OP-0250 -
The Safety and Efficacy of Ocrelizumab; a Humanized anti-CD20 Antibody Administered as a Single Infusion Regimen to Patients with Active Rheumatoid Arthritis
Tak, Ilivanova, Doyle, Gomez-Reino, van den Bosch, Pope, Boyd, Dixon, Martin, Chirinos-Rojas; Amsterdam, Netherlands.
Objectives
Like rituximab, ocrelizumab is a B cell depleting monoclonal antibody. It differs from rituximab in that it is fully humanized, a feature that may reduce infusion reactions, eliminate the need for supplemental glucocorticoid administration, and improve durability of response.
Methods
The study was conducted in two phases. In the first, dose-finding, phase, 40 patients were randomized to receive a single infusion of ocrelizumab at one of four doses (400, 1000, 1500, and 2000mg) or placebo. In the second phase, 135 patients were randomized to receive ocrelizumab at one of three doses (400, 1000, or 1500 mg) or placebo. Eligible patients had to have active disease, defined as eight or more swollen joints and eight or more tender joints with elevated inflammatory markers, failed prior DMARDs, and continue to receive background methotrexate. Per-protocol, patients did not receive glucocorticoids during infusion. ACR20 response at 24 weeks was the primary outcome measure. Safety, particularly the incidence of infusion reactions, was recorded throughout. Patients were eligible to enter an open-label extension phase after 24 weeks and receive further treatment courses.
Results
In the larger, double-blind portion of the study, 43, 44, and 45 patients were randomized to receive 400, 1000, and 1500 mg of ocrelizumab, respectively, and compared to 35 patients randomized to placebo. By week 24, 1, 4, and 4 patients had withdrawn from the respective ocrelizumab groups compared to 5 from the placebo group. One patient in the ocrelizumab 1500 mg group withdrew due to an infusion reaction. In the open-label extension, 18, 18, and 34 patients in the respective ocrelizumab groups received a second course of treatment. Patients had active disease with a mean of 28 swollen joints, 16 tender joints, and mean ESR > 40 balanced between the groups. Most (93%) were seropositive for rheumatoid factor.
Efficacy Outcomes at 24 Weeks
|
Placebo |
Ocrelizumab - 400 mg |
Combined Ocrelizumab Groups |
ACR20 |
34% |
58% |
49% |
ACR50 |
9% |
33% |
27% |
ACR70 |
3% |
19% |
14% |
Infusion reactions, mostly minor, occurred in the 60% of patients in the combined ocrelizumab groups vs. 29% of placebo subjects. There was no clear indication of an increased risk for other serious adverse events or infections associated with ocrelizumab. CD19 levels, an indicator of B cell depletion, were reduced to the same degree at all doses of ocrelizumab. The incidence of human anti-human antibodies was 0 – 9%, and did not correlate with clinical response or risk of infusion related events.
Conclusions
Ocrelizumab, given as a single infusion without concomitant glucocorticoids, was safe and more efficacious than placebo at relieving the signs and symptoms of moderate to severe RA in patients with a previous inadequate response to DMARDs
Editorial Comment
This design of this phase I/II trial is similar to that of the ACTION study, first presented at the 2006 American College of Rheumatology Meeting with the exception of higher doses used. The safety threshold of the drug is apparent from this study: below 2000 mg for a single infusion. The observation that the smallest dose performed as well as the higher doses for efficacy suggests that this may be the optimal dose to use in further Phase II/III trails. Despite being humanized, infusion reactions, including those leading to dose-modification, were fairly common---but still mild in general. Further study will determine whether the potential risks of infusion-related events outweigh the risk of glucocorticoids given at the time of infusion. There were not enough patients retreated in this study to reap valid conclusions about the safety of repeated administration.
