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Mechanism of Action
RAPTIVA (efalizumab) binds to CD11a, the α subunit of leukocyte function antigen-1 (LFA-1), which is expressed on all leukocytes, and decreases cell surface expression of CD11a. RAPTIVA (efalizumab) inhibits the binding of LFA-1 to intercellular adhesion molecule-1 (ICAM-1), thereby inhibiting the adhesion of leukocytes to other cell types. Interaction between LFA-1 and ICAM-1 contributes to the initiation and maintenance of multiple processes, including activation of T lymphocytes, adhesion of T lymphocytes to endothelial cells, and migration of T lymphocytes to sites of inflammation including psoriatic skin. Lymphocyte activation and trafficking to skin play a role in the pathophysiology of chronic plaque psoriasis. In psoriatic skin, ICAM-1 cell surface expression is upregulated on endothelium and keratinocytes. CD11a is also expressed on the surface of B lymphocytes, monocytes, neutrophils, natural killer cells, and other leukocytes. Therefore, the potential exists for RAPTIVA (efalizumab) to affect the activation, adhesion, migration, and numbers of cells other than T lymphocytes.
In patients with moderate to severe plaque psoriasis, following an initial SC RAPTIVA (efalizumab) dose of 0.7 mg/kg followed by 11 weekly SC doses of 1 mg/kg/wk, serum concentrations reached a steady-state at 4 weeks with a mean trough concentration of approximately 9 µg/mL (n = 26). After the last dose, the mean peak concentration was approximately 12 µg/mL (n = 25). Mean steady-state clearance was 24 mL/kg/day (range = 5-76 mL/kg/day, n = 25). Mean time to eliminate RAPTIVA (efalizumab) after the last steady-state dose was 25 days (range = 13-35 days, n = 17). The mean estimated RAPTIVA (efalizumab) SC bioavailability was 50%. In a population pharmacokinetic analysis of 1088 patients, body weight was found to be the most significant covariate affecting RAPTIVA (efalizumab) clearance. In patients receiving weekly SC doses of 1 mg/kg, RAPTIVA (efalizumab) exposure was similar across body weight quartiles. RAPTIVA (efalizumab) clearance was not significantly affected by gender or race. The pharmacokinetics of RAPTIVA (efalizumab) in pediatric patients have not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of RAPTIVA (efalizumab) have not been studied.
At a dose of 1 mg/kg/wk SC, RAPTIVA (efalizumab) reduced expression of CD11a on circulating T lymphocytes to approximately 15-25% of pre-dose values and reduced free CD11a binding sites to a mean of ≤ 5% of pre-dose values. These pharmacodynamic effects were seen 1-2 days after the first dose, and were maintained between weekly 1 mg/kg SC doses. Following discontinuation of RAPTIVA (efalizumab) , CD11a expression returned to a mean of 74% of baseline at 5 weeks and stayed at comparable levels at 8 and 13 weeks. Following discontinuation of RAPTIVA (efalizumab) , free CD11a binding sites returned to a mean of 86% of baseline at 8 weeks and stayed at comparable levels at 13 weeks. No assessments of CD11a expression or free CD11a binding sites were made after 13 weeks.
In clinical trials, RAPTIVA (efalizumab) treatment resulted in a mean increase (relative to baseline) in white blood cell (WBC) count of 34%, a doubling of mean lymphocyte counts and an increase in eosinophil counts of 29% due to decreased leukocyte adhesion to blood vessel walls and decreased trafficking from the vascular compartment to tissues. At Day 56 of 1 mg/kg/wk RAPTIVA (efalizumab) treatment, 32% (213/676) of patients had a shift in total WBC from low or normal baseline value to above normal, 46% (324/701) had a shift to above normal absolute lymphocyte counts, and 5% (35/675) had a shift to above normal eosinophil counts. Following discontinuation of RAPTIVA (efalizumab) treatment, the abnormal elevated lymphocyte counts took approximately 8 weeks to normalize among patients who had above normal lymphocyte counts. Plasma samples collected after first administration of 0.3 mg/kg IV RAPTIVA (efalizumab) indicate that at 2 hours TNF-oc and IL-6 plasma levels were elevated 9- and 90-fold, respectively, compared with baseline. Plasma samples collected after first administration of 0.7 mg/kg SC RAPTIVA (efalizumab) indicate that at 2 days, IL-6 levels were elevated (10 pg/mL as compared with 5 pg/mL at baseline), whereas TNF-α was not detectable. In RAPTIVA (efalizumab) -treated patients the mean levels of C reactive protein increased from baseline by 67% and the mean levels of fibrinogen increased by 15%.
RAPTIVA (efalizumab) was evaluated in four randomized, double-blind, placebo-controlled studies in adults with chronic ( > 6 months), stable, plaque psoriasis, who had a minimum body surface area involvement of 10% and who were candidates for, or had previously received systemic therapy or phototherapy. In these studies 54-70% of patients had previously received systemic therapy or phototherapy (PUVA) for psoriasis. Patients with clinically significant flares and patients with guttate, erythrodermic, or pustular psoriasis as the sole form of psoriasis were excluded from the studies. Patients were randomized to receive doses of 1 mg/kg or 2 mg/kg of RAPTIVA (efalizumab) or placebo administered once a week for 12 weeks. Patients randomized to RAPTIVA (efalizumab) received 0.7 mg/kg as the first dose prior to receiving the full assigned dose in subsequent weeks. During the studies, patients could receive concomitant low potency topical steroids. No other concomitant psoriasis therapies were allowed during treatment or the follow-up period.
Patients were evaluated using the Psoriasis Area and Severity Index (PASI) during the study. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of the psoriatic changes within the affected regions (erythema, infiltration/plaque thickness, and desquamation). Both treatment groups in all four studies had baseline median PASI scores of 17. Both treatment groups across all four studies had baseline median body surface area involvement ranging between 22-28%. Compared with placebo, more patients randomized to RAPTIVA (efalizumab) had at least a 75% reduction from baseline PASI score (PASI-75) 1 week after the 12-week treatment period (Table 1). RAPTIVA (efalizumab) 2 mg/kg was not superior to RAPTIVA (efalizumab) 1 mg/kg.
Table 1: Proportion of Patients with ≥ 75% Improvement
in PASI after 12 Weeks of Treatment (PASI-75)
|Placebo||RAPTIVA 1 mg/kg/wk||Difference (95%CI)|
|Study 1|| 4%
n = 187
n = 369
|Study 2|| 2%
n = 170
n = 162
|Study 3|| 5%
n = 122
n = 232
|Study 4|| 3%
n = 236
n = 450
|a p < 0.001 for comparison of RAPTIVA group with placebo group using Fisher's exact test within each study.|
All three components of the PASI (plaque induration, scaling, and erythema) contributed comparably to the improvement in PASI. Other clinical responses evaluated (Table 2) included the proportion of patients who achieved minimal or clear status by a static Physician Global Assessment (sPGA) and the proportion of patients with a reduction in PASI of at least 50% from baseline (PASI-50) 1 week following the 12-week treatment period. The sPGA is a 6 category scale ranging from “very severe” to “clear” indicating the physician's overall assessment of the psoriasis severity focusing on plaque, scaling and erythema. Treatment success of minimal or clear consisted of none or slight elevation in plaque, none or minimal white color in scaling, and up to moderate definite red coloration in erythema. Across all four studies, the percentage of patients with baseline sPGA classifications of moderate was 48-56%, severe 33-43%, and 3-6% were classified as very severe.
Table 2: Percentage of Patients Responding after 12 Weeks
|Outcome Measurement||Study||Placebo||RAPTIVA 1 mg/kg/wk|| Differencea
|sPGA: Minimal or Clear||1||3%||26%|| 23%
|> 50% improvement in PASI (PASI-50)||1||14%||59%|| 45%
|The number of patients in each study and treatment group is
the same as listed in Table 1.
a p < 0.001 for comparison of RAPTIVA (efalizumab) group to placebo group using Fisher's exact test for all comparisons between groups.
In Study 1, 12% of RAPTIVA (efalizumab) -treated patients achieved a PASI-50 at Week 4 compared with 5% for placebo. The median time to PASI-50 among PASI-75 achievers was approximately 6 weeks. Similar results were observed in Studies 2, 3, and 4.
In Study 3, sustained response to extended RAPTIVA (efalizumab) treatment was evaluated. RAPTIVA (efalizumab) -treated patients who achieved a PASI-75 response at Week 12 were re-randomized to receive RAPTIVA (efalizumab) or placebo for a second contiguous 12-week treatment period. Sixty-one of 79 patients (77%) re-randomized to a second 12-week treatment period with RAPTIVA (efalizumab) maintained PASI-75 response compared with 8 of 40 patients (20%) re-randomized to placebo. Sustained responses to RAPTIVA (efalizumab) have also been observed in uncontrolled, open-label extension treatment trials when patients received RAPTIVA (efalizumab) without interruption for 24 weeks.
In Study 2, response to intermittent RAPTIVA (efalizumab) treatment was evaluated among patients who achieved PASI-75 response with 12 weeks of RAPTIVA (efalizumab) treatment and were followed off-treatment until relapse of psoriasis (50% loss of treatment response). In patients who resumed RAPTIVA (efalizumab) treatment upon relapse of psoriasis, 31% (17/55) re-established a PASI-75 response (compared with the initial baseline). After 12 weeks of treatment, the median duration of a PASI-75 response after RAPTIVA (efalizumab) discontinuation was between 1 and 2 months.
The safety and efficacy of RAPTIVA (efalizumab) therapy beyond 1 year have not been established.
Last reviewed on RxList: 4/16/2009
This monograph has been modified to include the generic and brand name in many instances.
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