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 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.
ClinicalTrials.gov 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%).
GLOSSARY
- AE=
- adverse event;
- AUC=
- area under the time-concentration curve;
- BBB=
- blood-brain barrier;
- CTCAE=
- Common Terminology Criteria for Adverse Event;
- C-SSRS=
- Columbia–Suicide Severity Rating Scale;
- EAE=
- experimental autoimmune encephalomyelitis;
- DESC=
- Dose Escalation Safety Committee;
- DLT=
- dose-limiting toxicity;
- EDSS=
- Expanded Disability Status Scale;
- EOI=
- end of infusion;
- Gd=
- gadolinium;
- HAHA=
- human anti-human antibody;
- MTD=
- maximum tolerated dose;
- OPC=
- oligodendrocyte precursor cell;
- PD=
- pharmacodynamics;
- PK=
- pharmacokinetics;
- QTc=
- QT interval;
- SAE=
- serious adverse event;
- TEAE=
- treatment-emergent adverse event
Footnotes
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by Vaccinex, Inc.
Coinvestigators are listed at Neurology.org/nn.
Supplemental data at Neurology.org/nn
- Received November 8, 2016.
- Accepted in final form April 28, 2017.
- Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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