RA B-Cell Depletion

Clifton Bingham, M.D. - Jon Giles, M.D.

6 (Poster). Safety and Clinical Activity of Ocrelizumab (a Humanized Antibody Targeting CD20+ B Cells) in Combination with Methotrexate in Moderate-Severe Rheumatoid Arthritis Patients (Ph I/I I ACTION Study)

AUTHORS: MC Genovese, JL Kaine, MD Kohen, MB Lowenstein, J Del Giudice, AR Baldassare, J Schechtman, S Gujrathi, RG Trapp, NJ Sweiss, DG Spaniolo, W Dummer

METHODS: The safety and tolerability of ocrelizumab, a humanized monoclonal antibody directed against CD20, in addition to background MTX (10-25 mg/wk) in 237 rheumatoid-factor positive RA patients with moderate to severe disease.  In the phase I dose-escalation 45 patients were treated sequentially (IV infusion Days 1 and 15) with ocrelizumab (10, 50, 200, 500, 1000 mg per dose) or placebo (PLC). During the phase II period 192 patients were randomized to the same doses. No IV corticosteroids were given before infusions. Clinical assessments were made at Wks 4, 12, and 24.

RESULTS: 237 patients (196 ocrelizumab, 41 PLC) were enrolled with mean SJC/TJC, 22/32; RA duration 11 yrs; prior TNF antagonist 47%. 85% of ocrelizumab pts and 76% of PLC pts completed 24 weeks. The most frequent AEs were mild infusion-associated headaches, nausea, chills, fever, and dizziness. Infusion-associated AEs following the first infusion were similar among ocrelizumab dose groups and ~25% more frequent than in the PLC group, but similar to PLC after the second infusion. One serious infusion-associated AE occurred in the PLC group. The rate of SAEs and infection-related SAEs was similar in the groups. B cell depletion was observed with all doses of ocrelizumab and was sustained.

CONCLUSIONS: Ocrelizumab demonstrated clinical activity at all doses in pts with moderate-severe RA when given with MTX and was generally well tolerated.

EDITORIAL COMMENT:  This is an extremely large Phase I/IIa study of a humanized antibody directed against CD20 in DMARD refractory RF-positive RA patients, 47% of whom had also failed TNF antagonists.  The study is notable for the fact that no IV steroids were given. In the context of relatively low placebo responses, ACR 20/50/70 responses are encouraging.  The efficacy results demonstrated here confirm the efficacy seen with other agents targeting anti-CD20 and again confirm a role for the B cell depletion with CD20 as a treatment for at least a group of patients with RA. B cell depletion was long-lived with this antibody. A time course to clinical response was not reported, though CRP reductions were seen at 12 weeks. Even though this was a fully human antibody, first dose infusion-related reactions were more frequent than in the placebo group, thus raising questions as to whether the mechanism explaining these reactions are mechanism based anti-CD-20 mediated cell effects rather than a phenomenon related to chimeric versus humanized versus human antibody construct. The duration of efficacy of the drug is also unclear with no data presented beyond 24 weeks of treatment concerning loss of response.