Assessing Pharmacokinetics and Safety of Therapeutic Alpha-1-Microglobulin in First-in-Human Kidney Transplantation: A Noncomparative Open-Label Multiple-Dose Phase 1b Study

Abstract

Background. RMC-035 is a modified version of alpha-1-microglobulin, an endogenous protein developed as a renoprotective agent. Its intended use is to reduce the risk of irreversible loss of kidney function in cardiac surgery patients and to reduce delayed graft function in kidney transplant recipients. This first-in-human study aimed to evaluate the pharmacokinetics and safety of RMC-035 in kidney transplant recipients. Methods. Eight living-donor kidney transplant recipients were included in 2 dose cohorts. The study drug RMC-035 was administered starting with the first dose during transplantation. Four additional doses were administered once daily following transplantation. In the first cohort, all 5 doses of RMC-035 were equal, whereas in the second cohort, the last 3 doses were doubled. Safety monitoring, laboratory tests, and pharmacokinetic measurements were performed according to protocol for 4 d post-transplantation and during the 90-d follow-up period. Results. All 5 administrations of the study drug were completed in 5 out of 8 treated participants. Pharmacokinetic concentrations were approximately dose proportional, and AUC0–24h decreased between the first and fifth doses, reflecting improved kidney function and RMC-035 renal clearance over time. No accumulation was observed between the administrations. No clinically significant changes were observed in the hematological or biochemical laboratory parameters, electrocardiogram findings, or vital signs. A total of 22 treatment-emergent adverse events (AEs) were reported in 6 subjects. Mild and transient AEs suggestive of infusion-related reactions, such as chills, were reported in 5 patients. There was a clinically significant reduction in serum creatinine levels, reflecting post-transplant improvement in kidney function. Conclusions. Based on the safety data obtained from 8 subjects in the 2 dose cohorts treated with RMC-035, the drug was considered safe. Safety and AE profiles were in line with expectations of the target population, and infusion-related reactions were short-lived and manageable. Dose-limiting toxicity signals were not observed.