Tazarotene

Abstract

Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years, one of the major focuses in psoriasis research has been the development of novel biologic therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention, with the hope that such specificity will result in fewer side effects than traditional therapies. In addition to these therapies, there are also oral medications in development for psoriasis. The goal of this article is to review oral tazarotene, a novel retinoid, and oral pimecrolimus, a novel macrolactam therapy, for the treatment of moderate to severe psoriasis.

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Introduction

Psoriasis is a chronic inflammatory disorder with primarily cutaneous and musculoskeletal manifestations. According to recent evidence, both genetic and environmental factors contribute to a chronic activation of T-cells that result in the induction and maintenance of psoriatic plaques (1,2). Activated T-cells initiate and propagate the disease by secreting local cytokines that enhance the production of Th1 and Th2 type cytokines and growth factors, resulting in keratinocyte proliferation, augmentation of the inflammatory cascade, and vascular changes (3,4). The implication of an immunologic phenomena in the pathogenesis of psoriasis has led to research for new treatment options over the past few years. The result has been the birth of biologic therapies, those drugs targeting the activity of T-lymphocytes and cytokines responsible for the inflammatory nature of this disease. These biologic proteins are administered by one of three routes: subcutaneously, intramuscularly, or as intravenous infusions. In addition to these therapies, there are also oral medications in development for psoriasis. This article will review oral tazarotene, a novel retinoid, and oral pimecrolimus, a novel macrolactam therapy, for the treatment of moderate to severe psoriasis. Clinical data for these agents will be discussed, including the most recent phase II and/or III study results, as well as the most recent safety data.

[FIGURE 1 OMITTED]

Oral Tazarotene

The retinoid tazarotene (Fig. 1) appears to treat psoriatic skin by modulating all three of the disease's pathogenic factors. It normalizes the abnormal differentiation of keratinocytes and has potent antiproliferative effects on keratinocytes, both directly and also probably as a result of its differentiation-normalizing effects. Tazarotene also decreases the expression of inflammatory markers on keratinocytes, thereby decreasing the influx of inflammatory immune cells into the skin. These effects have been demonstrated in a variety of in vitro and in vivo models, as well as in psoriatic lesions in an ongoing series of clinical pharmacology studies with the topical form of tazarotene (5-8).

Tazarotene is a synthetic retinoid compound whose derivative, tazarotenic acid selectively binds to the b and g class of nuclear retinoic acid receptors (RARs), thereby influencing gene transcription. Tazarotene's effects on keratinocyte proliferation and differentiation and the expression of pro-inflammatory markers have made it valuable in the treatment of disorders of keratinocyte differentiation, including psoriasis.

Unlike the older retinoid acitretin, which activates RAR-[alpha], RAR-[beta], and RAR-[gamma] indiscriminately, tazarotene's targeted activation of specific RARs forms the basis of its effectiveness in clearing psoriatic lesions, its safety, and improved side-effect profile (5-8). In addition, tazarotene's short half-life ([t.sub.1/2] = 7-12 hours) makes it a more practical choice for women of childbearing age who can consider pregnancy within weeks of discontinuing therapy (9). Initial studies of topical tazarotene therapy for psoriasis confirmed its efficacy in treating the disease and paved the way for oral studies (10).

Walker et al.11 performed two multicenter, double-blind, randomized, placebo-controlled, phase III studies, in which patients with stable plaque psoriasis of at least 10% of their body surface area (BSA) and overall lesional assessment (OLA) of at least moderate severity received oral tazarotene capsule (4.5 mg) or placebo once daily for 12 weeks. The patients were followed without treatment for an additional 12 weeks, after which they were assessed for the clinical endpoints (OLA scale from 0-6 with success being at least a 2-grade improvement, overall plaque elevation from 0-4, and percent BSA involvement).

A total of 706 patients participated, with 348 receiving placebo and 358 receiving oral tazarotene. The mean severity of patients' psoriasis at baseline was as follows: a mean OLA score of 3.4, mean plaque elevation score of 2.3, mean scaling score of 2.4, mean erythema score of 2.4, and a mean BSA of 29%. From week 4 to 24, there was a 50% global improvement (54% treated versus 15% placebo) and a 75% improvement from week 8 to 24 (30% treated versus 7% placebo) in each study. A minimum of a 2-grade reduction in OLA score from week 8 to 24 was seen (28% versus 6%) in both studies at week 12. In 17% of those treated with the drug versus 3% placebo, no psoriasis or very minimal psoriasis was visible from week 12 to 24. Additionally, plaque elevation and scaling from week 4 to 24 reduced in score by 0.9 in the treated group versus 0.3 in the untreated group. Erythema decreased by a score of 0.8 versus placebo of 0.2 from week 8 to 24 in both studies, while % BSA diminished by 6.8% in the treated group compared to 0.8% in the placebo group. The authors concluded that oral tazarotene is highly effective in the treatment of moderate to very severe plaque psoriasis (11).

The most common adverse effects noted during the treatment period of the study in the group which received oral tazarotene included cheilitis, dry skin, headache, arthralgia, myalgia, and back painll. These side effects were generally mild in severity (the degree of cheilitis was mild in 50% of patients and moderate in 15% of those who developed it). In the placebo group, the severity of cheilitis was mild in 15% of patients and moderate in 2% of patients (11).

In November 2003, Allergan filed a new drug application with the FDA for oral tazarotene for the treatment of moderate to very severe psoriasis.

[FIGURE 2 OMITTED]

Oral Pimecrolimus

Pimecrolimus (Fig. 2), an ascomycin derivative, is one of the new classes of immunomodulating macrolactams specifically developed as a topical agent for the treatment of inflammatory skin diseases, primarily atopic dermatitis (12). The mechanism of action of pimecrolimus is the blockage of T-cell activation. This is achieved by the formation of a complex upon the binding of pimecrolimus to macrophilin-12 (13). The pimecrolimus-macrophilin-12 complex then binds to the cytosolic enzyme calcineurin phosphatase, inhibiting its action and thereby prevents the dephosphorylation of the cytoplasmic component of the nuclear factor of activated T-cells (NF-AT). NF-AT is responsible for regulating the mRNA transcription of many inflammatory cytokines like Th1 (IL-2, IFN-[gamma]) and Th2 (IL-4, IL-10) type cytokines. Pimecrolimus also targets mast cells, which play an important role in anti-inflammatory activities (14).

Rappersberger et al. (15) evaluated the safety, tolerability, and efficacy of oral pimecrolimus in the treatment of patients with moderate to severe chronic plaque psoriasis. In this phase I/II randomized, double-blind, placebo-controlled, multiple rising dose, proof of concept study of psoriasis, fifty patients were treated with oral pimecrolimus or placebo. Gene profiling identified a common genomic profile with a downregulation of genes associated with inflammation, but no changes in gene expression linked to drug-related side-effects. There was clear clinical efficacy in patients receiving 20 mg pimecrolimus twice daily and 30 mg twice daily with a mean reduction of PASI by 60% and 75%, respectively (15).

Histopathologically and immunopathologically, there was a reversion of the psoriatic phenotype towards normal. There were no notable clinical, laboratory, kidney function, or immunologic side-effects. The only consistent adverse event was a transient feeling of warmth in the upper chest occurring approximately 40 minutes after ingestion of the drug in a total of 10 patients across the 20 mg twice daily and 30 mg twice daily groups. This sensation did not occur every time after drug intake, and in 75% of all cases, it did not occur more often than three times during the study. Other mild side effects experienced by the patients were pruritus, headache, viral infection, and vertigo/malaise. The authors concluded that pimecrolimus taken orally is highly effective in a concentration-dependent manner in patients with psoriasis and on a short-term basis it is well tolerated; this is confirmed by its pharmacogenomic profile. The latter also indicates that pimecrolimus should be equally effective in other inflammatory skin diseases (15).

Based on the promising results thus far, phase III trials of oral pimecrolimus are planned.

References

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11. Walker PS, Gottlieb A, Guenther L, Kang S, King L, Koo J, et al. Oral tazarotene (4.5 mg capsule) in patients with moderate to very severe plaque psoriasis. Poster presented at: American Academy of Dermatology. Academy 2003: July 25-29, 2003; Chicago, IL.

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15. Rappersberger K, Komar M, Ebelin ME, Scott G, Burtin P, Greig G, et al. Pimecrolimus identifies a common genomic anti-inflammatory profile, is clinically highly effective in psoriasis, and is well tolerated. J Invest Dermatol 2002; 119:876-87.

FIZA SINGH BA, JEFFREY M WEINBERG MD

DEPARTMENT OF DERMATOLOGY, ST. LUKE'S-ROOSEVELT HOSPITAL CENTER AND BETH ISRAEL MEDICAL CENTER, NEW YORK, NEW YORK

ADDRESS FOR CORRESPONDENCE:

Jeffrey M Weinberg MD

Department of Dermatology

St. Lukes-Roosevelt Hospital Center

1090 Amsterdam Avenue, Suite 11D

New York, NY 10025

Phone: (212) 523-5898

Fax: (212) 523-5027

Email: jmw27@columbia.edu

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