The First Biologic: Mechanism and Clinical Summary

Data presented by Mark G. Lebwohl, MD, Professor and Chairman, Department of Dermatology, Mount Sinai School of Medicine, New York, New York, and Kenneth B. Gordon, MD, Director, Psoriasis Translational Research Center, Stritch School of Medicine, Maywood, Illinois

The remittive effects of alefacept, the first biologic in psoriasis, can exceed 6 months in responders, according to two phase III extension studies. In the extension study with the intramuscular (IM) formulation, those who achieved at least a 75% reduction in PASI score maintained a PASI reduction of 50% above baseline for a median 7 months (209 days) after their last dose of alefacept. In the subgroup of patients who cleared or almost cleared, the median duration of response was 8 months (245 days) off treatment. A similar durability was previously demonstrated with the IV formulation.

The remittive effect of alefacept is consistent with its ability to reduce the number of memory T cells and block T cell activation, two events important to the pathogenesis of psoriasis. In the clinical trials, patients exhibiting the greatest T cell reductions on alefacept demonstrate the greatest reduction in disease severity, confirming this mechanism of action. The progressive clinical improvement that accrues after the 12-week course of alefacept is completed appears to represent an inflammatory deactivation produced by the reduction in memory T cells.

Biologic Therapy Combined with UV Light

Consistent with pre-approval trials, alefacept has been safe and well tolerated both in routine use and in a continuing clinical trials program. Recently completed studies combining alefacept with ultraviolet light (one conducted with broad band and the other with narrow band) found this combination to accelerate benefit without evidence of significant adverse events. Other combinations in psoriasis, including those with traditional systemic therapies or newer biologics are anticipated.

As with other effective therapies, quality of life benefits with alefacept are commensurate with its ability to clear psoriatic lesions. Recent phase III subgroup analysis demonstrated a substantial advantage over placebo in patients refractory or unsuited to one or more traditional systemic therapies. This confirms that biologics provide disease control even among those with limited therapeutic options.
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Psoriasis: A Immune Mediated Inflammatory Disease

Data presented by Alice B. Gottlieb, MD, Director, Clinical Research Center, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Brunswick New Jersey, and Gerald Kreuger, MD, Professor, Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.

With the advent of biologics, immunosuppressive therapies like cyclosporine, although often highly effective, are now being perceived as blunt instruments for the control of psoriasis. Isolation of the specific immunologic mediators of psoriasis has generated an array of new therapies that promise greater clinical effects with fewer clinical risks. The specific targets of these therapies vary, but the goal is the same. By inhibiting an abnormal immune response, biologics quell the pro-inflammatory events that produce disease expression.

Since the last International Psoriasis Symposium, one biologic therapy has been approved and 3 more are in late stages of clinical testing. All four act on T cells, on cytokines produced by T cells, or on other signaling systems that affect T cell function. Alefacept, the approved biologic, interferes with antigen-activation of T cells and reduces the population of memory T cells. Infliximab and etanercept, not yet approved for psoriasis but used in other inflammatory diseases, inhibit tumor necrosis factor (TNF) alpha, a cytokine that participates in the vicious cycle of T cell activation. Efalizumab, also still in a testing phase, is a monoclonal antibody for LFA-1 (CD-11a), a T cell surface molecule that co-stimulates T cell activation.

Specificity of Action Represents New Orientation

The activity of the biologics on very specific mechanisms of inflammation represents a substantial departure from the therapeutic approach undertaken with cyclosporine or even methotrexate or retinoids, for which the mechanisms of action remain poorly defined. Importantly, the biologics so far have been remarkably well tolerated, suggesting that specific aspects of inappropriate immune activation can be safely turned off. With additional safety data, it is likely that each of the three unapproved biologics will become available for the treatment of psoriasis. Current data suggest that these agents will be used first line, redefining standards of care and the order in which therapies are selected to control moderate to severe disease.
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US and Europe: Therapy Dissatisfaction

Data presented by Gail M. Zimmerman, President and CEO National Psoriasis Foundation, Portland, Oregon, and S-H Salonen, European Federation of Psoriasis Patients Organizations, Helsinki, Finland

Two large surveys conducted independently in the U.S. and Europe establish remarkably similar patient dissatisfaction with current therapies. In the U.S, where detailed questionnaires were administered to 1798 patients within the context of a population-based survey of 27,000, 33% reported being unsatisfied with their therapy and 78% reported that they avoided traditional systemic therapies because of concern about side effects and lack of safety. The National Psoriasis Foundation commissioned both the survey and the questionnaire.

In Europe, 70% of 17,990 patients in 9 countries who answered questionnaires reported low or moderate satisfaction with current therapy options. This survey was commissioned by the European Federation of Psoriasis Patients Organizations (EUROPSO). In both the U.S. and Europe surveys, approximately 75% of patients identified psoriasis as a problem or major problem in their lives, exerting an important adverse impact on a broad array of activities of daily living.
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Biologics and Traditional Systemic Therapies: Study in RA

Data presented by Gerald G. Kreuger, MD, Professor, Department of Dermatology, University of Utah, Salt Lake City, Utah.

One of the first studies to combine a biologic with a traditional systemic therapy in an inflammatory immune-mediated disease has suggested that these combinations may be safe and effective. The study, conducted in rheumatoid arthritis (RA), combined methotrexate with alefacept, a biologic approved for treatment of moderate to severe psoriasis. Results were presented almost simultaneously at the International Psoriasis Symposium in New York and the annual meeting of the European League Against Rheumatism (EULAR) in Lisbon.

In the study, 36 patients with RA who had been maintained on a stable dose of methotrexate were randomized to remain on methotrexate alone, remain on methotrexate while taking weekly courses of 3.75 alefacept, or remain on methotrexate while taking weekly courses of 7.5 mg alefacept. Alefacept was administered over 12 weeks, and then patients were followed for an additional 12 weeks after the last alefacept dose. The primary endpoint was change in joint symptoms as measured with the American College of Rheumatology (ACR) scoring system

ACR 20 Response Increased on Combination

Three months after the last alefacept dose, more than 40% of patients on either of the alefacept groups plus methotrexate achieved an ACR 20 versus 10% of those who remained on methotrexate alone. On the more rigorous outcome of ACR 50, more than 25% on the alefacept/methotrexate combination achieved benefit versus none of those on methotrexate alone.

A reduction in memory T cells, which is one of two mechanisms of benefit associated with alefacept in psoriasis, correlated with clinical response in the alefacept patients, reinforcing its activity. There was no change in memory T cell counts in those who received methotrexate alone. This is the first data in RA to demonstrate that suppression of these cells is associated with clinical improvement.

The absence of any difference in the rates and types of adverse events between those who received methotrexate and alefacept versus methotrexate alone reinforces the potential for added benefit for this and other biologics when combined with traditional systemic therapies.
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Psoriasis: Seeking a Magic Bullet

Data presented by James G. Krueger, MD, PhD, Professor and Laboratory Head, Rockefeller University, New York, New York

It is clear that psoriasis develops when homeostasis among immune mediators is lost. More than 50 growth factors, cytokines, and chemokines are known to be elevated in psoriatic skin lesions. Although it is as yet unclear what factor, if any, is critical to the loss of balance between pro- and anti-inflammatory mediators, it is possible that the molecular basis for these events are common or very similar among immune-related disorders.

Due to evidence that pro-inflammatory signals, once turned on, are amplified by reciprocal activation of common mediators, inflammation appears to be difficult to suppress once it has started. Tumor necrosis factor (TNF) alpha, interferon gamma, intracellular adhesion molecule (ICAM-1) and a variety of interleukins (IL) such as IL-20, appear to cross talk, activating T cells to release additional pro-inflammatory cytokines in a signal cycle that appears to have multiple redundancies. At the same time, those who progress to diseases like psoriasis appear to fail to mount a regulatory or anti-inflammatory response that would turn off this process as would be expected in normal individuals.

Therapeutic Targets in Psoriasis Expand

Biologics have been targeted at several of the known factors in the abnormal immune response, such as preventing T cell activation through inhibition of signals between antigen and T cells or suppression of TNF alpha. However, the potential targets are impressively varied. This not only includes inhibition of as-of-yet untargeted pro-inflammatory factors, but stimulation of the regulatory or anti-inflammatory factors that might restore homeostasis. Moreover, therapies could be targeted at the genes that regulate the inflammatory response or the messenger RNA that carries their signals. Targets may emerge from the 159 genes that have now been found to be consistently activated in psoriatic lesions.

The question raised by the increasing detail with which the pathogenesis of psoriasis is being understood is whether there is any hope for a single drug that could turn off this process and return the immune system to healthy homeostasis.
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Era of Biologics: Changing the Paradigm

Data presented by Menno de Rie, MD, Academic Medical Center, Amsterdam, The Netherlands

The era of biologics in psoriasis, initiated with regulatory approval of alefacept in January 2003, changes the paradigm of psoriasis therapy. Due to the toxicity of traditional systemic therapies, several strategies, such as step ladder or rotational schemes, have been proposed to move patients between therapies to limit toxicity. The better tolerated biologics are expected to change the algorithms used to select first-line therapies, change therapies, and evaluate quality of life.

The introduction of biologics represents a substantial change in the management of psoriasis. The role of biologics in outlining the pathophysiology of psoriasis has altered perceptions about this disease and increased optimism about the potential to exert control. Most importantly, by expanding therapeutic choice, the likelihood of a patient finding a therapy with acceptable efficacy and tolerability increases.