Alefacept: An Overview

Overview

Alefacept is the first biological agent approved by the United States Food and Drug Administration (USFDA). It is a recombinant fusion protein (CD2-directed LFA-3/Fc) used to treat moderate to severe stages of plaque psoriasis (dry, itchy, and scaly patches on the skin) in adult patients who are recommended systemic therapy or phototherapy (uses light to treat skin). The FDA approved it in May 2003. It is an immunosuppressant drug and must be given only under the supervision of a doctor.

What Is Alefacept?

Alefacept is a prescription drug used to treat moderate to severe psoriasis with plaque formation. It is a genetically engineered immunosuppressant medication administered to patients who have not found any improvement in their condition from other medicines. This medicine must be given only by or under the supervision of a doctor. Alefacept is a protein that affects the immune system and decreases plaque or dead skin cells.

How Does Alefacept Work?

Alefacept is a genetically engineered immunosuppressive drug belonging to the class of biological response modifiers called T-cell blockers. It binds to the CD2 (cluster of differentiation) receptors on the T-cells and acts by blocking the T-cell activation and proliferation. This prevents the T cells from releasing cytokines, which are primarily responsible for inflammation, redness, itching, and flaky skin patches in psoriasis. Alefacept also causes apoptosis of memory-effector T-cells since these are involved in the inflammation that characterizes psoriasis. This dual mechanism of action facilitates the improvement of chronic plaque psoriasis, especially in less severity and its progression over a period of time.

What Are the Indications of Alefacept?

• Alefacept is indicated in the management of moderate to severe stages of chronic plaque psoriasis in adult patients who are advised systemic therapy or phototherapy.

• Patients who cannot take classic corticosteroids for a long time due to the side effects, which include osteoporosis (decrease in bone mass), peptic ulcer (sore in the stomach), and emaciation (state of being abnormally weak).

• Patients with psoriasis-like conditions may benefit from combined treatment with phototherapy or other systemic agents that provide better control of chronic plaque psoriasis.

What Are the Contraindications of Alefacept?

• Alefacept is contraindicated in patients with HIV (human immunodeficiency virus) infections as it reduces the CD4+T lymphocyte counts and might accelerate the disease progression or increase the complications of the disease in the patients.

• It is also contraindicated in patients with hypersensitivity to Alefacept or other composition ingredients.

What Is the Dosage of Alefacept?

• Alefacept is recommended at a dose of 15 mg (milligram) to be administered intramuscularly once a week for 12 weeks. The CD4+ T lymphocyte counts must be determined before initiating the treatment, and it must be monitored every two weeks throughout the dosing regimen.

• Alefacept must not be administered if the CD4+ T lymphocyte counts are below normal. If the count is below 250 cells/microliter, Alefacept must be withheld, and weekly monitoring must be considered. Alefacept must be discontinued if the counts remain less than 250 cells/microliter for one month.

• An additional 12-week course may be considered if at least 12 weeks have passed since the previous treatment regimen and CD4+ counts are normal.

• Missed dose - When the scheduled dose is missed, inform the healthcare provider immediately and schedule the next dosage according to the physician’s guidance. Avoid self-medication.

• Overdose - As the drug is administered under professional supervision, chances of overdose are minimal. However, beware of the side effects of overdose, such as hypersensitivity reactions, nausea, or itching, and seek medical advice as soon as possible if any of the early signs are encountered.

What Are the Drug Warnings and Precautions?

• Alefacept can cause hypersensitivity reactions, such as urticaria (an itchy rash) and angioedema (swelling under the skin). Therefore, if any anaphylactic reaction is observed, Alefacept must be discontinued immediately, and appropriate treatment must be considered.

• Alefacept is an immunosuppressive agent and can increase the risk of infection or may reactivate latent chronic infections. Therefore, it must not be administered in patients with clinically significant infections, and care must be taken while using the drug in patients with a history of chronic or recurrent infections. Patients must be closely monitored during the treatment with Alefacept, and if any serious infections develop, the drug must be discontinued.

• Clinical studies have suggested that Alefacept is associated with the risk of malignancies (cancers); hence, caution must be exercised when considering Alefacept in patients with a high risk of malignancies, and the drug must be discontinued if the patient develops a malignancy.

• Alefacept can reduce the circulating CD4+ and CD8+ T lymphocyte counts. CD4+ counts must be normal before treatment is initiated and must be monitored throughout it.

• Patients with signs and symptoms of liver injury must be completely evaluated, and the drug must be discontinued if the patients develop any signs of liver injury.

• Patients receiving treatment with other immunosuppressive agents or phototherapy must not receive concurrent therapy with Alefacept due to the possibility of excessive immunosuppression.

What Are the Adverse Effects of Alefacept?

Some of the serious adverse reactions include;

• Hypersensitivity reactions.

• Serious infections requiring hospitalization.

• Lymphopenia (reduced white blood cells).

• Malignancies.

• Hepatotoxicity (liver damage).

Some of the common side effects include;

• Injection site reactions.

• Nausea.

• Chills.

• Dizziness.

• Pharyngitis (inflammation of the pharynx).

• Cough.

• Pruritus (itchy skin).

• Myalgia (muscle pain).

For Patients

How Is Alefacept Given?

Alefacept is given intramuscularly (into the muscle) under the supervision of a doctor. This is followed by a two-week observation period. A second course can be administered at any time after the observation period. The interval period between the treatments can be extended if patients follow topical therapy for the management of psoriasis.

What Are the Risk Factors of Alefacept?

• During the treatment with Alefacept, the doctor recommends frequent blood tests to monitor the T-lymphocyte counts (white blood cells).

• As Alefacept is an immunosuppressant drug, patients are more prone to infections, especially those with a risk of chronic or recurrent infections.

• Alefacept is associated with the risk of malignancies; hence, patients must inform the doctor immediately if they notice any symptoms of malignancies.

• Hypersensitivity reactions may occur during the treatment with Alefacept; hence, patients must inform the doctor immediately if they notice symptoms such as nausea, vomiting, loss of appetite, jaundice, abdominal pain, facial swelling, fatigue, easy bruising, dark urine, pale stools, etc.

• Immunizations or vaccinations must not be taken during the treatment with Alefacept without the consent of the doctor.

What Must the Patient Inform the Doctor Before Taking Alefacept?

• If the patient is allergic to or has a history of hypersensitivity reactions to any medications, including Alefacept or its ingredients, the doctor must be informed before treatment is initiated.

• If the patient is suffering from any medical conditions such as HIV, liver diseases, chronic infections, etc., the doctor must be informed before the treatment.

• Female patients should inform the doctor if they are pregnant or planning to become pregnant or breastfeeding before initiating treatment with Alefacept. Female patients must also inform the doctor if they become pregnant within eight weeks of discontinuing Alefacept.

• Before the initiation of treatment with Alefacept, the doctor must be informed if the patient is taking any other medications, herbal or vitamin supplements, over-the-counter medicines, etc.

What Are the Side Effects of Alefacept?

Some of the common side effects include;

• Fever.

• Chills.

• Cough.

• Hoarseness.

• Lower back pain.

• Pain and difficulty in urination.

Less common side effects include;

• Runny nose.

• Difficulty in swallowing.

• Congestion.

• Body ache.

• Sore throat.

• Swollen and tender glands in the neck.

• Some of the rare side effects include;

• Pain or discomfort in the arms, jaw, neck, and back.

• Nausea and vomiting.

• Sweating.

• Chest pain, discomfort, or chest tightness.

• Fast or irregular heartbeat.

For Doctors

Description

Alefacept is a CD2-directed fusion protein that consists of a CD-2 binding protein of the human leukocyte function antigen-3 (LFA-3), which is linked to the Fc portion of the human immunoglobulin IgG1. It is manufactured using recombinant DNA technology and is supplied as a clear, sterile, preservative-free lyophilized powder for intramuscular injection. A 0.5 ml (milliliters) reconstituted solution contains the following ingredients;

• Alefacept -15 mg.

• Glycine - 5 mg.

• Citric acid monohydrate - 0.06 mg.

• Sodium citrate dihydrate - 3.6 mg.

• Sucrose -12.5 mg.

What Is Clinical Pharmacology?

Mechanism of Action

Alefacept is a dimeric human fusion protein that acts by interfering with the CD2 receptor located on T-cells, thus inhibiting the interaction between CD2 and ligand LFA-3/CD2 (lymphocyte function-associated antigen). This blocks the activation of CD4+ and CD8+ cells. It also induces apoptosis of effector memory T-cell subsets, thus depleting them.

Pharmacodynamics

During clinical trials, it was observed that Alefacept therapy resulted in a dose-dependent reduction in the circulating lymphocytes, which predominantly affected the effector memory T cell subsets, CD4+, and CD8+ compartments (the predominant phenotypes in psoriatic lesions). The circulating T lymphocytes and natural killer cell counts were minimally susceptible to Alefacept, while the circulating B lymphocytes appeared to be not affected by Alefacept therapy.

Pharmacokinetics

Administration of 7.5 mg Alefacept to patients suffering from moderate or severe plaque psoriasis showed a mean volume of distribution of 94 mL/kg (milliliter per kilogram), and the mean clearance was 0.25 mL/h/kg. The mean half-life of Alefacept was approximately 270 hours. After an intramuscular administration, the bioavailability was around 63 percent.

What Are the Drug Interactions?

• Drug interaction studies have not been performed with regard to Alefacept, and the safety of Alefacept in combination with other immunosuppressive agents or phototherapy has also not been evaluated.

• However, frequent dose monitoring or individual dose adjustments are required in patients treated with Alefacept and CYP450 substrates with a narrow therapeutic index.

• No live vaccines should be taken at the same time as Alefacept because it may affect the effectiveness of the vaccines and lead to severe infections.

• It also increases the risk of infection or neoplasia by co-administering Alefacept with other immunosuppressive drugs.

Clinical Trials

Two randomized, placebo-controlled, double-blind trials were conducted in those adults suffering from plaque psoriasis for more than a year and with a minimum involvement of ten percent of the body surface area. Individuals included in the studies had previously received either systemic therapy or phototherapy as a part of their treatment. A 7.5 mg bolus dose of Alefacept was administered intravenously (study 1) or intramuscularly (study 2), and the control group was administered a placebo. The participants could receive low-potency steroids topically, but concomitant administration of phototherapy or systemic therapy was not allowed.

In study 1, the total number of patients included was 553; they received two courses of Alefacept administered at an interval of 12 weeks. In study 2, 10 or 15 mg of Alefacept was administered intramuscularly. The treatment response was assessed using the reduction in psoriasis area and severity index (PSAI) of 75 percent, at least from the baseline after a period of 12 weeks. In Study 1, the median duration to response was almost 3.5 months after a course of therapy and was one month for the individuals in the placebo-treated group. In study 2, the number of responders was higher in the intervention group, receiving a 10 mg intramuscular dose compared to the placebo.

Nonclinical Toxicology

• In the toxicity studies conducted in two groups of Cynomolgus monkeys, intravenous Alefacept was administered at the dose of 1 mg/kg/dose and 20 mg/kg/dose weekly for 52 weeks. B-cell lymphoma was observed in one animal from the high-dose group after 28 weeks of dosing, and some animals in both groups developed B-cell hyperplasia of the lymph nodes and spleen. After one year post-treatment, there was no evidence of lymphoma or B-cell hyperplasia related to Alefacept in any of the remaining treated monkeys.

• Formal carcinogenicity studies and fertility studies have not been conducted with regard to Alefacept.

• No evidence of mutagenicity was observed in the in vitro and in vivo tests.

Use of Alefacept in Specific Populations

• Pregnancy: Adequate and well-controlled studies of Alefacept have not been performed in pregnant women.

• Nursing Mothers: It is not known whether Alefacept is excreted in human milk. However, as many drugs can pass into the breast milk, it may cause adverse reactions to the infant. Hence, a decision must be made whether to discontinue breastfeeding or the drug.

• Pediatric Use: Research on Alefacept safety and effectiveness in children has not occurred.

• Geriatric Use: The clinical trials conducted with Alefacept failed to establish differences between treatment responses from older and younger testers. Doctors should apply caution during Alefacept treatment for elderly patients because the drug entails a high risk of developing malignancies.