Treating Psoriasis by Selective T-Cell Targeting: Considerations for Incorporating Biologic Therapies into Clinical Practice

Data presented by Mark G. Lebwohl, MD, Professor and Chairman of the Department of Dermatology, Mount Sinai School of Medicine, New York, New York and Kenneth Gordon, MD, Associate Professor of Medicine, Division of Dermatology; Director, Psoriasis Clinical and Research Program, Loyola University Medical Center, Maywood, Illinois

The targeted effects of immunobiologic agents represent an important advancement in the treatment of psoriasis. Unlike the immunosuppressive activities of systemic agents such as methotrexate and cyclosporine, the effects of immunobiologic agents are highly specific, suppressing inappropriate immune activation. The promise of this approach is both improved clinical efficacy and a reduction in extra-cutaneous toxicity.

The premise of biologic treatments falls into 4 interventional strategies: selectively targeting pathogenic T cells (alefacept); inhibiting T-cell activation (alefacept, efalizumab); inducing immune deviation; and inhibiting cytokines (etanercept, infliximab). At the present time, alefacept is the only biologic agent approved by the FDA for the treatment of psoriasis. The mechanism of action of alefacept is to inhibit T-cell activation and selectively reduce pathogenic memory T cells.

Duration of Benefit From Alefacept Following Intramuscular Administration Comparable to Intravenous Administration

In phase 3 studies, patients were randomized to a first course of weekly intramuscular alefacept either 15 mg or 10 mg or placebo for a period of 12 weeks with a subsequent observation period of 12 weeks. During the second course of therapy, patients received intramuscular alefacept 15 mg, 10 mg, and 10 mg, respectively.

After 2 courses of therapy with 15 mg intramuscular alefacept, 69% of patients demonstrated ≥50% PASI reduction and 43% showed ≥75% PASI reduction. These results are comparable to those observed with intravenous administration of alefacept 7.5 mg (71% and 40%, respectively). Moreover, the median duration of ≥50% PASI reduction in patients who achieved ≥75% PASI reduction at any time during the study with intramuscular alefacept was 7 months, comparable to intravenous alefacept, also 7 months. The median duration of ≥50% PASI reduction in patients who achieved a PGA of "almost clear" or "clear" at any time during the study was 8 months for intramuscular alefacept, comparable to intravenous alefacept, also 8 months.

The availability of intramuscular alefacept offers the clinician a treatment option that has demonstrated comparability to the intravenous formulation in terms of safety and efficacy, duration of response, and tolerability.

Treatment Option for Refractory Patients

A pooled analysis demonstrated alefacept was efficacious for patients who are contraindicated or refractory to methotrexate, cyclosporine, PUVA, UVB or retinoids. For this patient population, alefacept administration (n = 488) resulted in ≥75% PASI reduction in 26.8% of patients compared to 8.8% of placebo-treated patients (P<.001). For alefacept and placebo-treated patients respectively, 53.1% and 25.7% experienced ≥50% PASI reduction.

Extensive Safety Data

As a result of numerous clinical trials, the alefacept safety database is extensive. The safety database is classified by courses of alefacept therapy (1 to 7 courses). The incidence of adverse events does not increase even in patients who have received multiple courses of therapy.

Similarly, the overall rates of infection were low (≤10%) and consistent with those seen with placebo administration. The incidence of serious infections is similarly low (<1%) for patients having received between 1 and 3 courses of therapy. For patients having received between 4 and 6 courses of therapy, there have been no reported serious infections. Malignancies of any kind have been rare. The overall malignancy rate associated with alefacept administration is 25.6 per 1000 person-years exposure compared to the expected malignancy rate of 29 in psoriasis patients. This data reveals the alefacept-treated patients have no higher malignancies than the general psoriatic patient population.
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Keynote Address

Data presented in a Keynote Address by Menno de Rie, MD, Dept. Dermatology, Academic Medical Centre, Amsterdam, The Netherlands

Laboratory and clinical evidence suggests that psoriasis is a T-cell lymphocyte-mediated inflammatory disease. An understanding of T-Cell activation and inhibition proteins have enabled the development of new biologic therapies to treat psoriasis. Traditional therapies such as cyclosporin and methotrexate have been associated with limitations and toxicities in treating psoriasis leaving the clinician and the patient with few choices in managing the disease. Understanding the immunologic basis of psoriasis has led to the development of biologic treatment strategies.

The approval of alefacept in January 2003 ushered in the era of immunobiologics for psoriasis and provided a new benchmark for comparison of alternative molecular targets. Phase II and III studies have shown that efalizumab and the TNF-α inhibitors infliximab and entanercept show promise in this dynamic field.

A new era of psoriasis therapy has begun with the approval of alefacept. As new biologics are added to the treatment armamentarium clinicians will now have drugs to selectively modulate various stages in the pathogenesis of this chronic disease.
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Using Biologic Therapies in Clinical Practice to Treat Psoriasis

Data presented by Kenneth Gordon, MD, Associate Professor of Medicine, Division of Dermatology; Director, Psoriasis Clinical and Research Program, Loyola University Medical Center, Maywood, Illinois

According to the results of a study presented here, CD4+ memory T-cell reductions are related to clinical response rates observed with intravenous alefacept administration. In a multicenter, double-blind, 2-course, placebo-controlled study, a total of 553 patients with chronic plaque psoriasis were randomized to 1 of 3 cohorts: alefacept 7.5 mg (course 1 and 2); alefacept 7.5 mg in course 1 and placebo in course 2; placebo in course 1 and alefacept 7.5 mg in course 2. Treatment was administered once weekly for 12 weeks followed by a 12-week observational period.

Study assessments included serial blood samples (baseline, weekly, and every 2-4 weeks during follow-up) of circulating total lymphocytes, CD4+ and CD8+ memory and naпve T cells, CD19+ B cells, CD16+/CD56+ natural killer cells. PASI and PGA were also assessed.

Patients were divided into four quartiles based on the degree of reduction in CD4+ memory T cells. The results showed the greater the reduction in memory T cells, the greater the likelihood of achieving PASI 75% reduction.

Improvement in Quality of Life

Quality of life improvements have also been observed with alefacept administration. There has been a strong correlation between degree of objective response seen with alefacept administration and the degree of benefit as measured by quality of life. The Dermatology Life Quality Index (DLQI), is a validated 10-item questionnaire for measuring the impact of skin diseases on patient lives. DLQI ranges from 0, no impact, to 30, high impact. The overall change in DLQI has been highly significant for responders to alefacept versus non-responders (P<.001). For example, patients experiencing ≥75% PASI reduction, alefacept responders had a mean change in DLQI of -8.6 as compared to -2.8 in non-responders (P<.001). Reflecting persistent control of the disease, these scores have remained comparable and consistently significant when responders are compared to non-responders at both 2 and 12 weeks after the last dose alefacept (intravenous or intramuscular).

Positive Response of Refractory Patients or Patients Unsuitable for Traditional Therapies

Of particular note, quality of life improvements have been observed after alefacept use in patients who are refractory to or contraindicated to methotrexate, cyclosporine, PUVA, UVB light, or retinoids. The percentage of refractory or contraindicated patients experiencing ≥75% PASI reduction was significantly higher in responders to alefacept as compared to non-responders. The mean change in DLQI in responders to intramuscular and intravenous alefacept was -7.34 and -9.64, respectively, as compared to -2.89 and -2.87 in non-responders, respectively (P<.001).
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Genentech Symposium

Data presented by: Craig Leonardi, MD, Clinical Professor of Dermatology, St. Louis University Medical School, St. Louis, Missouri; Mark G. Lebwohl, MD, Professor and Chair, Department of Dermatology, Mount Sinai School of Medicine, New York, New York; and Alan Menter, MD, Chief, Division of Dermatology, Baylor University Medical Center, Dallas Texas

The monoclonal antibody efalizumab, is intended to control psoriasis by inhibiting activated T cells from migrating from the lymph glands to the epidermis. The goal of this therapy, comparable to that of other immunobiologics, is to inhibit the inflammation that characterizes plaque formation and disease progression. Efalizumab is currently under review by the FDA.

Extensive phase III trials of subcutaneously administered efalizumab have been conducted in patients with psoriasis. In a pooled analysis of completed trial data, which included 1172 patients who received efalizumab and 479 who received placebo, the PASI 75 score at 12 weeks was 27.9% for those receiving 1 mg/kg/week and 27.6% for those receiving 2 mg/kg/week. In comparison, the placebo response was 3.8% (P<.001). The improvement in DLQI scores at 12 weeks on active drug versus placebo was consistent with the PASI benefits and was also statistically significant (P<.001).

Efalizumab must be administered continuously in weekly doses to maintain response. After therapy was discontinued, the median time to disease relapse was 64 to 70 days. In 14.7% of patients on efalizumab versus 11.4% of patients on placebo, discontinuation of therapy was followed by rebound, defined as a PASI score at least 125% of baseline. In responders who remained on therapy, there was no tachyphylaxis observed in follow-up of 15 months.

The side effects that occurred more frequently in the efalizumab group than in the placebo group in controlled trials were headache, chills, nausea, fever, myalgia, and asthenia. All were most common following the first two injections. Less than 1% of patients in clinical trials discontinued therapy due to an adverse event. There was no evidence of increased infections or malignancies.

Based on the results to date, efalizumab was characterized as both effective and well tolerated. The lower of the two tested dosages is expected to move forward in the absence of any evidence of a dose response. Due to the rapid return of psoriasis after discontinuation as well as the potential for rebound, a chronic dosing scheme is expected.