Wikipedia

Ocrelizumab

Not to be confused with eculizumab.

Ocrelizumab, sold under the brand name Ocrevus, is a medication used for the treatment of multiple sclerosis. It is a humanized anti-CD20 monoclonal antibody.[8] It _targets CD20 marker on B lymphocytes and is an immunosuppressive drug.[10] Ocrelizumab binds to an epitope that overlaps with the epitope to which rituximab binds.[10] It is administered by intravenous infusion.[8] The fixed-dose combination ocrelizumab/hyaluronidase is administered by subcutaneous injection.[9]

Ocrelizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
_targetCD20
Clinical data
Trade namesOcrevus
AHFS/Drugs.comMonograph
MedlinePlusa617026
License data
Pregnancy
category
Routes of
administration		Intravenous infusion, subcutaneous injection
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC6494H9978N1718O2014S46
Molar mass145818.03 g·mol−1
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It was approved by the US Food and Drug Administration (FDA) in March 2017,[11] and the first FDA approved drug for the primary progressive form of multiple sclerosis; it was discovered and developed and is marketed by Hoffmann–La Roche's subsidiary Genentech.[12][8] With the approval, the FDA also required the company to conduct several phase IV clinical trials to better understand whether the medication is safe and effective in young people, cancer risks, and effects on pregnant women and children they might bear.[13] The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[14]

Medical uses

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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.[8]

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.[9]

Contraindications

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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.[8]

Adverse effects

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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 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.[10]

There is an increased risk of infections of all kinds, including respiratory infections, in people taking immunosuppressive drugs like ocrelizumab.[8] 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.[8] 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.[8] In controlled trials, malignancies, including breast cancer, occurred more frequently in people treated with ocrelizumab.[8] Breast cancer occurred in 6 of 781 females treated with ocrelizumab for multiple sclerosis in clinical trials.[8] None of 668 females treated in Rebif (interferon beta-1a) or placebo arms of the clinical trials developed breast cancer.[8]

Pharmacology

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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.[10][15]

Chemistry

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Ocrelizumab is a humanized monoclonal antibody that binds to a CD20 epitope that overlaps partially with the epitope to which rituximab binds.[10] 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.[16]

History

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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.[10][17] 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.[12]

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.[10][18] It was also studied in hematological cancer.[19]

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.[20] In February 2016, the US Food and Drug Administration (FDA) granted breakthrough therapy designation for primary progressive multiple sclerosis.[21]

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.[22][11] 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.[13]

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.[22][23] Both studies compared ocrelizumab to another MS drug, Rebif (interferon beta-1a).[22] In both studies, the participants receiving ocrelizumab had reduced relapse rates and reduced worsening of disability compared to Rebif.[22][23] The trials were conducted in the US, Canada, Europe, Latin America, Africa, and Australia.[23]

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.[22][23] The study was conducted in the US, Canada, and Europe.[23]

The application for ocrelizumab was granted breakthrough therapy, fast track, and priority review designations.[22] The FDA granted approval of Ocrevus to Genentech, Inc.[22]

Ocrelizumab was approved for use in the European Union in January 2018.[9] In June 2024, the European Commission granted marketing authorization for the fixed-dose combination ocrelizumab/hyaluronidase to be used for subcutaneous injection.[9][24] The FDA approved the fixed-dose combination ocrelizumab/hyaluronidase as a subcutanious formulation in September 2024.[25]

References

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  1. ^ "Ocrelizumab (Ocrevus) Use During Pregnancy". Drugs.com. 13 August 2019. Retrieved 28 March 2020.
  2. ^ a b "Ocrevus PI" (PDF). Retrieved 31 March 2024.
  3. ^ "Prescription medicines: registration of new chemical entities in Australia, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 9 April 2023.
  4. ^ "Prescription medicines and biologicals: TGA annual summary 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 31 March 2024.
  5. ^ "Regulatory Decision Summary for Ocrevus". Drug and Health Product Register. 23 October 2014.
  6. ^ "Neurological therapies". Health Canada. 9 May 2018. Retrieved 13 April 2024.
  7. ^ "Ocrevus 300 mg concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). 30 December 2019. Retrieved 28 March 2020.
  8. ^ a b c d e f g h i j k l m "Ocrevus- ocrelizumab injection". DailyMed. 13 December 2019. Retrieved 25 April 2020.
  9. ^ a b c d e "Ocrevus EPAR". European Medicines Agency (EMA). 11 January 2018. Retrieved 25 April 2020.   This article incorporates text from this source, which is in the public domain.
  10. ^ a b c d e f g 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.
  11. ^ a b "Ocrevus (ocrelizumab) Injection". U.S. Food and Drug Administration (FDA). 9 May 2017. Retrieved 25 April 2020.
  12. ^ a b Winslow R (28 March 2017). "After 40-year odyssey, first drug for aggressive MS wins FDA approval". STAT.
  13. ^ a b "BLA Approval Letter" (PDF). U.S. Food and Drug Administration (FDA). 28 March 2017.
  14. ^ New Drug Therapy Approvals 2017 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2018. Retrieved 16 September 2020.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ Reid K (8 March 2010). "Update 2. Roche suspends arthritis treatment after deaths". Reuters.
  19. ^ 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.
  20. ^ Hughes S (8 October 2015). "First Data From Ocrelizumab Phase 3 Studies in MS". Medscape. Retrieved 17 October 2024.
  21. ^ Nather D (19 February 2016). "New drug for severe form of MS generates glimmer of hope". STAT.
  22. ^ a b c d e f g "FDA approves new drug to treat multiple sclerosis". U.S. Food and Drug Administration (FDA) (Press release). 29 March 2017. Retrieved 25 April 2020.   This article incorporates text from this source, which is in the public domain.
  23. ^ a b c d e "Drug Trials Snapshots: Ocrevus". U.S. Food and Drug Administration (FDA). 28 March 2017. Retrieved 25 April 2020.   This article incorporates text from this source, which is in the public domain.
  24. ^ "Roche's Ocrevus subcutaneous administration approved by European Commission, as first and only twice-a-year injection for relapsing and primary progressive multiple sclerosis" (Press release). F. Hoffmann-La Roche. 25 June 2024. Retrieved 17 October 2024 – via GlobeNewswire.
  25. ^ "FDA Approves Ocrevus Zunovo as the First and Only Twice-A-Year 10-Minute Subcutaneous Injection for People With Relapsing and Progressive Multiple Sclerosis". Genentech (Press release). 13 September 2024. Archived from the original on 14 September 2024. Retrieved 13 September 2024.
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  • Clinical trial number NCT01247324 for "A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis" at ClinicalTrials.gov
  • Clinical trial number NCT01412333 for "A Study of Ocrelizumab in Comparison With Interferon Beta-1a (Rebif) in Participants With Relapsing Multiple Sclerosis" at ClinicalTrials.gov
  • Clinical trial number NCT01194570 for "A Study of Ocrelizumab in Participants With Primary Progressive Multiple Sclerosis" at ClinicalTrials.gov
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