RESEARCH - Ocrelizumab in the treatment of RA: a phase I/II randomized, blinded, placebo-controlled, dose-ranging study

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Arthritis Rheum. 2008 Sep;58(9):2652-61.

Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the

treatment of patients with rheumatoid arthritis: A phase I/II

randomized, blinded, placebo-controlled, dose-ranging study.

Genovese MC, Kaine JL, Lowenstein MB, Giudice JD, Baldassare A,

Schechtman J, Fudman E, Kohen M, Gujrathi S, Trapp RG, Sweiss NJ,

Spaniolo G, Dummer W; ACTION Study Group.

Stanford University, Stanford, California.

OBJECTIVE: Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was

studied in a first-in-human trial in rheumatoid arthritis (RA)

patients receiving concomitant methotrexate (MTX).

METHODS: The ACTION trial was a combined phase I/II study of placebo

plus MTX versus ocrelizumab plus MTX in 237 RA patients

(intent-to-treat population). During phase I, 45 patients were treated

with 1 of 5 escalating doses of study drug (infusions on days 1 and

15, 10-1,000 mg per each infusion). An additional 192 patients were

randomized during phase II. Eligible patients had active disease, an

inadequate response to treatment with at least MTX, rheumatoid factor

positivity, and elevated levels of acute-phase reactants. The total

study duration was 72 weeks. B cell pharmacodynamics over time was

investigated.

RESULTS: Baseline demographics were similar among the treatment

groups. Based on the entire 72-week data set, the incidence of serious

adverse events in the ocrelizumab-treated patients was 17.9%, as

compared with 14.6% in placebo-treated patients. The incidence of

serious infections was 2.0% in all ocrelizumab-treated patients and

4.9% in placebo-treated patients. Infusion-associated adverse events

were mostly grade 1 or grade 2 and were more frequent around the time

of the first infusion. No serious infusion-associated adverse events

were reported in the ocrelizumab group. Evidence of clinical activity

was observed at all doses evaluated. Peripheral B cell depletion after

infusion was rapid at all doses, with earlier repletion of B cells at

doses of 10 mg and 50 mg. Human anti-human antibodies were detected in

19% and 10%, respectively, of those receiving 10 mg and 50 mg of

ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000

mg.

CONCLUSION: Ocrelizumab therapy in combination with MTX was well

tolerated. Doses of 200 mg (2 infusions) and higher showed better

clinical responses, better reduction of C-reactive protein levels, and

very low immunogenicity.

PMID: 18759293

http://www.ncbi.nlm.nih.gov/pubmed/18759293

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