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At least 19 recordsLinked to original sources

PubMed2003

Clinical response to alefacept: results of a phase 3 study of intravenous administration of alefacept in patients with chronic plaque psoriasis.

BACKGROUND: There is a current lack of safe and effective psoriasis therapies that provide patients with lasting remissions after treatment is discontinued. Alefacept, a novel and selective biological agent, has demonstrated durable efficacy in patients with chronic plaque psoriasis, and its efficacy has been correlated with reductions in memory-effector T cells. OBJECTIVE: To demonstrate the efficacy and safety of both one and two 12-week courses of alefacept 7.5 mg given once weekly as an intravenous (IV) bolus injection in patients with chronic plaque psoriasis. METHODS: Multicentre (51 centres in the USA and Canada), randomized, double-blind, parallel-group study comparing once-weekly alefacept 7.5 mg IV or placebo for two 12-week treatment courses. Each course had a 12-week follow-up phase. Patients were eligible for enrollment if they were > or =16 years of age, had chronic plaque psoriasis for > or =12 months involving > or =10% body surface area, and had CD4+ T-cell counts at or above the lower limit of normal. RESULTS: 553 patients received treatment in Course 1, and 449 were treated in Course 2. The cohorts were well balanced for demographic and baseline disease characteristics. During the treatment and follow-up period of Course 1, 28% of patients treated with alefacept achieved > or =75% reduction in Psoriasis Area and Severity Index (PASI), compared with 8% of placebo-treated patients (P < 0.001). Patients achieving > or =75% reduction in PASI following a single 12-week course of alefacept maintained > or =50% reduction in PASI for a median of over 7 months. Among patients who received a second course of alefacept therapy, 71% achieved > or =50% reduction in PASI, and 40% achieved > or =75% reduction in PASI over two treatment courses. One or two 12-week courses of alefacept were similarly well tolerated. CONCLUSIONS: Treatment with alefacept 7.5 mg IV provided highly significant improvements in all measures of psoriasis disease activity compared with placebo. A second course of alefacept provided additional benefit.

Adolescent↗

PubMed2003

Clinical response to alefacept: results of a phase 3 study of intramuscular administration of alefacept in patients with chronic plaque psoriasis.

BACKGROUND: Recognition of psoriasis as a T-cell-mediated immune disease has led to the development of various therapeutic approaches directed against the pathogenic T cells. Alefacept, a novel and selective biological recombinant protein, binds CD2 on T cells to block T-cell activation and proliferation and interacts with FcgammaRIII receptors on accessory cells to produce selective T-cell apoptosis. OBJECTIVE: To demonstrate the efficacy and safety of once-weekly alefacept IM compared with placebo given for 12 weeks to patients with chronic plaque psoriasis. METHODS: Multicentre (63 sites in Europe, the USA, and Canada), randomized, double-blind, parallel-group study comparing 10 mg and 15 mg of alefacept and placebo administered IM once weekly for 12 weeks. Patients were followed for an additional 12 weeks after cessation of therapy. Patients were eligible for enrollment if they were > or = 18 years of age, had chronic plaque psoriasis for > or = 12 months involving > or = 10% body surface area, and had CD4+ T-cell counts at or above the lower limit of normal. RESULTS: 507 patients were enrolled into three treatment groups, which were well balanced for demographic, baseline disease characteristics, and treatment history. A significantly greater percentage of patients treated with alefacept 15 mg IM achieved > or = 75% PASI reduction from baseline 2 weeks after the last dose compared with placebo (21% vs. 5%, P < 0.001); 12% of patients treated with alefacept 10 mg IM reached this level of improvement (P = NS vs. placebo). Alefacept was well tolerated, with adverse events similar to that of placebo. CONCLUSIONS: Treatment with alefacept 15 mg IM provided highly significant improvements in all measures of psoriasis disease activity compared with placebo. Pharmacodynamic data confirmed that alefacept is a selective biological agent that reduces memory-effector T cells (CD4+CD45RO+ and CD8+CD45RO+), the source of the pathogenic mediators of psoriasis, while having relatively no effect on naive T-cell populations.

Adolescent↗

PubMed2002

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.

Adolescent↗

PubMed2004

Clinical update on alefacept: consideration for use in patients with psoriasis.

OBJECTIVE: Alefacept was the first of the biologic agents to be approved for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. This fully human fusion protein inhibits the activation of and reduces levels of memory (CD45RO+) T cells, a subpopulation of lymphocytes that plays a critical role in the pathogenesis of psoriasis. The purpose of this article is to provide a clinical update on the use of this agent in patients with psoriasis. SUMMARY: A single course of alefacept, defined as 12 weekly injections followed by 12 treatment-free weeks, provides clinically meaningful improvements in the symptoms of psoriasis for a majority of patients. Patients who achieved a response have been shown to maintain the benefit for a median duration of about 7 months, without the need for systemic therapy or phototherapy. With each additional course of alefacept, the percentage of patients responding increases, confirming the incremental benefit of repeated administration. More than 1,300 patients have received alefacept in controlled clinical trials. Over multiple courses of therapy, alefacept-induced reductions in circulating lymphocyte counts were consistent and not cumulative. The incidences of serious adverse events, discontinuations, malignancies, and antialefacept antibodies were low and did not increase with subsequent courses. No relationship was observed between decreases in lymphocyte counts and incidences of infections or malignancies. No cases of opportunistic infections, including tuberculosis, have been reported. The favorable safety profile of alefacept was maintained in patients who received concomitant or prior immunosuppressants. Alefacept did not cause reactivation of tuberculosis in case studies of patients who showed a purified protein derivative reaction prior to the initiation of therapy. Immune responses to a neoantigen and recall antigen remained intact in alefacept-treated patients, suggesting that vaccinations may be possible during therapy. CONCLUSION: Alefacept is an effective intermittent therapy for psoriasis that can provide extended treatment-free and disease-free periods, which may lessen the need for treatment over time. The incremental efficacy seen with each subsequent course of alefacept suggests that physicians should administer 2 courses to determine efficacy before altering therapeutic interventions. The selective mechanism of action of alefacept affords multiple safety advantages and no apparent increased risk of infections or malignancies.

Alefacept↗

PubMed2004

Improved health-related quality of life following a randomized controlled trial of alefacept treatment in patients with chronic plaque psoriasis.

BACKGROUND: Psoriasis has a negative impact on patients' quality of life. Treatment strategies should address both the cutaneous manifestations of the disease and their impact on quality of life. OBJECTIVES: To evaluate the effect of alefacept on quality of life in 553 patients with chronic plaque psoriasis. METHODS: In this multicentre, double-blind, parallel-groups study, patients were randomized to receive alefacept for two courses, alefacept in course 1 and placebo in course 2, or placebo in course 1 and alefacept in course 2. In each course, alefacept 7.5 mg or placebo was administered once weekly by 30-s intravenous injection for 12 weeks followed by 12 weeks of observation. The Dermatology Life Quality Index (DLQI), Dermatology Quality of Life Scales (DQOLS) and Short Form-36 Health Survey (SF-36) were administered at baseline, 2 weeks after the last dose in both courses, at the beginning of course 2, and at the end of the observation period in both courses. RESULTS: In course 1, alefacept significantly reduced (improved) mean DLQI scores compared with placebo: 4.4 vs. 1.8 at 2 weeks after the last dose (P<0.0001) and 3.4 vs. 1.4 at 12 weeks after the last dose (P<0.001). Patients who received two courses of alefacept experienced additional enhancement of quality of life measures during the second course. Similar results were observed for the DQOLS. The SF-36 survey confirmed that alefacept had no negative impact on general quality of life. CONCLUSIONS: Alefacept improved quality of life in patients with chronic plaque psoriasis and maintained this benefit for at least 12 weeks following cessation of treatment. A second course of alefacept provided additional quality of life benefit.

Adolescent↗

PubMed2003

Treatment of psoriasis with alefacept: correlation of clinical improvement with reductions of memory T-cell counts.

OBJECTIVE: To examine the relationship between the pharmacodynamic and antipsoriatic effects of alefacept, a biologic agent that targets CD4+ and CD8+ memory T cells. DESIGN: Randomized, double-blind, placebo-controlled study of 3 parallel groups. SETTING: Fifty-one study centers. PATIENTS: Five hundred fifty-three patients with chronic plaque psoriasis. INTERVENTIONS: Patients were randomized (1:1:1) to 1 of the following 3 cohorts: alefacept, 7.5 mg, in both courses (cohort 1); alefacept, 7.5 mg, in the first course and placebo in the second course (cohort 2); or placebo in the first course and alefacept, 7.5 mg, in the second course (cohort 3). In each course, alefacept or placebo was administered by intravenous bolus once weekly for 12 weeks, followed by 12 weeks of observation. MAIN OUTCOME MEASURES: Circulating lymphocyte levels and the Psoriasis Area Severity Index. RESULTS: One or 2 courses of alefacept reduced CD4+ and CD8+ memory T-cell counts, while sparing the naive population. At 12 weeks after the last dose of alefacept in courses 1 and 2, 88% and 83% of patients, respectively, had CD4+ cell counts greater than the lower limit of normal. In course 1, alefacept-treated patients with the largest decreases in memory T-cell counts experienced the greatest reductions in disease activity (P<.001). The duration of clinical benefit seemed to be longer among patients who had the greatest reduction in CD4+ and CD8+ memory T-cell counts. CONCLUSIONS: One or 2 courses of intravenous alefacept reduced circulating memory T-cell counts while sparing the naïve T-cell population. The reductions in memory T-cell counts were related to all measures of disease activity evaluated and the duration of response to therapy, suggesting that prolonged remissions of psoriasis can be attained with reduction of the pathogenic T-cell count.

Adolescent↗

PubMed2002

Alefacept, an immunomodulatory recombinant LFA-3/IgG1 fusion protein, induces CD16 signaling and CD2/CD16-dependent apoptosis of CD2(+) cells.

Alefacept, an immunomodulatory recombinant fusion protein composed of the first extracellular domain of LFA-3 fused to the human IgG1 hinge, C(H)2, and C(H)3 domains, has recently been shown in phase II and III clinical trials to safely reduce disease expression in patients with chronic plaque psoriasis. Alefacept modulates the function of and selectively induces apoptosis of CD2(+) human memory-effector T cells in vivo. We have sought to gain further understanding of the mechanisms of action that influence the biological activity of alefacept and may contribute to its efficacy and patient responsiveness. Specifically evaluated is the ability of alefacept to activate intracellular signals mediated via CD2 and/or Fc gamma RIII (CD16). Experimentation using isoforms of alefacept engineered to have amino acid substitutions in the IgG1 C(H)2 domain that impact Fc gamma R binding indicate that alefacept mediates cognate interactions between cells expressing human CD2 and CD16 to activate cells, e.g., increase extracellular signal-regulated kinase phosphorylation, up-regulate cell surface expression of the activation marker CD25, and induce release of granzyme B. In the systems used, this signaling is shown to require binding to CD2 and CD16 and be mediated through CD16, but not CD2. Experimentation using human CD2-transgenic mice and isoforms of alefacept confirmed the requirement for Fc gamma R binding for detection of the pharmacological effects of alefacept in vivo. Thus alefacept acts as an effector molecule, mediating cognate interactions to activate Fc gamma R(+) cells (e.g., NK cells) to induce apoptosis of sensitive CD2(+) target cells.

Adjuvants, Immunologic↗

PubMed2003

Alefacept selectively promotes NK cell-mediated deletion of CD45R0+ human T cells.

Modulation of the immune response using immunoglobulin fusion proteins has shown great promise for clinical immunotherapy of autoimmune diseases. Alefacept is an immunoglobulin fusion protein composed of the first extracellular domain of human LFA-3 fused to the hinge, C(H)2 and C(H)3 domains of human IgG(1). Alefacept has previously been reported to inhibit T cell proliferation. Here, we analyzed the effects of alefacept on lymphocytes in vitro and characterized the role of autologous NK cells in its mechanism of action. Alefacept, but not a C(H)2 binding mutant of Alefacept, inhibited CD3-induced T cell proliferation only in the presence of live NK cells, consistent with an important role for FcgammaR engagement. Alefacept caused preferential depletion of CD69+CD45R0+CD25+ T cell subsets. Cytotoxicity assays revealed that alefacept, but not the C(H)2 binding mutant, induced NK cell-mediated death of activated T cells and sorting into CD45R0+ and CD45RA+ subpopulations showed that lymphocyte deletion occurred preferentially in the CD45R0+ subset. Activated CD45R0+ cells expressed higher levels of CD2 than CD45R0- cells, providing a possible explanation for the selective targeting of this subset. Our results suggest that selective targeting of CD45R0+ T cells by NK cells represents a potential therapeutic mechanism of action of alefacept.

Alefacept↗

PubMed2003

An overview of infliximab, etanercept, efalizumab, and alefacept as biologic therapy for psoriasis.

BACKGROUND: Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European populations. One of the major focuses in psoriasis research has been the development of biologic therapies that provide selective, immunologically directed intervention with fewer adverse effects than traditional therapies. OBJECTIVE: The aim of this review was to summarize the progress of 4 biologic agents available or under investigation for clinical use: infliximab, etanercept, efalizumab, and alefacept. METHODS: Relevant information was identified through a MEDLINE search of the literature (1966 to May 2003) using the terms biologic therapy, psoriasis, infliximab, etanercept, efalizumab, and alefacept. In addition, meeting posters from the American Academy of Dermatology (2003) and International Investigative Dermatology (2003) were reviewed and included if perceived to be reliable and relevant. RESULTS: In a Phase II trial of infliximab, the percentages of patients reaching > or =75% improvement from baseline in the psoriasis area and severity index (PASI 75) at week 10 were as follows: 6% with placebo (3/51), 72% with infliximab 3 mg/kg (71/98), and 88% with infliximab 5 mg/kg (87/99). In a Phase III study, 34% of patients receiving etanercept 25 mg SC twice weekly (55/162) achieved PASI 75 at 12 weeks and 44% (71/162) at 24 weeks. Also, 49% of those receiving etanercept 50 mg (81/164) achieved PASI 75 at 12 weeks, and 59% (97/164) at 24 weeks. In 2 Phase III trials with SC efalizumab 1.0 mg/kg or 2.0 mg/kg or placebo, 30% in the 1.0-mg/kg per week group (117/394) achieved PASI 75; in the 2.0-mg/kg per week group, 28% (113/409) did. In the placebo, 3.4% (10/292) achieved PASI 75. In a Phase III trial of IM alefacept 15 mg once weekly for 12 weeks, IM alefacept 10 mg once weekly for 12 weeks, or placebo, 21% of the 15-mg dose group (35/166) achieved PASI 75 at 2 weeks after the last dose, compared with 5% of the placebo group (8/168). In a Phase III study of the efficacy and tolerability of once-weekly alefacept 7.5 mg via IV bolus, 14% (53/367) and 4% (7/186) of patients receiving alefacept and placebo achieved PASI 75 at week 14, respectively. Among those who received 2 courses of alefacept, 40% (73/183) and 71% (130/183) achieved PASI 75 and > or = 50% improvement in PASI, respectively. All 4 drugs have been generally well tolerated. CONCLUSIONS: In the patients treated to date, infliximab, etanercept, efalizumab, and alefacept have achieved successful therapy of psoriasis without the organ toxicity seen with traditional systemic therapies. Potential limitations in the use of these agents include the expected high costs of treatment, lack of long-term follow-up, and the selective nature of the patient populations treated thus far.

Alefacept↗

PubMed2003

CD4+ T-cell-directed antibody responses are maintained in patients with psoriasis receiving alefacept: results of a randomized study.

BACKGROUND: Alefacept, human LFA-3/IgG(1) fusion protein, selectively reduces memory-effector (CD45RO(+)) T cells, a source of the pathogenic mediators of psoriasis. OBJECTIVE: To evaluate the effect of alefacept on immune function, T-cell-dependent humoral responses to a neoantigen (PhiX174) and recall antigen (tetanus toxoid) were assessed. METHODS: Patients with psoriasis were randomized to the control group or to receive alefacept (7.5 mg intravenously weekly for 12 weeks). The alefacept group received PhiX174 immunizations at weeks 6, 12, 20, and 26 and tetanus toxoid at week 21; control subjects received PhiX174 at weeks 6 and 12 and tetanus at week 10. RESULTS: Mean anti-PhiX174 titers were comparable in both groups. There was no difference in the percentage of responders (anti-PhiX174 IgG >/=30% of the total anti-PhiX174) between the alefacept group and the control group (86% and 82%, respectively; P =.73). The percentage of patients with anti-tetanus toxoid titer increases >/=2 times baseline also was similar (alefacept, 89%; control 91%). CONCLUSION: A single 12-week course of alefacept did not impair primary or secondary antibody responses to a neoantigen or memory responses to a recall antigen. The selective immunomodulatory effect of alefacept against a potentially pathogenic T-cell subset is associated with maintenance of a significant aspect of immune function (antibody response) to fight infection and respond to vaccinations.

Adult↗

PubMed2002

Selective targeting of T cell subsets: focus on alefacept - a remittive therapy for psoriasis.

Psoriasis is an immune-mediated disease in which memory-effector (CD45RO+), skin-homing T cells play a key role in driving the disease process. Available therapies are often poorly tolerated, none are curative and most only suppress disease symptoms without attacking the underlying cause of the illness. Alefacept (Ameviv, Biogen, Inc.) is a fully human lymphocyte function associated antigen-3/immunoglobulin G1 fusion protein that targets memory-effector T cells by binding CD2 on the T cell and Fc phi receptor III IgG receptors on accessory cells, thereby preventing T cell activation and proliferation and causing selective T cell apoptosis. To date, alefacept has been studied in moderate-to-severe chronic plaque psoriasis and in a pilot study of psoriatic arthritis. In chronic plaque psoriasis, alefacept produced significant and sustained improvements in psoriasis symptoms. There was no evidence of disease rebound or worsening of psoriasis following treatment cessation. Multiple courses provided consistent efficacy, with a trend for more rapid and greater clinical improvement in subsequent courses. Alefacept reduced circulating CD4+ and CD8+ memory-effector T cells, with relatively no change in naive (CD45RA+) T cells or B cells. Alefacept also reduced IFN-phi-secreting Tcells in lesional biopsies of psoriatic skin. These reductions all correlated with the observed clinical effect. Alefacept was well-tolerated throughout these studies, with a side effect profile similar to placebo. There was no evidence of generalised immunosuppression or increased risk of infection or malignancy. Alefacept did not alter the primary or acquired immune response in psoriatic patients. Clinical data obtained to date support the use of alefacept as a safe and remittive therapy for psoriasis.

Alefacept↗

PubMed2003

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↗

PubMed2003

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↗

PubMed2003

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↗

PubMed2003

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↗

PubMed2004

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↗

PubMed2003

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↗

PubMed2002

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↗