Safety, Tolerability, Pharmacokinetics, and Immunogenicity of BXOS110, a Novel PSD-95 Inhibitor: A First-in-Human Trial

Background/Objectives: BXOS110 is a first-in-class eicosapeptide designed to target the post-synaptic density protein 95 (PSD-95)-mediated signaling cascade, which plays a key role in ischemic brain injury. In this randomized, double-blind, placebo-controlled phase I trial, we evaluated the safety, tolerability, pharmacokinetics and immunogenicity of BXOS110 in 86 healthy adults. Methods: Participants were assigned to receive either single ascending doses (SAD; 30–320 mg) or multiple ascending doses (MAD; 120–240 mg once daily for 10 days) via intravenous infusion. Plasma concentrations of BXOS110 were quantified using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were derived from the concentration–time profiles using a standard non-compartmental analysis method. Safety and tolerability were assessed throughout the study using adverse events, vital signs, physical examinations, laboratory parameters, etc. Results: Pharmacokinetic analysis demonstrated approximately dose-proportional increases in peak plasma concentration (Cmax) and area under the curve (AUC) across the SAD cohort (30–320 mg). No marked drug accumulation was observed in the MAD cohort. No serious adverse events were reported. Treatment-related adverse events (TRAEs) were generally mild or moderate in severity, occurring in 16.7% (SAD) and 30% (MAD) of BXOS110 recipients, compared to 7.1% and 16.7% in the respective placebo groups. The incidence of anti-drug antibody (ADA) positivity was low, with no apparent association between immunogenicity and TRAE occurrence. Conclusions: BXOS110 demonstrated a favorable safety and tolerability profile. Our findings support its continued clinical development, and we recommend further investigation of multiple-dose regimens not exceeding 240 mg/50 mL or body weight-based dosing to better balance safety and efficacy.