Alefacept Effective, Well Tolerated for Plaque Psoriasis
Alefacept given weekly by intramuscular injection is effective and well tolerated for the treatment of plaque psoriasis, according to the results of an international, double-blind, randomized trial published in the June issue of the Archives of Dermatology. The editorialist suggests that this and future immunobiologicals will change the practice of dermatology.
"It is now becoming clear that psoriasis is probably an autoimmune disease, with activation of skin-directed T cells playing a major role," write Mark Lebwohl, MD, from the Mount Sinai School of Medicine in New York City, and colleagues from the Alefacept Clinical Study Group. "To avoid the tolerability issues associated with generalized immunosuppression, newer strategies for the treatment of psoriasis have focused on selectively targeting the T cells implicated in the pathogenesis of the disease."
Alefacept is a human lymphocyte function-associated antigen 3/immunoglobulin 1 fusion protein. By binding to CD2 molecules on the surface of activated T cells, it selectively targets memory-effector (CD45RO +) T cells, which make up more than 75% of T cells in psoriatic plaques.
In this parallel-group trial, 507 patients with chronic plaque psoriasis were randomized to receive once-weekly intramuscular injection of 10 mg alefacept, 15 mg alefacept, or placebo for 12 weeks followed by 12 weeks of observation.
In a dose-related fashion, alefacept treatment was associated with significant improvements from baseline in the Psoriasis Area Severity Index (PASI). Throughout the study, a higher percentage of patients in the 15-mg group than in the placebo group had a significant reduction in PASI.
Of patients in the 15-mg group in whom PASI decreased by at least 75% two weeks after the last dose, 71% maintained at least 50% improvement in PASI throughout the 12-week follow-up. No patients developed opportunistic infections or had evidence of disease rebound.
"Intramuscular administration of alefacept was a well-tolerated and effective therapy for chronic plaque psoriasis and thus represents a convenient alternative to intravenous dosing," the authors write. "[It] effectively improves psoriasis and produces durable remissions without appearing to compromise normal immune function.... Patients receiving alefacept may experience prolonged, disease-free intervals with less need for maintenance therapy and potentially fewer retreatment periods."
Biogen Inc. supported this research, data monitoring, and analysis. The authors have served as investigators for Biogen, and Dr. Lebwohl is a consultant for Biogen.
In an accompanying editorial, Alice Gottlieb, MD, PhD, from the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School in New Brunswick, notes that safe and effective long-term management for moderate to severe psoriasis poses a special challenge. However, the discovery that psoriasis is an immune-mediated disease has led to a "renaissance in drug development."
Dr. Gottlieb writes, "Immunobiologic agents offer the hope for safe, long-term control of psoriasis because they lack targeted organ toxic effects. The long-lived remissions observed after cessation of treatment with alefacept or infliximab (anti-tumor necrosis factor [TNF]-alpha monoclonal antibody) lead me to speculate that these immunobiologic agents may actually alter the natural history of the cutaneous manifestations of psoriasis.... These and future immunobiologic agents will change the practice of dermatology in a number of ways."
The David Ju Foundation, Johnson & Johnson's Focused Giving Program, and Merck & Co Inc. funded this work in part. Dr. Gottlieb is an investigator, consultant, and speaker bureau member for Biogen, Amgen, Wyeth, Novartis, and Centocor Inc., and a consultant and investigator for Genentech Inc. and Xoma Corp.
Arch Dermatol. 2003;139:719-727, 791-793
Psoriasis is one of the most common chronic skin diseases and can produce symptoms for decades. Its prevalence in the general population is around 2.5%, according to a study by Christophers in the June 2001 issue of Clinical & Experimental Dermatology, and the severity of disease ranges from mild skin irritation to plaques and rashes that can limit activities of daily living. In one cohort of patients with psoriasis reviewed by Krueger and colleagues in the March 2001 issue of the Archives of Dermatology, 8% to 10% of psoriasis patients contemplated suicide because of the severity of their symptoms and their impact on the patients' quality of life.
There is new hope for patients with psoriasis as more is understood about the disease's pathophysiology. It appears that psoriasis is a T-cell modulated immune disorder. After an initial exposure to an as-yet-undetermined antigen occurs, memory T cells are stored in lymph tissue. They can remain latent for years before a secondary event triggers their migration to the skin, where they stimulate the release of cytokines. It is these proteins that directly mediate the inflammation associated with psoriasis.
Treatments available to ameliorate this inflammatory process include topical corticosteroids, coal tar, vitamin D analog creams, and phototherapy. In recent years, immune modulating agents such as methotrexate and cyclosporine have been employed to target T-cell function directly and help patients with psoriasis. This therapy has been limited by the toxic effects and/or inconvenience of use of these agents, as emphasized in the editorial by Gottlieb that accompanies the current study.
Alefacept is a recombinant biologic protein that limits T-cell activation and proliferation while also producing selective T-cell apoptosis. In a study by Ellis and colleagues in the July 26, 2001, issue of the New England Journal of Medicine, alefacept treatment over a 12-week period produced significant improvement in the symptoms of psoriasis. The authors of the current study sought to determine the efficacy and safety of alefacept during a placebo-controlled active 12-week treatment period followed by a 12-week follow-up period without treatment.
- Patients selected were at least 18 years old with a history of chronic plaque psoriasis. Patients with other types of psoriasis were excluded from participation. Recruitment took place at 64 centers in the U.S., Europe, and Canada.
- Subjects were randomized to one of three groups: weekly intramuscular injection with 10 mg of alefacept, 15 mg of alefacept, or placebo.
- Patients were evaluated weekly with severity scales for psoriasis during the active treatment period of 12 weeks as well as every 2 weeks during a 12-week follow-up period. Laboratory values and rates of infection and new malignancy were also followed during this time. Dermatologists following the patients were blinded to treatment type.
- 168 participants were randomized to the placebo group, 173 to the 10 mg alefacept group, and 166 to the 15 mg alefacept group. Most patients had moderate to severe psoriasis at the outset of the study. Average disease duration was 19 years; 27% had not received prior systemic therapy for psoriasis.
- Both alefacept groups had reduced scores of psoriasis severity compared with the placebo group, but there was no significant difference between the 10- and 15-mg dose of alefacept. The greatest efficacy of alefacept was at 6 weeks' after active treatment. The maximum mean improvement in psoriasis severity was 46%, 41%, and 25% in the 15 mg alefacept group, 10 mg alefacept group, and placebo group, respectively.
- Rates of participants achieving >75% reduction in psoriasis severity were 33%, 28%, and 13% in the 15 mg alefacept group, 10 mg alefacept group, and placebo group, respectively.
- Improvement in psoriasis severity was sustained after the treatment terminated, but all groups were trending back toward baseline by the end of the 24-week study. Of the subjects in the 15 mg alefacept group who had >75% reduction in psoriasis severity, 74% maintained a >50% reduction in severity by the end of the study period. No post-treatment flares of psoriasis after treatment with alefacept were noted.
- Participants naïve to systemic therapy and those with more severe disease had stronger improvements with alefacept.
- Adverse events reported in the alefacept groups more often than in the placebo group included headache, pruritus, infection, rhinitis, injection site pain, and injection site inflammation.
- Infection rates were slightly higher in the alefacept groups, with common colds being by far the most common infection. Only 2 cases of CD4 counts < 250 cells/µl were noted in alefacept groups; both of these patients had colds.
- Serious adverse events were rare, and rates of these events were comparable among the study groups. No malignancies were noted during the study period, although the study period was too short to detect long-term consequences of alefacept therapy.
- No difference in blood chemistry profiles were noted between alefacept and placebo.
- Psoriasis appears to be an inflammatory skin condition mediated by T-cell activation.
- Alefacept is a safe treatment for moderate to severe chronic plaque psoriasis. It is effective when given weekly for 12 weeks, and alefacept may prove to be a means to control psoriasis with intermittent therapy.