daclizumab

Daclizumab was used to treat adults with relapsing forms of multiple sclerosis.FDA {{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761029Orig1s000ltr.pdf | archive-url = https://web.archive.org/web/20160705144357/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/761029Orig1s000ltr.pdf | url-status = dead | archive-date = July 5, 2016 | title = BLA Approval letter | date = 27 May 2016 | publisher = U.S. Food and Drug Administration }} It is administered subcutaneously.{{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 }}

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. A 2013 Cochrane systematic review concluded that there was insufficient evidence to determine the efficacy of daclizumab relative to placebo in people with relapsing-remitting MS and, prior to its being discontinued, the need to investigate longer lengths of treatment and follow-up.{{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 }}

Daclizumab was approved and used to prevent acute rejection of kidney transplant, along with cyclosporine and corticosteroids.{{cite web | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/103749s5059lbl.pdf | archive-url = https://web.archive.org/web/20140430020742/http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/103749s5059lbl.pdf | url-status = dead | archive-date = April 30, 2014 | title = Rejection label Supplement label update | date = September 2005 | publisher = U.S. Food and Drug Administration }} For that indication, side effects with a frequency of at least 10% included sleeplessness, tremor, headache, arterial hypertension, dyspnoea, gastrointestinal side effects and oedema. In rare cases, the drug could cause severe anaphylaxis.{{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 }}

In the US, daclizumab (while approved) was contraindicated in people with liver impairment, including significantly elevated liver enzymes (ALT, AST) and autoimmune hepatitis.{{Drugs.com|pro|zinbryta}} for Zinbryta.

The European Medicines Agency (EMA) originally approved the drug without any contraindications apart from known hypersensitivity, but required Biogen to implement a hepatic risk management guide for physicians.{{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}} In July 2017, the EMA has issued a provisional contraindication for patients with pre-existing liver disease or liver impairment.{{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}} 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.{{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}}

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%).

As an antibody, daclizumab is expected to have a very low potential for pharmacokinetic interactions with other drugs.{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2016|language=de}}

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 (CD122) 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 CD56^bright natural killer cells.

After subcutaneous injection of a single dose, daclizumab has a bioavailability of about 90% and reaches highest blood plasma 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 proteases to peptides and finally amino acids, and that it does not interact with cytochrome P450 liver enzymes.

The biological half-life is 21 days. Patients who developed antibodies against daclizumab eliminated it 19% faster.

Daclizumab was created by scientists at PDL BioPharma (called "Protein Design Labs" at that time) by humanizing the mouse mAb called anti-Tac, which targets CD25, the IL-2 receptor α chain; it blocks the interaction of IL-2 with the IL-2 receptor and prevents activation of T cells.{{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 }} Anti-Tac had been discovered by Thomas A. Waldmann, M.D., chief of the Metabolism Branch at the National Cancer Institute 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.{{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 }} PDL and the NIH scientists then approached Roche, 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. 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.{{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 }}{{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 }} 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. It was approved in Europe in 1999.{{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 }}

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.{{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 }} In August 2005, PDL and Biogen Idec agreed to collaborate to develop daclizumab in indications outside the fields of organ rejection and respiratory disease.{{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 }} In November 2005 Roche and PDL agreed to try to develop a formulation of daclizumab that would be useful as a subcutaneous injection for longterm maintenance in organ transplant.{{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 }} The next year Roche and PDL announced that the collaboration for all indications was ending,{{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 }} 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."{{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 }}{{cite web | work = Roche | publisher = U.S. Food and Drug Administration | url = https://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM194907.pdf | archive-url = https://web.archive.org/web/20100112081757/http://www.fda.gov/downloads/Drugs/DrugSafety/DrugShortages/UCM194907.pdf | url-status = dead | archive-date = January 12, 2010 | title = Letter to Healthcare Professionals | date = September 2009 }}

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.{{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 | date = 31 August 2009 }}{{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 }} In 2009 Biogen attempted a hostile buy out of Facet for $350M;{{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 }} Facet rejected that offer and was purchased by Abbvie for $450 million in cash the next year.{{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 }} 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.{{cite web | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504000.htm | archive-url = https://web.archive.org/web/20160529120600/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504000.htm | url-status = dead | archive-date = May 29, 2016 | work = FDA News Release | title = FDA approves Zinbryta to treat multiple sclerosis | date = 27 May 2016 | publisher = U.S. Food and Drug Administration }}

Daclizumab has been studied in a small clinical trial of people with birdshot chorioretinopathy.{{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 }}

{{Reflist}}

{{Immunosuppressants}}

{{Monoclonals for immune system}}

{{Interleukin receptor modulators}}

{{Authority control}}

Category:Monoclonal antibodies

Category:Immunosuppressants

Category:Drugs developed by AbbVie

Category:Drugs developed by Hoffmann-La Roche