Adalimumab
Encyclopedia
Adalimumab 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 disease
s. 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 syringe
s and also in preloaded pen device
s (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 $5 billion in annual sales.
) 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.
inhibitor competitors, infliximab
and etanercept
, has proven versatile in its effectiveness in treating several conditions.
(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.
(AS) in adults.
. Its efficacy in maintaining clinical remission needs to be confirmed in a randomized controlled trial.
, 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 infection
s including TB (tuberculosis
) and infections caused by viruses, fungi, or bacteria, rare reports of lymphoma
and solid tissue cancer
s, 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.
(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.
TNF inhibitor
Tumor necrosis factor promotes the inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, hidradenitis suppurativa and refractory asthma. These disorders are...
, after infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
and etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
, to be approved in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. 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
Mouse
A mouse is a small mammal belonging to the order of rodents. The best known mouse species is the common house mouse . It is also a popular pet. In some places, certain kinds of field mice are also common. This rodent is eaten by large birds such as hawks and eagles...
-human chimeric antibody and etanercept is a TNF receptor-IgG fusion protein
Fusion protein
Fusion proteins or chimeric proteins are proteins created through the joining of two or more genes which originally coded for separate proteins. Translation of this fusion gene results in a single polypeptide with functional properties derived from each of the original proteins...
. TNFα inactivation has proven to be important in downregulating the inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
reactions associated with autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s. As of 2008 adalimumab has been approved by the FDA
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
for the treatment of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, psoriatic arthritis
Psoriatic arthritis
Psoriatic arthritis is a type of inflammatory arthritis that, according to the National Psoriasis Foundation, will develop in up to 30 percent of people who have the chronic skin condition psoriasis...
, ankylosing spondylitis
Ankylosing spondylitis
Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...
, Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
, moderate to severe chronic psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
and juvenile idiopathic arthritis
Juvenile idiopathic arthritis
Juvenile idiopathic arthritis is the most common form of persistent arthritis in children. JIA is a subset of arthritis seen in childhood, which may be transient and...
.
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 syringe
Syringe
A syringe is a simple pump consisting of a plunger that fits tightly in a tube. The plunger can be pulled and pushed along inside a cylindrical tube , allowing the syringe to take in and expel a liquid or gas through an orifice at the open end of the tube...
s and also in preloaded pen device
Autoinjector
An autoinjector is a medical device designed to deliver a single dose of a particular drug....
s (called Humira Pen), both injected subcutaneously
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
, typically by the patient at home. It cannot be administered orally
Route of administration
A route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
, 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
Phage display
Phage display is a method for the study of protein–protein, protein–peptide, and protein–DNA interactions that uses bacteriophages to connect proteins with the genetic information that encodes them. Phage Display was originally invented by George P...
, and was discovered through a collaboration between BASF Bioresearch Corporation (Worcester, Massachuetts, a unit of BASF
BASF
BASF SE is the largest chemical company in the world and is headquartered in Germany. BASF originally stood for Badische Anilin- und Soda-Fabrik . Today, the four letters are a registered trademark and the company is listed on the Frankfurt Stock Exchange, London Stock Exchange, and Zurich Stock...
) and Cambridge Antibody Technology
Cambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
as D2E7, then further manufactured at BASF Bioresearch Corporation and developed by BASF
BASF
BASF SE is the largest chemical company in the world and is headquartered in Germany. BASF originally stood for Badische Anilin- und Soda-Fabrik . Today, the four letters are a registered trademark and the company is listed on the Frankfurt Stock Exchange, London Stock Exchange, and Zurich Stock...
Knoll (BASF Pharma) and, ultimately, manufactured and marketed by Abbott Laboratories
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
after the acquisition of BASF Pharma by Abbott.
In 2009, HUMIRA had over $5 billion in annual sales.
History
Adalimumab was discovered as a result of the collaboration between BASF Bioresearch Corporation (Worcester, Massachuetts, a unit of BASFBASF
BASF SE is the largest chemical company in the world and is headquartered in Germany. BASF originally stood for Badische Anilin- und Soda-Fabrik . Today, the four letters are a registered trademark and the company is listed on the Frankfurt Stock Exchange, London Stock Exchange, and Zurich Stock...
) and Cambridge Antibody Technology
Cambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
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
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
, 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 ACRAmerican College of RheumatologyThe American College of Rheumatology is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with arthritis and rheumatic and...
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 TNFTumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
inhibitor competitors, infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...
and etanercept
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...
, 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 arthritisRheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
(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 spondylitisAnkylosing spondylitis
Ankylosing spondylitis , previously known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strümpell disease is a chronic inflammatory disease of the axial skeleton with variable involvement of peripheral joints and nonarticular structures...
(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 colitisUlcerative colitis
Ulcerative colitis is a form of inflammatory bowel disease . Ulcerative colitis is a form of colitis, a disease of the colon , that includes characteristic ulcers, or open sores. The main symptom of active disease is usually constant diarrhea mixed with blood, of gradual onset...
. 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 four 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 TNFTumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
, 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 infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s including TB (tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
) and infections caused by viruses, fungi, or bacteria, rare reports of lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and solid tissue cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s, rare reports of serious liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
injury, and rare reports of demyelinating central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
disorders, rare reports of cardiac failure, the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
issued a black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
to doctors appearing in the product labeling of adalimumab and the other TNF
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
drugs instructing them to screen and monitor potential patients more carefully.
Royalty litigation
In March 2003, British company Cambridge Antibody TechnologyCambridge Antibody Technology
Cambridge Antibody Technology was a biotechnology company headquartered in Cambridge, United Kingdom...
(CAT) stated its wish to "initiate discussions regarding the applicability of the royalty offset provisions for HUMIRA" with Abbott Laboratories
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
in the High Court
High Court of Justice
The High Court of Justice is, together with the Court of Appeal and the Crown Court, one of the Senior Courts of England and Wales...
of London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...
. In November 2004, the trial began, and in December 2004, the Judge, The Hon. Mr Justice Laddie
Hugh Laddie
Sir Hugh Ian Lang Laddie was a British High Court judge, lawyer, professor, and a specialist in intellectual property law. He was considered one the leading English judges and academics in the field of intellectual property law...
, 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
Medical Research Council (UK)
The Medical Research Council is a publicly-funded agency responsible for co-ordinating and funding medical research in the United Kingdom. It is one of seven Research Councils in the UK and is answerable to, although politically independent from, the Department for Business, Innovation and Skills...
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.