Alefacept
Encyclopedia
Alefacept is a genetically engineered
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...

 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:...

 sold under the brand name Amevive in Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

, the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, Israel
Israel
The State of Israel is a parliamentary republic located in the Middle East, along the eastern shore of the Mediterranean Sea...

, Switzerland
Switzerland
Switzerland name of one of the Swiss cantons. ; ; ; or ), in its full name the Swiss Confederation , is a federal republic consisting of 26 cantons, with Bern as the seat of the federal authorities. The country is situated in Western Europe,Or Central Europe depending on the definition....

 and Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

. It is used to control inflammation
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...

 in 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...

 with plaque formation, where it interferes with lymphocyte
Lymphocyte
A lymphocyte is a type of white blood cell in the vertebrate immune system.Under the microscope, lymphocytes can be divided into large lymphocytes and small lymphocytes. Large granular lymphocytes include natural killer cells...

 activation. It is also being studied in the treatment of cutaneous T-cell lymphoma and T-cell non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....

.

Alefacept is a 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...

: it combines part of an antibody
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...

 with a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

 that blocks the growth of some types of T cells.

Mode of action

The exact mode of action is very complicated and involves dual mechanisms, one of which inhibits the activation of CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...

+ and CD8
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...

+ T cell
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...

s by interfering with CD2
CD2
CD2 is a cell adhesion molecule found on the surface of T cells and natural killer cells.It has also been called T-cell surface antigen T11/Leu-5, LFA-2, LFA-3 receptor, erythrocyte receptor and rosette receptor....

 on the T cell membrane thereby blocking the costimulatory molecule LFA-3/CD2 interaction. The second mechanism is inducing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 of memory-effector T lymphocytes. If the T cells were to become activated they would stimulate proliferation
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...

 of keratinocyte
Keratinocyte
Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...

s resulting in the typical psoriatic symptoms. Therefore, alefacept leads to clinical improvement of moderate to severe psoriasis by blunting these reactions.Combinations of therapeutic modalities have been utilized to meet the challenge of difficult to treat psoriasis.

Drawbacks

Due to safety issues (immunosuppression, risk 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...

s, malignancies
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...

, and allergies
Allergy
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...

) the European Medicines Agency (EMEA
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...

) has so far rejected to approve alefacept.

Indications

Alefacept is indicated for the management of patients with moderate to severe chronic plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy. The concomitant use of low-potency topical 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 was permitted during the treatment phase with alefacept and does not seem to pose any additional risks.

The drug was approved based upon studies involving 1,869 patients altogether with plaques covering at least 10% of body surface. Either 7.5 mg IV or 15 mg IM once a week were applied. The long term results (reduction of at least 75% in pretreatment PASI scores) were 14% and 21%, respectively. Additional improvements ensuing after completion of the 12-week treatment phase or after completion of a second alefacept treatment were also seen. Often the remissions were maintained for 7 to 12 months after end of treatment.

Contraindications and precautions

  • Alefacept reduces CD4+ T cell
    T helper cell
    T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...

     counts and may worsen the clinical course of HIV infections. It is therefore contraindicated in patients with HIV infections.
  • Pretreatment CD4+ and/or CD8+ cell
    Cytotoxic T cell
    A cytotoxic T cell belongs to a sub-group of T lymphocytes that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses , or are otherwise damaged or...

     counts below the accepted lower limit
  • History of systemic malignancy
  • Caution: Patients at high risk to develop a systemic malignancy
  • Known hypersensitivity
    Hypersensitivity
    Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...

     to alefacept or to any other ingredient of the preparation
  • Caution: There is little experience in geriatric patients (65 years of age or older); so far no differences to the younger age group have been noted.

Pregnancy and lactation

  • Alefacept has been assigned to Pregnancy Category B in the US and to C in Australia.
  • Lactation : It is not known if the drug is excreted into human milk. Either the drug or breastfeeding
    Breastfeeding
    Breastfeeding is the feeding of an infant or young child with breast milk directly from female human breasts rather than from a baby bottle or other container. Babies have a sucking reflex that enables them to suck and swallow milk. It is recommended that mothers breastfeed for six months or...

     should be terminated, taking into account the importance of treatment to the mother.

Pediatric patients

No clinical experience exists in patients under 18 years of age. The drug should therefore not be used in pediatric patients.

Side effects

  • Lymphopenia : Most common in clinical trials was a significant and dose-related reduction of CD4+ and CD8+ counts in 10 to 59% of patients. However, only 0 to 2% of patients experienced reductions below the accepted lower limit. Consequences of lymphopenia may be infections and/or treatment related malignancies (see below).
  • Malignancies : In clinical studies among 1,869 patients 63 treatment-emerged malignancies in 43 patients were observed. Most of these were nonmelanoma and 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...

     skin cancer
    Skin cancer
    Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...

    s, other solid tumors, and 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...

    s.
  • Infections : In clinical studies 0.9% of patients experienced significant infections compared to 0.2% in the placebo group. Among the infections were serious ones such as sepsis
    Sepsis
    Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

    , pneumonia
    Pneumonia
    Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...

    , abscess
    Abscess
    An abscess is a collection of pus that has accumulated in a cavity formed by the tissue in which the pus resides due to an infectious process or other foreign materials...

    es, wound infections and toxic shock syndrome
    Toxic shock syndrome
    Toxic shock syndrome is a potentially fatal illness caused by a bacterial toxin. Different bacterial toxins may cause toxic shock syndrome, depending on the situation. The causative bacteria include Staphylococcus aureus and Streptococcus pyogenes...

    .
  • Sensitivity reactions: Urticaria
    Urticaria
    Urticaria is a kind of skin rash notable for pale red, raised, itchy bumps. Hives is frequently caused by allergic reactions; however, there are many non-allergic causes...

     and angioedema
    Angioedema
    Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...

     were observed. If an anaphylactic reaction should occur symptomatic treatment should be initiated at once.
  • Forming of 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 alefacept : About 3% of patients developed low-titer antibodies with unknown importance for the clinical efficiency of the drug. Long-term immune effects have not been well explored.
  • Hepatic Toxicity : Postmarketing reports revealed asymtomatic increases in transaminases (ALT
    Alanine transaminase
    Alanine transaminase or ALT is a transaminase enzyme . It is also called serum glutamic pyruvic transaminase or alanine aminotransferase ....

     and/or AST
    Aspartate transaminase
    Aspartate transaminase , also called aspartate aminotransferase or serum glutamic oxaloacetic transaminase , is a pyridoxal phosphate -dependent transaminase enzyme . AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in...

    ), fatty liver degeneration, decompensation of preexisting liver cirrhosis, and acute treatment-related liver failure
    Liver failure
    Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...

    . It is not known if some or all of these manifestations are attributable to alefacept-therapy, but it is recommended to discontinue therapy as soon as any sign of liver toxicity develops.
  • Different Common Side Effects : side effects such as pharyngitis
    Pharyngitis
    Pharyngitis is an inflammation of the throat or pharynx. In most cases it is quite painful, and is the most common cause of a sore throat.Like many types of inflammation, pharyngitis can be acute – characterized by a rapid onset and typically a relatively short course – or chronic....

    , cough
    Cough
    A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes...

    , dizziness
    Dizziness
    Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

    , 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...

    , pruritus, myalgia
    Myalgia
    Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...

    s, chills
    Rigor (medicine)
    Rigor is a shaking occurring during a high fever. It occurs because cytokines and prostaglandins are released as part of an immune response and increase the set point for body temperature in the hypothalamus....

    , and reactions at injection sites were observed quite frequently.

Interactions

  • Patients currently undergoing immunosuppressive therapy (phototherapy, or concomitant application of other immunosuppressant agents) should not receive alefacept in order to avoid the risks of excessive immunosuppression. Studies concerning the combination with cyclosporine or methotrexate
    Methotrexate
    Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

     are conducted, but no results have been published so far.
  • Live vaccines : The efficiency of concomitant application of live vaccine
    Vaccine
    A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

    s has not been fully examined yet. However, the effect of tetanus
    Tetanus
    Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...

     toxoid
    Toxoid
    A toxoid is a bacterial toxin whose toxicity has been weakened or suppressed either by chemical or heat treatment, while other properties, typically immunogenicity, are maintained. In international medical literature the preparation also is known as Anatoxin or Anatoxine...

     was well preserved in clinical trials.

Necessary laboratory examinations

  • CD4+ cell counts should be obtained before initiation of therapy and during the 12-week course of therapy in intervals of 2 weeks.
  • It may be desirable to monitor liver function studies
    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...

    (AST and ALT) in patients at high risk to develop liver toxicity (e.g., preexisting hepatitis, or high daily consumption of alcohol).

Dosage regimes

The standard dosage regime is the weekly application of either 7.5 mg IV or 15 mg IM for a course of 12 weeks. The benefits and risks of repeated courses have not been explored in sufficient detail. Therapy should be conducted under the supervision of a physician experienced in the use of immunosuppressant agents.
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