Ocrelizumab

Not to be confused with eculizumab.
Ocrelizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetCD20
Names
Trade namesOcrevus
Clinical data
Pregnancy
category
  • AU: C[1]
  • US: N (Not classified yet)[1]
    Routes of
    use    		Intravenous infusion
    External links
    AHFS/Drugs.comMonograph
    US NLMOcrelizumab
    MedlinePlusa617026
    Legal
    License data
    Legal status
    • UK: POM (Prescription only) [2]
    • US: ℞-only
    • EU: Rx-only
    • In general: ℞ (Prescription only)
    Chemical and physical data
    FormulaC6494H9978N1718O2014S46
    Molar mass145818.03 g·mol−1

    Ocrelizumab, sold under the brand name Ocrevus, is a medication used to treat multiple sclerosis (MS).[3] Specifically it is used for relapsing MS (RMS) and primary progressive MS (PPMS).[4] It is given by gradual injection into a vein.[4]

    Common side effects include rash, itching, trouble breathing, and infection.[4] Other side effects may include cancer.[3] Safety in pregnancy is unclear.[5] It is a monoclonal antibody that binds to CD20 on B lymphocytes reducing their activity.[4]

    Ocrelizumab was approved for medical use in the United States in 2017 and Europe in 2018.[3][4] In the United Kingdom it costs the NHS about £4,800 per 300 mg as of 2021.[6] In the United States this amount costs about 18,000 USD.[7]

    Medical uses

    In the US, ocrelizumab is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults or for the treatment of primary progressive MS, in adults.[8] It is administered by intravenous infusion.[8]

    In the EU, ocrelizumab is indicated for the treatment of adults with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features and for the treatment of adults with early primary progressive multiple sclerosis (PPMS) in terms of disease duration and level of disability, and with imaging features characteristic of inflammatory activity.[4]

    Dosage

    The initial two doses are given two weeks apart and than doses are given every six months.[4]

    The first two doses are 300 mg followed by 600 mg after that.[6]

    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 to take; it is excreted in breast milk, and effects on infants are unknown.[8]

    Side 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 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.[9]

    There is an increased risk of infections of all kinds, including respiratory infections, in people taking immunosupressive drugs like ocrelizumab. 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.[8]

    An increased risk of malignancy with ocrelizumab may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in ocrelizumab-treated patients. Breast cancer occurred in 6 of 781 females treated with ocrelizumab for MS in clinical trials. None of 668 females treated in Rebif (interferon beta-1a) or placebo arms of the clinical trials developed breast cancer. Patients should follow standard breast cancer screening guidelines.[8]

    Pharmacology

    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.[9][10]

    Chemistry

    Ocrelizumab is a humanized monoclonal antibody that binds to an CD20 epitope that overlaps partially with the epitope to which rituximab binds.[9] 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.[11]

    History

    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.[9][12] 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.[13]

    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.[9][14] It was also studied in hematological cancer.[15]

    In MS, phase II results were announced in October 2010, and in October 2015, Genentech presented interim results of three Phase III clinical trials.[16] In February, 2016 the FDA granted Breakthrough Therapy Designation for primary progressive multiple sclerosis.[17]

    On March 28, 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.[18][19] 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.[20]

    The efficacy of ocrelizumab for the treatment of relapsing forms of MS was shown in two clinical trials in 1,656 participants treated for 96 weeks.[18][21] Both studies compared ocrelizumab to another MS drug, Rebif (interferon beta-1a).[18] In both studies, the patients receiving ocrelizumab had reduced relapse rates and reduced worsening of disability compared to Rebif.[18][21] The trials were conducted in the US, Canada, Europe, Latin America, Africa and Australia.[21]

    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.[18][21] The study was conducted in the US, Canada and Europe.[21]

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

    It was 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.[13][8] 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.[20] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[22]

    See also

    • Other anti-CD20 drugs:
      • Rituximab, a chimeric antibody that is directed against CD20.
      • Ofatumumab (HuMax-CD20) a fully human antibody that is directed against CD20
    • BIIB033 (Anti-LINGO-1): another monoclonal antibody designed for treating multiple sclerosis

    References

    1. 1 2 "Ocrelizumab (Ocrevus) Use During Pregnancy". Drugs.com. 13 August 2019. Archived from the original on 28 March 2020. Retrieved 28 March 2020.
    2. ↑ "Ocrevus 300 mg concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). 30 December 2019. Archived from the original on 28 March 2020. Retrieved 28 March 2020.
    3. 1 2 3 "Ocrelizumab Monograph for Professionals". Drugs.com. Archived from the original on 17 March 2021. Retrieved 6 November 2021.
    4. 1 2 3 4 5 6 7 "Ocrevus EPAR". European Medicines Agency (EMA). Archived from the original on 27 March 2020. Retrieved 25 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    5. ↑ "Ocrelizumab (Ocrevus) Use During Pregnancy". Drugs.com. Archived from the original on 28 March 2020. Retrieved 6 November 2021.
    6. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 906. ISBN 978-0857114105.
    7. ↑ "Ocrevus Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 5 March 2021. Retrieved 6 November 2021.
    8. 1 2 3 4 5 6 "Ocrevus- ocrelizumab injection". DailyMed. 13 December 2019. Archived from the original on 27 June 2020. Retrieved 25 April 2020.
    9. 1 2 3 4 5 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. doi:10.1080/14740338.2017.1250881. PMID 27756172. S2CID 36762194.
    10. ↑ Reddy V, Dahal LN, Cragg MS, Leandro M (August 2016). "Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer?" (PDF). Drug Discovery Today. 21 (8): 1330–8. doi:10.1016/j.drudis.2016.06.009. PMID 27343722. Archived (PDF) from the original on 2021-08-04. Retrieved 2021-07-01.
    11. ↑ World Health Organization (2006). "International nonproprietary names for pharmaceutical substances (INN) : recommended international nonproprietary names (Rec. INN) : list 56". WHO Drug Information. 20 (3): 220. hdl:10665/73839.
    12. ↑ 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. doi:10.1177/1756285615601933. PMC 4710102. PMID 26788130.
    13. 1 2 Winslow R (March 28, 2017). "After 40-year odyssey, first drug for aggressive MS wins FDA approval". STAT. Archived from the original on April 1, 2017. Retrieved July 1, 2021.
    14. ↑ Reid K (8 March 2010). "Update 2. Roche suspends arthritis treatment after deaths". Reuters. Archived from the original on 6 May 2021. Retrieved 1 July 2021.
    15. ↑ Hutas G (November 2008). "Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies". Current Opinion in Investigational Drugs. 9 (11): 1206–15. PMID 18951300.
    16. ↑ "First Data From Ocrelizumab Phase 3 Studies in MS. Oct 2015". Medscape Log. Archived from the original on 2021-01-16. Retrieved 2021-07-01.
    17. ↑ Nather D (19 February 2016). "New drug for severe form of MS generates glimmer of hope". STAT. Archived from the original on 17 January 2021. Retrieved 1 July 2021.
    18. 1 2 3 4 5 "FDA approves new drug to treat multiple sclerosis". U.S. Food and Drug Administration (FDA) (Press release). 29 March 2017. Archived from the original on 25 April 2020. Retrieved 25 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    19. ↑ "Ocrevus (ocrelizumab) Injection". U.S. Food and Drug Administration (FDA). 9 May 2017. Archived from the original on 27 March 2020. Retrieved 25 April 2020.
    20. 1 2 "BLA Approval Letter" (PDF). U.S. Food and Drug Administration (FDA). March 28, 2017. Archived (PDF) from the original on April 2, 2017. Retrieved July 1, 2021.
    21. 1 2 3 4 5 "Drug Trials Snapshots: Ocrevus". U.S. Food and Drug Administration (FDA). 28 March 2017. Archived from the original on 28 March 2020. Retrieved 25 April 2020. Public Domain This article incorporates text from this source, which is in the public domain.
    22. ↑ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Archived from the original on 23 October 2020. Retrieved 16 September 2020.
    External sites:
    Identifiers:
    This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.