Adalimumab

Adalimumab (HUMIRA, Abbott) is the third TNF inhibitor, after infliximab and etanercept, to be approved in the United States. Like infliximab and etanercept, adalimumab binds to TNFα, preventing it from activating TNF receptors; adalimumab 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. TNFα inactivation has proven to be important in downregulating the inflammatory reactions associated with autoimmune diseases. As of 2008 adalimumab has 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.

However, because TNFα is part of the immune system that protects the body from infection, prolonged treatment with adalimumab may slightly increase the risk of developing infections.

HUMIRA ("Human Monoclonal Antibody in Rheumatoid Arthritis") is marketed in both preloaded 0.8 mL syringes and also in preloaded pen devices (called Humira Pen), both 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, Massachuetts, 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.

In 2009, HUMIRA had over $5bn in annual sales

History
Adalimumab was discovered as a result of the collaboration between BASF Bioresearch Corporation (Worcester, Massachuetts, a unit of BASF) and Cambridge Antibody Technology which began in 1993.

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.

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 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

Indications
Adalimumab, like its TNF inhibitor competitors, infliximab and etanercept, has proven versatile in its effectiveness in treating several conditions.

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 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.

Psoriatic arthritis
Adalimumab (HUMIRA, Abbott Laboratories) is a fully human TNF-alpha monoclonal antibody approved for the treatment of rheumatoid arthritis and undergoing trials for use in treating other conditions, including psoriasis and psoriatic arthritis.

Ankylosing spondylitis
Adalimumab has been shown to reduce the signs and symptoms of, and is approved for treatment of, ankylosing spondylitis (AS) in adults.

Crohn’s disease
Adalimumab has been shown to reduce the signs and symptoms of, and is approved for treatment of, moderate to severe Crohn’s disease.

Ulcerative colitis
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.

Plaque psoriasis
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 4 years of age and older. It is commonly used in combination with methotrexate and administered via a 20 mg pre-filled pediatric syringe, 40 mg pre-filled syringe or a 40 mg pen.

Safety
Because adalimumab suppresses TNF, which is part of the immune system, latent infections, such as tuberculoses, 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 TB (tuberculosis) and infections caused by viruses, fungi, or bacteria; rare reports of lymphoma and solid tissue cancers; rare reports of serious liver injury; and 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 appearing in the product labeling of adalimumab and the other TNF drugs instructing them to screen and monitor potential patients more carefully.

Royalty litigation
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$255m, 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.

Similar agents

 * Infliximab
 * Etanercept