Experimental Medications: Ocrelizumab

Companies: Genentech and Roche Pharma AG

• Administered via intravenous infusion
• Ocrelizumab is being studied in RRMS and in primary-progressive MS (PPMS)Like Rituxan, this drug is an anti-CD20 monoclonal antibody. It has the potential advantage of being a more humanized antibody than Rituxan. As noted in the introduction to this section, humanized monoclonal antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans. «More humanized» refers to a protein sequence that is more similar to antibodies produced in humans, compared to another humanized monoclonal antibody (Rituxan in this instance).In a Phase II study of ocrelizumab²⁵ in 220 patients with RRMS, reductions in the total number of brain lesions detected by MRI scans (the primary endpoint of the study) were highly significant at 96 percent for 2,000-mg ocrelizumab and 89 percent for 600 mg compared to placebo. The annualized relapse rate was significantly lower versus placebo at week 24, with a reduction of 73 percent for ocrelizumab 2,000 mg, and 80 percent for ocrelizumab 600 mg. Ocrelizumab’s effectiveness was maintained through week 72 (about two weeks less than one year and five months); the proportion of relapse-free patients at week 72 was 84 percent for the 600-mg group, and 82 percent for the 2,000-mg ocrelizumab group.

  Infusion-related symptoms, which were generally mild to moderate, were seen in the ocrelizumab-treated groups. The number of serious adverse events was small and similar among the groups. However, one patient in the ocrelizumab 2,000-mg group died of a systemic inflammatory response of unknown etiology (e.g., the reason why this response occurred is not known). Although Phase III trials in rheumatoid arthritis had significant rates of serious and opportunistic infections, none were identified in this trial of 220 MS patients. Please note that the number of MS patients studied in this Phase II trial is small in comparison to the number of rheumatoid arthritis patients studied in the larger Phase III studies that have already been completed.

  Several Phase III trials of ocrelizumab are now underway. OPERA I²⁶ and II²⁷ are comparing ocrelizumab (600 mg, as above) to Rebif (44 mcg of interferon beta-1a given via subcutaneous injection three times per week) in RRMS and plan to enroll approximately 800 patients in each study. These trials are anticipated to run through mid-2015. The primary outcome measure is annualized relapse rate; secondary measures include time to onset of sustained disability progression, the proportion of relapse-free patients, MRI measures of disease activity, and change in Multiple Sclerosis Functional Composite (MSFC) Scale.

  In addition, because subgroup analysis of Rituxan in the OLYMPUS study suggested a benefit to younger patients and those with gadolinium-enhancing lesions, ocrelizumab is also being studied in primary-progressive MS (PPMS). The Phase III ORATORIO²⁸ safety and efficacy study of ocrelizumab in 630 patients with PPMS is currently recruiting participants. Patients will receive either ocrelizumab (300 mg given intravenously in two infusions separated by 14 days in each treatment cycle) or placebo. The study is scheduled to run through late 2017. The primary outcome measure is time to onset of sustained disability progression (for at least 12 weeks); secondary outcome measures include the time to sustained disability progression (for at least 24 weeks), change in the total volume of T2 lesions (as seen on MRI), as well as safety, tolerability, and the incidence of adverse events.