To assess the efficacy and safety of a 24-week course of efalizumab.
Phase 3, randomized, double-blind, parallel-group, placebo-controlled 12-week study followed by a 12-week open-label study.
Outpatient dermatology clinics. Patients A total of 556 patients with moderate to severe chronic plaque psoriasis who were seeing an outpatient dermatologist were included in the study. Intervention For weeks 1 to 12, the 556 patients were randomized to receive 1 mg/kg of efalizumab weekly or placebo subcutaneously. For weeks 13 to 24, 516 of these patients received 1 mg/kg of efalizumab weekly.
Proportion of patients with a 75% or greater improvement in Psoriasis Area and Severity Index (PASI-75), a 50% or greater improvement in PASI (PASI-50), static Physician's Global Assessment (sPGA) rating of minimal or clear, and improvements in Dermatology Life Quality Index (DLQI), itching scale, and Psoriasis Symptom Assessment (PSA) frequency and severity scores at weeks 12 and 24. Safety was evaluated by reviewing adverse events, laboratory parameters, vital signs, and anti-efalizumab antibodies.
At week 12, 26.6% of efalizumab-treated patients achieved PASI-75 and 58.5% achieved PASI-50. After 24 weeks of continuous efalizumab therapy, PASI responses increased: 43.8% of patients achieved PASI-75 and 66.6% achieved PASI-50. The percentage of patients who achieved an sPGA rating of minimal or clear increased from 25.7% to 35.9%. The mean percentage of improvement in all patient-reported outcomes (DLQI, itching scale, and PSA frequency and severity scores) at week 12 was maintained at week 24 (DLQI, 49.2%; itching scale, 42.2%; PSA frequency, 47.6%; PSA severity, 47.3%). There was a decline in overall reported adverse events from weeks 1 to 12 (80.4%) to weeks 13 to 24 (63.2%) without evidence of cumulative toxic effects. Conclusion Extending efalizumab treatment from 12 to 24 weeks leads to improved efficacy and maintenance of quality of life with no evidence of cumulative toxic effects noted in patients with moderate to severe chronic plaque psoriasis.
"Five RCTs evaluated the anti-T cell agents, with one alefacept study , and two efalizumab studies [30, 32] reporting results using FDA-approved doses. Seven RCTs evaluated the anti-TNF agents, with three infliximab studies [37, 38, 40], two adalimumab studies [41–43], and one etanercept study  reporting results using FDA-approved doses. "
[Show abstract][Hide abstract] ABSTRACT: Introduction
The objective of this review was to conduct a systematic review with meta-analysis and Bayesian mixed treatment comparisons (MTC) evaluating the impact of biologics on non-Psoriasis Area and Severity Index (PASI) health outcomes in patients with moderate-to-severe plaque psoriasis.
MEDLINE and Cochrane Central Register of Controlled Trials were searched from 1966 to May 2009. Citations were screened for randomized, controlled trials of biologics versus either placebo or each other in adults with moderate-to-severe plaque psoriasis and reported any of several outcomes. Traditional and Bayesian MTC meta-analyses were conducted for each endpoint using either a random- or fixed-effect model where appropriate.
Thirty-eight studies met eligibility criteria. All biologics showed significant improvement in achieving a good response on the static physician’s global assessment (PGA) versus placebo while, in the MTC, differences were noted between individual drugs. In achieving a good response on the dynamic PGA, all biologics showed significant improvements over placebo, while the MTC showed significant improvements with the anti-interleukins versus anti-T cells. Relative to placebo, antitumor necrosis factor (TNF) agents and anti-interleukins showed significant improvements in the Dermatology Life Quality Index (DLQI). Compared with placebo, the anti-TNF agents showed significant improvements in both 36-item Medical Outcomes Study Short-Form General Health Survey (SF-36) mental and physical component scores, while anti-T cell agents showed no improvements. The MTC showed no differences between any biologics for either the DLQI or SF-36.
Individual biologics and classes showed consistent benefits across non-PASI health outcomes in patients with moderate-to-severe plaque psoriasis while MTC meta-analyses suggested that some differences exist.
Dermatology and Therapy 12/2012; 2(1):9. DOI:10.1007/s13555-012-0009-3
"The long-term continuous efalizumab therapy not only sustained the efficacy without increasing cumulative and organ toxicity, but also resulted in additional clinical improvement, as demonstrated in two other clinical trials. In-fact in a phase III randomized double-blind placebo-controlled trial followed by an open-label study, 26.6% and 58.5% of patients, achieving PASI-75 and PASI-50 after 12 weeks therapy with the 1 mg/kg dose, rose to 43% and 66% after 24 weeks of continued treatment, respectively (Menter et al 2005). In a consecutive open-label trial, the PASI improvement was maintained throughout the 30-month treatment period (Gottlieb et al 2006). "
[Show abstract][Hide abstract] ABSTRACT: Chronic plaque psoriasis affects more than 2% of world population, has a chronic recurrent behavior, gives a heavy burden to the patients' quality of life, and hence remains a huge medical and social problem. The clinical results of conventional therapies of psoriasis are not satisfactory. According to the current knowledge of the molecular and cellular basis of psoriasis, it is defined as an immune-mediated chronic inflammatory and hyperproliferative skin disease. A new generation of biological drugs, targeting molecules and cells involved into perturbed pro-inflammatory immune response in the psoriatic skin and joints, has been recently designed and applied clinically. These biological agents are bioengineered proteins such as chimeric and humanized antibodies and fusion proteins. In particular, they comprise the antitumor necrosis factor-alpha agents etanercept, infliximab, and adalimumab, with clinical efficacy in both moderate-severe psoriasis and psoriatic arthritis, and the anti-CD11a efalizumab with selective therapeutic action exclusively in the skin. Here, we overview recent findings on the molecular pathways relevant to the inflammatory response in psoriasis and present our clinical experience with the drugs currently employed in the dermatologic manifestations, namely etanercept, infliximab, and efalizumab. The growing body of clinical data on the efficacy and safety of antipsoriasis biological drugs is reviewed as well. Particular focus is given to long-term safety concerns and feasibility of combined therapeutic protocols to ameliorate clinical results.
"Approximately 30% of patients will have at least 75% improvement of their skin disease following a standard 12-week course of therapy (drug is typically given subcutaneously at a weekly dose of 1 mg kg À1 ) (Gordon et al., 2003; Lebwohl et al., 2003; Leonardi et al., 2005; Menter et al., 2005). Sustained efficacy in the treatment of psoriasis patients over longer periods of time has also been described (Lebwohl et al., 2003; Leonardi et al., 2005; Menter et al., 2005). As patients improve, T-cell numbers are reduced in healing skin, whereas T-cell numbers are increased in peripheral blood (Krueger et al., 2000; Gottlieb et al., 2002; Vugmeyster et al., 2004), consistent with efalizumab's role in blocking T-cell extravasation into skin. "
[Show abstract][Hide abstract] ABSTRACT: Efalizumab is an mAb directed against CD11a, a molecule involved in T-cell activation and extravasation from blood into tissue. Ten patients with severe atopic dermatitis were treated with efalizumab for 84 days, and peripheral blood mononuclear cells were analyzed for expression of activation and adhesion markers. Efalizumab treatment led to decreases in CD11a mean fluorescence intensity (MFI) on naive, central memory, and effector memory CD4+ and CD8+ T cell subsets. MFI for CD18 was decreased in both CD4+ and CD8+ T cells. Percentages of cells positive for cutaneous lymphocyte antigen (CLA) were increased fourfold in all CD4+ and CD8+ T cell subsets. Increases in the percentages of CD4+ and CD8+ T cells expressing beta7 and CD49d were also observed. No significant changes were observed in the percentages of CD4+ and CD8+ T cells that produced either IFN-gamma or IL-4. In summary, efalizumab treatment resulted in (i) decreases in CD11a and CD18 expression in all circulating T-cell subsets and (ii) increases in the percentages of blood T cells expressing tissue homing markers (CLA, beta7, CD49d). These data suggest that blockade of T-cell extravasation into tissue is the major pathway by which efalizumab leads to improvement in cutaneous inflammation.
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