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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↗
PubMed2005

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.

Adult↗
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↗
PubMed2005

An extended 16-week course of alefacept in the treatment of chronic plaque psoriasis.

BACKGROUND: The efficacy and safety of one and two courses of alefacept have been demonstrated in phase 2 and 3 clinical trials, with a course of alefacept defined as 12 weeks of once-weekly treatment followed by 12 weeks of observation. METHODS: This randomized, single-center study compared the safety and efficacy of a standard 12-week versus extended 16-week alefacept dosing period in 20 patients with chronic plaque psoriasis. RESULTS: Both dose groups showed marked improvement in mean Psoriasis Area and Severity Index (PASI) score from baseline through week 24 (between-group difference: not significant). In each group, 60% of patients achieved PASI 50 (> or =50% reduction from baseline PASI score) at any time between weeks 12 and 24. For patients who received 16 weeks of alefacept, the mean percentage change from week-12 PASI score was higher and continued to increase through week 24 compared with that for patients who received 12 weeks of alefacept (P < .05). Adverse events were similar between the two groups and comparable with those observed in phase 2 and 3 clinical studies of alefacept. CONCLUSIONS: This was an open-label, single-center study of 20 patients. Further study is warranted to assess the effect of alefacept when administered for more than 12 weeks. Extended dosing with alefacept appeared to have a similar safety profile to 12-week dosing and may offer further benefit to some patients for disease improvement.

Alefacept↗
PubMed2005

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↗
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↗
PubMed2005

Alefacept in the treatment of psoriasis in patients for whom conventional therapies are inadequate.

BACKGROUND: Many patients with moderate to severe chronic plaque psoriasis fail to respond to or are not appropriate candidates for conventional systemic therapies and/or phototherapy. OBJECTIVES: To assess the efficacy, quality of life and safety of alefacept among the proportion of patients who participated in the phase III studies and who were not suitable candidates for conventional systemic psoriasis therapies or phototherapy. METHODS: The patient's historical responses at the baseline visit during the phase III studies of alefacept were used to identify a subpopulation in whom the use of methotrexate, ciclosporin, retinoids, ultraviolet B or psoralen plus ultraviolet A was ineffective or inappropriate. Endpoints included Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI) and adverse events. RESULTS: Most patients (69%) who were treated with alefacept in the phase III programme were not candidates for > or =1 of the above-mentioned therapies, and 41 and 21% were not candidates for > or =2 and > or =3, respectively. A reduction in PASI of > or =75% was achieved by 27, 23 and 26% of alefacept-treated patients who were not candidates for > or =1, > or =2 and > or =3 conventional systemic psoriasis therapies or phototherapy, respectively (all p < or = 0.001 vs. placebo). The corresponding results for PASI 50 were 53, 52 and 50% (all p < or = 0.001 vs. placebo). At 2 weeks after the last dose of alefacept, mean DLQI overall scores were reduced by -4.2, -3.9 and -5.2, respectively (all p < or = 0.001 vs. placebo). The incidence of adverse events was similar in the alefacept and placebo groups. CONCLUSIONS: The efficacy, quality of life effects and safety of alefacept in patients who were not candidates for conventional systemic psoriasis therapies or phototherapy were similar to those reported previously for the overall alefacept-treated population in the phase III studies.

Alefacept↗
PubMed2004

Alefacept: a novel biologic in the treatment of psoriasis.

Recognition of psoriasis as a T-cell-mediated immune disease has led to the development of various therapeutic approaches directed against the T cell and T-cell processes such as activation, trafficking and cytokine release. The novel and selective biologic agent alefacept, with an effect of selective apoptotic reduction in memory-effector T cells, has been given FDA approval for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. The clinical profile of this novel biologic agent is presented here. Two pivotal multicenter, randomized, placebo-controlled, double-blind studies enrolling 1060 patients were designed to support the efficacy and safety of alefacept in the treatment of moderate to severe chronic plaque psoriasis. With either intramuscular or intravenous administration, well over half of patients treated with a single course of alefacept achieved a 50% reduction in PASI (Psoriasis Area and Severity Index), and a second course of therapy provided further benefit by increasing response rates and providing long-lasting off-treatment responses regardless of the route of administration. In all studies, alefacept was well tolerated. There was no evidence of an increased risk of infections or malignancies and no opportunistic infections were reported. Consistent with its composition as a fully human fusion protein, alefacept had a low incidence of immunogenicity and no evidence of an increased rate of antibody development over time. There was no evidence that primary or secondary responses to a new antigen or memory response to a recall antigen were blunted in patients treated with alefacept. In conclusion, alefacept is the first biologic therapy to demonstrate positive effects in an immune-mediated disease while maintaining immune responses to novel and recall antigens. This selective effect on the immune system distinguishes alefacept from immunosuppressive therapies that are nonselective.

Alefacept↗
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↗
PubMed2005

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↗