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Revision as of 11:44, 2 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'DrugBank', 'ChEMBL').← Previous edit Latest revision as of 19:23, 6 November 2024 edit undoOAbot (talk | contribs)Bots440,440 editsm Open access bot: pmc updated in citation with #oabot. 
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{{Short description|Pharmaceutical drug}}
{{drugbox
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 458621431
| image = | image =
| alt =


<!--Monoclonal antibody data--> <!-- Monoclonal antibody data -->
| type = mab | type = mab
| mab_type = mab | mab_type = mab
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| target = ] | target = ]


<!--Clinical data--> <!-- Clinical data -->
| tradename = Zinbryta (multiple sclerosis)<br/>Zenapax (acute transplant rejection, discontinued in 2009)
| tradename = Zenapax
| Drugs.com = {{drugs.com|monograph|daclizumab}} | Drugs.com = {{drugs.com|parent|zinbryta}}
| pregnancy_AU = B3
| pregnancy_category = C
⚫ | routes_of_administration = ], ]
| legal_status = European marketing authorisation withdrawn
⚫ | routes_of_administration = ]


| legal_AU = S4
⚫ <!--Pharmacokinetic data-->
| legal_AU_comment = <ref>{{cite web | title=Prescription medicines: registration of new chemical entities in Australia, 2016 | website=Therapeutic Goods Administration (TGA) | date=21 June 2022 | url=https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2016 | access-date=10 April 2023}}</ref>
| bioavailability =
| legal_CA = Rx-only
⚫ | protein_bound =
| legal_CA_comment = <ref>{{cite web | title=Health Canada New Drug Authorizations: 2016 Highlights | website=] | date=14 March 2017 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2016-highlights.html | access-date=7 April 2024}}</ref>
⚫ | metabolism =
| legal_US = Rx-only
⚫ | elimination_half-life = 20 days
| legal_US_comment = /&nbsp;Withdrawn<ref name="FDA PR" />
| legal_status = Rx-only


<!--Identifiers--> <!-- Pharmacokinetic data -->
| ChemSpiderID = NA | bioavailability = 90%
⚫ | protein_bound =
⚫ | metabolism = ]s
⚫ | elimination_half-life = 21 days (11–38 days)
<!-- Identifiers -->
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = none
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 152923-56-3 | CAS_number = 152923-56-3
| ATC_prefix = L04 | ATC_prefix = L04
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| ATC_supplemental = | ATC_supplemental =
| PubChem = | PubChem =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00111 | DrugBank = DB00111
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = CUJ2MVI71Y | UNII = CUJ2MVI71Y
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 1201605 -->
| ChEMBL = 1201605
⚫ | C=6332 | H=9808 | N=1678 | O=1989 | S=42
| KEGG_Ref = {{keggcite|changed|kegg}}
| molecular_weight = 142612.1 g/mol
| KEGG = D03639
⚫ <!-- Chemical data -->
⚫ | C=6332 | H=9808 | N=1678 | O=1989 | S=42
}} }}
'''Daclizumab''' (trade name '''Zenapax''') is a therapeutic humanized ] to the alpha subunit of the ] of ]. It is used to prevent ] in ]ation, especially in ] transplants. '''Daclizumab''' (trade name '''Zinbryta''') is a therapeutic humanized ] which was used for the treatment of adults with relapsing forms of ] (MS). Daclizumab works by binding to ], the alpha subunit of the ] of ].


In March 2018, it was voluntarily withdrawn from the market by ] and ] after reports of ] ] in Europe.<ref>{{cite web|title=Biogen, AbbVie withdraw multiple sclerosis drug Zinbryta|url=https://www.reuters.com/article/us-biogen-zinbryta/biogen-abbvie-withdraw-multiple-sclerosis-drug-zinbryta-idUSKCN1GE1BV|website=Reuters|date=2018}}</ref><ref>{{cite web| vauthors = Loftus P |title=Biogen and Abbvie Take Multiple Sclerosis Drug Off Market|url=https://www.wsj.com/articles/biogen-and-abbvie-take-multiple-sclerosis-drug-off-market-1520007411|website=The Wall Street Journal|date=2 March 2018}}</ref><ref name="FDA PR">{{cite web|title=FDA working with manufacturers to withdraw Zinbryta from the market in the United States|url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-working-manufacturers-withdraw-zinbryta-market-united-states |website=U.S. ] (FDA) |access-date=15 March 2018 }}</ref>
Daclizumab is currently in phase II clinical trials in the U.S.


==Medical uses==
In April 2008, ], the pharmeceutical company that markets Daclizumab (under the name "Zenapax") in Europe, submitted an application to have its marketing authorisation withdrawn in the EU for commercial reasons. The drug faced diminishing market demand, according to the company. There were no safety concerns with its use. As of January 2009, its marketing authorisation has been withdrawn and the product discontinued completely.<ref>British National Formulary, Edition 57</ref><ref></ref>
Daclizumab was used to treat adults with relapsing forms of ].<ref name=BLAapproval>FDA {{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761029Orig1s000ltr.pdf | title = BLA Approval letter | date = 27 May 2016 | publisher = U.S. Food and Drug Administration }}</ref> It is administered subcutaneously.<ref name=2015rev>{{cite journal | vauthors = Lycke J | title = Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes | journal = Therapeutic Advances in Neurological Disorders | volume = 8 | issue = 6 | pages = 274–293 | date = November 2015 | pmid = 26600872 | pmc = 4643868 | doi = 10.1177/1756285615605429 }}</ref>


In clinical trials, decreases of 45% in annualized relapse rate have been reported, as well as a 41% reduction in the proportion of patients who relapsed, and a 54% reduction in the number of new lesions.<ref name=2015rev/> A 2013 ] ] concluded that there was insufficient evidence to determine the efficacy of daclizumab relative to placebo in people with ] and, prior to its being discontinued, the need to investigate longer lengths of treatment and follow-up.<ref>{{cite journal | vauthors = Liu J, Wang LN, Zhan S, Xia Y | title = Daclizumab for relapsing remitting multiple sclerosis | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD008127 | date = December 2013 | pmid = 24363032 | doi = 10.1002/14651858.CD008127.pub4 | pmc = 11491876 }}</ref>
It is given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. These saturate the receptors and prevent T cell activation and thus prevent formation of ] against the transplant.


===Discontinued use===
Like the similar drug ], daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of ].
Daclizumab was approved and used to prevent acute rejection of kidney transplant, along with cyclosporine and corticosteroids.<ref name=RejectionLabel>{{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/103749s5059lbl.pdf | title = Rejection label Supplement label update | date = September 2005 | publisher = U.S. Food and Drug Administration }}</ref> For that indication, side effects with a frequency of at least 10% included sleeplessness, ], headache, ], ], gastrointestinal side effects and ]. In rare cases, the drug could cause severe ].<ref name="EPAR">{{cite web|url=http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000198/WC500057570.pdf|title=EPAR for Zenapax|publisher=European Medicines Agency|year=2007}}{{Dead link|date=October 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref>


==Contraindications==
Daclizumab usage may also be indicated in place of a calcineurin-inhibitor (] or ]) during the early phase after kidney transplantation, when the kidney is recovering and vulnerable to calcineurin-inhibitor toxicity. This has been shown to be beneficial in ] kidney transplantation.
In the US, daclizumab (while approved) was contraindicated in people with liver impairment, including significantly elevated liver enzymes (], ]) and ].<ref>{{Drugs.com|pro|zinbryta}} for Zinbryta.</ref>


The ] (EMA) originally approved the drug without any contraindications apart from known ],<ref name="AC" /> but required Biogen to implement a hepatic risk management guide for physicians.<ref>{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003862/WC500210598.pdf|title=Zinbryta Summary of Product Characteristics|publisher=European Medicines Agency|year=2016|access-date=2016-12-09|archive-date=2018-06-14|archive-url=https://web.archive.org/web/20180614150719/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003862/WC500210598.pdf|url-status=dead}}</ref> In July 2017, the EMA has issued a provisional contraindication for patients with pre-existing liver disease or liver impairment.<ref>{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Zinbryta_20/Under_evaluation/WC500230924.pdf|title=Zinbryta Article-20 referral - Summary of provisional measures|publisher=European Medicines Agency|date=20 July 2017|access-date=21 July 2017|archive-date=24 July 2018|archive-url=https://web.archive.org/web/20180724123611/http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Zinbryta_20/Under_evaluation/WC500230924.pdf|url-status=dead}}</ref> The marketing authorisation was withdrawn in the EU on 27 March 2018. An EMA review concluded that the medicine poses a risk of serious and potentially fatal immune reactions affecting the brain, liver and other organs.<ref>{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/referrals/zinbryta|title=EMA review of Zinbryta confirms medicine's risks outweigh its benefits|date=27 March 2018|website=European Medicines Agency}}</ref>
In the ], the ] has recommended its use be considered for all kidney transplant recipients.{{Citation needed|date=October 2010}}


==Adverse effects==
In 2006 it began a Phase II clinical trial that finished in 2007 as a possible ] treatment. Participants were nine patients with multiple sclerosis not controlled with ]. Daclizumab was effective in reducing lesions and improving clinical scores.<ref name="pmid17709711">{{cite journal |author=Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG |title=Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results |journal=Neurology |volume=69 |issue=8 |pages=785–789 |year=2007 |pmid=17709711 |doi=10.1212/01.wnl.0000267662.41734.1f}}</ref>
In clinical trials for MS, there were no treatment-related deaths or increased risk of cancer; side effects that occurred more frequently with daclizumab versus interferon included infections (65% versus 57%), skin rashes (37% versus 19%) and liver complications (approximately 18% versus 12%).<ref name=2015rev/>


== Interactions ==
⚫ Daclizumab has also been used to slow the progression of ]s, particularly that of ].<ref name="pmid18268208">{{cite journal |author=Sobrin L, Huang JJ, Christen W, Kafkala C, Choopong P, Foster CS |title=Daclizumab for treatment of birdshot chorioretinopathy |journal=Arch Ophthalmol. |volume=126 |issue=2 |pages=186–191 |year=2008 |pmid=18268208 |doi=10.1001/archophthalmol.2007.49}}</ref>


As an antibody, daclizumab is expected to have a very low potential for ] interactions with other drugs.<ref name="AC">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2016|language=de}}</ref>
⚫ ==References==

{{reflist|2}}
==Pharmacology==
===Mechanism of action===
Daclizumab blocks IL-2 receptors containing the alpha subunit (CD25), which include the high-affinity receptors. Medium-affinity receptors, on the other hand, consist of two beta subunits (]) and are not affected by daclizumab. While the exact mechanism is unknown, the net effect is a reduction of T-cell responses and expansion of ]<sup>bright</sup> ]s.<ref name="AC" />

===Pharmacokinetics===
After ] of a single dose, daclizumab has a ] of about 90% and reaches highest ] levels after 5 to 7 days. Given every four weeks, steady state concentrations are found after the fourth dose. It is expected that daclizumab, like other antibodies, is degraded by ]s to peptides and finally amino acids, and that it does not interact with ] liver enzymes.<ref name="AC" />

The ] is 21 days. Patients who developed antibodies against daclizumab eliminated it 19% faster.<ref name="AC" />

==History==
Daclizumab was created by scientists at ] (called "Protein Design Labs" at that time) by ] the mouse mAb called anti-Tac, which targets ], the IL-2 receptor α chain; it blocks the interaction of ] with the IL-2 receptor and prevents activation of ].<ref>{{cite journal | vauthors = Tsurushita N, Hinton PR, Kumar S | title = Design of humanized antibodies: from anti-Tac to Zenapax | journal = Methods | volume = 36 | issue = 1 | pages = 69–83 | date = May 2005 | pmid = 15848076 | doi = 10.1016/j.ymeth.2005.01.007 }}</ref> Anti-Tac had been discovered by Thomas A. Waldmann, M.D., chief of the Metabolism Branch at the ] and his team, and they had conducted animal studies and a small clinical trial of anti-Tac in people with T-cell leukemia, with promising results, but people quickly developed their own antibodies rejecting the mouse protein; Waldman, and his colleagues then approached Protein Design Labs to humanize the antibody.<ref name=JNCI>{{cite journal | vauthors = Swenson RS, Weisinger JR, Ruggeri JL, Reaven GM | title = Evidence that parathyroid hormone is not required for phosphate homeostasis in renal failure | journal = Metabolism | volume = 24 | issue = 2 | pages = 199–204 | date = February 1975 | pmid = 1113683 | doi = 10.1016/0026-0495(75)90021-9 }}</ref> PDL and the NIH scientists then approached ], a leader in transplant medicine development, to get the drug developed and approved, as PDL didn't have the resources to actually bring the product to market.<ref name=JNCI/> In March 2018 the drug was removed from the market worldwide.

In December 1997 daclizumab was approved by the FDA for use in preventing acute rejection of kidney transplants, in combination with ciclosporin and corticosteroids; it was the first humanized antibody approved anywhere in the world.<ref>{{cite web | vauthors = Fisher LM | work = The New York Times | date = 12 December 1997 | url = https://www.nytimes.com/1997/12/12/us/genetically-engineered-drug-approved-for-kidney-transplants.html | title = Genetically Engineered Drug Approved for Kidney Transplants }}</ref><ref name=PLfirst>{{cite web | date = 17 December 1997 | url = http://www.thepharmaletter.com/article/roche-s-zenapax-gets-first-approval-for-transplants | title = Roche's Zenapax Gets First Approval For Transplants | website = The Pharma Letter }}</ref> At launch, the average wholesale price for the drug was estimated to be $6,800 for five doses and it was estimated that annual sales would be between $100 million and $250 million within five years of the launch and it was thought that the drug's use would be expanded for use in other organ transplants.<ref name=PLfirst/> It was approved in Europe in 1999.<ref>{{cite web | work = Roche Press Release | date = 4 March 1999 | url = http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=7568 | title = Zenapax (daclizumab), The First Humanized Monoclonal Antibody To Prevent Organ Rejection, Approved In The European Union | access-date = 1 June 2016 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828053356/https://www.evaluate.com/ | url-status = dead }}</ref>

PDL began clinical trials of daclizumab on its own, and in September 2004 after the drug had shown promise in a Phase II trial, PDL and Roche agreed to expand their relationship to include codevelopment of daclizumab for asthma and other respiratory conditions.<ref>{{cite web | vauthors = Hoffmann C | work = First Word Pharma | date = 16 September 2004 | url = http://www.firstwordpharma.com/node/217798?tsid=17#axzz4AHJfVHyr | title = Roche in new deal to co-development asthma drug }}</ref> In August 2005, PDL and ] agreed to collaborate to develop daclizumab in indications outside the fields of organ rejection and respiratory disease.<ref name="pmid16211058">{{cite journal | vauthors = Thiel KA | title = A very firm handshake: biotech's growing negotiating power | journal = Nature Biotechnology | volume = 23 | issue = 10 | pages = 1221–1226 | date = October 2005 | pmid = 16211058 | doi = 10.1038/nbt1005-1221 | s2cid = 19365410 }}</ref> In November 2005 Roche and PDL agreed to try to develop a formulation of daclizumab that would be useful as a ] for longterm maintenance in organ transplant.<ref>{{cite web | work = PharmaTimes | date = 1 November 2005 | url = http://www.pharmatimes.com/news/roche_inks_new_deal_for_transplant_drug_997651 | title = Roche inks new deal for transplant drug }}</ref> The next year Roche and PDL announced that the collaboration for all indications was ending,<ref>{{cite web | work = PharmaTimes | date = 23 November 2006 | url = http://www.pharmatimes.com/news/roche_ducks_out_of_transplant_drug_alliance_995643 |title = Roche ducks out of transplant drug alliance }}</ref> and in 2009 it announced that it was discontinuing Zenapax worldwide "in view of available alternative treatments and the diminishing market demand" and "not due to any safety issue."<ref>{{Cite web |url=http://www.ema.europa.eu/humandocs/PDFs/EPAR/Zenapax/68376508en.pdf |title=EMEA: Withdrawal of the marketing authorisation in the European Union |access-date=2010-03-11 |archive-date=2010-02-17 |archive-url=https://web.archive.org/web/20100217052026/http://www.ema.europa.eu/humandocs/PDFs/EPAR/Zenapax/68376508en.pdf |url-status=dead }}</ref><ref>{{cite web | work = Roche | publisher = U.S. Food and Drug Administration | url = https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM194907.pdf | title = Letter to Healthcare Professionals | date = September 2009 }}</ref>

in 2008 PDL spun out its active development programs into a company called Facet Biotech and development of daclizumab for multiple sclerosis and the partnership with Biogen was included in that spinout.<ref>{{cite web | vauthors = Carroll J | work = FierceBiotech | url = http://www.fiercebiotech.com/special-report/emerging-drug-developer-facet-biotech | title = Emerging Drug Developer: Facet Biotech }}</ref><ref name=2008sec>{{cite web | url = https://www.sec.gov/Archives/edgar/data/882104/000110465908078237/a08-30875_18k.htm | title = PDL BioPharma, Inc. Form 8-K | date = 17 December 2008 }}</ref> In 2009 Biogen attempted a hostile buy out of Facet for $350M;<ref>{{cite web | vauthors = Timmerman L | work = Xconomy | date = 4 September 2009 | url = http://www.xconomy.com/boston/2009/09/04/biogen-idec-makes-hostile-350m-takeover-bid-for-facet-biotech/ | title = Biogen Idec Makes Hostile $350M Takeover Bid for Facet Biotech }}</ref> Facet rejected that offer and was purchased by ] for $450 million in cash the next year.<ref>{{cite web | work = New York Times Dealbook | date = 9 March 2010 | url = https://dealbook.nytimes.com/2010/03/09/abbott-to-buy-facet-biotech-for-67-premium/ | title = Abbott to Buy Facet Biotech for 67% Premium }}</ref> In May 2016 the FDA approved daclizumab for the treatment of relapsing multiple sclerosis in adults in 2016 under the trade name Zinbryta, with requirements for postmarketing studies and to submit a formal Risk Evaluation and Mitigation Strategy.<ref name=BLAapproval/><ref>{{cite web | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504000.htm | work = FDA News Release | title = FDA approves Zinbryta to treat multiple sclerosis | date = 27 May 2016 | publisher = U.S. Food and Drug Administration }}</ref>

==Research==
⚫ Daclizumab has been studied in a small clinical trial of people with ].<ref name="pmid18268208">{{cite journal | vauthors = Sobrin L, Huang JJ, Christen W, Kafkala C, Choopong P, Foster CS | title = Daclizumab for treatment of birdshot chorioretinopathy | journal = Archives of Ophthalmology | volume = 126 | issue = 2 | pages = 186–191 | date = February 2008 | pmid = 18268208 | doi = 10.1001/archophthalmol.2007.49 }}</ref>

⚫ == References ==
{{Reflist}}


{{Immunosuppressants}} {{Immunosuppressants}}
{{Monoclonals for immune system}} {{Monoclonals for immune system}}
{{Interleukin receptor modulators}}
{{Authority control}}


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