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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↗

An integrated analysis of thirteen trials summarizing the long-term safety of alefacept in psoriasis patients who have received up to nine courses of therapy.

BACKGROUND: Information on longer-term safety and tolerability is needed to confidently prescribe alefacept therapy for chronic plaque psoriasis beyond 1 or 2 courses. OBJECTIVE: The aim of this work was to further examine the safety profile of alefacept by integrating data from clinical trials involving patients with chronic plaque psoriasis who received up to 9 courses of therapy over a 5-year period. METHODS: Data from 13 clinical trials conducted in patients with plaque psoriasis were integrated because they had similar inclusion/exclusion criteria and assessments. Patients who enrolled in the analyzed trials were aged > or =15 years with chronic plaque psoriasis for > or =12 months that involved > or =10% of body surface area, and CD4+ T lymphocyte counts above the lower limit of normal (>404 cells/microL). The incidences of adverse events (AEs), serious AEs, discontinuations for AEs, infections, serious infections, malignancies, and anti-alefacept antibodies were summarized for each course of alefacept. The incidence of infections was stratified according to CD4+ T lymphocyte counts (<250 cells/microL vs > or =250 cells/microL). RESULTS: Data from 13 clinical trials of alefacept were integrated and summarized (multicenter, randomized, double-blind studies, n = 6; multicenter, open-label studies, n = 5; other, n = 2). The analyzed population (n = 1869) included 1291 (69.1%) men and 578 (30.9%) women, between the ages of 15 and 84 years (mean, 44.8 years), of whom 1648 (88.2%) were white. Weights ranged from 40 kg to 206 kg (mean, 90.0 kg). A total of 1369 of these patients had been included in a previous analysis. Among the most commonly reported AEs in each treatment course were headache (0%-14.2%), nasopharyngitis (7.7%-25.0%), influenza (0%-8.1%), upper respiratory tract infection (0%-12.5%), and pruritus (0%-7.5%). The rates of discontinuations due to AEs (0%-4.8%), serious AEs (0%-4.8%), serious infections (0%-0.9%), or malignancies (0%-4.8%) did not appear to increase with repeated exposure. Fewer than 1 % of patients in each course developed a serious infection. No opportunistic infections or infection-related deaths were reported. The incidence of infections appeared to be unrelated to CD4+ T lymphocyte counts. Fewer than 2.5% of patients tested positive for anti-alefacept antibodies during any course of therapy. CONCLUSIONS: This integrated analysis of data from 13 trials with 1869 patients supports the safety and tolerability of alefacept for longer-term treatment of psoriasis.

Adolescent↗

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.

Adolescent↗

Repeat courses of intravenous alefacept in patients with chronic plaque psoriasis provide consistent safety and efficacy.

BACKGROUND: Psoriasis is a chronic, relapsing skin disease that may require multiple treatment courses. Alefacept targets the memory T cells implicated in psoriasis pathogenesis. This open-label study evaluated the safety and tolerability, efficacy, and pharmacodynamics of repeat courses of alefacept in men and women with chronic plaque psoriasis. This article reports the interim results of this ongoing study. METHODS: Patients (n = 174) who participated in previous phase II studies of alefacept were included in this retreatment study. Intravenous alefacept (7.5 mg) was administered once weekly for 12 weeks followed by 12 weeks of observation. Initial and subsequent retreatment courses were only given when, in the opinion of the investigators, disease had returned and necessitated treatment; CD4+ T-cell counts had to be at or above the lower limit of normal. RESULTS: Adverse events were similar regardless of the retreatment course. No opportunistic infections, rebound of disease, or flares were reported. Low titers of anti-alefacept antibodies occurred in a few patients without related safety issues. Sixty-six per cent of patients achieved a >/= 50% reduction in the Psoriasis Area and Severity Index (PASI) at any time after the first dose of retreatment course 1. Patients who received two retreatment courses (n = 50) had consistent or improved responses after the second course; 64% and 68% of these patients achieved a >/= 50% PASI improvement at any time after the first dose of retreatment courses 1 and 2, respectively. Alefacept selectively reduced memory T cells without cumulative effects. CONCLUSIONS: Repeat courses of alefacept were well tolerated, and subsequent retreatment courses were at least as effective as the initial course of therapy.

Aged↗

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↗

Alefacept: a safety profile.

Alefacept is a selective immunomodulating, antipsoriatic drug that blocks the LFA-3/CD2 interaction necessary for the activation and proliferation of memory effector T cells by binding to CD2 expressed on the T cell surface. Because the CD4+ count is reduced by alefacept, it is recommended that this count be monitored on a regular basis to ensure that it does not drop below 250 cells/mul. Few side effects have been related to the use of alefacept that differ from placebo even when CD4+ counts drop below 250 cells/microl. The side effects that have been reported are minor and include: headache, nasopharyngitis, rhinitis, influenza, upper respiratory tract infections, pruritus, arthralgias, fatigue, nausea, accidental injury and increases in liver enzymes. Serious infections and malignancies do not appear linked to the use of alefacept. The percentage of patients who developed antibodies against alefacept is very low. Alefacept is a very safe biological therapy for moderate-to-severe chronic plaque psoriasis with few side effects reported. The utility of checking CD4 counts while administering alefacept for 12 weeks appears minimal.

Alefacept↗

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.

Adult↗

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.

Adolescent↗

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↗

Effect of calcipotriol on epidermal cell populations in alefacept-treated psoriatic lesions.

BACKGROUND AND OBJECTIVES: The effect of the established antipsoriatic treatment with topical calcipotriol (with a maximum of 100 g per week) in addition to systemic treatment with alefacept, a new biological agent for psoriasis, on epidermal cell populations in the psoriatic lesion was investigated using a combination of the Zenon labelling technique and microscopic image analysis. Epidermal cell populations were measured quantitatively with this sensitive method. PATIENTS/METHODS: Frozen sections of non-treated psoriatic epidermis and psoriatic epidermis treated with either alefacept intramuscular or alefacept intramuscular in combination with topical calcipotriol for 12 weeks were compared immunohistochemically. Antibodies against keratin 6, 10 and 15 were labelled with the Zenon technique, whereas antibodies against the Ki-67 antigen and beta-1 integrin were covalently Fluorescein Isothiocyanate (FITC)-labelled. Using image analysis, these markers were measured in the epidermis in a standardized manner. RESULTS AND CONCLUSIONS: Treatment of psoriasis with alefacept resulted in a good clinical response in several patients and in a normalization of epidermal expression of the immunohistochemical parameters for differentiation and proliferation. The addition of topical calcipotriol resulted in a faster clinical improvement with a similar overall clinical response and a similar response of epidermal cell populations as compared to treatment with alefacept monotherapy after 12 weeks of treatment. This study also suggests that the appearance of keratin 15 has a predictive value for the duration of remission. It can be concluded that the addition of a low-dose calcipotriol treatment does not contribute to the clinical efficacy of alefacept, both at the clinical level and with respect to markers for epidermal proliferation and differentiation.

Administration, Topical↗

Explorative immunohistochemical study to evaluate the addition of a topical corticosteroid in the early phase of alefacept treatment for psoriasis.

The aim of this study was to explore the additional effect of betamethasone dipropionate cream in the early phase of an intramuscular (IM) alefacept course, on plaque severity and on modulating T-cell subsets, cells expressing NK-receptors, epidermal proliferation and keratinocyte differentiation in lesional psoriatic skin. Therefore, sixteen patients with moderate-to-severe chronic plaque psoriasis received 15 mg alefacept IM for 12 weeks, followed by a 12-week follow-up period. The first 4 weeks, patients were randomized 1:1 to either betamethasone dipropionate, or the vehicle cream, once daily. Plaque severity (SUM) was assessed and serial biopsies were immunohistochemically stained for T-cell subsets (CD3, CD4, CD8, CD45RO, CD45RA, CD2, CD25, GITR), cells expressing NK-receptors (CD94 and CD161), epidermal proliferation (Ki67) and differentiation (K10), which were quantified using manual and digital image analysis. Alefacept monotherapy resulted in statistically significant improvement in plaque severity. Subsequently, immunohistochemical assessments on T-cell subsets, epidermal proliferation (Ki67) and keratinization (K10) revealed marked time-related improvements with respect to the mentioned parameters, without significant differences between both treatment regimens. Alefacept monotherapy induces improvement of plaque severity, which is accompanied by a reduction in activated (CD2+, CD25+, CD45RO+) dermal CD4+ and activated epidermal CD8+ T cells, epidermal proliferation and differentiation. Once daily treatment with betamethasone dipropionate cream during the first 4 weeks of an intramuscular alefacept course did not provide substantial additional clinical and immunohistochemical improvement.

Administration, Topical↗

The efficacy of alefacept in the treatment of chronic plaque psoriasis.

With the completion of several phase 2 and phase 3 clinical studies, the efficacy and tolerability of alefacept in patients with chronic plaque psoriasis is now well studied. The majority of patients treated with a single course of intravenous or intramuscular alefacept experienced a clinically meaningful response. The efficacy of alefacept correlated with its ability to selectively target and reduce the number of pathogenic memory T cells. A second course of alefacept resulted in further clinical improvement, with increasing response rates and prolonged response duration following treatment cessation. Subpopulation analyses demonstrated that alefacept is effective in a broad spectrum of patients with psoriasis, regardless of disease severity, history of and response to prior antipsoriatic treatment, or whether patients are refractory to or have contraindications to other systemic psoriasis therapies or phototherapy.

Adolescent↗

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↗

Treatment of palmoplantar psoriasis with intramuscular alefacept.

Alefacept is a dimeric fusion protein that consists of the extracellular CD2-binding portion of human lymphocyte function-associated antigen-3, which is linked to the Fc segment of human IgG1. Alefacept inhibits T-cell activation and proliferation, and induces apoptosis of memory-effector (CD45RO+) T cells in vitro, limiting the inflammatory and uncontrolled keratinocyte proliferation seen in psoriatic lesions. Alefacept is the first biologic approved in the United States for the treatment of moderate to severe chronic plaque psoriasis. This report describes the use of alefacept in 2 patients with extensive and recalcitrant palmoplantar psoriasis who achieved significant improvements on alefacept therapy.

Alefacept↗

Development and use of alefacept to treat psoriasis.

Activated memory T cells, expressing CD2, are key components in the pathogenesis of psoriasis. Alefacept binds to CD2, blocks co-stimulatory signaling, and selectively induces apoptosis of pathogenic T cells. Our objective is to present safety and efficacy results which lead to the new drug application (NDA) of alefacept for the treatment of psoriasis. We reviewed the key phase II and III trials in over 1300 patients and found that during treatment and follow-up of patients receiving 12 weekly intramuscular or intravenous injections of alefacept, about 1/3 will achieve a reduction in psoriasis area and severity index (PASI) of > or =75% and nearly 2/3 a reduction in PASI of > or =50%. Patients who achieved a > or =75% reduction from baseline PASI during or after a single course maintained a > or =50% reduction in PASI for a median duration of >7 months. Among patients who received 2 courses of alefacept, 40% and 71% of patients achieved a > or =75% and > or =50% reduction in PASI, respectively and duration of effect was prolonged. Adverse events in the placebo and active treatment arms did not differ. We conclude that alefacept significantly improves psoriasis and produces durable clinical improvement with a very favorable safety profile.

Alefacept↗

Pharmacokinetics, biologic activity, and tolerability of alefacept by intravenous and intramuscular administration.

Alefacept, human LFA-3/IgG1 fusion protein, is currently under clinical development for the treatment of chronic plaque psoriasis and other T cell mediated disorders. This recombinant protein binds CD2 on T cells and Fc gamma RIII on accessory cells (e.g., natural killer cells, macrophages), inhibiting T cell activation/proliferation and inducing selective T cell apoptosis. These effects are associated with selective reductions in memory-effector (CD4+ CD45RO+ and CD8+ CD45RO+) T cells. Two open-label studies were conducted in healthy male volunteers to evaluate the pharmacokinetics, biologic activity, and tolerability of a single dose of alefacept when administered as a 0.15 mg/kg 30-sec i.v. bolus (n = 12), 0.04 mg/kg intramuscular (i.m.) injection (n = 8), or 0.04 mg/kg 30-min intravenous (i.v.) infusion (n = 8). i.v. infusion produced a higher Cmax (0.96 +/- 0.26 mcg/ml vs. 0.36 +/- 0.19 mcg/ml) and a shorter Tmax (2.8 +/- 1.9 hr vs. 86 +/- 60 hr) when compared to i.m. injection. Based on AUC0-last and AUC0-infenity values, the relative bioavailability of i.m. to i.v. infusion was approximately 60%. After absorption from the i.m. injection was complete, the rate of alefacept elimination from the serum appeared consistent with the i.v. infusion half-life (approximately 12 days). Biologic activity was demonstrated by transient reductions in absolute number of CD2+ lymphocytes, with notable specificity for memory T-cell subsets. Alefacept was well tolerated; the most common adverse effects were headache, pharyngitis, rash, and myalgia. IM administration was not associated with significant local reactions. Results of these studies support i.v. bolus or i.m. administration of alefacept. An i.m. dose of approximately 150 to 200% of the i.v. dose is an appropriate and convenient alternative to i.v. administration.

Adolescent↗

Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report.

We evaluated the effect of alefacept (Amevive), a novel dimeric fusion protein, in steroid resistant/dependent acute graft-versus-host-disease (aGVHD). Seven patients were treated in eight aGVHD episodes. GVHD grade at treatment initiation and at peak ranged 2-4 (median 2.5) and 2-4 (median 4), respectively. System involvement at GVHD peak included skin (n=7), gastrointestinal tract (n=5) and liver (n=3). All patients responded. However, one patient with skin GVHD and two with gastrointestinal GVHD featuring an early initial response (IR) exacerbated and CR was not achieved. Skin GVHD responded rapidly with a median of 1 day to IR and 7 days to CR. Intestinal response was slower with median 7.5 days to IR. Of the four patients that achieved IR, CR was achieved in only one (40 days to CR). None of the patients had significant hepatic GVHD before treatment so no hepatic effect of alefacept could be determined. No immediate alefacept-related side effects were observed. Late side effects included infections (aspergillus sinusitis, pneumonia, bacteremia, pharyngeal thrush), pancytopenia and hemorrhagic cystitis. Three patients had CMV reactivation while on alefacept. We conclude that alefacept may have a beneficial effect in controlling aGVHD. Further investigations in larger cohorts of patients and controlled studies are warranted.

Acute Disease↗

Alefacept: an expert review concerning the treatment of psoriasis.

Psoriasis is a chronic, inflammatory skin disease. Historically, phototherapy or immunosuppressive agents have been the first line of treatment for patients with severe psoriasis; however, the long-term use of these agents is limited by dose-dependent toxicities. Alefacept was the first biological agent approved in both the US and Canada for the treatment of adults with moderate-to-severe chronic plaque psoriasis. Alefacept is a remittive therapy that selectively reduces memory T cells. The efficacy and safety of up to two courses of alefacept have been demonstrated in clinical trials, and thus, this review focuses on new data to optimise the use of this biological agent. Emerging data indicates that multiple courses of alefacept for the long-term treatment of psoriasis are safe and effective. In addition, data are reviewed on the use of alefacept in combination with other agents and in other diseases, including psoriatic arthritis.

Alefacept↗