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Ocrelizumab is believed to influence the immune system response by binding to CD20 on the surface of B cells, leading to cell lysis (breaking down of a cell). Ocrelizumab is approved for the treatment of relapsing forms of MS.
Ocrelizumab is the humanized form of Rituximab, a mouse antibody to CD20 that has been met with some success in the treatment of RRMS. The humanized ocrelizumab is expected to be less immunogenic and therefore less likely to cause infusion reactions.
B cells are believed to be involved in the abnormal immune response in MS. Ocrelizumab is thought to influence the immune system response in MS through its involvement with B cells. Ocrelizumab binds to CD20, found on the surface of B cells, and causes cell lysis leading to a dose-dependent depletion of B cells.
Phase III Trial: ORATORIO
ORATORIO is a phase III, randomized, double-blind, placebo-controlled, multi-center clinical trial designed to investigate the effectiveness of ocrelizumab in reducing clinical disability progression in people living with PPMS. The trial recruited 732 adults with primary progressive MS (PPMS) that were randomly assigned in a 2:1 ratio to receive either ocrelizumab (via 2 intravenous infusions of 300mg two weeks apart) or placebo, respectively. Treatment with ocrelizumab significantly reduced the proportion of individuals that experienced disability progression at 12 weeks compared with placebo (32.9% treated with ocrelizumab versus 39.3% with placebo), as measured by EDSS. Additionally, ocrelizumab significantly reduced the proportion of patients with disability progression at 24 weeks (29.6% on ocrelizumab compared to 35.7% with placebo). Ocrelizumab was also superior to placebo in a number of secondary endpoints. For example, at 120 weeks, 38.9% of individuals on ocrelizumab and 55.1% on the placebo had declined on the time required to walk 25 feet (measured using the Timed 25-Foot Walk test). Also, other improvements with ocrelizumab were seen in imaging measures like lesion volume and brain loss.
The most common adverse events reported in the ocrelizumab treatment group were infusion-related reactions and infections (nasopharyngitis, urinary tract infections, influenza and upper respiratory tract infections). Five deaths were reported in the ORATORIO trial, four of which were in the ocrelizumab group and included pulmonary embolism, pneumonia, and pancreatic cancer. Once participant from the placebo group died as a result of a non-medical reason.
The U.S. Food and Drug Administration (FDA) approved ocrelizumab for the treatment of relapsing forms of MS (including secondary progressive MS with relapses) and primary progressive MS, based on the pivotal phase III data.
Health Canada approved Ocrevus™ (ocrelizumab), with conditions, for the treatment of adults with early primary progressive MS (PPMS). Early PPMS will be defined by duration of disease and level of disability (measured using Expanded Disability Status Scale, EDSS).
An NOC/c is authorization to market a drug (i.e. a Notice of Compliance (NOC), with the condition that the sponsor undertake additional studies to verify the clinical benefit. Notice of Compliance with Conditions - Conduct a new clinical study in patients with PPMS to confirm the efficacy and clinical benefit of OCREVUS.
Phase III Trial: O’HAND
O’HAND is a phase IIIb, randomized, double-blind, placebo-controlled, multi-center clinical trial testing the efficacy and safety of ocrelizumab in people with PPMS, including those who are later in their disease course (older adults up to 65 years of age). The trial will recruit and screen 1000 participants that will be randomly assigned to receive either ocrelizumab (via 2 intravenous infusions of 300mg two weeks apart) or placebo for at least 120 weeks. The study will also contain two follow-up visits, an optional open-label extension phase, and a B-cell monitoring phase. The primary outcome measures will assess time to upper limb disability progression after 12 weeks of treatment, while secondary outcome measures will evaluate disability progression and MRI lesions. Participant recruitment for the O’HAND trial is ongoing.
The anticipated study completion date is April 2028.
Montalban X, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med 2017; 376:209-220