What is the pathophysiology associated with Ocrevus (ocrelizumab)?

From the Guidelines

Ocrevus (ocrelizumab) has been shown to effectively reduce brain atrophy in multiple sclerosis (MS) patients by depleting CD20-positive B cells, which are involved in the disease's pathophysiology. The medication works by binding to the CD20 antigen on B cell surfaces, causing their depletion through antibody-dependent cellular cytotoxicity, complement-dependent cellular cytotoxicity, and apoptosis, as seen in studies such as the one published in Nature Reviews Neurology 1. This reduction in B cells leads to decreased inflammation and new lesion formation in the central nervous system. In terms of brain atrophy, studies have demonstrated that powerful anti-inflammatory drugs like ocrelizumab can overcome the pseudoatrophy effect, which is a brain volume loss linked to the resolution of inflammatory activity and edema, and actually decrease the accrual of atrophy 1.

Some key points to consider when using ocrevus include:

• The medication is administered as an intravenous infusion, with the first dose split into two 300mg infusions given two weeks apart, followed by 600mg infusions every six months thereafter.
• Ocrevus is effective for both relapsing-remitting MS and primary progressive MS, showing significant reductions in relapse rates, disability progression, and MRI lesion activity.
• Side effects may include infusion reactions, increased risk of infections, and potential long-term effects on immune function due to B cell depletion.
• The use of brain volume measures as secondary or tertiary outcomes in clinical trials of ocrelizumab and other newer drugs has provided positive results overall, indicating the effectiveness of these medications in reducing brain atrophy 1.

Overall, the current evidence suggests that ocrevus is a valuable treatment option for MS patients, with its ability to reduce brain atrophy and slow disease progression, as supported by the study published in Nature Reviews Neurology 1.

From the FDA Drug Label

You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses, including consultation with a qualified specialist, to assess whether a protective immune response was mounted [see Use in Specific Populations (8.1)]. 5. 3 Progressive Multifocal Leukoencephalopathy Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients with MS treated with ocrelizumab in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability 5. 4 Reduction in Immunoglobulins As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with ocrelizumab treatment

The pathophysiology with Ocrevus involves:

• B-cell depletion, leading to decreased immunoglobulin levels and increased risk of serious infections
• Immunocompromisation, increasing the risk of opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML) caused by the JC virus
• Potential for malignancies, including breast cancer
• Risk of immune-mediated colitis, which can be severe and require hospitalization or surgical intervention 2

From the Research

Pathophysiology with Ocrevus

• Ocrelizumab (Ocrevus®) is an intravenously administered, humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS) 3.
• The efficacy of ocrelizumab in reducing relapse rates and disease activity in patients with RMS was demonstrated in pivotal trials and supporting single-arm studies in specific subpopulations 3.
• In patients with PPMS, ocrelizumab reduced measures of clinical and MRI progression relative to placebo 3.

Predictors of Ocrelizumab Effectiveness

• Patients who cease fingolimod are at heightened relapse risk in the first 3 months on ocrelizumab 4.
• The risk of disability worsening during switch to ocrelizumab is reduced by short treatment gaps 4.
• Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05-2.00), p = 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05-6.10), p = 0.039) 5.

Ocrelizumab in Older Progressive Multiple Sclerosis Patients

• The risks and benefits of ocrelizumab use in older patients with progressive forms of MS are not well known 6.
• A retrospective chart review found that 40% of patients older than 55 with primary or secondary progressive MS experienced confirmed disability progression (CDP) while 60% remained stable or improved after 2 years of ocrelizumab treatment 6.
• Ocrelizumab was well tolerated and no difference in infection rate was seen using the within-subject control 6.

Comparison of Efficacy and Safety of Oral Agents

• Fingolimod, teriflunomide, and dimethyl fumarate are oral agents approved for the treatment of relapsing-remitting multiple sclerosis 7.
• Results of Phase III clinical trials and their extension studies showed that the three oral agents significantly reduced the annualized relapse rate - a superior efficacy compared to placebo 7.
• Fingolimod had more safety issues than the other two agents, including risks of infections, cancers, and certain transitory effects such as irregular cardiac function, decreased lymphocyte count, and a higher level of liver enzymes 7.