. Assessments occurred on days 6/13/20/28;

ü  Safety included platelet/leukocyte counts, renal function, and body weight.

     Healthy Model: High-dose pegmolesatide (0.6 mg/kg) increased Hb by 19 g/L vs. saline controls at day 8, with effects lasting until day 13. Pegmolesatide-roxadustat combinations showed synergistic effects; At day 6, low-dose pegmolesatide (0.06 mg/kg) + roxadustat (20 mg/kg) elevated Hb by 11 g/L and 6 g/L compared to either monotherapy (unpaired t test, p < 0.05) (see the figure). No significant changes in PLT/WBC or body weight were observed.

n   Renal-Impaired Model: Both pemostimotide monotherapy doses (0.1 and 1.0 mg/kg) significantly elevated hemoglobin levels by 34 g/L and 48 g/L versus model controls at day 6, with sustained efficacy persisting until day 13 (low dose) and day 20 (high dose), respectively. The roxadustat monotherapy group exhibited progressive Hb elevation throughout the treatment period, culminating in a 61 g/L increase compared to the model control group at day 28. All pegmolesatide-roxadustat groups exhibited enhanced Hb responses, with peak synergy observed at day 13 (13-29 g/L increase over monotherapies, unpaired t test, p < 0.05). Combined therapy achieved earlier Hb plateaus (day 20 vs. day 28 for roxadustat alone). Transient PLT reduction (day 13, high-dose pegmolesatide; resolved by day 20) and brief WBC elevation (day 6; normalized by day 13) occurred without renal function impairment or weight loss.

The combination of pegmolesatide and roxadustat demonstrates potent, synergistic erythropoietic effects in both healthy and CKD-modeled rats, with a favorable safety profile. The findings highlight the potential to address unmet needs in refractory CKD anemia management through mechanistically complementary therapies.