MTRX1011A, a humanized anti-CD4 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A Phase I randomized, double-blind, placebo-controlled study incorporating pharmacodynamic biomarker assessments.

Scheerens, H., Su, Z., Irving, B., Townsend, M.J., Zheng, Y., Stefanich, E., Chindalore, V., Bingham, C.O. 3rd, Davis, J.C. Jr.

Journal	Arthritis Res Ther.	Year	2011
Species	Human	Volume	13 (5)
Analytes Measured	GM-CSF, IFN-γ, IL-1β, IL-10, IL-12 p70, IL-2, IL-6, IL-8, TNF-α	Page #	R177
Matrix Tested	Serum	Category	Cytokines & Chemokines

Abstract

INTRODUCTION: The purpose of this study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the humanized anti-CD4 monoclonal antibody MTRX1011A in a randomized, double-blind placebo-controlled Phase 1 study in patients with rheumatoid arthritis (RA).

METHODS: In the single ascending dose (SAD) portion of the study, patients received single doses of a placebo or MTRX1011A at 0.3, 1.0, 3.5 and 7.0 mg/kg intravenously (IV) or 1.0 and 3.5 mg/kg subcutaneously (SC), followed by five weeks of evaluation. In the multi-dose (MD) portion of the study, placebo or MTRX1011A was administered weekly for eight doses at 1.5 or 3.5 mg/kg SC, or 5 mg/kg IV, followed by eight weeks of evaluation.

RESULTS: MTRX1011A was well tolerated in the SAD phase up to 7 mg/kg IV and in the MD phase up to 1.5 mg/kg SC. At weekly doses of 3.5 mg/kg SC and 5 mg/kg IV, a moderate pruritic papular rash was observed in some MTRX1011A-treated patients, which was considered a dose-limiting toxicity for this clinical indication. No serious adverse events occurred in any cohort. Reduction in disease activity was modest. PD assessments demonstrated that MTRX1011A induced a dose-dependent down-modulation of CD4 expression on peripheral blood CD4 T cells, CD4 receptor occupancy, increases in serum sCD4-MTRX1011A complexes and up-regulation of CD69 on T cells, but was non-depleting.

CONCLUSIONS: The maximum tolerated dose of MTRX1011A was 1.5 mg/kg SC administered weekly. At this dose MTRX1011A did not achieve maximum PD activity expected to be required for reduction in disease activity.