Ocrelizumab

Medical uses

In the US, ocrelizumab is indicated for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults or for the treatment of primary progressive multiple sclerosis in adults.

In the EU, ocrelizumab is indicated for the treatment of adults with relapsing forms of multiple sclerosis with active disease defined by clinical or imaging features and for the treatment of adults with early primary progressive multiple sclerosis in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity.

Contraindications

Ocrelizumab should not be used in people with hepatitis B infection or a history of severe reaction to this drug. If someone has an infection or infectious disease, treatment should be delayed until the infection is resolved. It has not been tested in pregnant women, but based on animal studies does not appear to be safe for pregnant women; it is excreted in breast milk, and effects on infants are unknown.

Adverse effects

As of October 2016, the three phase III clinical trials of ocrelizumab used to obtain approval had not been published. Based on published data from clinical trials at that time, the most common adverse events were infusion reactions including itchy skin, rash, hives, flushing, throat and mouth irritation, fever, fatigue, nausea, rapid heartbeat, headache, and dizziness. One person died from systemic inflammatory response syndrome and in another trial, rates of cancer were three times higher (2.3% vs. 0.8%) in people taking the drug than people taking placebo. Clinical trials in rheumatoid arthritis and lupus were halted because rates of serious infections were too high; these results were not seen in published trials in people with multiple sclerosis, and the differences may be due to the differences in the bodies of people with the different diseases, as well as other drugs they were taking.

There is an increased risk of infections of all kinds, including respiratory infections, in people taking immunosuppressive drugs like ocrelizumab. In clinical trials submitted to the US Food and Drug Administration (FDA), more people taking ocrelizumab got infections than people taking Interferon beta-1a did, including upper and lower respiratory infections, herpes, and hepatitis B reactivation. The risk of progressive multifocal leukoencephalopathy, a disease caused by viral infection of the brain, is also increased.

An increased risk of malignancy with ocrelizumab may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in people treated with ocrelizumab. Breast cancer occurred in 6 of 781 females treated with ocrelizumab for multiple sclerosis in clinical trials. None of 668 females treated in Rebif (interferon beta-1a) or placebo arms of the clinical trials developed breast cancer.

Pharmacology

Ocrelizumab is an immunosuppressive drug; it binds to CD20, which is selectively made and membrane expressed by B cells. When ocrelizumab binds to CD20 on B cells, these cells are deleted by antibody-dependent cell-mediated cytotoxicity and, to a lesser extent, complement-dependent cytotoxicity.

Chemistry

Ocrelizumab is a humanized monoclonal antibody that binds to a CD20 epitope that overlaps partially with the epitope to which rituximab binds.

History

A study of rituximab in multiple sclerosis with strong results published in 2008, drove interest in B-cell depletion as a strategy to treat multiple sclerosis and has led to extensive off-label use of rituximab to treat primary and relapsing multiple sclerosis. Rituximab is a mouse protein, and is immunogenic in humans, and Genentech and its parent Roche decided to focus on the similar, but humanized mAb that they already had, ocrelizumab, for multiple sclerosis instead.

Clinical trials in people with rheumatoid arthritis and lupus were halted in 2010 because people with these conditions developed too many opportunistic infections when taking ocrelizumab. It was also studied in hematological cancer.

In multiple sclerosis, phase II results were announced in October 2010, and in October 2015, Genentech presented interim results of three Phase III clinical trials. In February 2016, the US Food and Drug Administration (FDA) granted breakthrough therapy designation for primary progressive multiple sclerosis.

In March 2017, the FDA approved ocrelizumab for relapsing-remitting and primary-progressive multiple sclerosis. It is the first FDA-approved treatment for the primary progressive form. When the FDA approved the drug, it required Roche to conduct several Phase IV clinical trials, including: a two-part study in people between ten and 17 years old with relapsing multiple sclerosis to determine dosing, then safety and efficacy in these people, required to be completed by 2024; a prospective five-year study to better understand the risk of cancer, required to be completed by 2030; a prospective study creating a registry of women with MS exposed to ocrelizumab before and during pregnancy, women with MS not exposed to ocrelizumab, and women without MS, to understand the effect on women and children they might bear, due by 2029; an additional pregnancy outcomes study due by 2024; and an additional non-human primate study on fetal development and outcomes due by 2019.

The efficacy of ocrelizumab for the treatment of relapsing forms of multiple sclerosis was shown in two clinical trials in 1,656 participants treated for 96 weeks. Both studies compared ocrelizumab to another MS drug, Rebif (interferon beta-1a). In both studies, the participants receiving ocrelizumab had reduced relapse rates and reduced worsening of disability compared to Rebif. The trials were conducted in the US, Canada, Europe, Latin America, Africa, and Australia.

In a study of PPMS in 732 participants treated for at least 120 weeks, those receiving ocrelizumab showed a longer time to the worsening of disability compared to placebo. The study was conducted in the US, Canada, and Europe.

The application for ocrelizumab was granted breakthrough therapy, fast track, and priority review designations. The FDA granted approval of Ocrevus to Genentech, Inc.

Ocrelizumab was approved for use in the European Union in January 2018. In June 2024, the European Commission granted marketing authorization for the fixed-dose combination ocrelizumab/hyaluronidase to be used for subcutaneous injection. The FDA approved the fixed-dose combination ocrelizumab/hyaluronidase as a subcutaneous formulation in September 2024.

References

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