Approved Immunobiologics: Alefacept Quality of Life

Data presented by Peter van de Kerkoff, MD, University Hospital, Nijmegen, The Netherlands

In phase III trials with alefacept, psoriasis patients who were refractory to, or contraindicated for, one or more traditional therapies achieved a similar relative improvement in quality of life as those without treatment restrictions. When this group was further stratified, those refractory or contraindicated to 3 or more therapies did at least as well as those refractory or contraindicated to only one therapy (3.6 versus 2.2 improvement on the 30-point Dermatology Life Quality Index (DLQI)).

A total of 706 patients who were randomized to alefacept or placebo from the 2 phase III trials are included in this analysis. Of these, 21% were refractory to, or contraindicated for, 3 or more of the 5 major psoriasis therapies (methotrexate, cyclosporine, retinoids, UVB, or PUVA), 41% for 2 or more, and 69% for at least one existing therapy. Highly significant improvements (P<.001) in QOL were achieved in all three groups relative to placebo. The improvements in QOL as measured with DLQI were comparable to those observed in the overall study population.

Improvements in QOL and PASI Correlate

Improvements in QOL in the phase III trials with alefacept were seen in those achieving greater than or equal to 50% reduction in PASI. An even greater improvement in quality of life in those with a PASI of 75% or greater was seen when compared to those with a reduction of 50% or greater in both the overall study population and in those unsuitable for other therapies. The correlation between QOL and PASI emphasizes the opportunity for new therapies to benefit even those individuals whose treatment options are limited.
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Regulatory T Cells: The Other Half of the Equation

Data presented by Kenneth D. Cooper, MD, Director, Skin Diseases Research Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio

The pro-inflammatory factors that drive psoriasis are being mapped in increasing detail, but attention has now also been turned to the inability of regulatory T cells to modify this process. Regulatory T cells have been previously identified as important for restraining auto-immunity, but work to target this side of the pathogenic equation in psoriasis has been relatively recent.

The most important steps in this direction have been the studies demonstrating that regulatory T cells are dysfunctional in psoriatic skin. When psoriatic antigen presenting cells are used to stimulate resting T cells to proliferate in vitro, adding T regulatory cells from control subjects reduces cell proliferation by 90%. When regulatory T cells from psoriatics are added, proliferation is reduced by only 60% (P = .0001). When psoriatic T cells were introduced into normal antigen presenting cells, they were also found to be defective in inhibiting a proliferative response.

Regulatory T Cells: Dysfunctional and Deficient

The number of regulatory T cells in psoriatic skin needed to inhibit effector T cell responses has been found deficient. On the basis of the number of regulatory T cells needed to block effector cell activation, this deficiency has been calculated to be approximately 15%. However, the dysfunctionality of the regulatory T cells appears to exacerbate the effect of the deficit.

These findings suggest several potential new strategies to intervene, including treatment with the cytokine interleukin 12, which has been shown to stimulate production of T regulatory cells. Although experiments with anti-inflammatory cytokines are at an early stage, a phase I trial with IL-12 in 18 patients has already been completed with promising results.
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Keynote Speaker: 50 Years of Psoriasis Therapy

Data presented by Gerald Weinstein, MD, Chairman, Department of Dermatology, School of Medicine, University of California, Irvine, California

Five months after the approval of the first immunobiologic agent for use in moderate to severe psoriasis, it is not yet clear whether these therapies will replace or complement traditional therapies. Over the past 50 years, five major therapeutic options have been added for psoriasis at approximately 10-year intervals. Although it now appears that some earlier therapies, particularly methotrexate and cyclosporine, act at least in part through immunomodulation, the immunobiologics appear to act more specifically and may act more safely on key mechanisms of disease.

Rotational or sequential use of anti-psoriatic therapies have been employed to circumvent the toxicities associated with each of the first five major psoriasis drugs. Safety data will guide the new paradigm. Like previous adjustments in the definition of an acceptable benefit-to-risk ratio in the trajectory from the 1940s, when arsenic was a dominant therapy for psoriasis, to the current era of immunobiologics, the evidence of improved safety in the context of efficacy will guide treatment choices.

Regardless of how immunobiologics are incorporated into treatment schemes, it now appears that the position of methotrexate as the gold standard for therapy may be in jeopardy. Due to the introduction of immunobiologics, new first line therapies in moderate to severe psoriasis are likely to evolve.
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Combination Therapies: Immunobiologics

Data presented by Mark G. Lebwohl, MD, Professor and Chair, Department of Dermatology, Mount Sinai School of Medicine, New York, New York

Preliminary results with immunobiologic agents in combinations with traditional drugs, particularly methotrexate, are promising. Anecdotally, these combinations appear to add incremental relief of psoriasis with acceptable safety. Currently there is debate over whether use of these combinations are safe to use outside of controlled trials due to the risk of excess immunomodulatory effects.

In the limited experience combining methotrexate with alefacept or etanercept, there is evidence to suggest increased efficacy or additive anti-psoriatic effect. There have been no reports of opportunistic infections (OIs) with alefacept. Infliximab, however, has been associated with an increased risk of inducing latent tuberculosis (70/147,000; Keane et al. N Engl J Med. 2001;345:1098-1104). While this risk can be reduced by TB testing prior to infliximab, it reinforces the need to employ these agents where safety and efficacy have already been demonstrated.

Combining Immunobiologics for Safety

Some researchers project that immunomodulatory agents may not only be more effective but safer when employed together. Preliminary evidence that methotrexate might reduce the risk of neutralizing antibodies that cause infusion reactions associated with infliximab is an example. Due to the potential for at least additive if not synergistic effects from drugs with different mechanisms of action, studies of combinations that include the newer biologics are useful to provide dermatologists with data to inform treatment decisions.
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Redefining Clinical Response: 50% PASI Reduction

Data presented by Gerald G. Krueger, MD, Professor, Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City

The greatest positive change in quality of life (QOL) is observed when PASI (Psoriasis Activity and Severity) scores climb above a 50% reduction, according to analysis conducted with data from phase III studies of immunobiologics. These findings suggest that the 75% or greater reduction in PASI score that has been employed as the Food and Drug Administration (FDA) benchmark for demonstrating efficacy of immunobiologics is arguably too rigorous.

Although an objective tool for measuring change in skin involvement, PASI scores have limitations. PASI scores do not capture the greater importance of lesion regression on the face, hands, or feet relative to other body parts. Furthermore, they can change only modestly despite large reductions in the involved body surface area (BSA) if persistent lesions do not change in redness, scaliness and thickness.

PASI 50 Reductions Indicate Benefit

When the outcome in more than 2000 patients participating in phase III trials with alefacept, efaluzimab, and etanarecept were stratified by PASI reductions between 50 and 75, 75 and 90, and 90 and 100, the greatest incremental improvement in QOL was achieved between PASI 50 and 75. These data indicate that a PASI 50 reduction or greater is a valid marker of clinical benefit and should be employed as a primary endpoint in clinical trials.

There is a large pool of anecdotal cases of large improvements in patient satisfaction when bothersome lesions regress despite modest PASI reductions. These new data indicate the limitation of PASI scoring to measure clinical benefits.
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Etanercept: Amgen/Wyeth Symposium

Data presented by: Brian J. Nickoloff, MD, PhD, Director, Skin Cancer Research Laboratories, Loyola University Medical Center, Maywood, Illinois; Alice B. Gottlieb, MD, PhD, Director, Clinical Research Center, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey; and Kim A. Papp, MD, PhD, Research Director, Department of Medicine, University of Western Ontario, London, Canada

Two phase III trials with etanercept, a tissue necrosis factor (TNF) inhibitor administered by subcutaneous injection, have generated preliminary safety and efficacy data for psoriasis. In both, the highest tested dose of 50 mg twice weekly was the most effective.

In a recently completed trial, 583 patients were randomized to placebo, 25 mg etanercept twice weekly, or 50 mg twice weekly. For the 25 mg twice-weekly dose, about one-third of the patients achieved a 75% or greater improvement in PASI score at 3 months, the primary endpoint. Results of this trial, conducted in Canada, France, Germany, the Netherlands, the United Kingdom, and the U.S. were consistent with those of the 652-patient phase III U.S. trial presented at the American Academy of Dermatology in March, 2003.

Preliminary Safety Data Reassuring

Long-term safety data from the phase III trials in psoriasis are not yet available, but the tolerability profile of etanercept in follow-up conducted so far has been similar to that reported with this drug in patients treated for rheumatoid or psoriatic arthritis, for which it is currently indicated. The most common side effect has been injection site reactions. Data on the durability of response or risk of rebound after discontinuation of etanercept in patients with psoriasis has not yet been released. As the most effective dose of etanercept was twice as large as that currently indicated for use in rheumatoid and psoriatic arthritis, long term safety studies specific to these increased doses are needed.