Ocrelizumab: Difference between revisions

{{Short description|Anti-CD20 monoclonal antibody}}

{{Distinguish|eculizumab}}

{{Use dmy dates|date=December 2023}}

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<!-- Monoclonal antibody data -->

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| pronounce =

| tradename = Ocrevus

| Drugs.com = {{Drugs.com|monograph|ocrelizumab}}

| MedlinePlus = a617026

| DailyMedID = Ocrelizumab

| pregnancy_AU = C

| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Ocrelizumab (Ocrevus) Use During Pregnancy | website=Drugs.com | date=13 August 2019 | url=https://www.drugs.com/pregnancy/ocrelizumab.html | access-date=28 March 2020}}</ref><ref name="Ocrevus PI" />

| pregnancy_category=

| routes_of_administration = [[Intravenous infusion]]

| ATC_prefix = L04

| ATC_suffix = AG08

<!-- Legal status -->

| legal_AU = S4

| legal_AU_comment = <ref name="Ocrevus PI">{{cite web | title=Ocrevus PI | url=https://www.guildlink.com.au/gc/ws/ro/pi.cfm?product=ropocrev10717 | format=PDF | access-date=31 March 2024}}</ref><ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-registration-new-chemical-entities-australia-2017 | access-date=9 April 2023}}</ref><ref>{{cite web | title=Prescription medicines and biologicals: TGA annual summary 2017 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 | access-date=31 March 2024}}</ref>

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| legal_CA_comment = /{{nbsp}}Schedule D<ref>{{cite web | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00333 | title=Regulatory Decision Summary for Ocrevus | work=Drug and Health Product Register | date=23 October 2014 }}</ref><ref>{{cite web | title= Neurological therapies | website=[[Health Canada]] | date=9 May 2018 | url=https://www.canada.ca/en/services/health/drug-health-products/drug-medical-device-highlights-2017/approved-drugs/neurological-therapies.html | access-date=13 April 2024}}</ref>

| legal_DE = <!-- Anlage I, II, III or Unscheduled-->

| legal_DE_comment =

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| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref>{{cite web | title=Ocrevus 300 mg concentrate for solution for infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=30 December 2019 | url=https://www.medicines.org.uk/emc/product/8898/smpc | access-date=28 March 2020}}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name="Ocrevus FDA label" />

| legal_EU = Rx-only

| legal_EU_comment = <ref name="Ocrevus EPAR" />

| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->

| legal_UN_comment =

| legal_status = Rx-only

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<!-- Identifiers -->

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 637334-45-3

| PubChem =

| DrugBank = DB11988

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

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| KEGG = D05218

<!-- Chemical data -->

| C=6494 | H=9978 | N=1718 | O=2014 | S=46

'''Ocrelizumab''', sold under the brand name '''Ocrevus''', is a [[medication]] used for the treatment of [[multiple sclerosis]] (MS). It is a [[Humanized antibody|humanized]] anti-[[CD20]] [[monoclonal antibody]].<ref name="Ocrevus FDA label" /> It targets CD20 marker on [[B cell|B lymphocyte]]s and is an [[immunosuppressive drug]].<ref name=McGinley2017rev>{{cite journal | vauthors = McGinley MP, Moss BP, Cohen JA | title = Safety of monoclonal antibodies for the treatment of multiple sclerosis | journal = Expert Opinion on Drug Safety | volume = 16 | issue = 1 | pages = 89–100 | date = January 2017 | pmid = 27756172 | doi = 10.1080/14740338.2017.1250881 | s2cid = 36762194 }}</ref> Ocrelizumab binds to an [[epitope]] that overlaps with the epitope to which [[rituximab]] binds.<ref name=McGinley2017rev/>

It was approved by the US [[Food and Drug Administration]] (FDA) in March 2017,<ref name="FDA approval">{{cite web | title=Ocrevus (ocrelizumab) Injection | website=U.S. [[Food and Drug Administration]] (FDA) | date=9 May 2017 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761053Orig1s000TOC.cfm | access-date=25 April 2020}}</ref> 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.<ref name=STATapproval>{{cite news| title=After 40-year odyssey, first drug for aggressive MS wins FDA approval |url=https://www.statnews.com/2017/03/28/multiple-sclerosis-ms-drug-ocrelizumab/ |date=March 28, 2017 | first = Ron | last = Winslow |publisher=STAT}}</ref><ref name="Ocrevus FDA label">{{cite web | title=Ocrevus- ocrelizumab injection | website=DailyMed | date=13 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9da42362-3bb5-4b83-b4bb-b59fd4e55f0d | access-date=25 April 2020}}</ref> With the approval, the FDA also required the company to conduct several [[Phases of clinical research#Phase IV|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.<ref name=FDABLAapproval>{{cite web|title=BLA Approval Letter|url=https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761053Orig1s000ltr.pdf|publisher=U.S. [[Food and Drug Administration]] (FDA)|date=March 28, 2017}}</ref>

The US [[Food and Drug Administration]] (FDA) considers it to be a [[first-in-class medication]].<ref>{{cite report | title=New Drug Therapy Approvals 2017 | website=U.S. [[Food and Drug Administration]] (FDA) | date=January 2018 | url=https://www.fda.gov/media/110526/download | format=PDF | access-date=16 September 2020}}</ref>

==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.<ref name="Ocrevus FDA label" /> It is administered by intravenous infusion.<ref name="Ocrevus FDA label" />

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.<ref name="Ocrevus EPAR" />

==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.<ref name="Ocrevus FDA label" />

==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, [[urticaria|hives]], flushing, throat and mouth irritation, fever, fatigue, nausea, [[tachycardia|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.<ref name=McGinley2017rev/>

There is an increased risk of infections of all kinds, including respiratory infections, in people taking [[immunosuppressive drug]]s 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.<ref name="Ocrevus FDA label" />

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.<ref name="Ocrevus FDA label" />

==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]].<ref name=McGinley2017rev/><ref>{{cite journal | vauthors = Reddy V, Dahal LN, Cragg MS, Leandro M | title = Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer? | journal = Drug Discovery Today | volume = 21 | issue = 8 | pages = 1330–8 | date = August 2016 | pmid = 27343722 | doi = 10.1016/j.drudis.2016.06.009 | url = https://eprints.soton.ac.uk/403213/1/DRUDIS-D-16-00044%2520submitted%2520manuscript.pdf }}</ref>

==Chemistry ==

Ocrelizumab is a [[Humanized antibody|humanized monoclonal antibody]] that binds to a CD20 [[epitope]] that overlaps partially with the epitope to which [[rituximab]] binds.<ref name=McGinley2017rev/> 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.<ref name=INN>{{cite journal | vauthors=((World Health Organization)) | title=International nonproprietary names for pharmaceutical substances (INN) : recommended international nonproprietary names (Rec. INN) : list 56 | journal=WHO Drug Information | year=2006 | volume=20 | issue=3 | page=220 | hdl=10665/73839 | hdl-access=free }}</ref>

==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.<ref name=McGinley2017rev/><ref>{{cite journal | vauthors = Sorensen PS, Blinkenberg M | title = The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects | journal = Therapeutic Advances in Neurological Disorders | volume = 9 | issue = 1 | pages = 44–52 | date = January 2016 | pmid = 26788130 | pmc = 4710102 | doi = 10.1177/1756285615601933 }}</ref> Rituximab is a mouse protein, and is [[Immunogenicity|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.<ref name=STATapproval/>

[[Clinical trial]]s in people with [[rheumatoid arthritis]] and [[lupus]] were halted in 2010 because people with these conditions developed too many [[opportunistic infection]]s when taking ocrelizumab.<ref name=McGinley2017rev/><ref>{{cite web | first = Katie | last = Reid | date = 8 March 2010 | url = https://www.reuters.com/article/idUSLDE62705720100308 | title = Update 2. Roche suspends arthritis treatment after deaths. | work = Reuters }}</ref> It was also studied in [[hematological cancer]].<ref>{{cite journal | vauthors = Hutas G | title = Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies | journal = Current Opinion in Investigational Drugs | volume = 9 | issue = 11 | pages = 1206–15 | date = November 2008 | pmid = 18951300 }}</ref>

In MS, phase II results were announced in October 2010, and in October 2015, [[Genentech]] presented interim results of three Phase III clinical trials.<ref name=Oct2015>{{cite web|url=http://www.medscape.com/viewarticle/852408|title=First Data From Ocrelizumab Phase 3 Studies in MS. Oct 2015|publisher=Medscape Log}}</ref> In February, 2016 the FDA granted [[Breakthrough Therapy]] Designation for primary progressive multiple sclerosis.<ref>{{cite news |last1=Nather |first1=David |title=New drug for severe form of MS generates glimmer of hope|url=https://www.statnews.com/2016/02/19/progressive-multiple-sclerosis-ocrelizumab/|work=STAT|date=19 February 2016}}</ref>

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.<ref name="FDA PR">{{cite press release | title=FDA approves new drug to treat multiple sclerosis | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 March 2017 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-multiple-sclerosis | access-date=25 April 2020}} {{PD-notice}}</ref><ref name="FDA approval" /> When the FDA approved the drug, it required Roche to conduct several [[Phases of clinical research#Phase IV|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.<ref name=FDABLAapproval/>

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.<ref name="FDA PR" /><ref name="FDA snapshot" /> Both studies compared ocrelizumab to another MS drug, Rebif (interferon beta-1a).<ref name="FDA PR" /> In both studies, the patients receiving ocrelizumab had reduced relapse rates and reduced worsening of disability compared to Rebif.<ref name="FDA PR" /><ref name="FDA snapshot" /> The trials were conducted in the US, Canada, Europe, Latin America, Africa, and Australia.<ref name="FDA snapshot">{{cite web | title=Drug Trials Snapshots: Ocrevus | website=U.S. [[Food and Drug Administration]] (FDA) | date=28 March 2017 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-ocrevus | access-date=25 April 2020}} {{PD-notice}}</ref>

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.<ref name="FDA PR" /><ref name="FDA snapshot" /> The study was conducted in the US, Canada, and Europe.<ref name="FDA snapshot" />

The application for ocrelizumab was granted [[breakthrough therapy]], [[Fast track (FDA)|fast track]], and [[priority review]] designations.<ref name="FDA PR" /> The FDA granted approval of Ocrevus to Genentech, Inc.<ref name="FDA PR" />

Ocrelizumab was approved for use in the European Union in January 2018.<ref name="Ocrevus EPAR">{{cite web | title=Ocrevus EPAR | website=[[European Medicines Agency]] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/ocrevus | access-date=25 April 2020}} {{PD-notice}}</ref>

== References ==

{{reflist}}

{{Demyelinating diseases of CNS}}

{{Immunosuppressants}}

{{Monoclonals for immune system}}

{{Portal bar | Medicine}}

{{Authority control}}

[[Category:Monoclonal antibodies]]

[[Category:Drugs developed by Genentech]]

[[Category:Drugs developed by Hoffmann-La Roche]]