Evaluating the Tolerability and Safety Profile of Switching From Rituximab to Ocrelizumab: A Real World Evaluation of Patients With Relapsing Forms of Multiple Sclerosis

Studies of rituximab, a chimeric monoclonal antibody against CD20 have shown that B-cell depletion is of clinical benefit as a potential treatment in relapsing forms of multiple sclerosis (MS).1 Ocrelizumab is a humanized monoclonal antibody that targets CD20 and selectively depletes CD20 expressing cells, while preserving the capacity for B cell reconstitution. When compared with rituximab, ocrelizumab is associated with increased antibody-dependent cell-mediated cytotoxic effects, and reduced complement-dependent cytotoxic effects in vitro.2 By increasing antibody-dependent cell mediated cytotoxic effects, ocrelizumab might modulate tissue-dependent mechanisms of pathogenic response more effectively compared to rituximab. As a humanized molecule, ocrelizumab is expected to be less immunogenic with repeated infusions and might thus present a more favorable safety profile when compared to rituximab.2

Despite rituximab's current off label use in the treatment of MS, currently there is only data available from phase 2 trials. The HERMES group conducted a phase 2, double-blind, 48-week trial involving 104 patients with relapsing forms of MS; 69 patients received 1000 mg of intravenous rituximab and 35 patients received placebo on days 1 and 15.3 A significantly higher number of patients in the rituximab group (78.3%) versus the placebo group (40.0%) had an infusion related reaction (IRR) events within 24 hours after the first infusion. Within 24 hours after the second infusion, fewer patients in the rituximab group (20.3%) than in the placebo group (40%) had similar events. A majority of the rituximab group with IRR events (92.6%) were classified as mild to moderate (grade 1 or 2) in severity.

Safety data from the Investigators Brochure on the OPERA I and II phase 3 trials comparing ocrelizumab to interferon β-1a on relapsing MS patients showed that IRRs were the most common adverse events experienced by patients treated with 600 mg of ocrelizumab.4 The percentage of patients experiencing IRRs was higher in the ocrelizumab group (relapsing forms of MS: 34.3%; primary progressive forms of MS 39.9%) compared with the interferon β-1a (active control) group who received placebo infusions (relapsing forms of MS: 9.7%; primary progressive forms of MS: 25.5%). The rate of IRRs was highest during the first infusion or Dose 1 (27.5% on Day 1; 4.71% on Day 15 of Dose 1) and decreased over time (13.7%; 9.6% and 7.8% following Dose 2, 3, and 4 respectively) for the ocrelizumab treated group. Comparatively, interferon β-1a users experienced 6.5% of IRRs on Day 1, 2.58% on Day 15, < 2.00% after doses 2, 3 and 4 respectively. The reported IRRs were primarily mild-to-moderate in severity (Grades 1 and 2). Serious IRRs occurred in 0.1% and 1.0% respectively of relapsing and progressive patients and treated with ocrelizumab.

Clinical data describing the efficacy and tolerability profile of rituximab and ocrelizumab has utilized populations with different prior treatment characteristics. In the phase 2 HERMES trials, a majority (78.5%) of rituximab patients had been previously been treated with a disease modifying therapy in the last 2 years.3 In contrast, the OPERA I and II phase 3 clinical trials, a majority of ocrelizumab patients (72.9% in OPERA I and 73.8% in OPERA II) represented a treatment naïve population.4 Examining IRRs in patients who have switched from rituximab to ocrelizumab versus those continuing on rituximab will examine the magnitude of the IRRs and subsequent tolerability of ocrelizumab in a real world population.

Earlier concepts of MS disease pathology have suggested that pathogenic T cells are sufficient for the full expression of MS. However, it is now evident that full autoimmune B cells and humoral immune mechanisms also play key roles. 5 Ocrelizumab is a humanized monoclonal antibody that targets CD20 and selectively depleted CD-20 expressing B cells. CD20 is a B cell surface molecule that is expressed on pre B cells and mature B cells, but not expressed earlier in the development of B cells or on mature plasma cells. In all three ocrelizumab studies (with relapsing and progressive populations), treatment with 600 mg of ocrelizumab led to rapid and complete depletion of circulating CD19+ B cells within 14 days post treatment. 4 B cell depletion was sustained throughout treatment period. The median time to repletion of B cells was 72 weeks (range 27-175 weeks). We hypothesize that in switching rituximab treated patients to ocrelizumab, the proportion of patients with B cell depletion (< 1%) 6 months after the first and third infusion of ocrelizumab will be the same as the baseline assessment which will be 6 months after the last dose of rituximab and similar to findings in OPERA I and II.