|Pregnancy cat.||C (AU) B (US)|
|Legal status||POM (UK) ℞-only (US)|
|Bioavailability||64% (subcutaneous), 0% (oral)|
|Mol. mass||144190.3 g/mol|
| (what is this?)
Adalimumab, trade name Humira, is a TNF inhibiting anti-inflammatory drug. AbbVie's trade name is derived from the acronym of "human monoclonal antibody in rheumatoid arthritis" (HUMIRA). Adalimumab binds to tumor necrosis factor-alpha (TNFα), preventing it from activating TNF receptors; TNFα inactivation has proven to be important in downregulating the inflammatory reactions associated with autoimmune diseases. Adalimumab has been approved in the United States for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, moderate to severe chronic psoriasis and juvenile idiopathic arthritis. Because TNFα is part of the immune system that protects the body from infection, treatment with adalimumab may increase the risk of infections.
It is marketed in 0.8 mL vials, preloaded 0.8 mL syringes and also in preloaded pen devices (called Humira Pen), injected subcutaneously, typically by the patient at home. It cannot be administered orally because the digestive system would destroy the drug.
Adalimumab was the first fully human monoclonal antibody drug approved by the FDA. It was derived from phage display, and was discovered through a collaboration between BASF Bioresearch Corporation (Worcester, Massachusetts, a unit of BASF) and Cambridge Antibody Technology as D2E7, then further manufactured at BASF Bioresearch Corporation and developed by BASF Knoll (BASF Pharma) and, ultimately, manufactured and marketed by Abbott Laboratories after the acquisition of BASF Pharma by Abbott.
- 1 History
- 2 Notable clinical and marketing milestones
- 3 Indication
- 4 Safety
- 5 Royalty litigation
- 6 Patent litigation
- 7 Similar agents
- 8 References
- 9 External links
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. 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. 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.
On 2 January 2013, Abbott Laboratories separated into two independent companies, Abbott and AbbVie. As a result AbbVie are taking responsibility for the further development and marketing of Humira.
As of 2008 adalimumab had been approved by the U.S. Food and Drug Administration (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.
Notable clinical and marketing milestones
- 1999: Preliminary results of early clinical trials with the fully human anti-TNFalpha monoclonal antibody D2E7
- 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.
- 2002: Broke ground on a new state-of-the-art biologics manufacturing facility.
- 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.
- 2002, December 31: Humira approved by the U.S. Food and Drug Administration (FDA) for treatment of rheumatoid arthritis.
- 2003: Launched Humira for rheumatoid arthritis and continued clinical studies for additional indications.
- 2005: Launched Humira for psoriatic arthritis. Exceeded $1 billion in annual sales for the first time.
- 2005, 10 December: Eisai Submits New Drug Application for Rheumatoid Arthritis Drug Adalimumab (D2E7) in Japan.
- 2006: Submitted Humira for the Crohn’s disease indication and launched it for AS. Exceeded $2 billion in annual sales.
- 2007: Launched Humira for Crohn’s disease in the United States, 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.
- 2007, 10 December: Abbott Opens New Biotechnology Manufacturing Facility in Puerto Rico
- 2009, 10 June: Five-Year Data Demonstrate Initial Use of Humira Plus Methotrexate May Prevent Further Joint Damage in Early Rheumatoid Arthritis Patients 
- 2012, 16 March: Humira could be associated with a significant decrease in vascular inflammation, a major risk factor of cardiovascular disease 
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 years of age and older, and is approved for use in the treatment of that condition. In RA it can be used alone or with methotrexate or similar medicines.
Adalimumab is undergoing trials for use in treating psoriasis and psoriatic arthritis.
Adalimumab may be effective and well tolerated in Ulcerative colitis. Its efficacy in maintaining clinical remission needs to be confirmed in a randomized controlled trial. It has been approved by the FDA for treatment of moderate-to-severe cases in adults.
Adalimumab has been shown to treat moderate to severe chronic (lasting a long time) plaque psoriasis (Ps) 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). 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 (JIA) in children four years of age and older. For patients 15 kg (33 lbs) to 30 kg (66 lbs) administer 20 mg subcutaneously every other week. For patients weighing more than 30 kg (66 lbs) administer 40 mg subcutaneously every other week.
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.
According to the product labeling, 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 (TB) and infections caused by viruses, fungi, or bacteria, rare reports of lymphoma and solid tissue cancers, rare reports of serious liver injury, rare reports of demyelinating central nervous system disorders, rare reports of cardiac failure, the U.S. Food and Drug Administration issued a black box warning to doctors which appears in the product labeling of adalimumab and the other TNF drugs instructing them to screen and monitor potential patients more carefully. Anaphylaxis or serious allergic reactions may occur.
In March 2003, British company 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, the Judge, The Hon. Mr Justice Laddie, ruled for CAT. In an unusual step, a draft of the judgement was not made available in advance.
A short version of the full statement of the proceedings was released. 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."
Abbott was required to pay CAT US$255 million, some of which was to be passed to its partners in development. 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.
On May 29, 2009, Johnson & Johnson's Centocor unit, the maker of Remicade, which is also a TNF inhibitor, won a ruling for $1.67 billion from Abbott Laboratories, the maker of Humira, for patent infringement on the process for making Humira. However, this judgment was overturned by the Federal Circuit.
- Brekke OH , Sandlie I (January 2003). "Therapeutic antibodies for human diseases at the dawn of the twenty-first century". Nat Rev Drug Discov 2 (1): 52–62. doi:10.1038/nrd984. PMID 12509759.
- Kempeni J (January 1999). "Preliminary results of early clinical trials with the fully human anti-TNFα monoclonal antibody D2E7". Ann Rheum Dis 58 (suppl 1): I70–2. doi:10.1136/ard.58.2008.i70. PMC 1766582. PMID 10577977.
-  Cambridge Antibody Technology website
- Jespers LS, Roberts A, Mahler SM, Winter G, Hoogenboom HR (September 1994). "Guiding the selection of human antibodies from phage display repertoires to a single epitope of an antigen". Biotechnology (N.Y.) 12 (9): 899–903. doi:10.1038/nbt0994-899. PMID 7521646.
- Rau R (January 2002). "Adalimumab (a fully human anti-tumour necrosis factor α monoclonal antibody) in the treatment of active rheumatoid arthritis: the initial results of five trials". Ann Rheum Dis 61 (Suppl 2): ii70–3. doi:10.1136/ard.61.suppl_2.ii70. PMC 1766697. PMID 12379628.
- Scheinfeld, N (2003). "Adalimumab (HUMIRA): a review". J Drugs Dermatol 2 (4): 375–7. PMID 12884458.
- "Ankylosing Spondylitis". Humira (adalimumab) drug information website. Abbott Laboratories. Retrieved 29 October 2011.
- Podolsky, Daniel K. (August 2002). "Inflammatory bowel disease". N Engl J Med 347 (6): 417–29. doi:10.1056/NEJMra020831. PMID 12167685.
- Fiorino G, Peyrin-Biroulet L, Repici A, Malesci A, Danese S (January 2011). "Adalimumab in ulcerative colitis: hypes and hopes". Expert Opin Biol Ther 11 (1): 109–16. doi:10.1517/14712598.2011.541435. PMID 21133817.
- "FDA approves Humira to treat ulcerative colitis". U.S. Food and Drug Administration. Sept. 28, 2012.
- Croom, Katherine F; McCormack, Paul L (2009). "Adalimumab". Am J Clin Dermatol 10 (1): 43–50. doi:10.2165/0128071-200910010-00008. PMID 19170412.
- FDA label - http://www.rxabbott.com/pdf/humira_medguide.pdf
- Karen M. Frank, et al, Investigation of the cause of death in a gene-therapy trial, N Engl J Med 361:161, July 9, 2009
- "Biotech firm wins royalty fight". BBC News. 2004-12-20. Retrieved 2010-04-23.
- Murray-, Rosie (2005-10-27). "Drug maker CAT surges after royalty settlement". The Daily Telegraph (London). Retrieved 2010-04-23.
- "J&J Wins Record .67 Billion Verdict From Abbott (Update2)". Bloomberg. 30 June 2009.
- [www.patentlyo.com/files/10-1144.pdf] Centocor v. Abbott, 10-1144 (Fed. Cir. 2011)