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Efalizumab in the Treatment of Psoriasis

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Efalizumab in the Treatment of Psoriasis DRUG PROFILE Efalizumab in the treatment of psoriasis Christine Della Croce†, MA, Efalizumab was approved by the US Food and Drug Administration in 2003 for the Vicky Kwan Wong, CCRC, treatment of moderate-to-severe plaque psoriasis. In Phase I, II and III trials, efalizumab has & Mark G Lebwohl, MD shown significant improvement in the psoriasis area and severity index and quality of life †Author for correspondence Mt Sinai School of Medicine, measures in those patients treated with the drug. The most frequently reported side 5 East 98th Street, Box 1048, effects were acute adverse events that occurred within 48 h of the first two doses Department of Dermatology (predefined during the trials as headache, chills, nausea, fever, myalgia and vomiting). New York, NY 10029, USA Tel.: +1 212 241 3288 Fax: +1 212 876 8961 [email protected] Psoriasis is an incurable autoimmune disease that of patients need phototherapy and/or systemic is mediated by T-lymphocytes [1–17]. It is a therapy [5]. All of these treatments do have the chronic skin disorder characterized by inflamma- potential for serious side effects, such as hepatox- tion producing red, thickened areas with a flaky icity and nephrotoxicity (methotrexate, white build-up [2]. Normally, skin cells mature cyclosporine), teratogenicity (oral retinoids and gradually and are shed approximately every methotrexate) and skin cancer (long-wave ultravi- 30 days. New skin cells replace the outer layers of olet radiation photochemotherapy [PUVA]), the skin surface that are shed. In psoriasis, skin which limits their long-term use [6]. With the cells do not mature but instead move rapidly up number of side effects and contraindications of to the surface of the skin and build up, forming existing treatments, new psoriasis therapies are in the characteristic psoriasis plaque [101]. The areas high demand. Several biologics interfering with range in size from small to large and typically key steps in the immunopathogenesis of the dis- occur on the knees, elbows, scalp, hands, feet or ease have the potential to treat moderate-to-severe lower back. Psoriasis tends to be most prevalent psoriasis [5]. in adults and those of the Caucasian race [3]. Well over 40 biologic compounds are being Plaque-type psoriasis is the most common form developed for psoriasis, some of which have of the disease, occurring in approximately 80% already been approved by the US Food and of cases [3]. Guttate psoriasis occurs in about 10% Drug Administration (FDA). Along with efali- of patients and erythrodermic and pustular zumab, two other biologic therapies have been psoriasis each occur in fewer than 3% [3]. approved by the FDA for the treatment of Presently, there are several strategies of treat- chronic plaque psoriasis: etanercept and ale- ment for psoriasis; light, systemic, topical and facept. Etanercept is a fully human recombinant biologic treatment. The unmet need for safe tumor necrosis factor (TNF)-receptor fusion and effective therapies has generated the devel- protein [6,7]. Etanercept counteracts the effects opment of biologic therapies for psoriasis [1]. of endogenous TNF by inhibiting its interac- Efalizumab is a biologic therapy designed to tar- tion with cell surface receptors [6,7]. It has been get one possible step in the pathogenesis of pso- shown to be effective in patients with rheuma- riasis. It is a humanized monoclonal toid and psoriatic arthritis [7]. Etanercept has immunoglobulin (Ig)G1 antibody that inhibits proven to be effective in clinical trials. In a 24- T-cell activation and the binding of T-lym- week, double-blind study, 672 patients were phocytes to endothelial cells and their subse- randomized. Of these, 652 patients received quent migration [2]. Phase I and II studies either placebo or etanercept subcutaneously at a Keywords: biologic therapies, demonstrated that efalizumab treatment results low (25 mg once weekly), medium (25 mg efalizumab, psoriasis in histologic improvement and clinical benefit twice weekly), or high dose (50 mg twice in patients with moderate-to-severe psoriasis [4]. weekly) [7]. At week 24, there was at least 75% improvement in the psoriasis area and severity Overview index (PASI) percent of the patients in the low- Psoriasis is one of the most common diseases in dose group, 44% in those in the medium-dose dermatology. Most psoriasis patients are treated and 59% in the high-dose group [7]. The PASI Future Drugs Ltd with topical treatments, but approximately 20% assess the extent of psoriasis on four body 10.1586/14750708.1.2.197 © 2004 Future Drugs Ltd ISSN 1475-0708 Therapy (2004) 1(2), 197–202 197 DRUG PROFILE – Della Croce, Kwan Wong & Lebwohl surface areas (head, trunk and upper and lower Pharmacodynamics, pharmacokinetics & limbs) and the degree of plaque erythema, scal- metabolism ing and thickness. The PASI scores account for Various Phase I and II studies investigated the both the extent of body surface area affected by pharmacodynamic properties of efalizumab in the erythema, scaling and thickness and the intravenous studies. The studies were carried severity of these measures. The score ranges from out either as a single intravenous dose of 0.01– 0 (no disease) to 72 (maximal disease). The PASI 30 mg/kg [9,10] or repeated weekly administra- improvements were similar in responses in the tions of 0.01–1.0 mg/kg/week for up to 8 weeks global assessments by physicians and the [11,12]. Blood samples from treated patients were patients’ quality of life measures [7]. subjected to fluorescence-activated cell sorter Alefacept is a fully human fusion protein analyses. These analyses reveal the relationship which has the extracellular domain of the lym- of CD11a and lymphocytes. In the single-dose phocyte function-associated antigen (LFA)3 study, treatment with efalizumab caused a rapid fused to an IgG1 T-cell modulator. Alefacept reduction in CD11a expression on T-cells and interferes with the activation of T-lymphocytes concentrations of efalizumab increased with by blocking the costimulator CD2 molecule dose [9–13]. CD11 levels on lymphocytes and mediates T-cell elimination by inducing remained controlled as long as efalizumab programmed cell death [6]. It is believed that remained in the circulation [9–12]. Doses above these two processes contribute to the drug’s 0.3 mg/kg were required for the full pharmaco- clinical effectiveness. Alefacept has also proven dynamic effect [9–13]. After multiple weekly to be effective in clinical trials. In a review of doses, circulating lymphocytes remained Phase II and III studies, a third of the patients elevated but did not increase [9,10]. studied achieved a reduction in PASI of either According to statistics provided by the manufac- greater than or equal to 75% and of nearly two- turer of efalizumab, at a dose of 1 mg/kg, efalizu- thirds in PASI of either greater than or equal to mab reduced expression of CD11 on circulating T- 50% [8]. lymphocytes to approximately 12 to 55% of pre- dose values and reduced free CD11a binding sites Introduction & chemistry of the to a mean of either greater than or equal to 5% of compound predose values. These pharmacodynamic effects Biologic therapies are designed to target the were observed 1 to 2 days after the first dose and mechanisms that cause diseases. In order for a were maintained between weekly 1 mg/kg doses. biologic to target psoriasis, one of these four Following discontinuation of efalizumab CD11a strategies are activated: reduction of pathogenic expression returned to a mean of 74% of baseline T-cells; inhibition of T-cell activation and at five weeks and remained at comparable levels at migration; correction of cytokine deviation; or weeks 8 and 13. At complete discontinuation of blocking proinflammatory cytokines [6]. Efali- efalizumab, free CD11a binding sites returned to a zumab employs inhibition of T-cell activation mean of 86% of baseline [Genentech Inc.: Raptiva® and migration. It is a humanized monoclonal (efalizumab) package insert (2003)]. antibody to CD11A, which in combination Histological analyses of psoriasis lesions from with CD18, forms the heterodimer integrin patients in studies showed constant reductions in LFA-1 on the surface of T-cells [1–5]. CD11a is epidermal thickness after efalizumab administra- also expressed on the surface of B-lymphocytes, tion [9,11–13]. The number of T-cells in the der- monocytes, neutrophils, natural killer cells and mis and epidermis was reduced by greater than other leukocytes [Genentech Inc.: Raptiva® (efalizumab) 50% on day 28 for patients who received package insert (2003)]. The interaction between LFA- repeated does of the drug [11–13]. On day 28, the 1 on T-cells and intracellular cell adhesion mol- majority of patients showed no apparent CD11a ecule (ICAM)-1 on antigen presenting cells is binding sites in their skin [11,13]. The clinical, an important costimulatory signal resulting in histological and pharmacodynamic data from T-cell activation [1]. ICAM-1 on endothelial these studies demonstrated that by reducing the cells also interacts with LFA-1 on circulating T- available CD11a on circulating and cutaneous T- cells, a necessary step for migration of T-cells cells, efalizumab can block the inflammatory into inflamed skin [1]. Efalizumab can thus process that defines psoriasis [13]. interfere with development of psoriasis by In an early study, 39 patients with moderate- blocking T-cell migration into the skin and by to-severe psoriasis were treated with intravenous preventing T-cell activation. doses of efalizumab for 7 weeks. In an open-label, 198 Therapy (2004) 1(2) Efalizumab – DRUG PROFILE multiple-dose escalation, Phase I/II study. Sub- 1 month. Patients in category 3 experienced a jects received the following levels of efalizumab in mean decrease in PASI score from baseline of a dose-escalation design: 47% at day 56 compared with 45% in category 2 • Group A: 0.1 mg/kg every other week and 10% in category 1 (p < 0.001) [14].
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