A Study of Pegmolesatide of in Dialysis Chronic Kidney Disease (CKD) Patients With Anemia Treated With Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI)

Efficacy and Safety of Pegmolesatide in Dialysis Chronic Kidney Disease (CKD) Patients With Anemia Treated With Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitor (HIF-PHI): a Multi-center, Prospective, Open-label, Randomized Parallel Controlled Trial

For patients with renal anemia treated with hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), there is a clinical need of switching to long-acting and safe medications.

Pegmolesatide, a polyethylene glycol (PEG)-conjugated erythropoiesis-stimulating peptide, is a long-acting erythropoiesis-stimulating agent (ESA) with sustained activity. It was approved for marketing by the National Medical Products Administration (NMPA) in June 2023. Phase III clinical trials have demonstrated its efficacy and safety in dialysis patients with renal anemia who were previously treated with recombinant human erythropoietin (rHuEPO). However, there are currently no data regarding the efficacy and safety of switching from HIF-PHIs to pegmolesatide, and there is a lack of standard for the dose conversion.

This study is a multi-center, prospective, open-label, randomized parallel-controlled clinical trial, planning to enroll 96 patients.

All enrolled patients will receive 12 weeks of treatment and be followed up for 16 weeks.

For patients with renal anemia treated with HIF-PHIs, there is a clinical need of switching to long-acting and safe medications.

Pegmolesatide, a polyethylene glycol (PEG)-conjugated erythropoiesis-stimulating peptide, is a long-acting erythropoiesis-stimulating agent (ESA) with sustained activity. It was approved for marketing by the National Medical Products Administration (NMPA) in June 2023. Phase III clinical trials have demonstrated its efficacy and safety in dialysis patients with renal anemia who were previously treated with recombinant human erythropoietin (rHuEPO). However, there are currently no data regarding the efficacy and safety of switching from HIF-PHIs to pegmolesatide, and there is a lack of standard for the dose conversion.

This study is a multi-center, prospective, open-label, randomized parallel-controlled clinical trial, planning to enroll 96 patients.

Based on the weekly dose of Roxadustat before randomization, patients are divided into two cohorts: the low-dose Roxadustat cohort (weekly dose ≤210 mg) and the high-dose Roxadustat cohort (weekly dose >210 mg and ≤360 mg), with 48 patients in each cohort. Each cohort is stratified by hemoglobin (HB) level, with a 1:1 ratio for HB <10.0 g/dl and HB ≥10.0 g/dl, meaning that there are 24 patients in both cohorts.

Within each cohort, patients are randomly assigned to 2 groups at a 1:1 ratio based on the initial treatment dose of pegmolesatide. Specifically, the patients in low-dose Roxadustat cohort are randomized into the Pegmolesatide initial dose 2 mg group or 4 mg group; the patients in high-dose Roxadustat cohort are randomized into the Pegmolesatide initial dose 4 mg group or 6 mg group, with 24 patients in each group entering the trial period. Pegmolesatide is administered subcutaneously once every 4 weeks, and the dosage is adjusted according to the drug's instructions for use. All enrolled patients will receive 12 weeks of treatment and be followed up for 16 weeks.

Inclusion Criteria:

1. Age between 18-75 years, regardless of gender;
2. Body weight ≥ 45 kg, and body mass index (BMI) ≥ 18.5 kg/m²;
3. Diagnosis of chronic renal failure, and having undergone a stable regimen of peritoneal dialysis or hemodialysis for at least 12 weeks prior to enrollment (with stable hemofiltration at a frequency of every 2 or 4 weeks if applicable). Stable dialysis frequency and no plans to change the dialysis modality during the trial;
4. An up to standard dialysis adequacy testing result before randomization: spKt/V ≥ 1.2 for hemodialysis, Kt/V ≥ 1.7 for peritoneal dialysis;
5. Roxadustat dose ≤ 360 mg/week within 4 weeks before randomization, with stable dose; [Stable dose is defined as: (the maximum weekly dose within 4 weeks before randomization - the average weekly dose within 4 weeks before randomization) ÷ the maximum weekly dose within 4 weeks before randomization ≤ 30%];
6. Two pre-dialysis HB test values within 4 weeks before randomization of 8.0 - 12.0 g/dl, with an absolute difference between the two Hb values ≤ 1.3 g/dl, and an interval of ≥ 7 days between the two HB tests;
7. Serum ferritin level ≥ 100 μg/L and transferrin saturation (TAST) ≥ 20% at the time of testing before randomization, serum folate ≥ the lower limit of normal, and vitamin B12 ≥ the lower limit of normal;
8. Understanding of the study procedures and voluntary signing of the written informed consent form.

Exclusion Criteria:

1. Known autoimmune diseases, hematologic disorders (including congenital and acquired conditions such as thalassemia, Fanconi anemia, pure red cell aplasia, myelodysplastic syndrome, hemolytic anemia, and coagulation disorders), or other causes of anemia apart from CKD (such as gastrointestinal bleeding or hookworm disease).
2. Confirmed diagnosis of acquired immunodeficiency syndrome (AIDS), syphilis, or tuberculosis and currently undergoing treatment.
3. Known allergy to iron agents or polyethylene glycol molecules.
4. Treatment history with ESAs in combination with HIF-PHIs drugs within 8 weeks prior to randomization.
5. Underwent red blood cell or whole blood transfusion within 12 weeks prior to randomization.
6. Poorly controlled blood pressure (uncontrolled hypertension is defined as: during the screening period, systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg in two or more blood pressure measurements, or although the blood pressure values are below the aforementioned criteria, the investigator deems it necessary to adjust antihypertensive medications).
7. Active hepatitis or any of the following abnormal test results during the screening period (ALT ≥ 2 times the upper limit of normal, AST ≥ 2 times the upper limit of normal, DBIL ≥ 2 times the upper limit of normal, serum albumin < 2.5 g/dl).
8. Participants judged by the investigator to have uncontrolled or symptomatic secondary hyperparathyroidism, or those with blood iPTH > 800 pg/mL during the screening period.
9. C-reactive protein ≥ 30 mg/L during the screening period.
10. Cardiac function assessed as NYHA Class III or IV during the screening period.
11. Pregnant or breastfeeding women, or those planning to become pregnant during the study period.
12. Participants who plan to undergo kidney transplantation during the trial period or have already been kidney donors, or those who plan to undergo elective surgery during the trial period.
13. Participants deemed by the investigator to have any other factors that make them unsuitable for participation in this trial.