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.
BACKGROUND
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 (i.v.) or 1.0 and 3.5 mg/kg subcutaneously (s.c.), 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 s.c., or 5 mg/kg i.v., followed by eight weeks of evaluation.


RESULTS
MTRX1011A was well tolerated in the SAD phase up to 7 mg/kg i.v. and in the MD phase up to 1.5 mg/kg s.c.. At weekly doses of 3.5 mg/kg s.c. and 5 mg/kg i.v., 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.
Genentech Research and Early Development, 1 DNA Way, South San Francisco, CA 94080, USA.
Heleen
H
Scheerens
Zheng
Z
Su
Bryan
B
Irving
Michael J
MJ
Townsend
Yanan
Y
Zheng
Eric
E
Stefanich
Vishala
V
Chindalore
Clifton O
CO
Bingham
John C
JC
Davis
D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D015415:Biomarkers / Q000097:blood; D015704:CD4 Antigens / Q000276:immunology* / Q000378:metabolism; D015331:Cohort Studies; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D015704:CD4 Antigens