Adalimumab

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Adalimumab
Adalimumab structure.png
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetTNF alpha
Clinical data
Trade namesHumira, Mabura, Exemptia, others
AHFS/Drugs.comMonograph
MedlinePlusa603010
License data
Pregnancy
category
  • AU: C
  • US: B (No risk in non-human studies)
Routes of
administration
Subcutaneous
Drug classTNF inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability64% (subcutaneous), 0% (By mouth)
Elimination half-life10–20 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
ECHA InfoCard100.224.376 Edit this at Wikidata
Chemical and physical data
FormulaC6428H9912N1694O1987S46
Molar mass144190.3 g·mol−1
 ☒N☑Y (what is this?)  (verify)

Adalimumab, sold under the brand name Humira among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis.[1][2] Use is generally only recommended in people who have not responded to other treatments.[2] It is used by injection under the skin.[1]

Common side effects include upper respiratory tract infections, pain at the site of injection, rash, and headache.[1] Other side effects may include serious infections, cancer, anaphylaxis, reactivation of hepatitis B, multiple sclerosis, heart failure, liver failure, and aplastic anemia.[1] Use during pregnancy is not recommended, while some feel use during breastfeeding may be safe.[2][3] Adalimumab is a disease-modifying antirheumatic drug and monoclonal antibody that works by inactivating tumor necrosis factor-alpha (TNFα).[1]

Adalimumab was approved for medical use in the United States in 2002.[1] A month supply in the United Kingdom costs the NHS about £704.28 as of 2018.[2] In the United States the wholesale cost of this amount is about US$5,041.12.[4] In 2014, a biosimilar came to market in India at a price of US$400 per month.[5] While the patent expired in the United States in 2016 it may take a number of years before generic versions become available there.[5] In 2016 it was the 150th most prescribed medication in the United States with more than 4 million prescriptions.[6]

Medical uses[edit]

Like other TNF inhibitors, it is an immunosuppresive medication, used to treat autoimmune diseases such as rheumatoid arthritis.

Adalimumab is administered by subcutaneous injection.[1] For most indications, the maintenance treatment is an injection every other week.[1]

Rheumatoid arthritis[edit]

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe rheumatoid arthritis in adults. It may be used alone or in combination with DMARDs.[7] It has also been shown to have efficacy in moderate to severe polyarticular juvenile idiopathic arthritis in children 4 and older, and is approved for the treatment of that condition. In rheumatoid athritis, it has been approved for use alone, or with methotrexate or similar medicines, in the U.S. since 2002.[8][9] It has a similar effectiveness as methotrexate and, in combination, nearly doubles the response rate of methotrexate alone.[10]

Psoriatic arthritis[edit]

In 2003, adalimumab began undergoing trials for use in treating psoriasis and psoriatic arthritis.[11]

Ankylosing spondylitis[edit]

Adalimumab has been shown to reduce the signs and symptoms of, and is approved for treatment of, ankylosing spondylitis in adults.[12]

Crohn’s disease[edit]

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe Crohn's disease.[13] It has been approved for that use in the UK since 2009.[14]

Ulcerative colitis[edit]

Adalimumab may be effective and well tolerated in ulcerative colitis. It has been approved by the FDA for treatment of moderate to severe cases in adults.[15]

Plaque psoriasis[edit]

Adalimumab has been shown to treat moderate to severe chronic plaque psoriasis in adults who have the condition in many areas of their body and who may benefit from taking injections or pills (systemic therapy) or phototherapy (treatment using ultraviolet light alone or with pills).[16] Adalimumab has been shown to be effective therapy when used either continuously or intermittently in patients with moderate to severe psoriasis.

Hidradenitis suppurativa[edit]

Adalimumab has been approved for hidradenitis suppurativa.[17]

Juvenile idiopathic arthritis[edit]

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe polyarticular juvenile idiopathic arthritis in children 4 and older.

Adverse effects[edit]

Components of a Humira autoinjector pen.

There is strong evidence that adalimumab increases risk of serious infections, such as tuberculosis. It also increases the risk of cancers, including lymphoma and solid malignancies. The risk of cancer is higher with higher doses of adalimumab.[18]

There are rare reports of serious liver injury; rare reports of demyelinating central nervous system disorders; and rare reports of cardiac failure—the U.S. Food and Drug Administration (FDA) issued a black box warning to doctors, which appears in the product labeling of adalimumab and other TNF-inhibiting drugs, instructing them to screen and monitor potential patients more carefully.[19] Anaphylaxis or other serious allergic reactions may also occur.[19]

History[edit]

Adalimumab is the first fully human monoclonal antibody approved by the U.S. Food and Drug Administration. It was derived from phage display.[20]

Adalimumab was discovered as a result of a collaboration between BASF Bioresearch Corporation and Cambridge Antibody Technology, U.K., itself a collaboration of the government-funded Medical Research Council and three academics, which began in 1993.[21]

Initially named D2E7,[22] it was then further manufactured at BASF Bioresearch Corporation, developed by BASF Knoll (BASF Pharma), and ultimately manufactured and marketed by Abbott Laboratories after Abbott's acquisition of BASF Pharma. On January 1, 2013, Abbott split into two companies, one retaining the Abbott name and the other named AbbVie.[23] As a result, AbbVie took over development and marketing of Humira.[24] The brand name Humira stands for "human monoclonal antibody in rheumatoid arthritis", and was named by one of Abbott's employees, Richard J. Karwoski, who was also responsible for leading the effort to get Humira FDA approved.

It was the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. It was constructed from a fully human monoclonal antibody, while infliximab is a mouse-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein.

The drug candidate was discovered initially using CAT's phage display technology and named D2E7.[22] The key components of the drug were found by guiding the selection of human antibodies from phage display repertoires to a single epitope of an antigen TNF alpha.[25] The ultimate clinical candidate, D2E7, was created and manufactured at BASF Bioresearch Corporation and taken through most of the drug development process by BASF Knoll, then further development, manufacturing and marketing by Abbott Laboratories, after Abbott acquired the pharmaceutical arm of BASF Knoll.[26]

As of 2008, adalimumab had been approved by the FDA for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, moderate to severe chronic psoriasis and juvenile idiopathic arthritis. Although only approved for ulcerative colitis from late 2012 by the FDA in the disease's management, it had been used for several years in cases that have not responded to conventional treatment at standard dosing for Crohn's disease.

Marketing[edit]

  • 1999: Preliminary results of early clinical trials with the fully human anti-TNFα monoclonal antibody D2E7[22]
  • 2001, June: Results from ARMADA, a double-blind, placebo-controlled clinical trial involving 271 patients with active rheumatoid arthritis despite treatment with methotrexate are announced. Among the results are that 50% of patients show a 50% improvement in ACR score.[27]
  • 2002: Broke ground on a new state-of-the-art biologics manufacturing facility.[28]
  • 2002: Adalimumab results from five separate trials show that it is effective at reducing signs and symptoms of rheumatoid arthritis. In these studies, adalimumab had a rapid onset of action and sustained efficacy. Furthermore, adalimumab was safe and effective when given alone or in combination with MTX as a subcutaneous injection.[29]
  • 2002, December 31: Humira approved by the U.S. Food and Drug Administration (FDA) for treatment of rheumatoid arthritis.[28]
  • 2003: Launched Humira for rheumatoid arthritis and continued clinical studies for additional indications.[28]
  • 2005: Launched Humira for psoriatic arthritis. Exceeded $1 billion in annual sales for the first time.[28]
  • 2005, 10 December: Eisai Submits New Drug Application for Rheumatoid Arthritis Drug Adalimumab (D2E7) in Japan.[30]
  • 2006: Submitted Humira for the Crohn's disease indication and launched it for AS. Exceeded $2 billion in annual sales.[28]
  • 2007: Launched Humira for Crohn's disease in the United States,[28] submitted Humira for global regulatory approval for psoriasis — the fifth new Humira disease indication at this time, achieved more than $3 billion in worldwide Humira sales.[31]
  • 2007, 10 December: Abbott Opens New Biotechnology Manufacturing Facility in Puerto Rico[32]
  • 2008: Launched Humira for plaque psoriasis
  • 2009, 10 June: Five-Year Data Demonstrate Initial Use of Humira Plus Methotrexate May Prevent Further Joint Damage in Early Rheumatoid Arthritis Patients [33]
  • 2012, 16 March: Humira could be associated with a significant decrease in vascular inflammation, a major risk factor of cardiovascular disease [34]
  • 2013: Due to the split of Abbott, Humira rights are now owned by AbbVie.
  • 2014: Humira recognized by IMS Health as the "world's best selling drug."[35]
  • 2014: In December 2014, Indian drugmaker Cadila Healthcare declared the launch of the first adalimumab biosimilar at a fifth of its U.S. price. The generic has been launched under the brand name Exemptia.[36]
  • 2015: Launched Humira for moderate to severe hidradenitis suppurativa, an orphan indication. No other treatment has been rigorously tested and found to be safe and effective in treating this painful and scarring condition.
  • 2016: The best selling drugs list researched by Genetic Engineering & Biotechnology News, published in March 2017, details that Humira occupied the number 1 position for 2015 ($14.012 billion) and 2016 ($16.078 billion)[37]
  • 2017: AbbVie reports that Humira achieved $18.427 billion of sales in 2017.[38]

Society and culture[edit]

Economics[edit]

From 2012 until the US patent expiry in 2016, Humira led the list of top-selling pharmaceutical products, and in 2016, it had $16 billion of global sales.[39]

Royalty litigation[edit]

In March 2003, Cambridge Antibody Technology (CAT) stated its wish to "initiate discussions regarding the applicability of the royalty offset provisions for Humira" with Abbott Laboratories in the High Court of London. In November 2004, the trial began, and in December 2004, Justice Hugh Laddie ruled for CAT.

A short version of the full statement of the proceedings was released.[40] In it Justice Laddie remarked, "Abbott was in error when it made its first royalty payment to CAT calculated on the basis that only 2% of the Net Sales was due. It should have calculated on the basis of the full royalty of just over 5% and should have paid and continued to pay CAT accordingly." Justice Laddie went on to observe "...that the construction advanced by Abbott does violence to the language of the agreements, renders them obscure and makes little or no commercial sense. For this reason CAT wins the action."[41]

Abbott was required to pay CAT US$255 million, some of which was to be passed to its partners in development.[42] Of this sum, the Medical Research Council received US$191M, and in addition, Abbott was asked to pay the MRC a further US$7.5M over five years from 2006, providing that Humira remains on the market. The MRC also is to receive a further £5.1M (sterling) in respect of past royalties.[43]

Patent litigation[edit]

On May 29, 2009, Johnson & Johnson's Centocor unit, the maker of infliximab, won a ruling for $1.67 billion from Abbott Laboratories for patent infringement on the process for making Humira.[44] However, in 2011 this judgment was overturned by the United States Court of Appeals for the Federal Circuit.[45]

Biosimilars[edit]

In 2014, Indian drugmaker Cadila Healthcare declared the launch of the first adalimumab biosimilar at a fifth of its U.S. price. The generic has been launched under the brand name Exemptia.[5] In 2016, Indian drugmaker Torrent Pharmaceuticals launched its biosimilar for adalimumab, called Adfrar. It was the second generic biosimilar of adalimumab.[46]

In 2016, the FDA approved Amgen's biosimilar, sold under the brand name Amjevita.[47] It is not available as of June 2019.[48] In 2017, the FDA approved German pharmaceutical company Boehringer Ingelheim's biosimilar, Cyltezo.[49] In 2019, the European Commission approved the biosimilar, Idacio.[50]

Adalimumab biosimilars became available in Europe in late 2018,[51] allowing the National Health Service to make record-breaking cost-savings,[52] as this is the single most expensive drug used in NHS hospitals, costing more than £400 million a year for about 46,000 patients.[53] It may not become available in the US until 2023.[51]

Similar agents[edit]

References[edit]

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  2. ^ a b c d British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1074. ISBN 9780857113382.
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  45. ^ [3] Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011), reversing 669 F. Supp. 2d 756 (E.D. Tex. 2009).
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  48. ^ "Prices and coupons for Amjevita". Retrieved 19 June 2019.
  49. ^ https://www.boehringer-ingelheim.com/press-release/adalimumab-biosimilar-cyltezo-receives-fda-approval. Retrieved 19 March 2019. Missing or empty |title= (help)
  50. ^ "Idacio". European Medicines Agency. 29 January 2019. Retrieved 22 April 2019.
  51. ^ a b "First wave of Humira biosimilars enters EU market". Biopharma-reporter.com. Retrieved 26 November 2018.
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External links[edit]