Pharmacodynamic consequences of administration of VLA-4 antagonist CDP323 to multiple sclerosis subjects: a randomized, double-blind phase 1/2 study.

Abstract

BACKGROUND:

Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS).

OBJECTIVE:

Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS.

METHODS:

Seventy-one RMS subjects aged 18-65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo.

RESULTS:

Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α4-integrin on VCAM-1-binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions.

CONCLUSIONS:

CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00726648.

• Authors: Christian Wolf, Jagdev Sidhu, Christian Otoul, Dexter L Morris, Jennifer Cnops, Jorg Taubel, Barbara Bennett
• Journal: PloS one (PLoS One) Vol. 8 Issue 3 Pg. e58438 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23472197 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• CDP323
• Integrin alpha4beta1
• Naphthyridines
• Vascular Cell Adhesion Molecule-1
• Integrin alpha4
• Phenylalanine

Topics

• Adult
• Double-Blind Method
• Drug Administration Schedule
• Female
• Flow Cytometry
• Humans
• Integrin alpha4 (metabolism)
• Integrin alpha4beta1 (antagonists & inhibitors)
• Lymphocytes (drug effects)
• Male
• Middle Aged
• Multiple Sclerosis (drug therapy)
• Naphthyridines
• Phenylalanine (administration & dosage, analogs & derivatives, pharmacology)
• Recurrence
• Treatment Outcome
• Vascular Cell Adhesion Molecule-1 (metabolism)