Pharmacology

Ocrelizumab is a recombinant humanized MAb that binds to a CD20 epitope that partially overlaps with the epitope to which rituximab binds. It is a glycosylated immunoglobulin G1 (IgG1) with a molecular mass of approximately 145 kDa. B cell-depleting MAbs are used as treatment for autoimmune diseases, including multiple sclerosis, because B cells play a central role in the pathogenesis of multiple sclerosis, including being involved in the activation of proinflammatory T cells, secretion of proinflammatory cytokines, and production of autoantibodies directed against myelin (16). Most of the immunological studies have been performed on rituximab, and it is assumed that ocrelizumab has a similar mode of action. Therefore, both drugs are referred to as anti-CD20 therapy.

Pharmacodynamics. Ocrelizumab selectively targets cells that express the B-lymphocyte antigen, CD20, on their surface. Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. The CD20 molecule is expressed on a broad range of cells of the human B-cell lineage, with increasing concentrations from pre-B cell through naive and memory B cell, whereas CD20 is not expressed on stem cells. Therefore, antibodies targeting CD20 do not alter the concentration of IgG and IgM antibodies in the blood or in the CSF. CD20 likely amplifies calcium signals that are transduced through the B-cell antigen receptor during antigen recognition by B cells.

According to another view, the efficacy of ocrelizumab does not negate the essential role of T cells, but rather suggests that B cells and T cells jointly contribute to pathogenesis; anti-CD20 therapy is not entirely specific for B cells, but also depletes CD20+ T cells, which repopulate in blood earlier than B cells (07). In clinical studies, B cell counts returned to either baseline or lower limits of normal between 27 and 175 weeks after the last ocrelizumab infusion. Within 2.5 years after the last infusion, B cell counts rose to either baseline or lower limits of normal in 90% of the patients.

Pharmacokinetics. Pharmacokinetic studies of ocrelizumab, conducted during clinical trials of the drug for follicular lymphoma, showed that it had a mean terminal half-life of 23 to 28 days and a slow systemic clearance (0.19–0.71 l/day) at steady state (13). In clinical studies of ocrelizumab for multiple sclerosis, the mean maximum concentration was 212 mcg/mL in patients with relapsing multiple sclerosis (600 mg infusion) and 141 mcg/mL in patients with primary progressive multiple sclerosis (two 300 mg infusions administered within 2 weeks). The pharmacokinetics of ocrelizumab was essentially linear and dose proportional between 400 and 2000 mg.

Passage across the blood-brain barrier. Most of the MAbs do not easily cross the blood-brain barrier because they are large molecules. Rituximab remains detectable within the CSF after intravenous administration for up to 24 weeks, and levels of rituximab in CSF correlate significantly with the integrity of the blood CSF barrier (15). Intrathecal rituximab has been investigated, but it does not enhance the efficacy, and this approach is not practical. There are no definite studies of the passage of ocrelizumab across the blood-brain barrier, but it is assumed that it crosses into the brain to be effective. The pathogenic immune response in primary progressive multiple sclerosis might be sequestered behind the blood-brain barrier, and the development of carrier-mediated transport of ocrelizumab across the blood-brain barrier may be useful for enhancing delivery to the brain (06).

Routes of administration. Ocrelizumab is administered by intravenous infusion.

Clinical trials

Clinical trials of ocrelizumab are shown in Table 1.

Table 1. Clinical Trials of Ocrelizumab

Indications

Ocrelizumab is indicated in adult patients with relapsing forms of multiple sclerosis and primary progressive multiple sclerosis.

Contraindications

Ocrelizumab is contraindicated in patients with hepatitis B infection or a history of severe reaction to this drug. In those suffering from an infectious disease, treatment should be delayed until the infection is resolved.

Goals and duration of treatment

The goal of ocrelizumab therapy is to reduce inflammatory brain lesions in primary progressive and relapsing-remitting multiple sclerosis. Efficacy was demonstrated in clinical trials of duration up to 96-weeks. Long-term open-label extension studies are ongoing. B lymphocyte cell depletion by ocrelizumab offers a promising new option for multiple sclerosis patients, but there is a need for detecting potential long-term sequelae that are currently unknown (09). Results of a systematic review of the literature indicate that ocrelizumab is more effective than or not inferior to any other currently approved disease-modifying therapy for multiple sclerosis, and it has a similar safety profile (11).

In a post hoc exploratory analysis of patients from clinical trials with increased baseline disability, ocrelizumab reduced the risk of confirmed disability progression versus interferon beta-1a in patients with relapsing-onset multiple sclerosis and versus placebo in patients with progression-onset multiple sclerosis (18). A study to assess the onset of ocrelizumab efficacy on brain MRI measures of disease activity in a phase II study in relapsing-remitting multiple sclerosis and the relapse rate in the pooled phase III studies in relapsing multiple sclerosis provides class II evidence that ocrelizumab suppresses MRI activity within 4 weeks and clinical disease activity within 8 weeks (01).

Dosing

The recommended starting dose of ocrelizumab is 300 mg by slow intravenous infusion over a period of 2.5 hours, followed by a second 300 mg intravenous infusion 2 weeks later. The maintenance dose of ocrelizumab is 600 mg by intravenous infusion over a period of 3.5 hours every 6 months.

Special considerations

Renal impairment. Patients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics of ocrelizumab was observed in those patients.

Hepatic impairment. Patients with mild hepatic impairment were included in clinical trials. No significant change in the pharmacokinetics of ocrelizumab was observed in those patients.

Pregnancy and nursing. There are no studies of ocrelizumab therapy in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to ocrelizumab. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Ocrelizumab can cross the placental barrier. This drug should be used during pregnancy only if clearly needed.

Women of childbearing potential should use contraception while receiving ocrelizumab and for 6 months after the last infusion of ocrelizumab.

Large molecules like monoclonal antibodies are unlikely to be excreted into human breast milk or absorbed into the baby’s circulation in any significant amount. However, animal studies have shown the presence of ocrelizumab in monkey milk but the existence of ocrelizumab in human milk has not been documented.

Elderly patients. Clinical studies of ocrelizumab did not include adequate numbers of patients aged 65 years and older to determine whether they respond differently than younger patients. Because the only report of progressive multifocal leukoencephalopathy so far was in an elderly patient, the risks and benefits of ocrelizumab should be thoroughly discussed in elderly patients, who are at higher risk for infections.

Children. The safety and effectiveness of ocrelizumab in pediatric multiple sclerosis patients below the age of 18 years has not been studied.

Interactions

No drug interactions have been reported. Use of ocrelizumab in combination with other multiple sclerosis therapies has not been studied. The potential for increased immunosuppressive effect should be considered if concomitant immunosuppressant therapies are used.

The safety of immunization with live or live-attenuated vaccines following ocrelizumab therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion. No data are available on the effects of live or non-live vaccination in patients receiving ocrelizumab.

Adverse effects

The most common adverse events reported in clinical trials were reactions following infusion of ocrelizumab, including itching, skin rash, hives, flushing, fever, fatigue, nausea, tachycardia, headache, and dizziness. In multiple sclerosis clinical trials, the incidence of infusion reactions in ocrelizumab-treated patients was 34% to 40%, with the highest incidence during or following the first infusion. There were no fatal infusion reactions, but 0.3% of infusion reactions were serious, requiring hospitalization in some cases. Methylprednisolone 100 mg or an equivalent steroid and an antihistaminic, eg, diphenhydramine, should be given one half to 1 hour prior to each infusion as premedication to reduce the risk of infusion reactions. The intensity of the reaction can be further reduced by giving the infusion very slowly and stopping at the earliest sign of a reaction as well as by giving appropriate treatment to manage the symptoms. Patients should be observed for 1 hour following the infusion, but reactions can occur as late as 24 hours following the infusion.

The incidence of cancer was 3 times greater in patients treated with ocrelizumab compared with those taking the placebo. In placebo-controlled clinical trials for rheumatoid arthritis, ocrelizumab combined with methotrexate was associated with a higher risk of serious infections compared with a combination of placebo and methotrexate (02).

One of the safety concerns for MAbs for multiple sclerosis is progressive multifocal leukoencephalopathy, which was initially reported following natalizumab therapy. The first case of progressive multifocal leukoencephalopathy has been reported with ocrelizumab monotherapy in a 78-year-old man with progressive multiple sclerosis without prior immunomodulation and was likely a result of the immunomodulatory function of ocrelizumab as well as age-related immunosenescence (14). Ocrelizumab was discontinued and replaced with off-label pembrolizumab but the patient’s condition deteriorated rapidly and he died.

Comorbidity is a risk factor for severity of COVID-19 infection. However, an assessment of data from clinical trials and postmarketing surveys provided evidence that COVID-19 in multiple sclerosis patients treated with ocrelizumab is predominantly mild to moderate in severity with most patients not requiring hospitalization (08).