DEFENDING THE DERMIS

COVER STORY DEFENDING THE DERMIS Many new drugs are in the pipeline to treat psoriasis, eczema, and acne Skin diseases are more than skin-deep. They can be expensive and time-consuming. They affect self-esteem, personal relationships, and career. They also have health implicationspredisposing individuals to infection, scarring, and other diseases. Dermatological concerns are among the "most common consults pharmacists get if you consider hair, skin, and nails," stated Dennis West, Ph.D., FCCP, professor of dermatology, Northwestern University. And pharmacists need to be aware that therapy in dermatology, particularly in the treatment of psoriasis and eczema, is changing significantly as new approaches to therapy reach the market and already-marketed products find new uses. Skin diseases affect substantial numbers of individuals. The National Psoriasis Foundation estimates seven million people in the United States have psoriasis. The American Academy of Dermatology estimates that one-fifth of all school-aged children have eczema. Of these, 60% continue to have symptoms even as adults. For as many as 80% of adolescents, acne is regarded as a "rite of passage." Given these statistics, it is not surprising that nonprescription and prescription skin therapy products are abundant and generate millions of dollars in pharmaceutical sales. Options for psoriasis Current psoriasis therapy options are numerous. They include topical moisturizers, emollients, coal tar, topical corticosteroids, dithranol, calcipotriene (Dovonex, Bristol-Myers Squibb), acitretin (Soriatane, Roche), and tazarotene (Tazorac, Allergan). More severe disease is treated by systemic medications, including cyclosporine, tacrolimus, mycophenolate mofetil (CellCept, Roche), methotrexate, sulfasalazine, retinoids, and biologic therapy. Phototherapy and denileukin diftitox (Ontak, Ligand Pharmaceuticals) have also been used. The fact that numerous options exist does not mean all patients are successfully treated. Kenneth Arndt, M.D., clinical professor of dermatology, Harvard Medical School, commented, "An enormous group of people have basically given up. They have gone to a lot of doctors, used all the various things, and found them either too toxic or too messy." The good news for these people is that as a result of the increased understanding of the molecular mechanisms of psoriasis, there are 30 to 40 drugs in phase II or III trials. Some will reach the market in the near future. Psoriasis is considered an autoimmune disease; T cells are believed to be key to the induction and propagation of the disease. Psoriasis develops when T cells are activated, transit from the lymph nodes and circulation into the skin, and then secrete various cytokines that induce the characteristic pathological changes. From this knowledge of psoriasis pathogenesis, targets for therapy using biologic agents have emerged. Decision Resources Inc., a market research firm in Waltham, Mass., projects that by 2010 biologics will dominate the psoriasis market with a 68% market share. This will be a significant shift, skyrocketing these agents from ground zero in the year 2000 to 68% in 10 short years. The two biologic therapies closest to market are the fusion protein, Amevive (alefacept) by Biogen, and the monoclonal antibody, Xanelim (efalizumab) by Genentech and XOMA Corp. Alefacept, given as an intravenous injection once a week for a 12-week course of therapy, selectively reduces the memory-effector (T cells). "What's most dramatic are the long-term remissions that are gained," stated Gerald Krueger, M.D., professor of dermatology, University of Utah. Side effects of alefacept were generally mild. They included an increased incidence of accidental injury (not related to the study protocol), dizziness, nausea, chills, and cough. Alefacept does not appear to broadly suppress T-cell function. One trial, utilizing parallel design, treated patients in the active (alefacept) and control group with either a new antigen or a common recall antigen to evaluate immune response. "We found complete preservation of the antibody response to new antigens and recall antigens [during drug therapy]," explained Gloria Viliani, M.D., v.p. of medical research and immunology, Biogen. Efalizumab, given as a weekly subcutaneous injection, inhibits the binding of T cells to other cell types and targets the key processes that lead to symptoms of psoriasis. In a phase III trial, efalizumab demonstrated a more than 75% improvement in disease severity in 22%-28% of patients with moderate to severe plaque psoriasis. Side effects, which generally diminished after the first dose, included mild to moderate headache, pain, chills, nausea, and fever. Two already-marketed products, etanercept (Enbrel, Immunex) and infliximab (Remicade, Centocor), show efficacy in treating severe psoriasis or psoriasis with arthritis by inhibiting tumor necrosis factor (TNF) alpha. Etanercept is approved by the Food & Drug Administra-tion for use in moderate to severe rheumatoid arthritis (RA); infliximab is approved for Crohn's disease (CD) and RA. In comparison with the placebo group, etanercept-treated RA patients exhibited injection site reactions and a higher rate of headaches and dizziness. In comparison with placebo, infliximab-treated RA or CD patients had side effects of infusion reaction (fever and chills) and an increased incidence of upper respiratory infection or headache. The manufacturers of both etanercept and infliximab have updated their labeling to warn about the risk of serious infections and sepsis, including fatalities. Many of these serious events have occurred in patients with underlying diseases that could have predisposed them to infection. Though neither drug currently includes psoriasis as an indication, Arndt noted, "I think the off-label use for psoriasis probably will increase with time. That's because there are some patients I have seen for years who have run out of all optionswho are resistant or have side effects with all drugs." Molly Marshall, marketing and public relations manager for the National Psoriasis Foundation, views biologic agents with excitement. "They seem to be safer than anything we've had in the past," she said. "Even though they're injections or infusions or IVs [which seem a little intrusive], it's not 30 visits to a psoralen ultraviolet A [PUVA] box. They're something patients can fit into their lives, and they can be life-altering." Despite patient inconvenience, phototherapy is still considered to be a disease-remitting therapy for psoriasis. In recent years, it has fallen into disfavor because PUVA requires multiple visitsoften three times a week for eight to 10 weeks, in conjunction with psoralen use. Third-party payers have also passed an ever-greater percentage of treatment costs to those who are insured, thereby increasing the patient's cost of therapy. Eczema drug therapy For decades, conventional treatment for atopic dermatitis, commonly known as eczema, consisted of emollients for the dry skin stage and intermittent use of topical corticosteroids to treat flares. Earlier this year, patients gained an important new therapeutic option: the topical immunomodulator (TIM), tacrolimus ointment (Protopic, Fujisawa). Pimecrolimus cream, (Elidel, Novartis), another TIM, remains poised for FDA approval. "There's no question that this family of compounds is a very exciting breakthrough," said Robert McAlister, Ph.D., executive director of the National Eczema Association for Science and Education. "They don't cause cutaneous atrophy, skin thinning, striae formation, or many of the other side effects of topical steroids. They don't appear to have any impact at all on the HPA [hypothalamic-pituitary-adrenal] axis, which is a real concern in young children." In atopic dermatitis, tacrolimus and pimecrolimus inhibit T-cell activation and the release of preformed mediators. "What these do is basically shut down T-cell activation so the skin won't be so reactive and so itchy," explained West. Studies of more than 4,000 adults and children showed that tacrolimus improved or completely cleared eczema in more than 67% of patients. This has caused many experts to view it as the most significant advance in the treatment of eczema in a generation. Nevertheless, it has some drawbacks. McAlister noted that tacrolimus is expensive, and the patient experiencing a flare may find initial use quite uncomfortable. Indeed, the most common side effects are skin burning and itching. According to West, these effects are minimized when the ointment is applied to cool, dry skin. In a large international study, it was demonstrated that pimecrolimus could prevent flares more effectively than conventional therapy: 61% of patients completed six months without a flare, in comparison with only 35% of those using conventional therapy. The most frequently reported side effect of pimecrolimus was a transient feeling of warmth or mild sensation of burning upon application. Because tacrolimus is used systemically as an immunosuppressant in organ transplantation therapy, one of the early concerns about its topical use was systemic absorption and immunosuppression. Pooled results from two pharmacokinetic studies indicate tacrolimus is absorbed after topical application of 0.1% ointment, but its absolute bioavailability is believed to be less than 0.5%. Pimecrolimus shows similar absorption. Treatments for acne Acne is primarily a disease of teenagers and adolescents, though some experience acne later in adulthood. During the year 2000, prescription acne medication sales rose by 16%, primarily due to prescriptions for adult women. Whether this reflects increased prevalence of acne in this group or greater sensitivity about it is unknown. Nevertheless, use of acne products by adult women represented a new target for advertisers. The goal of acne treatment is to minimize symptoms and prevent scarring, which West termed "the permanent end point of acne." In the past few years, several new agents have increased therapeutic options. These include adapalene (Differin, Galderma), tazarotene, two new topical tretinoin formulations, azelaic acid, a new formulation of sodium sulfacetamide, and the approval of an oral contraceptive for treatment of acne. A new player expected to soon enter the acne market is dapsone topical gel (Atrisone), currently in phase III trials. Dapsone possesses both potent antimicrobial and anti-inflammatory activity. Last month, Atrix Laboratories announced it licensed the product's exclusive marketing and distribution rights to Fujisawa. Fujisawa is planning to make Atrisone its entry into the $500 million U.S. topical acne market. The approval of Ortho Tri Cyclen from Ortho-McNeil for treating moderate acne vulgaris in women is being emulated by other oral contraceptive makers seeking approval of similar indications. Other acne products have been formulated in liposomal, encapsulated, or micro sponge delivery systems. Such formulations are not unique to acne products, but as a vehicle for a therapeutic agent, they can minimize irritation, as typified by the tretinoin gel microsphere 0.1% (Retin-A Micro, A.P. Pharma). This product incorporates tretinoin into spongelike spheres that gradually release it over a sustained period. A similar result is achieved by using tretinoin cream 0.025% in polyolprepolymer-2 (Avita, Bertek). This vehicle retains the drug on and in the upper layers of skin. Theoretically, because the drug's migration into the deeper layers of the epidermis is limited, tretinoin-induced irritation is reduced. Drug delivery vehicles can also maximize the topical effect of the active medication while minimizing penetration into the blood stream. Healthpoint Ltd. plans to utilize its recently licensed ResiDerm reservoir technology for clindamycin. The goal is to improve drug delivery while limiting the side-effect profile. West noted, "With the new advanced systems, everything is very uniform; there is very little variability. So if you've identified the right spherical size for your material, encapsulated or liposomal, the percutaneous absorption becomes much more uniform and, therefore, predictable." Roche Pharmaceuticals is planning to launch a micronized isotretinoin in 2002, coincident with the patent expiration of the current oral formulation. Recently published studies suggest the micronized formulation offers advantages over the current formulation, both in bioavailability and side-effect profile. The increased bioavailability of micronized isotretinoin allows it to be used once a day (without food) rather than the twice-daily dosing of the current formulation (with food.) Micronized isotretinoin appears to carry a lower risk of mucocutaneous events and hypertriglyceridemia than the current formulation. However, the safety profile does not seem to differ between the two formulations. Currently, isotretinoin (Accutane, Roche) therapy has become a political hot potato. Despite concern about its side effects of depression and teratogenicity, West noted that "it is generally viewed as the most effective pharmacological approach to severe acne." To further address teratogenicity prevention, the FDA recently announced a new program called SMART (System to Manage Accutane-Related Teratogenicity). Program materials will be distributed to prescribers and pharmacists on Jan. 2, 2002. The SMART program requires that prescribers study the SMART "Guide to Best Practices" provided by Roche and sign and return a "letter of understanding" to Roche. The FDA also encourages participation in the Roche continuing medical education course. Prescribers then receive special, self-adhesive Accutane Qualification Stickers. All prescriptions for Accutane should have the yellow sticker attached to the prescriber's regular prescription form. At a recent dermatology meeting, 1,000 patients for whom isotretinoin had been prescribed were reviewed. Of these patients, isotretinoin was prescribed for 55% in accordance with FDA labeling; not so for the other 45%. Of these 45%, 38% had moderate acne and 7% had mild acne. The consensus recommendation from this conference was that isotretinoin therapy was justified in patients with less severe acne with scarring or significant psychological distress associated with their disease. Combining acne therapies can increase their effectiveness, as evidenced by trials such as CLEAR (Combination Leads to Efficacious Acne Results). In this trial, patients were randomized to either monotherapies or combination therapies. Monotherapy groups used either clindamycin phosphate lotion twice daily or tazarotene 0.1% gel daily. Combination therapy groups used tazarotene 0.1% gel in combination with twice-daily benzoyl peroxide gel, erythromycin-benzoyl peroxide gel, or clindamycin lotion. The combination regimens showed greater efficacy over monotherapy in improvement rates, treatment success (75%-100% clearing), and in reducing noninflammatory and inflammatory lesions. All in all, pharmacists can play a big role in helping patients plagued by skin diseases. Patients already ask numerous questions about dermatology; new therapies will open even greater opportunities to facilitate patient education and more effective disease management. Often the pharmacist is the most accessible professional for the patient with skin disease. Are you ready to meet this challenge? Kathy Hitchens, Pharm.D., MSBA The author is a clinical writer in the Indianapolis area. Kathy Hitchens. DEFENDING THE DERMIS. Drug Topics 2001;22:30.