"A US Food and Drug Administration (FDA) advisory panel has backed a new biologic for psoriasis, though the panelists recommended strong warnings about the potential for suicide and self-injurious behavior (SIB) with the drug.
Mechanism of Action
AMEVIVE® interferes with lymphocyte activation by specifically binding to the lymphocyte antigen, CD2, and inhibiting the interaction between CD2 and its ligand, LFA-3. 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.
AMEVIVE® also causes a reduction in subsets of CD2+ T lymphocytes and circulating total CD4+ and CD8+ T lymphocyte counts. In clinical studies of AMEVIVE®, minor changes in the numbers of circulating cells other than T lymphocytes have been observed.
At doses tested in clinical trials, AMEVIVE® therapy resulted in a dose-dependent decrease in circulating total lymphocytes. 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 naive 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].
In patients with moderate to severe plaque psoriasis, following a 7.5 mg intravenous 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 injection, bioavailability was 63%.
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 (intravenous for Study 1, intramuscular 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 intravenous 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
|Course 1 (No. of patients)||Course 2 (No. of patients)|
|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® intramuscular. One hundred seventy-three patients were randomized to receive 10 mg of AMEVIVE® intramuscular, 166 to receive 15 mg of AMEVIVE® intramuscular, 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) 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
|Study 1||Study 2|
| Treatment response:
(reduction in disease activity from baseline)
7.5 mg intravenous
|Difference (95% CI)|| Placebo
15 mg intramuscular
|≥ 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)|
|*Cohorts 1 and 2 are combined.|
In Study 2, the proportion of responders to the 10 mg intramuscular dose was higher than placebo, but the difference was not statistically significant.
In both studies, onset of response to AME VIVE® 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 (intravenous 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 (intramuscular 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.
Among responders in Study 1 who received AMEVIVE® 7.5 mg intravenous or in Study 2 who received AMEVIVE® 15 mg intramuscular and were followed off active treatment before AMEVIVE® retreatment, a 50% or greater reduction in PASI was maintained 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.
Patients in Study 1 who had completed the first intravenous 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 intravenous 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).
Figure 1. Median PASI Score Over Time
Last reviewed on RxList: 11/29/2016
This monograph has been modified to include the generic and brand name in many instances.
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