Adalimumab

Adalimumab

Monoclonal antibody
Type	Whole antibody
Source	Human
Target	TNF alpha
Clinical data
Trade names	Humira, Exemptia
AHFS/Drugs.com	Monograph
MedlinePlus	a603010
Pregnancy category	AU: C US: B (No risk in non-human studies)
Routes of administration	Subcutaneous
ATC code	L04AB04 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	64% (subcutaneous), 0% (oral)
Biological half-life	10–20 days.
Identifiers
CAS Number	331731-18-1 Y
DrugBank	DB00051 Y
ChemSpider	none
UNII	FYS6T7F842
KEGG	D02597 Y
ChEMBL	CHEMBL1201580 N
ECHA InfoCard	100.224.376
Chemical and physical data
Formula	C6428H9912N1694O1987S46
Molar mass	144190.3 g/mol
NY (what is this?)  (verify)

Adalimumab, sold under the trade name Humira among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, chronic psoriasis, hidradenitis suppurativa, and juvenile idiopathic arthritis. In rheumatoid arthritis, adalimumab has a response rate similar to methotrexate, and in combination, it nearly doubles the response rate of methotrexate alone.^[1]

Adalimumab is a TNF-inhibiting, anti-inflammatory, biologic medication. It binds to tumor necrosis factor-alpha (TNFα), which normally binds to TNFα receptors, leading to the inflammatory response of autoimmune diseases. By binding to TNFα, adalimumab reduces this inflammatory response. Because TNFα is also part of the immune system, which protects the body from infection, treatment with adalimumab may increase the risk of infections.

Humira costs approximately $4370 per month(2017), like the TNFα inhibitor etanercept. From 2012 to US patent expiry in 2016, Humira led the list of top-selling pharmaceutical products, and in 2016, it had $16 billion of global sales.^[2] Also in 2014, in India, the first adalimumab biosimilar came to market at a price of $200. Two years later, another Indian drugmaker, Torrent Pharmaceuticals, launched a second biosimilar.^[3] Humira's U.S. patent expired in 2016.^[4]

Medical uses

Adalimumab is administered by subcutaneous injection.^[5] For most indications, the maintenance treatment is an injection every other week.^[5]

Like other TNF inhibitors—such as infliximab, etanercept, certolizumab pegol, and golimumab—it may be used to treat several conditions where the suppression of the immune response is desired. Not all of the listed applications have been approved worldwide.

Rheumatoid arthritis

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe rheumatoid arthritis (RA) in adults. It has also been shown to have efficacy in moderate to severe polyarticular juvenile idiopathic arthritis (JIA) in children 4 and older, and is approved for the treatment of that condition. In RA, it has been approved for use alone, or with methotrexate or similar medicines, in the U.S. since 2002.^[6][7]

Psoriatic arthritis

In 2003, adalimumab began undergoing trials for use in treating psoriasis and psoriatic arthritis.^[8]

Ankylosing spondylitis

Adalimumab has been shown to reduce the signs and symptoms of, and is approved for treatment of, ankylosing spondylitis in adults.^[9]

Crohn’s disease

Adalimumab has been shown to reduce the signs and symptoms of moderate to severe Crohn's disease.^[10] It has been approved for that use in the UK since 2009.^[11]

Ulcerative colitis

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.^[12]

Plaque psoriasis

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).^[13] Adalimumab has been shown to be effective therapy when used either continuously or intermittently in patients with moderate to severe psoriasis.

Juvenile idiopathic arthritis

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

Side effects

Components of a Humira autoinjector pen. See file details for explanation of parts.

Because adalimumab suppresses TNF, which is part of the immune system, latent infections such as tuberculosis can be reactivated, and the immune system may be unable to fight new infections. This has led to fatal infections in some patients.^[14]

After a number of studies and reports of adverse events in patients receiving adalimumab—including serious and sometimes fatal blood disorders; serious infections, including tuberculosis and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma^[15] and solid tissue cancers; 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.^[16] Anaphylaxis or other serious allergic reactions may also occur.^[16]

History

Adalimumab was the first fully human monoclonal antibody approved by the U.S. Food and Drug Administration. It was derived from phage display^[17] and was discovered through a collaboration between BASF Bioresearch Corporation (a unit of BASF based in Worcester, Massachusetts) and Cambridge Antibody Technology. Initially named D2E7,^[18] 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. Humira is now owned by AbbVie.

Adalimumab was discovered as a result of a collaboration between BASF Bioresearch Corporation and Cambridge Antibody Technology, which began in 1993.^[19] The brand name Humira stands for "human monoclonal antibody in rheumatoid arthritis".

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.^[18] 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.^[20] 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.^[21]

On 2 January 2013, Abbott Laboratories separated into two independent companies, Abbott and AbbVie.^[22] As a result, AbbVie is taking responsibility for the further development and marketing of Humira.^[23]

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

• 1999: Preliminary results of early clinical trials with the fully human anti-TNFα monoclonal antibody D2E7^[18]
• 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.^[24]
• 2002: Broke ground on a new state-of-the-art biologics manufacturing facility.^[25]
• 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.^[26]
• 2002, December 31: Humira approved by the U.S. Food and Drug Administration (FDA) for treatment of rheumatoid arthritis.^[25]
• 2003: Launched Humira for rheumatoid arthritis and continued clinical studies for additional indications.^[25]
• 2005: Launched Humira for psoriatic arthritis. Exceeded $1 billion in annual sales for the first time.^[25]
• 2005, 10 December: Eisai Submits New Drug Application for Rheumatoid Arthritis Drug Adalimumab (D2E7) in Japan.^[27]
• 2006: Submitted Humira for the Crohn’s disease indication and launched it for AS. Exceeded $2 billion in annual sales.^[25]
• 2007: Launched Humira for Crohn’s disease in the United States,^[25] 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.^[28]
• 2007, 10 December: Abbott Opens New Biotechnology Manufacturing Facility in Puerto Rico^[29]
• 2009, 10 June: Five-Year Data Demonstrate Initial Use of Humira Plus Methotrexate May Prevent Further Joint Damage in Early Rheumatoid Arthritis Patients ^[30]
• 2012, 16 March: Humira could be associated with a significant decrease in vascular inflammation, a major risk factor of cardiovascular disease ^[31]
• 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."^[32]
• 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.^[33][34]

Society and culture

Royalty litigation

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.^[35] 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."^[36]

Abbott was required to pay CAT US$255 million, some of which was to be passed to its partners in development.^[37] 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.^[38]

Patent litigation

On May 29, 2009, Johnson & Johnson's Centocor unit, the maker of Remicade (infliximab), won a ruling for $1.67 billion from Abbott Laboratories, the maker of Humira, for patent infringement on the process for making Humira.^[39] However, in 2011 this judgment was overturned by the United States Court of Appeals for the Federal Circuit.^[40]

Biosimilars

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.^[4][41]

In January 2016, Indian drugmaker Torrent Pharmaceuticals launched its biosimilar for adalimumab, called Adfrar. It was the second generic biosimilar of adalimumab.^[3]

In September 2016, the FDA approved Amgen's biosimilar, sold under the brand name Amjevita.^[42]

Similar agents

• Infliximab
• Etanercept
• Certolizumab pegol
• Golimumab

References

External links

• Official website
  • Humira - full prescribing information
• Official website of Exemptia (adalimumab biosimilar)
• Humira Adverse Events Reported to the FDA