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 Cmax, area under the time-concentration curve, and mean half-life increased with dose level; at 20 mg/kg, the T1/2 was 20 days. Cellular SEMA4D saturation occurred at serum antibody concentrations ≤0.3 μg/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 neurodegenerative diseases. CLINICALTRIALSGOV IDENTIFIER NCT01764737. CLASSIFICATION OF EVIDENCE This study provides Class III evidence that anti-semaphorin 4D antibody VX15/2503 at various doses was safe and well tolerated vs placebo, although an increase in treatment-emergent adverse events in the treatment group could not be excluded (risk difference -0.7%, 95% CI -28.0% to 32.7%).

DOI: 10.1212/NXI.0000000000000367

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@inproceedings{LaGanke2017SafetytolerabilityOT, title={Safety/tolerability of the anti-semaphorin 4D Antibody VX15/2503 in a randomized phase 1 trial}, author={Christopher C. LaGanke and Lawrence M Samkoff and Keith Edwards and Lily K Jung Henson and Pavle Repovic and Sharon G. Lynch and Lael Stone and David H. Mattson and Aaron Galluzzi and Terrence L. Fisher and Christine Anne Reilly and Laurie A. Winter and John E. Leonard and Maurice Zauderer}, booktitle={Neurology(R) neuroimmunology & neuroinflammation}, year={2017} }