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

Christopher LaGanke, Lawrence Samkoff, Keith Edwards, Lily Jung Henson, Pavle Repovic, Sharon Lynch, Lael Stone, David Mattson, Aaron Galluzzi, Terrence L. Fisher, Christine Reilly, Laurie A. Winter, John E. Leonard, Maurice Zauderer

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

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 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 neurodegenerative diseases.

Original languageEnglish (US)
JournalNeurology: Neuroimmunology and NeuroInflammation
Volume4
Issue number4
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    LaGanke, C., Samkoff, L., Edwards, K., Henson, L. J., Repovic, P., Lynch, S., Stone, L., Mattson, D., Galluzzi, A., Fisher, T. L., Reilly, C., Winter, L. A., Leonard, J. E., & Zauderer, M. (2017). Safety/tolerability of the anti-semaphorin 4D antibody VX15/2503 in a randomized phase 1 trial. Neurology: Neuroimmunology and NeuroInflammation, 4(4). https://doi.org/10.1212/NXI.0000000000000367