Ocrelizumab …

K K Jain MD†

Neuroimmunology

Updated 03.17.2021
Released 04.11.2017
Expires For CME 03.17.2024

Ocrelizumab

Author: K K Jain MD†

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Ocrelizumab

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Introduction

Historical note and terminology

The history of the development of ocrelizumab starts with rituximab, another monoclonal antibody (MAb) that was developed for the treatment of autoimmune disorders and was approved for the treatment of CD20-positive follicular non-Hodgkin lymphoma in 1994. In a clinical trial in 2008, rituximab was shown to reduce inflammatory brain lesions and relapses for 48 weeks in patients with relapsing-remitting multiple sclerosis (05). This spiked interest in B-lymphocyte depletion as a strategy to treat multiple sclerosis and led to extensive off-label use of rituximab to treat primary and relapsing multiple sclerosis. However, rituximab is a chimeric MAb and is immunogenic in humans, and the manufacturer decided to focus on the similar but fully humanized MAb, ocrelizumab, for multiple sclerosis instead. Ocrelizumab is designed to selectively target CD20-positive B cells, which are key contributors to myelin and axonal damage that can lead to disability in patients with multiple sclerosis. It was granted approval by the U.S. Food and Drug Administration (FDA) in 2017 as the first treatment indicated for both relapsing and primary progressive forms of multiple sclerosis (03). Following approval, the FDA requires the manufacturer to conduct several phase IV clinical trials to assess drug safety and effectiveness in younger patients (10 to 17 years of age) and pregnant women. Other required studies include a prospective 5-year study to better understand the risk of cancer as well as the creation of a registry of women with multiple sclerosis exposed to ocrelizumab before and during pregnancy, which are both required to be completed by 2029.

Prior to approval for multiple sclerosis, ocrelizumab was also tested in clinical trials for rheumatoid arthritis, lupus nephritis, and B-cell malignancies, but its development for systemic lupus erythematosus and neuromyelitis optica was discontinued.

Ocrelizumab has also been approved by the European Medicines Agency. The drug requires administration by intravenous infusion every 6 months. Ocrelizumab has a reported list price of $65,000, which is approximately 25% below that of the high-dose interferon beta 1a. Genentech, the manufacturer, offers patient assistance programs through Genentech Access Solutions for patients who qualify.

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

Study	Results	References
Multicenter, randomized, parallel, double-blind, placebo-controlled trial on patients with relapsing-remitting mutiple sclerosis using different doses of ocrelizumab or interferon beta 1a.	Ocrelizumab was more effective than interferon beta 1a in reducing gadolinium-enhancing lesions on MRI and supported the role of B cells in mutiple sclerosis pathogenesis.	(10)
Phase 3, randomized trial in primary progressive mutiple sclerosis using intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks. Primary endpoint was progression of disability at 12 weeks.	Ocrelizumab was associated with lower rates of clinical and MRI progression than placebo.	(12)
Two identical phase 3 trials on patients with relapsing mutiple sclerosis using intravenous ocrelizumab 600 mg for 24 weeks or subcutaneous interferon beta 1a 44 μg 3 times weekly for 96 weeks. The primary endpoint was the relapse rate.	The relapse rate was lower with ocrelizumab than with interferon beta 1a in both trials. Disease activity and progression was lower with ocrelizumab than interferon beta 1a over a period of 96 weeks.	(04)
A phase 3, prospective, multicenter, open-label study to assess the efficacy and safety of ocrelizumab in relapsing-remitting mutiple sclerosis with previous suboptimal response to disease-modifying therapy. Follow-up period of at least 2 years.	The study is still active but is not recruiting patients. Estimated completion date is September 14, 2021.	ClinicalTrials.gov identifier: NCT02861014
A prospective, multicenter, open-label, single-arm, phase 3b study to evaluate the effectiveness and safety of ocrelizumab in early-stage relapsing-remitting mutiple sclerosis. The open-label treatment period will be 192 weeks, with a follow-up period of at least 48 weeks.	The study is still active but is not recruiting patients. Estimated completion date is August 27, 2024.	ClinicalTrials.gov identifier: NCT03085810
Patients with relapsing multiple sclerosis were randomized to either ocrelizumab 600 mg by intravenous infusion for 24 weeks or subcutaneous IFN β-1a 44 µg 3 times per week during the 96-week treatment period.	Significant treatment benefit of ocrelizumab vs. IFN β-1a seen in OPERA I (NCT01247324) and OPERA II (NCT01412333) was maintained across most subgroups for all endpoints.	(17)

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.

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).

References

01: Barkhof F, Kappos L, Wolinsky JS, et al. Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis. Neurology 2019;93(19):e1778-86. PMID 31484710
02: Emery P, Rigby W, Tak PP, et al. Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program. PLoS One 2014;9(2):e87379. PMID 24498318
03: Frampton JE. Ocrelizumab: first global approval. Drugs 2017;77(9):1035-41. PMID 28523586
04: Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376(3):221-34.** PMID 28002679
05: Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008;358(7):676-88. PMID 18272891
06: Hohlfeld R, Dornmair K, Meinl E, Wekerle H. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol 2016;15(3):317-31. PMID 26724102
07: Hohlfeld R, Meinl E. Ocrelizumab in multiple sclerosis: markers and mechanisms. Lancet Neurol 2017;16(4):259-61. PMID 28327329
08: Hughes R, Whitley L, Fitovski K, et al. COVID-19 in ocrelizumab-treated people with multiple sclerosis. Mult Scler Relat Disord 2020;49:102725. PMID 33482590
09: Jakimovski D, Weinstock-Guttman B, Ramanathan M, et al. Ocrelizumab: a B-cell depleting therapy for multiple sclerosis. Expert Opin Biol Ther 2017;17(9):1163-72. PMID 28658986
10: Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 2011;378(9805):1779-87. PMID 22047971
11: McCool R, Wilson K, Arber M, et al. Systematic review and network meta-analysis comparing ocrelizumab with other treatments for relapsing multiple sclerosis. Mult Scler Relat Disord 2019;29:55-61.** PMID 30677733
12: Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376(3):209-20. PMID 28002688
13: Morschhauser F, Marlton P, Vitolo U, et al. Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol 2010;21(9):1870-6. PMID 20157180
14: Patel A, Sul J, Gordon ML, et al. Progressive multifocal leukoencephalopathy in a patient with progressive multiple sclerosis treated with ocrelizumab monotherapy. JAMA Neurol 2021.** [Epub ahead of print] PMID 33724354
15: Petereit HF, Rubbert-Roth A. Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders. Mult Scler 2009;15(2):189-92. PMID 18971221
16: Sorensen PS, Blinkenberg M. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord 2016;9(1):44-52. PMID 26788130
17: Turner B, Cree BAC, Kappos L, et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. J Neurol 2019;266(5):1182-93.** PMID 30820738
18: Wolinsky JS, Engmann NJ, Pei J, Pradhan A, Markowitz C, Fox EJ. An exploratory analysis of the efficacy of ocrelizumab in patients with multiple sclerosis with increased disability. Mult Scler J Exp Transl Clin 2020;6(1):2055217320911939. PMID 32206332

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Ocrelizumab

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Neuroimmunology

Ocrelizumab …

Ocrelizumab

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Ocrelizumab

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Also in This Category

Autoantibodies: mechanism and testing

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Ocrelizumab

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Ocrelizumab

Indications

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Autoantibodies: mechanism and testing

Multiple sclerosis: treatment of its symptoms

Anti-GQ1b antibody syndrome

Paraneoplastic syndromes

Anti-IgLON5 disease

Balo concentric sclerosis

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

This is an article preview.
Start a Free Account
to access the full version.