|Source||Humanized (from mouse)|
|Chemical and physical data|
|Molar mass||148 kg/mol|
|(what is this?)|
Ocrelizumab is a humanized anti-CD20 monoclonal antibody. It targets CD20 marker on B lymphocytes and hence is an immunosuppressive drug candidate. Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds.
It was approved by the FDA in March 2017 as a treatment for multiple sclerosis, and the first FDA approved drug for the primary progressive form of MS; it was discovered and developed and is marketed by Hoffmann–La Roche's subsidiary Genentech under the trade name Ocrevus. With the approval, the FDA also required the company to conduct several Phase IV clinical trials to better understand whether the drug is safe and effective in young people, cancer risks, and effects on pregnant women and children they might bear.
At launch, the drug was priced at $65,000 (annual cost, for two infusions per year).
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 to take; it is excreted in breast milk and effects on infants are unknown.
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 heart beating, headache, and dizziness. One person died from a 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 MS, 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 immunosupressive drugs like ocrelizumab; however, in clinical trials submitted to the 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.
There is an increased risk of breast cancer with ocrelizumab; 6 of 781 females with MS who participated in clinical trials submitted to the FDA developed breast cancer, while none of the 668 females in the other arms of the clinical trials developed breast cancer.
Ocrelizumab is an immunosuppresive drug; it binds to CD20, which is selectively made by B cells, and when ocrelizumab binds to CD20 it kills B cells by causing antibody-dependent cell-mediated cytotoxicity and, to a lesser extent, complement-dependent cytotoxicity.
Ocrelizumab is a humanized monoclonal antibody that binds to an CD20 epitope that overlaps partially with the epitope to which rituximab binds. It has an immunoglobulin G1 with a variable region against human CD20, with a human-mouse monoclonal 2H7 γ1-chain, bound via disulfide links with human-mouse monoclonal 2H7 κ-chain in a dimer.
A study of rituximab in MS with strong results, published in the New England Journal of Medicine in 2008, drove interest in B-cell depletion as a strategy to treat MS and has led to extensive off-label use of rituximab to treat primary and relapsing MS. 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 MS 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 MS, phase II results were announced in October 2010, and in October 2015, Genentech presented interim results of three Phase III clinical trials. Progression of disability was reduced at 12 and 24 weeks. In February, 2016 the FDA granted Breakthrough Therapy Designation for primary progressive multiple sclerosis.
On March 29, 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.
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At launch, the drug was priced at $65,000 per year.
- Other anti-CD20 drugs:
- BIIB033 (Anti-LINGO-1): another monoclonal antibody designed for treating multiple sclerosis
- McGinley, MP; Moss, BP; Cohen, JA (January 2017). "Safety of monoclonal antibodies for the treatment of multiple sclerosis.". Expert opinion on drug safety. 16 (1): 89–100. PMID 27756172. doi:10.1080/14740338.2017.1250881.
- Ron Winslow (March 28, 2017). "After 40-year odyssey, first drug for aggressive MS wins FDA approval". STAT.
- "Ocrelizumab label" (PDF). FDA. March 2017. Retrieved 1 April 2017. See FDA index page for BLA 761053 for updates.
- "BLA Approval Letter" (PDF). FDA. March 28, 2017.
- Reddy, V; Dahal, LN; Cragg, MS; Leandro, M (August 2016). "Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer?". Drug discovery today. 21 (8): 1330–8. PMID 27343722. doi:10.1016/j.drudis.2016.06.009.
- "Recommended INN List 56" (PDF). WHO Drug Information, Vol. 20, No. 3, 2006. 20 (3): 220. 2006.
- Sorensen, PS; Blinkenberg, M (January 2016). "The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects.". Therapeutic advances in neurological disorders. 9 (1): 44–52. PMC . PMID 26788130.
- Katie Reid (2010-03-08). Update 2. Roche suspends arthritis treatment after deaths. Reuters. Retrieved 2010-03-08.
- Hutas, G (2008). "Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies". Current opinion in investigational drugs (London, England : 2000). 9 (11): 1206–15. PMID 18951300.
- "First Data From Ocrelizumab Phase 3 Studies in MS. Oct 2015". Medscape Log.
- "In Third Trial, Ocrelizumab Shows Promise in Progressive MS". Neurology Today. October 12, 2015.
- Nather, David (19 February 2016). "New drug for severe form of MS generates glimmer of hope". STAT.