Alefacept for the treatment of psoriasis: a review of the current literature and practical suggestions for everyday clinical use

Alefacept is the first biologic therapy approved by the United States Food and Drug Administration for the management of patients with moderate-to-severe chronic plaque psoriasis. Alefacept is a fully human fusion protein with a dual mechanism of action inhibiting T-cell activation as well as selectively reducing memory T cells. More than 2000 psoriasis patients have been treated with alefacept in clinical trials. These studies reveal an excellent clinical response, with 33% of patients achieving a Psoriasis Area Severity Index (PASI) score of 75 and 57% of patients achieving a PASI 50 after one course of alefacept. Patients achieving both PASI 75 and PASI 50 have significant improvements in their quality of life. The best responders can have long remissions, and there is a tendency toward continued improvement with subsequent courses of alefacept. The safety profile over the short and intermediate term is excellent. Preliminary data regarding alternate dosing regimens, transitioning patients from conventional systemics to alefacept, and combining alefacept with ultraviolet light therapy will be highlighted. We also will discuss our practical approach to patient selection, CD4 monitoring, management of infections while on alefacept, as well as decisions regarding retreatment and combination therapy.     

Alefacept

black triangle Alefacept (recombinant human LFA-3/IgG(1) fusion protein) is a novel biologic agent that selectively targets memory-effector CD45RO+ T lymphocytes, implicated in psoriasis pathogenesis. black triangle In placebo-controlled studies, once-weekly administration of alefacept 7.5mg intravenous (IV) and 15mg intramuscular (IM) for 12 weeks significantly improved psoriasis and produced durable clinical improvements in patients with moderate-to-severe chronic plaque psoriasis who responded. black triangle At any time during the first 12-week course of alefacept (followed by 12 weeks' treatment-free follow-up), approximately 30% of patients achieved the primary endpoint of a > or =75% improvement in psoriasis, while approximately 55% achieved a > or =50% improvement; the corresponding results during a second course were approximately 40% and 70%, respectively. black triangle Alefacept therapy significantly improved quality of life in responders, who reported improved perception of overall health, increased energy levels, and enhanced emotional well-being. black triangle One or two 12-week courses of IV alefacept 7.5 mg/week and IM alefacept 15 mg/week were similarly well tolerated, with a safety/tolerability profile similar to placebo. No organ-based toxicity or disease rebound after alefacept withdrawal has been reported. black triangle Alefacept exhibits a low potential for immunogenicity and has no clinical effects indicative of generalized immunosuppression. No opportunistic infections have been reported, nor is there evidence of an increased risk of malignancies.     

Alefacept therapy produces remission for patients with chronic plaque psoriasis

BACKGROUND: Alefacept, human LFA-3/IgG1 fusion protein, is a novel biological agent currently being developed for the treatment of chronic plaque psoriasis. Alefacept selectively reduces the memory-effector T cells that have been implicated in the pathogenesis of the disease; as a result, alefacept is classified as a therapy that induces remission (so-called 'remittive' therapy). In a previously published randomized, placebo-controlled phase II study of intravenous alefacept in 229 patients with chronic plaque psoriasis, clinical improvement was observed during dosing as well as in the postdosing follow-up period. OBJECTIVES: To assess the remission period following alefacept therapy. METHODS: The time before re-treatment was required was measured in patients who were 'clear' or 'almost clear' of disease according to a physician global assessment at the end of the follow-up phase. RESULTS: In these patients, responses were sustained for a median of 10 months, and for up to 18 months. No patient reported disease rebound after cessation of alefacept. CONCLUSIONS: Alefacept is a biological agent for the treatment of chronic plaque psoriasis that provides disease-free intervals and time off drug therapy.     

A randomized,double-blind,placebo-controlled phase III study evaluating efficacy and tolerability of 2 courses of alefacept in patients with chronic plaque psoriasis

BACKGROUND: In previous phase II studies, alefacept significantly improved psoriasis and was well tolerated. The clinical response to alefacept was durable. OBJECTIVE: Our purpose was to further evaluate efficacy and tolerability of alefacept in a phase III study of patients (n = 553) with chronic plaque psoriasis. METHODS: Two 12-week courses of once-weekly intravenous alefacept 7.5 mg or placebo were given in a randomized double-blind study; patients were followed up for 12 weeks after each course. RESULTS: During treatment and follow-up of course 1, a 75% or greater reduction in the Psoriasis Area Severity Index (PASI) was achieved by 28% of alefacept-treated and 8% of placebo-treated patients (P <.001). Patients who received a single course of alefacept and achieved a 75% or greater reduction from baseline PASI during or after treatment, without the use of phototherapy or systemic therapies, maintained a 50% or greater reduction in PASI for a median duration of more than 7 months. Among patients who received 2 courses of alefacept, 40% and 71% of patients achieved a 75% or greater and 50% or greater reduction in PASI, respectively, during the study period. Alefacept was well tolerated over both courses. In course 1, the incidence of transient chills was higher in the alefacept group compared with the placebo group; more than 90% of cases occurred within 24 hours after the first few doses. CONCLUSION: Alefacept significantly improved psoriasis and produced durable clinical improvements among patients who responded. A second course of alefacept increased efficacy and was equally well tolerated.     

The Remittive Effects of Alefacept

The duration of response to treatment with alefacept has been assessed in patients with moderate to severe chronic plaque psoriasis who responded to alefacept therapy in phase 2 and phase 3 clinical studies. In a phase 2 trial, duration of response was based on time to retreatment with alefacept. In two phase 3 studies, the more objective measure of maintenance of a ≥50% reduction from baseline Psoriasis Area and Severity Index (PASI 50) was used. Two patient subsets were analyzed: (1) those who achieved a PASI 75 at any time during the trials and (2) those who achieved a Physician Global Assessment of “clear” or “almost clear” at any time during the trials. Regardless of the criterion used or the route of alefacept administration (intravenous or intramuscular), the median duration of response to alefacept therapy ranged from 7 to 10 months across the three studies. Alefacept is a remittive therapy for psoriasis.     

The remittive effects of alefacept

The duration of response to treatment with alefacept has been assessed in patients with moderate to severe chronic plaque psoriasis who responded to alefacept therapy in phase 2 and phase 3 clinical studies. In a phase 2 trial, duration of response was based on time to retreatment with alefacept. In two phase 3 studies, the more objective measure of maintenance of a > or =50% reduction from baseline Psoriasis Area and Severity Index (PASI 50) was used. Two patient subsets were analyzed: (1) those who achieved a PASI 75 at any time during the trials and (2) those who achieved a Physician Global Assessment of "clear" or "almost clear" at any time during the trials. Regardless of the criterion used or the route of alefacept administration (intravenous or intramuscular), the median duration of response to alefacept therapy ranged from 7 to 10 months across the three studies. Alefacept is a remittive therapy for psoriasis.     

Alefacept for the treatment of psoriasis and other dermatologic diseases

Alefacept is a novel biologic agent for the treatment of plaque psoriasis. Alefacept is a fully human recombinant dimeric fusion protein composed of the terminal portion of Leukocyte Functioning Antigen-3 (LFA-3) and the Fc portion of human IgG(1). The drug likely works in part by inducing the apoptosis of memory effector (activated) T cells that play a central role in the pathophysiology of psoriasis. Alefacept also may interrupt the direct immunologic activation of T cells by antigen presenting cells. Alefacept is administered as a course of 12 intramuscular injections, but other dosing strategies have been explored. After a course of therapy, statistically more patients receiving alefacept achieve a psoriasis area and severity index (PASI) 75 response than those receiving a placebo. Some patients who achieve PASI 75 also experience long-term remissions from psoriasis. The drug is well-tolerated and adverse events are rare. Off-label use of the drug is growing and may be formally explored in the future.     

An open-label study of alefacept plus ultraviolet B light as combination therapy for chronic plaque psoriasis

BACKGROUND: Alefacept, a fully human LFA-3/IgG(1) fusion protein, is a selective biological agent approved in the United States for the treatment of chronic plaque psoriasis. In phase 3 trials, clinical improvement and prolonged off-treatment remission of psoriasis correlated with reductions in circulating memory T cells. Reductions in pathogenic epidermal T cells in psoriatic lesions also have been noted following phototherapy with ultraviolet B (UVB) light. Because alefacept and UVB target T cells in different ways, combination therapy with these two agents may lead to greater efficacy. OBJECTIVES: To determine the safety, tolerability, and efficacy trends of combination therapy with alefacept plus UVB light in patients with chronic plaque psoriasis. METHODS: In an open-label, parallel-group study conducted at two sites, one in France and one in the United States, patients with chronic plaque psoriasis who were candidates for phototherapy received 12-weekly intramuscular injections of alefacept, 15 mg. In addition, patients were randomized to one of three treatment arms: no UVB treatment, 6-week UVB treatment, and 12-week UVB treatment. UVB treatment consisted of narrowband (NB) UVB at the site in France and broadband (BB) UVB at the site in the United States. The 12-week treatment period was followed by a 12-week follow-up period. Clinic visits occurred weekly during treatment and every 2-4 weeks during follow-up. RESULTS: A total of 60 patients (n = 30/site) were enrolled in the study. Alefacept was well tolerated when administered in combination with UVB treatment and as monotherapy. There was no evidence of increased phototoxicity or photosensitivity with the combination. At each study site, alefacept/UVB provided a higher overall response rate and led to a more rapid onset of response compared with alefacept monotherapy. Of patients who achieved > or = 50% reduction from baseline Psoriasis Area Severity Index (PASI 50) at 2 weeks after the last dose of alefacept, 75-100% in the combination therapy groups maintained this response throughout follow-up in the absence of further psoriasis therapy. CONCLUSIONS: In patients with chronic plaque psoriasis, combination therapy with alefacept plus short-term (6-12 weeks) UVB treatment is well tolerated with a trend toward greater and more rapid efficacy than alefacept alone.     

Treatment of psoriasis with alefacept in patients with hepatitis C infection: a report of two cases

Alefacept is a fully human fusion protein for use in adult patients with moderate to severe chronic plaque psoriasis. Its dual mechanism of action involves inhibition of T-cell activation and selective reduction of memory T cells. We report the clinical course of two patients with hepatitis C virus (HCV) infection who have received alefacept for psoriasis. Consistent with its mechanism of action, administration of alefacept led to transient decreases in CD4+ and CD8+ T-cell counts. However, these reductions were not associated with an increase in HCV viral load or exacerbation of infection. Liver enzymes remained stable throughout the treatment and follow-up periods. Alefacept has a selective mechanism of action that specifically targets memory T cells and this selectivity may account for its safety and tolerability in patients with hepatitis.     

Alefacept is well tolerated in patients with chronic plaque psoriasis

Traditional systemic treatments for moderate to severe chronic plaque psoriasis are often poorly tolerated and are associated with safety concerns that restrict their long-term use. Alefacept is a fully human fusion protein that selectively targets memory T cells, and it is expected to provide enhanced safety over traditional nonselective agents. The safety and tolerability profile of alefacept is reviewed using data from the clinical development program. The most common adverse events were similar among alefacept and placebo groups. As expected from its mechanism of action, alefacept reduced the number of CD4(+) and CD8(+) T cells, with selectivity for the memory subsets. This reduction was not associated with an increase in the incidence of infections. Alefacept was not immunogenic. Patients have received up to 6 courses of alefacept therapy and the safety and tolerability profile over multiple courses is similar to that of a single course. Alefacept offers hope for a safer means to provide long-term management of psoriasis.     

Alefacept is safe and efficacious in the treatment of palmar plantar pustulosis

BACKGROUND: Alefacept blocks T-cell activation and induces apoptosis of memory T cells. It improves psoriasis vulgaris and may induce prolonged remissions. Experience with alefacept in palmar plantar pustulosis (PPP) is limited. OBJECTIVE: The objective of the study was to observe the effectiveness and safety of alefacept in the treatment of PPP. METHODS: Alefacept was administered weekly for 16 weeks by intramuscular (IM) injection of 15 mg to 15 patients with moderate to very severe PPP. Patients were followed for an additional 12 weeks. RESULTS: Four weeks after 16 weeks of treatment, there was a 49.6% reduction in the Palmoplantar Pustulosis Psoriasis Area and Severity Index (PPPASI) and a 38.6% and a 64.5% reduction in total and fresh pustules, respectively. Eight weeks after dosing, 53.3% achieved PPPASI 50, 26.7% achieved PPPASI 75, and one patient was clear. The mean percent reduction in total pustules and fresh pustules was 46.1% and 61.2%, respectively; 73% had no pain, 53% had no itching, and 80% had no functional impairment. The palms responded better than the soles. CONCLUSIONS: This pilot showed that 16 weeks of once-weekly alefacept 15 mg IM was safe, led to improvement in PPP in all 15 treated patients, and induced a remission in one patient. Larger double-blind studies are warranted.     

Open-label, single-center, safety dose escalation trial of alefacept for the treatment of moderate to severe chronic plaque psoriasis

BACKGROUND: Alefacept (Amevive) is a fully human LFA-3/IgG1 fusion protein with a dual mechanism of action inhibiting T-cell activation and selectively reducing memory T cells. Alefacept is currently approved as a 12-week course of weekly 15 mg intramuscular (IM) injections for the treatment of adults with moderate to severe chronic plaque psoriasis. In clinical trials using the currently approved dosing regimen, 33% and 57% of patients achieved a 75% or greater or 50% or greater reduction in Psoriasis Area and Severity Index score (PASI 75 and PASI 50), respectively, after one course of alefacept. OBJECTIVE: To evaluate the tolerability and efficacy of alefacept 15 mg IM weekly for 6 weeks followed by alefacept 30 mg IM weekly for 6 weeks. DESIGN: Open-label, single-center, dose escalation study of alefacept. PATIENTS: Adult patients with chronic plaque psoriasis involving a minimum body surface area of 10% and with a minimum PASI of 12. INTERVENTION: Patients were treated with alefacept 15 mg IM for 6 weeks followed by alefacept 30 mg IM for an additional 6 weeks; doses were held for CD4 counts < 200 cells/mm(3) or evidence of a clinically significant infection. MAIN OUTCOME MEASURE: Efficacy was evaluated by PASI and Physician Global Assessment (PGA) at baseline, week 7, and 2, 6, 12, and 24 weeks post-treatment. RESULTS: Sixteen patients were enrolled; at 6 weeks post-treatment, the PASI mean reduction was 39%, with continued improvement to 46% at 12 weeks post-treatment. The PASI 90, PASI 75, and PASI 50 responses at 12 weeks post-treatment were 6% (1 of 16), 13% (2 of 16), and 38% (6 of 16), respectively; 12% (2 of 16) of patients achieved a PGA of clear to almost clear at 12 weeks post-treatment. The overall PASI 75 and PASI 50 responses were 19% (3 of 16) and 38% (6 of 16), respectively. CONCLUSION: The treatment regimen of alefacept 15 mg IM for 6 weeks followed by alefacept 30 mg IM for 6 weeks was well tolerated by our patients. There was no increased incidence of infections when patients were treated with alefacept 30 mg compared with the 15 mg dose. The increased dose of alefacept 30 mg for the last 6 weeks of a 12-week course did not appear to yield a higher efficacy rate compared with historical controls.     

Alefacept in the treatment of recalcitrant palmoplantar and erythrodermic psoriasis

Alefacept is the first biologic agent approved by the US Food and Drug Administration for moderate to severe chronic plaque psoriasis. Prior clinical studies excluded patients with palmoplantar psoriasis or erythroderma. We report 2 patients with recalcitrant psoriasis who responded completely to a full course of alefacept. One patient presented with severe palmoplantar psoriasis recalcitrant to acitretin and methotrexate; another patient presented with erythroderma and was transitioned successfully from cyclosporine A. Alefacept provides another treatment option for palmoplantar and erythrodermic psoriasis and should be considered in the management of patients with these conditions.     

Current concepts and review of alefacept in the treatment of psoriasis

Alefacept is a novel biologic agent that selectively targets the memory T-cell population involved in the pathogenesis of psoriasis. Alefacept, administered by intramuscular (IM)or intravenous (IV) bolus injection, is safe and efficacious and improves quality of life ina broad spectrum of psoriasis patients. Disease remissions last approximately 7 months in responders following either IM or IV administration without further treatment.In clinical studies, treatment of patients with psoriasis with up to six courses of alefacept demonstrates the following: no evidence of an increased risk for infection or malignancy;no correlation between rates of infection, malignancy, and circulating CD4+ /CD8+ T-cell counts; and low immunogenicity. A preliminary study evaluating the use of alefacept for the treatment of active psoriatic arthritis parallels the psoriasis experience and supports the premise of targeting T cells as an intervention for this disease. Research continues to examine the use of alefacept in combination with other systemic psoriasis therapies and phototherapy and its potential as a treatment for other T-cell-mediated diseases, such as psoriatic arthritis, alopecia areata, and rheumatoid arthritis.     

Alefacept Is Well Tolerated in Patients with Chronic Plaque Psoriasis

Traditional systemic treatments for moderate to severe chronic plaque psoriasis are often poorly tolerated and are associated with safety concerns that restrict their long-term use. Alefacept is a fully human fusion protein that selectively targets memory T cells, and it is expected to provide enhanced safety over traditional nonselective agents. The safety and tolerability profile of alefacept is reviewed using data from the clinical development program. The most common adverse events were similar among alefacept and placebo groups. As expected from its mechanism of action, alefacept reduced the number of CD4⁺ and CD8⁺ T cells, with selectivity for the memory subsets. This reduction was not associated with an increase in the incidence of infections. Alefacept was not immunogenic. Patients have received up to 6 courses of alefacept therapy and the safety and tolerability profile over multiple courses is similar to that of a single course. Alefacept offers hope for a safer means to provide long-term management of psoriasis.     

An international,randomized, double-blind,placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis

BACKGROUND: Alefacept, human lymphocyte function-associated antigen 3/immunoglobulin 1 fusion protein, binds to CD2 molecules on the surface of activated T cells, selectively targeting memory-effector (CD45RO+) T cells, which comprise more than 75% of T cells in psoriatic plaques. OBJECTIVE: To examine the efficacy and tolerability of intramuscular alefacept. DESIGN: International, randomized, double-blind, placebo-controlled, parallel-group trial. PATIENTS: A total of 507 patients with chronic plaque psoriasis. INTERVENTION: Placebo, 10 mg of alefacept, or 15 mg of alefacept administered once weekly for 12 weeks followed by 12 weeks of observation. MAIN OUTCOME MEASURE: Psoriasis Area Severity Index (PASI). RESULTS: Alefacept treatment was associated with dose-related significant improvements in PASI from baseline. Throughout the study, a greater percentage of patients in the 15-mg group than in the placebo group achieved a significant reduction in PASI. Of patients in the 15-mg group who achieved at least 75% PASI reduction 2 weeks after the last dose, 71% maintained at least 50% improvement in PASI throughout the 12-week follow-up. There were no opportunistic infections and no cases of disease rebound. CONCLUSION: 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 use of alefacept in the treatment of psoriasis

Alefacept (AMEVIVE or LFA#TIP, Biogen) is the newest effective systemic therapy for chronic plaque psoriasis and was approved by the US FDA in January 2003. Clinical studies have shown that alefacept, given via weekly IM or IV injections for 12 weeks, was well tolerated, with no reported serious adverse events. Most significantly, it was found that alefacept provides a long-lasting remittive effect. These findings support the use of alefacept as a viable treatment of psoriasis, without the toxicities associated with some of the current systemic treatments available.     

Alefacept-induced decreases in circulating blood lymphocyte counts correlate with clinical response in patients with chronic plaque psoriasis

This international, double-blind study examined the effects of alefacept on circulating lymphocytes in 507 patients with chronic plaque psoriasis, and determined whether these effects were related to clinical improvement. Patients were randomized to intramuscular placebo, alefacept 10 mg, or alefacept 15 mg once weekly for 12 weeks followed by 12 weeks of observation. Alefacept dose-dependently reduced CD4+ and CD8+ memory T cells, while sparing the na ve population. The greatest reductions in disease activity occurred in patients with the largest decreases in memory T cells. For example, a 50 % reduction from baseline Psoriasis Area Severity Index at any time during treatment or follow-up was observed in 66 % of patients who had the greatest reductions in CD4+ memory T cells versus in 40 % of patients who had the smallest reductions in this T-cell subset. These results provide further support for the deleterious roles of CD4+ and CD8+ memory T-cell subpopulations in psoriasis pathogenesis.     

Alefacept modifies long-term disease severity and improves the response to other treatments

Alefacept treatment has been shown in several multicentre studies to result in prolonged post-treatment remission periods (median duration 241 days). This communication describes the clinical responses of 10 patients to multiple courses of 12 weekly intramuscular injections with alefacept given in combination with available antipsoriatic treatments. It was shown that in this group of 10 patients with moderate-severe psoriasis, 8 were no longer candidates for any more long-term continuous systemic treatment with methotrexate or acitretin, 7 had no options for UVB/PUVA courses and 8 were not suitable for treatment with cyclosporine. In 5 out of these 10 patients alefacept had resulted in a considerable long-term improvement with only mild disease expression, which lasted one year or longer. Patients indicated that these responses were outstanding as compared to the troublesome years before. Another patient reported a major improvement in the quality of life by reduction of itch. In two patients alefacept vastly enhanced the efficacy of dithranol treatment, as compared to previous treatments. Another patient was able to discontinue methotrexate without relapsing during alefacept, in contrast to severe rebound episodes following discontinuation of methotrexate in the past. The long-term responses of 8 out of the 10 patients described in this report indicate that alefacept, in the context of individualised care of patients with moderate to severe psoriasis, can have an important contribution. In particular, the long-term response after stopping alefacept makes this treatment a valuable tool, achieving prolonged disease control in at least some patients with moderate to severe psoriasis.     

Alefacept: a novel and selective biologic agent for the treatment of chronic plaque psoriasis

Psoriasis is a chronic immune-mediated disease affecting the skin and sometimes the joints. Approximately 14 million people in Europe have psoriasis and the disease has a profound effect on the quality of life of patients worldwide. Currently available therapies for psoriasis have several shortcomings, including organ-based toxicity, generalized immunosuppression, short duration of response, and inconvenient regimens. Alefacept is a recombinant, fully human fusion protein that selectively targets the memory T cell population implicated in psoriasis pathogenesis. Alefacept is unique among psoriasis treatments because of its selective therapeutic action, ability to induce lengthy disease remissions even in the absence of continued therapy, positive effect on quality of life, and favorable safety profile. Two courses of alefacept confer greater efficacy and duration of clinical improvement versus that observed with a single course. This novel biologic agent is currently approved in the United States and under regulatory review in Europe for moderate to severe chronic plaque psoriasis.