Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial.

Objective: To evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of VX15/2503 in a randomized, single-dose, dose-escalation, double-blind, placebo-controlled study enrolling adult patients with MS. Methods: Single IV doses of VX15/2503 or placebo were administered. Ten patients each were randomized (4: 1 randomization ratio) into 5 ascending dose cohorts of 1, 3, 6, 10, or 20 mg/kg. Safety, immunogenicity, PK/PD, MRI, ECG, and lymphocyte subset levels were evaluated. A Dose Escalation Safety Committee (DESC) approved each dose escalation. Results: VX15/2503 was well tolerated, and all participants completed the study. Antibody treatment-related adverse events were primarily grade 1 or 2 and included urinary tract infection (12.5%) and muscle weakness, contusion, and insomnia (each 7.5%). No dose-limiting toxicities were observed, and no maximum tolerated dose was determined. One subject (20 mg/kg) experienced disease relapse 3 months before study entry and exhibited a grade 3 (nonserious) increase in brain lesions by day 29, possibly related to VX15/2503. Twenty-nine patients exhibited human anti-humanized antibody responses; 5 with titer >= 100. No anti-VX15/2503 antibody responses were fully neutralizing. VX15/2503 C-max, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T-1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations <= 0.3 mg/mL, resulting in decreased cSEMA4D expression. At 20 mg/kg, cSEMA4D saturation persisted for > 155 days. Total sSEMA4D levels increased with dose level and declined with antibody clearance. Conclusions: These results support the continued investigation of VX15/2503 in neurodegener-ative diseases.