Safety, Pharmacokinetics, and Pharmacodynamics of Fixed-dose, Subcutaneous, and Intravenous Administration of VEL-101, an Anti-CD28 PEGylated Monoclonal Antibody Fragment, in Healthy Participants: A Randomized, Double-blind, Placebo-controlled, Dose Escalation, Phase 1 Study

BACKGROUND: VEL-101, also known as pegrizeprument, is a monovalent, humanized, anti-CD28 PEGylated monoclonal antibody fragment that selectively blocks CD28 costimulation, under development as a maintenance immunosuppressant in kidney transplant recipients. In development as a fixed-dose subcutaneous maintenance immunosuppressant in kidney transplant recipients, the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of VEL-101 were evaluated in this randomized, double-blind, placebo-controlled, dose escalation, phase 1 study (NCT05238493). METHODS: Sixty healthy participants were randomly assigned 3:1 to receive 1 of 7 dose levels of VEL-101 or placebo (2 intravenous and 5 subcutaneous) and followed for 50 d. Safety, pharmacokinetic, and pharmacodynamic analyses evaluated the nature and severity of treatment-emergent adverse events, serum VEL-101 levels, and CD28 receptor occupancy, respectively. RESULTS: Most adverse events were mild to moderate, with injection site pain the most frequently reported. One serious adverse event (rhabdomyolysis, grade 3) resolved with supportive care. No case of clinically elevated cytokines or cytokine release syndrome was observed. Following subcutaneous administration, all participants had detectable serum concentrations of VEL-101. Dose-exposure proportionality was maintained, and VEL-101 elimination was consistent regardless of subcutaneous or intravenous administration. CONCLUSIONS: Subcutaneous administration of VEL-101 resulted in dose-proportional increases in maximum concentration and area under the time-concentration curve 0-inf across the doses tested and a sustained receptor occupancy of ≥50% to ≥80%. Subcutaneous administration of VEL-101 was generally well-tolerated, yielding detectable CD28 receptor occupancy levels acceptable for future study in kidney transplant recipients.