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Amevive (Alefacept) - Description and Clinical Pharmacology

 
 



DESCRIPTION

AMEVIVE® (alefacept) is an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 (LFA-3) linked to the Fc (hinge, CH 2 and CH 3 domains) portion of human IgG1. Alefacept is produced by recombinant DNA technology in a Chinese Hamster Ovary (CHO) mammalian cell expression system. The molecular weight of alefacept is 91.4 kilodaltons.

AMEVIVE® is supplied as a sterile, white-to-off-white, preservative-free, lyophilized powder for parenteral administration. After reconstitution with 0.6 mL of the supplied Sterile Water for Injection, USP, the solution of AMEVIVE® is clear, with a pH of approximately 6.9.

AMEVIVE® is available in two formulations. AMEVIVE® for intramuscular injection contains 15 mg alefacept per 0.5 mL of reconstituted solution. AMEVIVE® for intravenous injection contains 7.5 mg alefacept per 0.5 mL of reconstituted solution. Both formulations also contain 12.5 mg sucrose, 5.0 mg glycine, 3.6 mg sodium citrate dihydrate, and 0.06 mg citric acid monohydrate per 0.5 mL.

CLINICAL PHARMACOLOGY

AMEVIVE® interferes with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting LFA-3/CD2 interaction. Activation of T lymphocytes involving the interaction between LFA-3 on antigen-presenting cells and CD2 on T lymphocytes plays a role in the pathophysiology of chronic plaque psoriasis. The majority of T lymphocytes in psoriatic lesions are of the memory effector phenotype characterized by the presence of the CD45RO marker1, express activation markers (e.g., CD25, CD69) and release inflammatory cytokines, such as interferon (gamma).

AMEVIVE® also causes a reduction in subsets of CD2+ T lymphocytes (primarily CD45RO+), presumably by bridging between CD2 on target lymphocytes and immunoglobulin Fc receptors on cytotoxic cells, such as natural killer cells. Treatment with AMEVIVE® results in a reduction in circulating total CD4+ and CD8+ T lymphocyte counts. CD2 is also expressed at low levels on the surface of natural killer cells and certain bone marrow B lymphocytes. Therefore, the potential exists for AMEVIVE® to affect the activation and numbers of cells other than T lymphocytes. In clinical studies of AMEVIVE® , minor changes in the numbers of circulating cells other than T lymphocytes have been observed.

PHARMACOKINETICS

In patients with moderate to severe plaque psoriasis, following a 7.5 mg intravenous (IV) administration, the mean volume of distribution of alefacept was 94 mL/kg, the mean clearance was 0.25 mL/h/kg, and the mean elimination half-life was approximately 270 hours. Following an intramuscular (IM) injection, bioavailability was 63%.

The pharmacokinetics of alefacept in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of alefacept have not been studied.

PHARMACODYNAMICS

At doses tested in clinical trials, AMEVIVE® therapy resulted in a dose-dependent decrease in circulating total lymphocytes2. This reduction predominantly affected the memory effector subset of the CD4+ and CD8+ T lymphocyte compartments (CD4+CD45RO+ and CD8+CD45RO+), the predominant phenotype in psoriatic lesions. Circulating na[iuml ]ve T lymphocyte and natural killer cell counts appeared to be only minimally susceptible to AMEVIVE® treatment, while circulating B lymphocyte counts appeared not to be affected by AMEVIVE® (see ADVERSE REACTIONS, Effect on Lymphocyte Counts).

CLINICAL STUDIES

AMEVIVE® was evaluated in two randomized, double-blind, placebo-controlled studies in adults with chronic (>/=1 year) plaque psoriasis and a minimum body surface area involvement of 10% who were candidates for or had previously received systemic therapy or phototherapy. Each course consisted of once-weekly administration for 12 weeks (IV for Study 1, IM for Study 2) of placebo or AMEVIVE® . Patients could receive concomitant low potency topical steroids. Concomitant phototherapy or systemic therapy was not allowed.

In Study 1, patients were randomized to receive one or two courses of AMEVIVE® 7.5 mg administered by IV bolus. The first and second courses in the two-course cohort were separated by at least a 12-week post-dosing interval. A total of 553 patients were randomized into three cohorts (Table 1).

Table 1. Treatment Group and Number of Patients Dosed in Study 1
    Course 1 (No. of patients) Course 2 (No. of patients)
Cohort 1 AMEVIVE® (183) AMEVIVE® (154)
Cohort 2 AMEVIVE® (184) Placebo (142)
Cohort 3 Placebo (186) AMEVIVE® (153)

Study 2 provided a basis for comparison of patients treated with either 10 mg or 15 mg AMEVIVE® IM. One hundred seventy-three patients were randomized to receive 10 mg of AMEVIVE® IM, 166 to receive 15 mg of AMEVIVE® IM, and 168 to receive placebo.

In Studies 1 and 2, 77% of patients had previously received systemic therapy and/or phototherapy for psoriasis. Of these, 23% and 19%, respectively, had failed to respond to at least one of these previous therapies.

Table 2 shows the treatment response in the first course of Study 1 and Study 2. Response to treatment in both studies was defined as the proportion of patients with a reduction in score on the Psoriasis Area and Severity Index (PASI) 3 of at least 75% from baseline at two weeks following the 12-week treatment period.

Other treatment responses included the proportion of patients who achieved a scoring of "almost clear" or "clear" by Physician Global Assessment (PGA) and the proportion of patients with a reduction in PASI of at least 50% from baseline two weeks after the 12-week treatment period.

Table 2. Percentage of Patients Responding to the First Course of Treatment in Study 1 (the Intravenous Study) and Study 2 (the Intramuscular Study) Two Weeks Post Dosing
Treatment response: (reduction in disease activity from baseline) Study 1 Study 2
  
Placebo (N=186)  
AMEVIVE®
7.5 mg IV (N=367) 1
  
Difference (95% CI)  
  
Placebo (N=168)  
AMEVIVE®
15 mg IM (N=166)
  
Difference (95% CI)  
>/=75% reduction PASI 4% 14% 10 * (6, 15) 5% 21% 16 * (9, 23)
>/=50% reduction PASI 10% 38% 28 * (22, 35) 18% 42% 24 * (14, 33)
PGA "almost clear" or "clear" 4% 11% 7 + (3, 12) 5% 14% 9 § (3, 15)
1 Cohorts 1 and 2 are combined.
*p values <0.001
+p value 0.004
§ p value 0.006

In Study 2, the proportion of responders to the 10 mg IM dose was higher than placebo, but the difference was not statistically significant.

In both studies, onset of response to AMEVIVE® treatment (at least a 50% reduction of baseline PASI) began 60 days after the start of therapy.

With one course of therapy in Study 1 (IV route), the median duration of response (defined as maintenance of a 75% or greater reduction in PASI) was 3.5 months for AMEVIVE® -treated patients and 1 month for placebo-treated patients. In Study 2 (IM route), the median duration of response was approximately 2 months for both AMEVIVE® -treated patients and placebo-treated patients.

Most patients who had responded to either AMEVIVE® or placebo maintained a 50% or greater reduction in PASI through the 3-month observation period.

The responders (n=52) in a subset of patients in Study 1 who crossed over to placebo for course 2 (Cohort 2) maintained a 50% or greater reduction in PASI for a median of 7 months.

Some patients achieved their maximal response beyond 2 weeks post-dosing. In Studies 1 and 2, an additional 11% (42/367) and 7% (12/166) of patients treated with AMEVIVE® , respectively, achieved a 75% reduction from baseline PASI score at one or more visits after the first 2 weeks of the follow-up period.

RETREATMENT

Patients in Study 1 who had completed the first IV treatment course were eligible to receive a second treatment course if their psoriasis was less than "clear" by PGA and their CD4+ T lymphocyte count was above the lower limit of normal. The level of response (decrease in median PASI score) over the two courses of IV treatment is shown in Figure 1. The median reduction in PASI score was greater in patients who received a second course of AMEVIVE® treatment (see Cohort 1) compared to patients who received placebo (see Cohort 2).

Data on the safety and efficacy of AMEVIVE® treatment beyond two courses are limited.

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