Natalizumab
Encyclopedia
Natalizumab is a humanized
monoclonal antibody against the cellular adhesion molecule α4-integrin
. Natalizumab is used in the treatment of multiple sclerosis
and Crohn's disease
. It is co-marketed by Biogen Idec
and Élan
as Tysabri, and was previously named Antegren. Natalizumab is administered by intravenous infusion
every 28 days. The drug is believed to work by reducing the ability of inflammatory
immune cells
to attach to and pass through the cell layers lining the intestine
s and blood-brain barrier
. Natalizumab has proven effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and significantly
improving quality of life
in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn's disease.
Natalizumab was approved in 2004 by the U.S. Food and Drug Administration (FDA). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy
(PML) when administered in combination with interferon beta-1a
, another immunosuppressive drug
often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency
. By January 2010, 31 cases of PML were attributed to natalizumab. The FDA did not withdraw the drug from the market because its clinical benefits outweigh the risks involved. In the European Union
, it has been approved for human use only for the treatment of multiple sclerosis and only then as a monotherapy because the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the deceased customers.
Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 5, 2008.
and Crohn's disease
and approved for treatment of multiple sclerosis in Europe, but is currently under review by the EMEA.
score between 0 and 5. In these trials natalizumab was shown to reduce relapses in individuals with MS by 68% vs. placebo
, a margin far greater than had been seen for other approved MS therapies. Natalizumab also slowed the progression of disability in patients with relapsing MS. In combination with interferon beta-1a
(IB1A), relapsing and disability progression were reduced more than IB1A alone. Other benefits of natalizumab use by patients with relapsing MS shown in manufacturer-funded studies included reduced visual loss, a significant increase in the proportion of disease-free individuals, significantly improved assessments of health-related quality of life in relapsing individuals, reduced cognitive decline of a portion of individuals with MS, reduced hospitalizations and steroid
use, and prevention of the formation of new lesion
s. Approximately 6% of individuals receiving natalizumab have been found to develop persistent antibodies
to the drug, which reduces its efficacy and produce reactions during the infusion
of the drug, as well as hypersensitivity. Natalizumab is approved in the United States and the European Union. It is indicated as monotherapy (not combined with other drugs) for the treatment of highly active relapsing remitting MS in spite of prior treatments. Natalizumab offers a limited improvement in efficacy compared to other treatments for MS, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.
s have demonstrated that natalizumab is effective in increasing rates of remission and maintaining symptom-free status in patients with Crohn's disease
. Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha such as infliximab
, with some evidence to support combination treatment of Crohn's disease with natalizumab and infliximab may be helpful in inducing remission. Treatment of adolescent patients with natalizumab demonstrates an effectiveness similar to that of adult patients.
In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease, though it has not been approved for this use in the European Union due to concerns over its risk/benefit ratio.
with a low risk of anaphylaxis
, headache
, nausea
, colds
and exacerbation of Crohn's disease in a minority of patients with the condition. Adolescents with Crohn's disease experience headache, fever
and exacerbation of Crohn's disease. Natalizumab is contraindicated
for people with known hypersensitivity to the drug or its components and in patients with a history of PML (see interactions).
Postmarketing surveillance
in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant liver
injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with jaundice
or other evidence of significant liver damage. This rate is comparable to other immune-suppressing drugs. Evidence of hepatotoxicity
in the form of elevated blood levels of bilirubin
and liver enzymes
can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment. Such signs reoccur upon rechallenge
in some patients, indicating that damage is not coincidental. In the absence of any blockage these liver function tests
are predictors of severe liver injury with possible sequela
e of liver transplantation
or death
.
Natalizumab has also been linked to melanoma
, though the association is unclear. The long-term effects of the drug are unknown and concern has been expressed over the risks of infection
and cancer
.
Progressive multifocal leukoencephalopathy
, an opportunistic infection caused by the JC virus
, and that typically occurs in patients who are immunocompromised, developed in seven patients who received natalizumab; three cases were noted in clinical trials in 2006 leading to the drug being temporarily pulled from the market; two cases were reported to the FDA in August 2008; and, two cases were announced in December 2008. A recent preliminary study suggests that patients on this drug for more than 12 months are at elevated risk for PML. By January 21, 2010 the FDA noted a total of 31 confirmed cases of PML, with the chance of developing the infection increasing as the number of infusions received by a patient increased. Because of this association, the drug label and packaging insert accompanying the drug will be updated to include this information.
Natalizumab is a humanized
monoclonal antibody
against alpha-4 (α4) integrin
, the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for white blood cell
s to move into organs
; natalizumab's mechanism of action
is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs.
-causing lesion
s of MS are believed to be caused when inflammatory
cells such as T-lymphocytes pass through the blood-brain barrier
through interaction with receptors on the endothelial cells
. Natalizumab appears to reduce the transmission of immune cells into the central nervous system
by interfering with the α4β1-integrin receptor molecules
on the surfaces of cells. The effect appears to occur on endothelial cells expressing the VCAM-1
gene, and in parenchyma
l cells expressing the osteopontin
gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of leukocytes into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.
Individuals with MS dosed with natalizumab demonstrated increased CD34
-expressing cells, with research suggesting a peak in expression after 72 hours.
(also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of venules in the small intestine and are critical in guiding T-lymphocytes to lymphatic tissues
in Peyer's patches. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. Animal model
s have found higher levels of VCAM-1 expression in mice with irritable bowel syndrome
and the VCAM-1 gene may also play a part in CD but its role is not yet clear.
(PML), an often-fatal opportunistic infection
caused by the JC virus
. In 2005, two people taking natalizumab in combination with interferon beta-1a
developed PML. One died, and the other recovered with disabling sequela
e. A third fatal case initially attributed to an astrocytoma
was reported in a patient being treated for Crohn's disease. Though the patient was being treated with natalizumab in combination with azathioprine
, corticosteroid
s and infliximab
, indications of PML infection appeared only after natalizumab monotherapy was re-introduced. No deaths have been linked to natalizumab when it was not combined with other immune-modulating drugs and other rates of opportunistic infections are not increased in patients taking natalizumab possibly due to the drug’s mechanism of action. Other than a prior history of PML, there is no known method to identify patients at risk of developing PML. Natalizumab's label indicates that it is contraindicated
for immunosuppressed
individuals or those with a history of PML. Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program. As of June 2009, ten cases of PML associated with natalizumab have been reported. At least one of them had not previously taken any other inmunomodulator therapy. By Jaunary 21st, 2010 the United States Food and Drug Administration reported a total of 31 confirmed cases of PML associated with natalizumab.
Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its black box warning
states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators. Corticosteroid
s may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment. The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months though the longer term risks of PML are unknown.
in 2004, through the FDA's accelerated Fast Track program
, due to the drug's efficacy in one-year clinical trial
s. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market and in June, 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a first-line or second-line therapy. Patients taking natalizumab must enter into a registry for monitoring. Natalizumab is the only drug after alosetron
withdrawn for safety reasons that returned to the US market.
In April, 2006 the Committee for Medicinal Products for Human Use
recommended authorizing natalizumab to treat relapsing-remitting MS, and several weeks later the European Medicines Agency
approved natalizumab in the European Union for highly-active relapsing remitting MS.
Health Canada
added natalizumab to Schedule F of the Food and Drug Regulations on April 3, 2008 as a prescription drug
requiring oversight from a physician
.
Humanized antibody
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans...
monoclonal antibody against the cellular adhesion molecule α4-integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
. Natalizumab is used in the treatment of multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
and 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...
. It is co-marketed by Biogen Idec
Biogen Idec
Biogen Idec, Inc. is a biotechnology company specializing in drugs for neurological disorders, autoimmune disorders and cancer. The company was formed in 2003 by the merger of Cambridge, Massachusetts-based Biogen Inc. and San Diego, California-based IDEC Pharmaceuticals...
and Élan
Élan
Élan Corporation plc is a major drugs firm based in Athlone, County Roscommon, Ireland which has major interests in the United States. In the late 1990s its value on the Irish Stock Exchange reached over €20bn. It has secondary listings on the London Stock Exchange and the New York Stock Exchange....
as Tysabri, and was previously named Antegren. Natalizumab is administered by intravenous infusion
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
every 28 days. The drug is believed to work by reducing the ability of 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...
immune cells
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
to attach to and pass through the cell layers lining the intestine
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
s and blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
. Natalizumab has proven effective in treating the symptoms of both diseases, preventing relapse, vision loss, cognitive decline and significantly
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
improving quality of life
Quality of life
The term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
in people with multiple sclerosis, as well as increasing rates of remission and preventing relapse in Crohn's disease.
Natalizumab was approved in 2004 by the U.S. Food and Drug Administration (FDA). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
(PML) when administered in combination with interferon beta-1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...
, another immunosuppressive drug
Immunosuppressive drug
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
. By January 2010, 31 cases of PML were attributed to natalizumab. The FDA did not withdraw the drug from the market because its clinical benefits outweigh the risks involved. In the European Union
European Union
The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...
, it has been approved for human use only for the treatment of multiple sclerosis and only then as a monotherapy because the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the deceased customers.
Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 5, 2008.
Indications
Natalizumab is FDA-approved for the treatment of multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
and 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...
and approved for treatment of multiple sclerosis in Europe, but is currently under review by the EMEA.
Multiple sclerosis
Natalizumab was evaluated in two randomized, double-blind, placebo-controlled trials in people with multiple sclerosis. The studies, supported and analyzed by Biogen Idec and Elan Pharmaceuticals, the makers of the drug, enrolled individuals with MS who experienced at least one clinical relapse during the prior year and had a Kurtzke EDSSExpanded Disability Status Scale
The Kurtzke Expanded Disability Status Scale is a method of quantifying disability in multiple sclerosis.The EDSS quantifies disability in eight Functional Systems and allows neurologists to assign a Functional System Score in each of these....
score between 0 and 5. In these trials natalizumab was shown to reduce relapses in individuals with MS by 68% vs. placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
, a margin far greater than had been seen for other approved MS therapies. Natalizumab also slowed the progression of disability in patients with relapsing MS. In combination with interferon beta-1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...
(IB1A), relapsing and disability progression were reduced more than IB1A alone. Other benefits of natalizumab use by patients with relapsing MS shown in manufacturer-funded studies included reduced visual loss, a significant increase in the proportion of disease-free individuals, significantly improved assessments of health-related quality of life in relapsing individuals, reduced cognitive decline of a portion of individuals with MS, reduced hospitalizations and steroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
use, and prevention of the formation of new lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s. Approximately 6% of individuals receiving natalizumab have been found to develop persistent antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
to the drug, which reduces its efficacy and produce reactions during the infusion
Infusion
An infusion is the outcome of steeping plants with desired chemical compounds or flavors in water or oil.-History:The first recorded use of essential oils was in the 10th or 11th century by the Persian polymath Avicenna, possibly in The Canon of Medicine.-Preparation techniques:An infusion is very...
of the drug, as well as hypersensitivity. Natalizumab is approved in the United States and the European Union. It is indicated as monotherapy (not combined with other drugs) for the treatment of highly active relapsing remitting MS in spite of prior treatments. Natalizumab offers a limited improvement in efficacy compared to other treatments for MS, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.
Crohn's disease
Several randomized controlled trialRandomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s have demonstrated that natalizumab is effective in increasing rates of remission and maintaining symptom-free status in patients with 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...
. Natalizumab may be appropriate in patients who do not respond to medications that block tumor necrosis factor-alpha such as 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...
, with some evidence to support combination treatment of Crohn's disease with natalizumab and infliximab may be helpful in inducing remission. Treatment of adolescent patients with natalizumab demonstrates an effectiveness similar to that of adult patients.
In January 2008, the FDA approved natalizumab for both induction of remission and maintenance of remission for moderate to severe Crohn's disease, though it has not been approved for this use in the European Union due to concerns over its risk/benefit ratio.
Adverse effects
Common adverse effects include fatigue and allergic reactionsAllergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
with a low risk of anaphylaxis
Anaphylaxis
Anaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, colds
Common cold
The common cold is a viral infectious disease of the upper respiratory system, caused primarily by rhinoviruses and coronaviruses. Common symptoms include a cough, sore throat, runny nose, and fever...
and exacerbation of Crohn's disease in a minority of patients with the condition. Adolescents with Crohn's disease experience headache, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
and exacerbation of Crohn's disease. Natalizumab is contraindicated
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
for people with known hypersensitivity to the drug or its components and in patients with a history of PML (see interactions).
Postmarketing surveillance
Postmarketing surveillance
Postmarketing surveillance is the practice of monitoring the safety of a pharmaceutical drug or device after it has been released on the market and is an important part of the science of pharmacovigilance...
in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant 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, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with jaundice
Jaundice
Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...
or other evidence of significant liver damage. This rate is comparable to other immune-suppressing drugs. Evidence of hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
in the form of elevated blood levels of bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
and liver enzymes
Elevated transaminases
In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase and aspartate transaminase , may be an indicator of liver damage...
can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment. Such signs reoccur upon rechallenge
Challenge-dechallenge-rechallenge
Challenge-dechallenge-rechallenge is a medical testing protocol in which a medicine or drug is administered, withdrawn, then re-administered, while being monitored for adverse effects at each stage...
in some patients, indicating that damage is not coincidental. In the absence of any blockage these liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
are predictors of severe liver injury with possible sequela
Sequela
A sequela) is a pathological condition resulting from a disease, injury, or other trauma.Chronic kidney disease, for example, is sometimes a sequela of diabetes, and neck pain is a common sequela of whiplash or other trauma to the cervical vertebrae. Post-traumatic stress disorder may be a...
e of liver transplantation
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
or death
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
.
Natalizumab has also been linked to melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
, though the association is unclear. The long-term effects of the drug are unknown and concern has been expressed over the risks of 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...
and 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...
.
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
, an opportunistic infection caused by the JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
, and that typically occurs in patients who are immunocompromised, developed in seven patients who received natalizumab; three cases were noted in clinical trials in 2006 leading to the drug being temporarily pulled from the market; two cases were reported to the FDA in August 2008; and, two cases were announced in December 2008. A recent preliminary study suggests that patients on this drug for more than 12 months are at elevated risk for PML. By January 21, 2010 the FDA noted a total of 31 confirmed cases of PML, with the chance of developing the infection increasing as the number of infusions received by a patient increased. Because of this association, the drug label and packaging insert accompanying the drug will be updated to include this information.
Mechanism of action
Humanized antibody
Humanized antibodies are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans...
monoclonal antibody
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
against alpha-4 (α4) integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
, the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for white blood cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
s to move into organs
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
; natalizumab's mechanism of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is believed to be the inhibition these immune cells from crossing blood vessel walls to reach affected organs.
In multiple sclerosis
The symptomMultiple sclerosis signs and symptoms
Multiple sclerosis can cause a variety of symptoms: changes in sensation , muscle weakness, abnormal muscle spasms, or difficulty moving; difficulties with coordination and balance; problems in speech or swallowing , visual problems , fatigue and acute or chronic pain syndromes, bladder and bowel...
-causing lesion
Lesion
A lesion is any abnormality in the tissue of an organism , usually caused by disease or trauma. Lesion is derived from the Latin word laesio which means injury.- Types :...
s of MS are believed to be caused when 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...
cells such as T-lymphocytes pass through the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
through interaction with receptors on the endothelial cells
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
. Natalizumab appears to reduce the transmission of immune cells into the 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...
by interfering with the α4β1-integrin receptor molecules
VLA-4
Integrin alpha4beta1 is an integrin dimer. It is composed of CD49d and CD29 .VCAM-1 binds to the integrin VLA-4 which are normally expressed on leukocyte plasma membranes, but they do not adhere to their appropriate ligands until the leukocytes are activated by chemotactic agents or other...
on the surfaces of cells. The effect appears to occur on endothelial cells expressing the VCAM-1
VCAM-1
Vascular cell adhesion protein 1 also known as vascular cell adhesion molecule 1 or cluster of differentiation 106 is a protein that in humans is encoded by the VCAM1 gene...
gene, and in parenchyma
Parenchyma
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...
l cells expressing the osteopontin
Osteopontin
Osteopontin , also known as bone sialoprotein I , early T-lymphocyte activation , secreted phosphoprotein 1 , 2ar and Rickettsia resistance , is a human gene product, which is also conserved in other species...
gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of leukocytes into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.
Individuals with MS dosed with natalizumab demonstrated increased CD34
CD34
CD34 molecule is a cluster of differentiation molecule present on certain cells within the human body. It is a cell surface glycoprotein and functions as a cell-cell adhesion factor. It may also mediate the attachment of stem cells to bone marrow extracellular matrix or directly to stromal cells...
-expressing cells, with research suggesting a peak in expression after 72 hours.
In Crohn's disease
The interaction of the α4β7 integrin and the addressinAddressin
Addressin also known as mucosal vascular addressin cell adhesion molecule 1 is a protein that in humans is encoded by the MADCAM1 gene....
(also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of venules in the small intestine and are critical in guiding T-lymphocytes to lymphatic tissues
Lymphatic system
The lymphoid system is the part of the immune system comprising a network of conduits called lymphatic vessels that carry a clear fluid called lymph unidirectionally toward the heart. Lymphoid tissue is found in many organs, particularly the lymph nodes, and in the lymphoid follicles associated...
in Peyer's patches. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. Animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s have found higher levels of VCAM-1 expression in mice with irritable bowel syndrome
Irritable bowel syndrome
Irritable bowel syndrome is a diagnosis of exclusion. It is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. In some cases, the symptoms are relieved by bowel movements...
and the VCAM-1 gene may also play a part in CD but its role is not yet clear.
Interactions
Natalizumab appears to interact with other immune-modulating drugs to increase the risk of progressive multifocal leukoencephalopathyProgressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy , also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations .It occurs almost exclusively in...
(PML), an often-fatal opportunistic infection
Opportunistic infection
An opportunistic infection is an infection caused by pathogens, particularly opportunistic pathogens—those that take advantage of certain situations—such as bacterial, viral, fungal or protozoan infections that usually do not cause disease in a healthy host, one with a healthy immune system...
caused by the JC virus
JC virus
The JC virus or John Cunningham virus is a type of human polyomavirus and is genetically similar to BK virus and SV40. It was discovered in 1971 and named using the two initials of a patient with progressive multifocal leukoencephalopathy...
. In 2005, two people taking natalizumab in combination with interferon beta-1a
Interferon beta-1a
Interferon beta-1a is a drug in the interferon family used to treat multiple sclerosis . It is produced by mammalian cells, while Interferon beta-1b is produced in modified E. coli. Interferons have been shown to produce about a 18–38% reduction in the rate of MS relapses, and to slow the...
developed PML. One died, and the other recovered with disabling sequela
Sequela
A sequela) is a pathological condition resulting from a disease, injury, or other trauma.Chronic kidney disease, for example, is sometimes a sequela of diabetes, and neck pain is a common sequela of whiplash or other trauma to the cervical vertebrae. Post-traumatic stress disorder may be a...
e. A third fatal case initially attributed to an astrocytoma
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
was reported in a patient being treated for Crohn's disease. Though the patient was being treated with natalizumab in combination with azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
, corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s and 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...
, indications of PML infection appeared only after natalizumab monotherapy was re-introduced. No deaths have been linked to natalizumab when it was not combined with other immune-modulating drugs and other rates of opportunistic infections are not increased in patients taking natalizumab possibly due to the drug’s mechanism of action. Other than a prior history of PML, there is no known method to identify patients at risk of developing PML. Natalizumab's label indicates that it is contraindicated
Contraindication
In medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
for immunosuppressed
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
individuals or those with a history of PML. Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program. As of June 2009, ten cases of PML associated with natalizumab have been reported. At least one of them had not previously taken any other inmunomodulator therapy. By Jaunary 21st, 2010 the United States Food and Drug Administration reported a total of 31 confirmed cases of PML associated with natalizumab.
Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its 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...
states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators. Corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment. The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months though the longer term risks of PML are unknown.
Legal status
Natalizumab was originally approved for treatment of multiple sclerosisMultiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
in 2004, through the FDA's accelerated Fast Track program
FDA Fast Track Development Program
The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days...
, due to the drug's efficacy in one-year clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market and in June, 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a first-line or second-line therapy. Patients taking natalizumab must enter into a registry for monitoring. Natalizumab is the only drug after alosetron
Alosetron
Alosetron is a 5-HT3 antagonist used for the management of severe diarrhea-predominant irritable bowel syndrome in women only. It is currently marketed by Prometheus Laboratories Inc...
withdrawn for safety reasons that returned to the US market.
In April, 2006 the Committee for Medicinal Products for Human Use
Committee for Medicinal Products for Human Use
The Committee for Medicinal Products for Human Use , formerly known as Committee for Proprietary Medicinal Products , is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regarding medicinal products for human use.E.g.: In June 2007 the CHMP...
recommended authorizing natalizumab to treat relapsing-remitting MS, and several weeks later the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
approved natalizumab in the European Union for highly-active relapsing remitting MS.
Health Canada
Health Canada
Health Canada is the department of the government of Canada with responsibility for national public health.The current Minister of Health is Leona Aglukkaq, a Conservative Member of Parliament appointed to the position by Prime Minister Stephen Harper.-Branches, regions and agencies:Health Canada...
added natalizumab to Schedule F of the Food and Drug Regulations on April 3, 2008 as a prescription drug
Prescription drug
A prescription medication is a licensed medicine that is regulated by legislation to require a medical prescription before it can be obtained. The term is used to distinguish it from over-the-counter drugs which can be obtained without a prescription...
requiring oversight from a physician
Physician
A physician is a health care provider who practices the profession of medicine, which is concerned with promoting, maintaining or restoring human health through the study, diagnosis, and treatment of disease, injury and other physical and mental impairments...
.