Ustekinumab
Encyclopedia
Ustekinumab is a human monoclonal antibody. It is directed against interleukin 12
and interleukin 23
, naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders.
In two Phase III trials for moderate to severe psoriasis
, the longest >76 weeks, ustekinumab was safe and effective.
A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with etanercept
in the treatment of moderate to severe plaque psoriasis. This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept. It also demonstrated the clinical benefit of ustekinumab among patients who failed to respond to etanercept.
Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.
, the drug is being investigated for the treatment of psoriatic arthritis
. It has also been tested in Phase II studies for multiple sclerosis
and sarcoidosis
, the latter versus golimumab
(Simponi).
On December 4, 2007, a Biologic License Application
(BLA) with the U.S. Food and Drug Administration (FDA) was filed by Centocor and Janssen-Cilag
International (collaborator) has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA).
On June 17, 2008, the Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) of the U.S. Food and Drug Administration unanimously recommended the approval of ustekinumab (CNTO 1275) for the treatment of adult patients with moderate to severe plaque psoriasis. The decision by the committee is non-binding and final decisions on approval of the drug are made by the FDA. The FDA approved the drug on September 25, 2009.
On November 21, 2008, the European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for ustekinumab for the treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to other systemic therapies.
On December 12, 2008 the Canadian Health Authority approved the use of ustekinumab for the treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.
In September 2008, Centocor released result of a study comparing etanercept
and ustekinumab. The entanercept group received subcutaneous injections of the drug twice weekly for 12-weeks while the ustekinumab group received 2 injections, one-month apart, of either 90 or 45 milligrams. At twelve weeks, psoriatic plaques were reduced by at least three-quarters in 68% of the low-dose ustekinumab group and 74% of the high-dose group. Both groups fared better than the etanercept group, 57% of whom saw such improvement. Dr. Alan Menter, chairman of psoriasis research at Baylor Research Institute
said of the results, "now we have a drug that will be used less frequently ... with a significant increase in effectiveness. These results are as good as we've seen in psoriasis."
s at doses of either 45 or 90 mg. The dosage and frequency varies by study and application (type of disease targeted). Generally the initial dosing interval once every three months, after the first two doses are administered four weeks apart.
through the suppression of certain cytokines. Specifically, CNTO 1275 blocks interleukin
IL-12
and IL-23
which help activate certain T-cells
.
Health-related quality of life (using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index) was improved to a significantly greater extent with ustekinumab than with placebo at week 12.
A double-blind placebo controlled randomised dose-ranging Phase II trial in patients with RRMS (relapsing-remitting multiple sclerosis) found that Ustekinumab was not efficacious in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions (the primary endpoint of the study) or the number of clinical or objective relapses (the secondary endpoint). The drug was relatively well tolerated compared to placebo.
and an increased risk of certain types of cancer
. As with some other immunosuppressant drugs like cyclosporine, the brain swelling of posterior reversible encephalopathy syndrome
is a risk. The pharmaceutical company also reports serious allergic reaction as a possible side effect. More common side effects are upper respiratory infection, headache
, and tiredness.
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...
and interleukin 23
Interleukin 23
Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. IL-23 is produced by dendritic cells and macrophages...
, naturally occurring proteins that regulate the immune system and immune-mediated inflammatory disorders.
In two Phase III trials for moderate to severe 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...
, the longest >76 weeks, ustekinumab was safe and effective.
A third Phase III trial, ACCEPT, compared the efficacy and safety of ustekinumab with 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...
in the treatment of moderate to severe plaque psoriasis. This trial found a significantly higher clinical response with ustekinumab over the 12-week study period compared to high-dose etanercept. It also demonstrated the clinical benefit of ustekinumab among patients who failed to respond to etanercept.
Ustekinumab is approved in Canada, Europe and the United States to treat moderate to severe plaque psoriasis.
, the drug is being investigated for the treatment of 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...
. It has also been tested in Phase II studies for 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 sarcoidosis
Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...
, the latter versus golimumab
Golimumab
Golimumab is a human monoclonal antibody which is used as an immunosuppressive drug and marketed under the brand name Simponi. Golimumab targets tumor necrosis factor alpha , a pro-inflammatory molecule and hence is a TNF inhibitor....
(Simponi).
Development
, there were 5 NIH-listed research studies involving CNTO 1275 on a multinational basis, including 3 Phase II and 2 Phase III trials. Three studies were focused on patients with psoriasis, one on psoriatic arthritis, and one on multiple sclerosis.On December 4, 2007, a Biologic License Application
Biologic License Application
As defined by the US FDA, a Biologic License Application is: Biological products are approved for marketing under the provisions of the Public Health Service Act. The Act requires a firm who manufactures a biologic for sale in interstate commerce to hold a license for the product...
(BLA) with the U.S. Food and Drug Administration (FDA) was filed by Centocor and Janssen-Cilag
Janssen-Cilag
Janssen-Cilag is a subsidiary of the Johnson & Johnson pharmaceutical company. The company was founded in the early 1950s by a merger between Janssen Pharmaceutica and Cilag....
International (collaborator) has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA).
On June 17, 2008, the Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) of the U.S. Food and Drug Administration unanimously recommended the approval of ustekinumab (CNTO 1275) for the treatment of adult patients with moderate to severe plaque psoriasis. The decision by the committee is non-binding and final decisions on approval of the drug are made by the FDA. The FDA approved the drug on September 25, 2009.
On November 21, 2008, the European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for ustekinumab for the treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to other systemic therapies.
On December 12, 2008 the Canadian Health Authority approved the use of ustekinumab for the treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.
In September 2008, Centocor released result of a study comparing 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...
and ustekinumab. The entanercept group received subcutaneous injections of the drug twice weekly for 12-weeks while the ustekinumab group received 2 injections, one-month apart, of either 90 or 45 milligrams. At twelve weeks, psoriatic plaques were reduced by at least three-quarters in 68% of the low-dose ustekinumab group and 74% of the high-dose group. Both groups fared better than the etanercept group, 57% of whom saw such improvement. Dr. Alan Menter, chairman of psoriasis research at Baylor Research Institute
Baylor University
Baylor University is a private, Christian university located in Waco, Texas. Founded in 1845, Baylor is accredited by the Southern Association of Colleges and Schools.-History:...
said of the results, "now we have a drug that will be used less frequently ... with a significant increase in effectiveness. These results are as good as we've seen in psoriasis."
Delivery
Patients enrolled in clinical trials of CNTO 1275 are scheduled to receive the drug by subcutaneous injectionSubcutaneous injection
A subcutaneous injection is administered as a bolus into the subcutis, the layer of skin directly below the dermis and epidermis, collectively referred to as the...
s at doses of either 45 or 90 mg. The dosage and frequency varies by study and application (type of disease targeted). Generally the initial dosing interval once every three months, after the first two doses are administered four weeks apart.
Mechanism of action
CNTO 1275 is designed to interfere with the triggering of the body's inflammatory responseInflammation
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...
through the suppression of certain cytokines. Specifically, CNTO 1275 blocks interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
IL-12
Interleukin 12
Interleukin 12 is an interleukin that is naturally produced by dendritic cells, macrophages and human B-lymphoblastoid cells in response to antigenic stimulation.-Gene and structure:...
and IL-23
Interleukin 23
Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. IL-23 is produced by dendritic cells and macrophages...
which help activate certain T-cells
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
.
Efficacy
In Phase III trials in patients with moderate to severe plaque psoriasis, significantly more subcutaneous ustekinumab 45 or 90 mg recipients (administered as two injections 4 weeks apart) than placebo recipients achieved a 75% improvement on the Psoriasis Area and Severity Index (PASI 75) score at 12 weeks.Health-related quality of life (using the Dermatology Life Quality Index and the Health Assessment Questionnaire disability index) was improved to a significantly greater extent with ustekinumab than with placebo at week 12.
A double-blind placebo controlled randomised dose-ranging Phase II trial in patients with RRMS (relapsing-remitting multiple sclerosis) found that Ustekinumab was not efficacious in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions (the primary endpoint of the study) or the number of clinical or objective relapses (the secondary endpoint). The drug was relatively well tolerated compared to placebo.
Adverse effects
According to information provided by Centrocor, maker of one medication based on ustekinumab, their version of the drug is associated with several types of serious adverse effects. These include an increased risk of infection, such as by tuberculosisTuberculosis
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 an increased risk of certain types of 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...
. As with some other immunosuppressant drugs like cyclosporine, the brain swelling of posterior reversible encephalopathy syndrome
Posterior reversible encephalopathy syndrome
Posterior reversible encephalopathy syndrome , also known as reversible posterior leukoencephalopathy syndrome , is a syndrome characterised by headache, confusion, seizures and visual loss. It may occur due to a number of causes, predominantly malignant hypertension, eclampsia and some medical...
is a risk. The pharmaceutical company also reports serious allergic reaction as a possible side effect. More common side effects are upper respiratory infection, 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...
, and tiredness.
Tolerability
Clinical trials have shown that subcutaneous ustekinumab was generally well tolerated. Most treatment-emergent adverse events were of mild severity.External links
- Centocor Ortho Biotech official site
- CNTO 1275 research studies registered with U.S. National Institutes of HealthNational Institutes of HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
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