Source: European Medicines Agency (EU) Revision Year: 2009 Publisher: Serono Europe Ltd., 56 Marsh Wall, London E14 9TP, United Kingdom
Pharmacotherapeutic group: selective immunosuppressive agents
ATC code: L04AA21
Efalizumab is a recombinant humanized monoclonal antibody that binds specifically to the CD11a subunit of LFA-1 (lymphocyte function-associated antigen-1), a leukocyte cell surface protein.
By this mechanism, efalizumab inhibits the binding of LFA-1 to ICAM-1, which interferes with T lymphocytes adhesion to other cell types. LFA-1 is present on activated T lymphocytes, and ICAM-1 is up-regulated on endothelial cells and keratinocytes in psoriasis plaques. By preventing LFA-1/ICAM binding, efalizumab may alleviate signs and symptoms of psoriasis by inhibiting several stages in the immunologic cascade.
In studies using an initial dose of 0.7 mg/kg followed by 11 weekly doses of 1.0 mg/kg, efalizumab maximally reduced expression of CD11a on circulating T lymphocytes to approximately 15-30% of pre-dose baseline values and saturated CD11a to <5% of baseline available CD11a binding sites. The full effect was seen 24 to 48 hours after the first dose, and was maintained between weekly doses. Within 5 to 8 weeks following the 12th and final dose of efalizumab administered at 1.0 mg/kg/wk, CD11a levels returned to within a range of ±25% of baseline values.
Another pharmacodynamic marker, consistent with the mechanism of action of efalizumab, was the increase in the absolute counts of circulating leukocytes observed during efalizumab treatment. Increased absolute counts were apparent within 24 hours of the first dose, remained elevated with weekly dosing, and returned to baseline after treatment cessation. The largest increase occurred in the absolute count of circulating lymphocytes. In clinical trials, mean lymphocyte counts approximately doubled relative to baseline in subjects receiving 1.0 mg/kg/wk of Raptiva. The increase included CD4 T-lymphocytes, CD8 T-lymphocytes, B-lymphocytes, and natural killer (NK) cells, although NK cells and CD4 cells increased less relative to other cell types. At a dose of 1.0 mg/kg/wk subcutaneous efalizumab, lymphocyte levels returned to within 10% of baseline by 8 weeks post last dose.
The efficacy of Raptiva versus other systemic therapies in patients with moderate to severe psoriasis has not been evaluated in studies directly comparing Raptiva with other systemic therapies. The present results of Raptiva versus placebo over 12 weeks of treatment with different populations indicate a PASI 75 response to Raptiva in 22% to 39% of patients (see Table 2). Based on the clinical development data generated (see Table 1) and long-term experience, Raptiva is recommended for use in patients as defined in section 4.1.
Failure on prior systemic therapies is defined as insufficient response (PASI <50 or PGA less than good), or worsening of disease in patients while on treatment, and who were adequately dosed for a sufficiently long duration to assess response with at least each of the 3 major systemic therapies as available.
The safety and efficacy of Raptiva in moderate to severe plaque psoriasis patients has been demonstrated in five randomized, double-blind, placebo-controlled trials at the recommended dose (n=1742). There are no comparative data with Raptiva versus other systemic psoriasis therapies. The largest study IMP24011 (n=793) included patients (n=526) who were not controlled by, contraindicated to, or intolerant to two or more systemic therapies as judged from the patients' histories of psoriasis treatment. In all studies, the primary endpoint was the proportion of patients with a ≥75% improvement in the Psoriasis Area and Severity Index score (a PASI 75 response) relative to baseline when assessed one week after a 12-week treatment course. Secondary endpoints included the proportion of subjects who achieved a rating of Minimal or Clear on a static global assessment by the physician, the Overall Lesion Severity (OLS), the proportion of patients with a ≥50% improvement in PASI score (a PASI 50 response) relative to baseline after 12 weeks of treatment, the time-course of mean PASI percentage improvement from baseline, improvement in the Dermatology Life Quality Index (DLQI), Psoriasis Symptom Assessment (PSA), the Physician’s Global Assessment (PGA) of change, change in the PASI thickness component, and change in the body surface area affected.
In all five studies, patients randomized to the Raptiva group achieved statistically significantly better responses than placebo on the primary endpoint. The same results were confirmed in patients that were unsuitable for other systemic therapies (see Table 1 below).
Table 1. Primary Endpoint: Proportion of Subjects with ≥75% improvement in PASI after 12 weeks of Treatment (PASI 75):
| Efalizumaba | |||
|---|---|---|---|
| Patient population IMP24011 | Placebo | 1.0 mg/kg/wk | Treatment Effect [95% CI] |
| All patients | 4% (n=264) | 31% (n=529)b | 27% [22%, 32%] |
| Patients who are not controlled by, contraindicated to, or intolerant to two or more systemic therapies* | 3% (n=184) | 30% (n=342)b | 27% [21%, 32%] |
a p-values compared efalizumab with placebo using logistic regression including baseline PASI score, prior treatment for psoriasis and geographical region as covariates.
b p<0.001.
c As judged from the patients' histories of psoriasis treatments
In all five studies, patients randomized to the Raptiva dose group achieved statistically significantly better responses than placebo on the primary endpoint (PASI 75 response) (see Table 2 below) and on all the secondary efficacy endpoints.
Table 2. Primary Endpoint: Proportion of Subjects with ≥75% improvement in PASI after 12 weeks of Treatment (PASI 75):
| Efalizumaba | |||
|---|---|---|---|
| Study | Placebo | 1.0 mg/kg/wk | Treatment Effect [95% CI] |
| ACD2390g* | 4% (n=187) | 27% (n=369)b | 22% [16%, 29%] |
| ACD2058g | 2% (n=170) | 39% (n=162)b | 37% [28%, 46%] |
| ACD2059g* | 5% (n=122) | 22% (n=232)b | 17% [9%, 27%] |
| ACD2600g* | 3% (n=236) | 24% (n=450)b | 21% [15%, 27%] |
| IMP24011* | 4% (n=264) | 31% (n=529)b | 27% [22%, 32%] |
a IMP24011: p-values compared efalizumab with placebo using logistic regression including baseline PASI score, prior treatment for psoriasis and geographical region as covariates. Other studies: p-values compared each efalizumab group with placebo using Fisher’s exact test within each study.
b p<0.001.
* The efalizumab used in the study is the Genentech manufactured product
Time to relapse (≥50% loss of improvement) was evaluated in Study ACD2058g and IMP 24011 for patients who were classified as responders (≥75% improvement on PASI) after 12 weeks of treatment. The median time to relapse among PASI responders ranged from 58 to 74 days following the last Raptiva dose in the initial treatment period. In study IMP24011, approximately half of the patients (46.8%) who were partial responders (50% to 74% improvement on PASI, similar to PGA good) after 12 weeks of Raptiva treatment achieved a PASI 75 response at week 24.
Data from extended treatment (more than 12 weeks) have been obtained from 4311 patients in open label uncontrolled studies. Over 600 patients have been treated for more than 1 year including 166 patients treated for more than 2 years and up to 3 years. Approximately half of the patients treated for more than 1 year were PASI 75 responders (when all dropouts were considered as non-responders).
After subcutaneous administration of efalizumab peak plasma concentrations are reached after 1-2 days. Comparison with intravenous data indicated an average bioavailability of about 50% at the recommended dose level of 1.0 mg/kg/wk subcutaneous.
Steady state was achieved at week 4. At the 1 mg/kg/wk dose level (with an initial dose of 0.7 mg/kg the first week), mean efalizumab plasma trough values were 11.1±7.9 µg/ml. Measurements of volume of distribution of the central compartment after single intravenous doses were 110 ml/kg at dose 0.03 mg/kg and 58 ml/kg at dose 10 mg/kg.
The metabolism of efalizumab is through internalisation followed by intracellular degradation as a consequence of either binding to cell surface CD11a or through endocytosis. The expected degradation products are small peptides and individual amino acids which are eliminated by glomerular filtration. Cytochrome P450 enzymes as well as conjugation reactions are not involved in the metabolism of efalizumab.
Efalizumab is cleared by nonlinear saturable elimination (dose dependent). Mean steady state clearance is 24 ml/kg/day (range 5-76 ml/kg/day) at 1 mg/kg/week subcutaneous. The elimination half-life was about 5.5-10.5 days at 1 mg/kg/week subcutaneous. Tend at steady state is 25 days (range 13-35 days). Weight is the most significant covariate affecting efalizumab clearance.
Efalizumab shows dose-dependent nonlinear pharmacokinetics which can be explained by its saturable specific binding to cell surface receptors CD11a. It appeared that the receptor mediated clearance of efalizumab was saturated when plasma efalizumab concentrations were above 1 μg/ml.
Through population pharmacokinetic analysis, weight was found to affect efalizumab clearance. Covariates as baseline PASI, baseline lymphocyte count and age had modest effects on clearance; gender and ethnic origin had no effect. The pharmacokinetics of efalizumab in paediatric patients have not been studied. The effect of renal or hepatic impairment on the pharmacokinetics of efalizumab has not been studied.
Antibodies to efalizumab were detected in only 6% of patients evaluated. In this small number of patients no differences were observed in either pharmacodynamic or pharmacokinetic parameters.
Efalizumab does not cross-react with CD11a from species other than humans and chimpanzees. Therefore, conventional non-clinical safety data with the medicinal product are limited and do not allow for a comprehensive safety assessment. Inhibitory effects were observed on the humoral and T-cell dependent immune responses. In pups of mice treated with an antibody analogue of efalizumab, a decrease in T-cell dependent immunity was observed up to at least 11 weeks of age. Only at 25 weeks of age was this decrease no longer significant.
Otherwise, the effects observed in non-clinical studies could be related to the pharmacology of efalizumab.
No lymphomas were observed following 6 months treatment with an antibody analogue of efalizumab in a 6 months study with p53 / wild type mice.
No teratogenic effects were seen in mice during organogenesis.
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