L ike a laser-guided missile finding its target, drugs in dermatology today offer increased accuracy with fewer side effects. New agents like biologic therapies and immunomodulators strive to pinpoint and attack disease. Advances in biotechnology will transform the dermatology market, notes research firm Datamonitor. Immunomodulatory drugs “will revolutionize the market by providing high efficacy coupled with a much needed improvement in side effects, as well as prolonging periods of disease remission,” according to a Datamonitor report on dermatology drugs. Dermatologists practice in a generation that attempts to go for therapeutic magic bullets, says Douglas Kress, M.D., director of clinical services and residency program director, University of Pittsburgh Department of Dermatology. Treatments have carried “some relatively unpleasant side effects,” says Timothy Pang, analyst at Datamonitor. However, newer treatments provide some safer alternatives. In atopic dermatitis, for instance, the topical immunomodulators tacrolimus (Pro-topic) from Fujisawa and pimecrolimus (Elidel) from Novartis “really provide us a new treatment option that comes away from topical corticosteroids,” he says. Of course, with new drugs, not all side effects are known, says Dr. Kress. Various agents affecting the immune system, for instance, show early evidence of promoting reactivation tuberculosis, he says. Still, he notes that methotrexate doesn’t have a “charming” side effect profile either. Same Drug, Different Condition As new biologic therapies are making treatment inroads, the traditional dermatology approach of using various drugs off-label continues. If the pathogenesis of conditions is similar, trying the agent for those related conditions makes sense, suggests Adrienne Rencic, M.D., Ph.D., dermatologist at Mercy Medical Center in Baltimore, MD, and clinical instructor at the University of Maryland. What’s more, as expensive new drugs come to market, others are going generic, says Mr. Pang. Accutane, for instance, a huge seller for Roche, went off patent in February 2002. In turn, Bertek Pharmaceuticals just launched Amnesteem (isotretinoin). In this article, we’ll take a look at the latest pharmaceuticals to treat various dermatologic conditions. This includes eczema, acne, actinic keratosis and skin cancers. We’ll start with psoriasis, where some of the most exciting work is being done. Psoriasis: Big News It’s hard to exaggerate the unanimity of excitement with which clinicians speak of biologic therapies for psoriasis. These agents hold out the promise of transforming the treatment of this common disease and avoiding the side effects of drugs like methotrexate and cyclosporine. Up to now, treatments for psoriasis have been poorly received by both patients and physicians, says Craig Leonardi, M.D., a dermatologist in St. Louis, MO, and clinical associate professor of dermatology at St. Louis University. Doctors have offered topical therapies to patients who are clearly candidates for a systemic approach. “It really has been a therapeutic wasteland for roughly 10 or 15 years,” he says. Quite a few products are in late-stage research or registration in psoriasis “that are really completely new therapies within that market,” says Mr. Pang. Biologic therapies for psoriasis represent the “news of the year,” according to Steven Feldman, M.D., Ph.D., professor of dermatology and pathology at Wake Forest University School of Medicine, Winston-Salem, NC. The excitement focuses around four agents: etanercept (Enbrel) from Amgen; infliximab (Remicade) from Centocor; alefacept (Amevive) from Biogen; and efalizumab (Raptiva) from Genentech/XOMA. These agents are either under FDA review or closest to FDA submission, notes a paper by Jeffrey Weinberg, M.D., director, Clinical Research Center, Department of Dermatology, St. Luke’s – Roosevelt Hospital Center and Beth Israel Medical Center, New York. Enbrel and Remicade, says Mark Lebwohl, M.D., professor and chairman, Department of Dermatology, Mt. Sinai School of Medicine, New York, are currently on the market for such indications as rheumatoid arthritis and Crohn’s disease. But dermatologists are prescribing them for psoriasis. It’s reasonable, says Dr. Feldman, to prescribe these drugs for patients who have failed approved treatments like methotrexate. Enbrel is a tumor necrosis factor (TNF) receptor; Remicade is a monoclonal antibody that binds to TNF-alpha. In May 2002, an FDA advisory committee voted to recommend Amevive for approval. This recombinant protein stops T-cell activation. Raptiva (formerly known as Xanelim), also a T-cell activation modulator is being co-developed by Genentech and XOMA). The companies filed for a Biologics License Application with FDA in late December. Among its advantages, according to Dr. Leonardi, are that it’s self-administered by subcutaneous injection only once a week; has mild side effects that disappear after one or two injections; and has been shown highly effective compared to placebo with 29% of study participants achieving a 75% reduction in their PASI scores after 12 weeks of therapy. But for all their advantages, such novel therapies are expensive. Though patients can take advantage of “biotechnology at its finest,” manufacturing such drugs, says Dr. Leonardi, involves a “terrifically complicated and expensive process.” The tab for Remicade infusions for inflammatory bowel disease, notes Mr. Pang, can run $20,000 to $25,000 annually. Because of such expense, agents such as these might be used in combination with more standard pharmaceutical treatments for psoriasis, says Dr. Rencic. Instead of using a biologic therapy indefinitely, you might use the drug just for flare-ups. Other drugs that hold promise for psoriasis include tacrolimus (Protopic) from Fujisawa, the breakthrough non-steroidal for atopic dermatitis that was approved in December 2000, and the diabetes drug rosiglitazone maleate (Avandia) from SmithKline Beecham. Also, the Bristol-Myers Squibb paclitaxel (Taxol), in oral form, is being tested for psoriasis, notes Dr. Rencic. In addition, Connectics’ clobetasol propionate (Olux Foam 0.05%) just received a supplemental indication for the short-term topical treatment of mild to moderate plaque-type psoriasis of non-scalp regions, excluding the face and intertriginous areas. Atopic Dermatitis/Eczema Besides psoriasis, drugs such as Amevive and Raptiva, suggests Dr. Leonardi, may find a place in treating other chronic inflammatory disorders, such as atopic dermatitis. Once the drugs are used for psoriasis, you’re likely to see them used elsewhere, and chronic eczema will be one of the first places. As mentioned earlier, in atopic dermatitis the topical immunosuppressants Protopic from Fujisawa and pimecrolimus (Elidel) from Novartis provide new treatment options. These agents are already “making a dramatic change,” says Dr. Kress. They work extremely well as maintenance therapies, he says, after initial treatment with topical steroids. Emmanuel Loucas, M.D., Advanced Dermatology, Manhattan and Long Island, NY, looks for these two drugs to be used in multiple skin conditions. They include alopecia areata, graft versus host disease, lichen planus, pyoderma gangrenosum, sarcoidosis and vitiligo. Acne and Rosacea Unlike psoriasis, no new blockbuster treatments promise treatment of acne in the near term. But treatments for rosacea are another story. Azelaic acid gel 15% (Finacea) was approved early this month for the treatment of the inflammatory papules and pustules caused by mild to moderate rosacea. Finacea is the first new therapy for rosacea in more than a decade. Berlex will launch its drug in the first quarter of this year. A study for a systemic treatment for rosacea is also underway. Last summer, CollaGenex Pharmaceuticals began Phase III clinical trials with its doxycycline hyclate tablets, 20 mg (Periostat). Galderma also launched a daily cleanser, sodium sulfacetamide 10%, sulfur 5% (Rosanil), which is meant to complement topical rosacea therapy. For acne, advances involve the way medications are combined, says Dr. Feldman. Recognition is growing, he says, that topical retinoids can help not only comedones but also inflammatory lesions. Clinicians may use retinoids with topical and oral antibiotics to treat different types of acne. Allergan’s oral tazarotene (Tazorac) offers a shorter half-life compared to Roche’s isotretinoin (Accutane), says Dr. Leonardi. Because of concerns about pregnancy and possibly depression when administering retinoids, any drug that works in the same fashion but offers a shorter half-life would represent an advance, he says. In addition, Stiefel Labs just launched its new product to treat inflammatory acne. Clindamycin, 1% - benzoyl peroxide, 5% (Duac Topical Gel) is approved for once-a-day dosing. Currently, trials are underway on topical dapsone gel, says Dr. Weinberg, also assistant clinical professor of dermatology at Columbia University College of Physicians and Surgeons, New York. Anecdotal evidence indicates that the antibiotic has an effect. Photodynamic therapy (PDT) is another area that holds promise. It involves administering a topical photosensitizing agent and then subjecting the area to a blue light. Doing so causes the release of free oxygen radicals, which can destroy the organism Propionibacterium acnes. Some methods involve high-intensity blue light without the photosensitizing agent. Actinic Keratosis Already approved for genital warts, 3M’s topical immunomodulator imiquimod (Aldara) cream 5% is the most exciting treatment for actinic keratoses, says Dr. Weinberg. Phase III trials are nearing completion, and researchers are studying several dose regimens, he says. (The literature also indicates that the drug is successful for nodular and superficial basal cell carcinoma and Bowen’s disease, he says.) Diclofenac sodium (Solaraze gel 3%) from Bioglan Pharma, Inc. is another effective approach. In theory, this NSAID inhibits the cyclooxygenase pathway, which leads to decreased prostaglandin synthesis. One benefit of this therapy is that patient compliance tends to be better, says Dr. Loucas. It’s much less irritating than traditional 5-fluorouracil medications. That means patients are more likely to apply Solaraze gel for longer periods of time. Recently approved by the FDA, Solaraze represents a “nice breakthrough,” he says. Carac (Dermik Laboratories), a diluted form of 5-fluorouracil, can also be of benefit. Clinicians are also using PDT for actinic keratoses. Non-Melanoma Clinicians are also studying Aldara to treat skin cancers, particularly basal cell carcinoma, says Dr. Loucas. Several studies, he says, showed complete resolution of skin cancer after 12 to 20 weeks of treatment. Extending the PDT trend, Novartis Ophthalmics and QLT Inc. have announced the start of patient enrollment in two Phase III clinical trials using PDT with verteporfin for the treatment of multiple basal cell carcinomas. A Phase II trial demonstrated preliminary safety and efficacy of verteporfin at three light doses in patients with non-melanoma skin cancer with multiple lesions. The group of patients that was exposed to the highest light dose had the best response rate. In this group, 98% of the assessed tumors showed a complete clinical response following 6 months of initial treatment. Melanoma For melanoma, current research focuses on vaccines to help broaden the immune attack against the disease. Researchers are looking at three ways to deliver antigen genes to the patient: into the blood using plasmid DNA; retrovirus; and adenovirus, says Dr. Loucas. Immunization, he notes, will likely require a combination of these three delivery systems. Future development of vaccines, says Dr. Weinberg, may offer a better alternative than interferon or interleukin as adjuvant therapy for advanced disease. More Potential Advances Besides drugs for these major conditions, other agents hold out hope for dermatology patients: • Thalidomide for pyoderma gangrenosum and refractory aphthous ulcers in the mouth. • Resiquimod (3M), a relative of imiquimod, for genital herpes. • In addition, although it’s not new, hydrocortisone buteprate 0.1% (Pandel) for psoriasis and atopic dermatitis will be relaunched in 2003 by CollaGenex. Gene Therapy for the Future Though biologic therapies and other advances are likely to transform dermatologists’ prescribing patterns in the near term, gene therapy holds the promise for long-range changes. Right now, gene therapy is in the “infant stage,” says Dr. Lebwohl. Genetics is “always just over the horizon,” says Datamonitor’s Mr. Pang. While some rare genetic defects produce skin diseases, most dermatology conditions are multifactorial, says Joseph Fowler, Jr., M.D., clinical professor of dermatology at the University of Louisville. That means genetic therapy may be most beneficial, he says, for a small group of patients with those genetic diseases. Beyond Dermatology Drugs in development today may have far-reaching effects in other areas. “The dermatology market,” says the Datamonitor report, “represents an effective route to other autoimmune diseases. Dermatological disorders provide a prototypic model for other autoimmune diseases, in terms of disease pathogenesis, and serve as an ideal proof-of-concept model since drug effectiveness can be easily assessed via changes in skin appearance. This will greatly increase the market potential for new biologics in development for the treatment of dermatological disorders.”
What`s New in Dermatology Drugs?
L ike a laser-guided missile finding its target, drugs in dermatology today offer increased accuracy with fewer side effects. New agents like biologic therapies and immunomodulators strive to pinpoint and attack disease. Advances in biotechnology will transform the dermatology market, notes research firm Datamonitor. Immunomodulatory drugs “will revolutionize the market by providing high efficacy coupled with a much needed improvement in side effects, as well as prolonging periods of disease remission,” according to a Datamonitor report on dermatology drugs. Dermatologists practice in a generation that attempts to go for therapeutic magic bullets, says Douglas Kress, M.D., director of clinical services and residency program director, University of Pittsburgh Department of Dermatology. Treatments have carried “some relatively unpleasant side effects,” says Timothy Pang, analyst at Datamonitor. However, newer treatments provide some safer alternatives. In atopic dermatitis, for instance, the topical immunomodulators tacrolimus (Pro-topic) from Fujisawa and pimecrolimus (Elidel) from Novartis “really provide us a new treatment option that comes away from topical corticosteroids,” he says. Of course, with new drugs, not all side effects are known, says Dr. Kress. Various agents affecting the immune system, for instance, show early evidence of promoting reactivation tuberculosis, he says. Still, he notes that methotrexate doesn’t have a “charming” side effect profile either. Same Drug, Different Condition As new biologic therapies are making treatment inroads, the traditional dermatology approach of using various drugs off-label continues. If the pathogenesis of conditions is similar, trying the agent for those related conditions makes sense, suggests Adrienne Rencic, M.D., Ph.D., dermatologist at Mercy Medical Center in Baltimore, MD, and clinical instructor at the University of Maryland. What’s more, as expensive new drugs come to market, others are going generic, says Mr. Pang. Accutane, for instance, a huge seller for Roche, went off patent in February 2002. In turn, Bertek Pharmaceuticals just launched Amnesteem (isotretinoin). In this article, we’ll take a look at the latest pharmaceuticals to treat various dermatologic conditions. This includes eczema, acne, actinic keratosis and skin cancers. We’ll start with psoriasis, where some of the most exciting work is being done. Psoriasis: Big News It’s hard to exaggerate the unanimity of excitement with which clinicians speak of biologic therapies for psoriasis. These agents hold out the promise of transforming the treatment of this common disease and avoiding the side effects of drugs like methotrexate and cyclosporine. Up to now, treatments for psoriasis have been poorly received by both patients and physicians, says Craig Leonardi, M.D., a dermatologist in St. Louis, MO, and clinical associate professor of dermatology at St. Louis University. Doctors have offered topical therapies to patients who are clearly candidates for a systemic approach. “It really has been a therapeutic wasteland for roughly 10 or 15 years,” he says. Quite a few products are in late-stage research or registration in psoriasis “that are really completely new therapies within that market,” says Mr. Pang. Biologic therapies for psoriasis represent the “news of the year,” according to Steven Feldman, M.D., Ph.D., professor of dermatology and pathology at Wake Forest University School of Medicine, Winston-Salem, NC. The excitement focuses around four agents: etanercept (Enbrel) from Amgen; infliximab (Remicade) from Centocor; alefacept (Amevive) from Biogen; and efalizumab (Raptiva) from Genentech/XOMA. These agents are either under FDA review or closest to FDA submission, notes a paper by Jeffrey Weinberg, M.D., director, Clinical Research Center, Department of Dermatology, St. Luke’s – Roosevelt Hospital Center and Beth Israel Medical Center, New York. Enbrel and Remicade, says Mark Lebwohl, M.D., professor and chairman, Department of Dermatology, Mt. Sinai School of Medicine, New York, are currently on the market for such indications as rheumatoid arthritis and Crohn’s disease. But dermatologists are prescribing them for psoriasis. It’s reasonable, says Dr. Feldman, to prescribe these drugs for patients who have failed approved treatments like methotrexate. Enbrel is a tumor necrosis factor (TNF) receptor; Remicade is a monoclonal antibody that binds to TNF-alpha. In May 2002, an FDA advisory committee voted to recommend Amevive for approval. This recombinant protein stops T-cell activation. Raptiva (formerly known as Xanelim), also a T-cell activation modulator is being co-developed by Genentech and XOMA). The companies filed for a Biologics License Application with FDA in late December. Among its advantages, according to Dr. Leonardi, are that it’s self-administered by subcutaneous injection only once a week; has mild side effects that disappear after one or two injections; and has been shown highly effective compared to placebo with 29% of study participants achieving a 75% reduction in their PASI scores after 12 weeks of therapy. But for all their advantages, such novel therapies are expensive. Though patients can take advantage of “biotechnology at its finest,” manufacturing such drugs, says Dr. Leonardi, involves a “terrifically complicated and expensive process.” The tab for Remicade infusions for inflammatory bowel disease, notes Mr. Pang, can run $20,000 to $25,000 annually. Because of such expense, agents such as these might be used in combination with more standard pharmaceutical treatments for psoriasis, says Dr. Rencic. Instead of using a biologic therapy indefinitely, you might use the drug just for flare-ups. Other drugs that hold promise for psoriasis include tacrolimus (Protopic) from Fujisawa, the breakthrough non-steroidal for atopic dermatitis that was approved in December 2000, and the diabetes drug rosiglitazone maleate (Avandia) from SmithKline Beecham. Also, the Bristol-Myers Squibb paclitaxel (Taxol), in oral form, is being tested for psoriasis, notes Dr. Rencic. In addition, Connectics’ clobetasol propionate (Olux Foam 0.05%) just received a supplemental indication for the short-term topical treatment of mild to moderate plaque-type psoriasis of non-scalp regions, excluding the face and intertriginous areas. Atopic Dermatitis/Eczema Besides psoriasis, drugs such as Amevive and Raptiva, suggests Dr. Leonardi, may find a place in treating other chronic inflammatory disorders, such as atopic dermatitis. Once the drugs are used for psoriasis, you’re likely to see them used elsewhere, and chronic eczema will be one of the first places. As mentioned earlier, in atopic dermatitis the topical immunosuppressants Protopic from Fujisawa and pimecrolimus (Elidel) from Novartis provide new treatment options. These agents are already “making a dramatic change,” says Dr. Kress. They work extremely well as maintenance therapies, he says, after initial treatment with topical steroids. Emmanuel Loucas, M.D., Advanced Dermatology, Manhattan and Long Island, NY, looks for these two drugs to be used in multiple skin conditions. They include alopecia areata, graft versus host disease, lichen planus, pyoderma gangrenosum, sarcoidosis and vitiligo. Acne and Rosacea Unlike psoriasis, no new blockbuster treatments promise treatment of acne in the near term. But treatments for rosacea are another story. Azelaic acid gel 15% (Finacea) was approved early this month for the treatment of the inflammatory papules and pustules caused by mild to moderate rosacea. Finacea is the first new therapy for rosacea in more than a decade. Berlex will launch its drug in the first quarter of this year. A study for a systemic treatment for rosacea is also underway. Last summer, CollaGenex Pharmaceuticals began Phase III clinical trials with its doxycycline hyclate tablets, 20 mg (Periostat). Galderma also launched a daily cleanser, sodium sulfacetamide 10%, sulfur 5% (Rosanil), which is meant to complement topical rosacea therapy. For acne, advances involve the way medications are combined, says Dr. Feldman. Recognition is growing, he says, that topical retinoids can help not only comedones but also inflammatory lesions. Clinicians may use retinoids with topical and oral antibiotics to treat different types of acne. Allergan’s oral tazarotene (Tazorac) offers a shorter half-life compared to Roche’s isotretinoin (Accutane), says Dr. Leonardi. Because of concerns about pregnancy and possibly depression when administering retinoids, any drug that works in the same fashion but offers a shorter half-life would represent an advance, he says. In addition, Stiefel Labs just launched its new product to treat inflammatory acne. Clindamycin, 1% - benzoyl peroxide, 5% (Duac Topical Gel) is approved for once-a-day dosing. Currently, trials are underway on topical dapsone gel, says Dr. Weinberg, also assistant clinical professor of dermatology at Columbia University College of Physicians and Surgeons, New York. Anecdotal evidence indicates that the antibiotic has an effect. Photodynamic therapy (PDT) is another area that holds promise. It involves administering a topical photosensitizing agent and then subjecting the area to a blue light. Doing so causes the release of free oxygen radicals, which can destroy the organism Propionibacterium acnes. Some methods involve high-intensity blue light without the photosensitizing agent. Actinic Keratosis Already approved for genital warts, 3M’s topical immunomodulator imiquimod (Aldara) cream 5% is the most exciting treatment for actinic keratoses, says Dr. Weinberg. Phase III trials are nearing completion, and researchers are studying several dose regimens, he says. (The literature also indicates that the drug is successful for nodular and superficial basal cell carcinoma and Bowen’s disease, he says.) Diclofenac sodium (Solaraze gel 3%) from Bioglan Pharma, Inc. is another effective approach. In theory, this NSAID inhibits the cyclooxygenase pathway, which leads to decreased prostaglandin synthesis. One benefit of this therapy is that patient compliance tends to be better, says Dr. Loucas. It’s much less irritating than traditional 5-fluorouracil medications. That means patients are more likely to apply Solaraze gel for longer periods of time. Recently approved by the FDA, Solaraze represents a “nice breakthrough,” he says. Carac (Dermik Laboratories), a diluted form of 5-fluorouracil, can also be of benefit. Clinicians are also using PDT for actinic keratoses. Non-Melanoma Clinicians are also studying Aldara to treat skin cancers, particularly basal cell carcinoma, says Dr. Loucas. Several studies, he says, showed complete resolution of skin cancer after 12 to 20 weeks of treatment. Extending the PDT trend, Novartis Ophthalmics and QLT Inc. have announced the start of patient enrollment in two Phase III clinical trials using PDT with verteporfin for the treatment of multiple basal cell carcinomas. A Phase II trial demonstrated preliminary safety and efficacy of verteporfin at three light doses in patients with non-melanoma skin cancer with multiple lesions. The group of patients that was exposed to the highest light dose had the best response rate. In this group, 98% of the assessed tumors showed a complete clinical response following 6 months of initial treatment. Melanoma For melanoma, current research focuses on vaccines to help broaden the immune attack against the disease. Researchers are looking at three ways to deliver antigen genes to the patient: into the blood using plasmid DNA; retrovirus; and adenovirus, says Dr. Loucas. Immunization, he notes, will likely require a combination of these three delivery systems. Future development of vaccines, says Dr. Weinberg, may offer a better alternative than interferon or interleukin as adjuvant therapy for advanced disease. More Potential Advances Besides drugs for these major conditions, other agents hold out hope for dermatology patients: • Thalidomide for pyoderma gangrenosum and refractory aphthous ulcers in the mouth. • Resiquimod (3M), a relative of imiquimod, for genital herpes. • In addition, although it’s not new, hydrocortisone buteprate 0.1% (Pandel) for psoriasis and atopic dermatitis will be relaunched in 2003 by CollaGenex. Gene Therapy for the Future Though biologic therapies and other advances are likely to transform dermatologists’ prescribing patterns in the near term, gene therapy holds the promise for long-range changes. Right now, gene therapy is in the “infant stage,” says Dr. Lebwohl. Genetics is “always just over the horizon,” says Datamonitor’s Mr. Pang. While some rare genetic defects produce skin diseases, most dermatology conditions are multifactorial, says Joseph Fowler, Jr., M.D., clinical professor of dermatology at the University of Louisville. That means genetic therapy may be most beneficial, he says, for a small group of patients with those genetic diseases. Beyond Dermatology Drugs in development today may have far-reaching effects in other areas. “The dermatology market,” says the Datamonitor report, “represents an effective route to other autoimmune diseases. Dermatological disorders provide a prototypic model for other autoimmune diseases, in terms of disease pathogenesis, and serve as an ideal proof-of-concept model since drug effectiveness can be easily assessed via changes in skin appearance. This will greatly increase the market potential for new biologics in development for the treatment of dermatological disorders.”
L ike a laser-guided missile finding its target, drugs in dermatology today offer increased accuracy with fewer side effects. New agents like biologic therapies and immunomodulators strive to pinpoint and attack disease. Advances in biotechnology will transform the dermatology market, notes research firm Datamonitor. Immunomodulatory drugs “will revolutionize the market by providing high efficacy coupled with a much needed improvement in side effects, as well as prolonging periods of disease remission,” according to a Datamonitor report on dermatology drugs. Dermatologists practice in a generation that attempts to go for therapeutic magic bullets, says Douglas Kress, M.D., director of clinical services and residency program director, University of Pittsburgh Department of Dermatology. Treatments have carried “some relatively unpleasant side effects,” says Timothy Pang, analyst at Datamonitor. However, newer treatments provide some safer alternatives. In atopic dermatitis, for instance, the topical immunomodulators tacrolimus (Pro-topic) from Fujisawa and pimecrolimus (Elidel) from Novartis “really provide us a new treatment option that comes away from topical corticosteroids,” he says. Of course, with new drugs, not all side effects are known, says Dr. Kress. Various agents affecting the immune system, for instance, show early evidence of promoting reactivation tuberculosis, he says. Still, he notes that methotrexate doesn’t have a “charming” side effect profile either. Same Drug, Different Condition As new biologic therapies are making treatment inroads, the traditional dermatology approach of using various drugs off-label continues. If the pathogenesis of conditions is similar, trying the agent for those related conditions makes sense, suggests Adrienne Rencic, M.D., Ph.D., dermatologist at Mercy Medical Center in Baltimore, MD, and clinical instructor at the University of Maryland. What’s more, as expensive new drugs come to market, others are going generic, says Mr. Pang. Accutane, for instance, a huge seller for Roche, went off patent in February 2002. In turn, Bertek Pharmaceuticals just launched Amnesteem (isotretinoin). In this article, we’ll take a look at the latest pharmaceuticals to treat various dermatologic conditions. This includes eczema, acne, actinic keratosis and skin cancers. We’ll start with psoriasis, where some of the most exciting work is being done. Psoriasis: Big News It’s hard to exaggerate the unanimity of excitement with which clinicians speak of biologic therapies for psoriasis. These agents hold out the promise of transforming the treatment of this common disease and avoiding the side effects of drugs like methotrexate and cyclosporine. Up to now, treatments for psoriasis have been poorly received by both patients and physicians, says Craig Leonardi, M.D., a dermatologist in St. Louis, MO, and clinical associate professor of dermatology at St. Louis University. Doctors have offered topical therapies to patients who are clearly candidates for a systemic approach. “It really has been a therapeutic wasteland for roughly 10 or 15 years,” he says. Quite a few products are in late-stage research or registration in psoriasis “that are really completely new therapies within that market,” says Mr. Pang. Biologic therapies for psoriasis represent the “news of the year,” according to Steven Feldman, M.D., Ph.D., professor of dermatology and pathology at Wake Forest University School of Medicine, Winston-Salem, NC. The excitement focuses around four agents: etanercept (Enbrel) from Amgen; infliximab (Remicade) from Centocor; alefacept (Amevive) from Biogen; and efalizumab (Raptiva) from Genentech/XOMA. These agents are either under FDA review or closest to FDA submission, notes a paper by Jeffrey Weinberg, M.D., director, Clinical Research Center, Department of Dermatology, St. Luke’s – Roosevelt Hospital Center and Beth Israel Medical Center, New York. Enbrel and Remicade, says Mark Lebwohl, M.D., professor and chairman, Department of Dermatology, Mt. Sinai School of Medicine, New York, are currently on the market for such indications as rheumatoid arthritis and Crohn’s disease. But dermatologists are prescribing them for psoriasis. It’s reasonable, says Dr. Feldman, to prescribe these drugs for patients who have failed approved treatments like methotrexate. Enbrel is a tumor necrosis factor (TNF) receptor; Remicade is a monoclonal antibody that binds to TNF-alpha. In May 2002, an FDA advisory committee voted to recommend Amevive for approval. This recombinant protein stops T-cell activation. Raptiva (formerly known as Xanelim), also a T-cell activation modulator is being co-developed by Genentech and XOMA). The companies filed for a Biologics License Application with FDA in late December. Among its advantages, according to Dr. Leonardi, are that it’s self-administered by subcutaneous injection only once a week; has mild side effects that disappear after one or two injections; and has been shown highly effective compared to placebo with 29% of study participants achieving a 75% reduction in their PASI scores after 12 weeks of therapy. But for all their advantages, such novel therapies are expensive. Though patients can take advantage of “biotechnology at its finest,” manufacturing such drugs, says Dr. Leonardi, involves a “terrifically complicated and expensive process.” The tab for Remicade infusions for inflammatory bowel disease, notes Mr. Pang, can run $20,000 to $25,000 annually. Because of such expense, agents such as these might be used in combination with more standard pharmaceutical treatments for psoriasis, says Dr. Rencic. Instead of using a biologic therapy indefinitely, you might use the drug just for flare-ups. Other drugs that hold promise for psoriasis include tacrolimus (Protopic) from Fujisawa, the breakthrough non-steroidal for atopic dermatitis that was approved in December 2000, and the diabetes drug rosiglitazone maleate (Avandia) from SmithKline Beecham. Also, the Bristol-Myers Squibb paclitaxel (Taxol), in oral form, is being tested for psoriasis, notes Dr. Rencic. In addition, Connectics’ clobetasol propionate (Olux Foam 0.05%) just received a supplemental indication for the short-term topical treatment of mild to moderate plaque-type psoriasis of non-scalp regions, excluding the face and intertriginous areas. Atopic Dermatitis/Eczema Besides psoriasis, drugs such as Amevive and Raptiva, suggests Dr. Leonardi, may find a place in treating other chronic inflammatory disorders, such as atopic dermatitis. Once the drugs are used for psoriasis, you’re likely to see them used elsewhere, and chronic eczema will be one of the first places. As mentioned earlier, in atopic dermatitis the topical immunosuppressants Protopic from Fujisawa and pimecrolimus (Elidel) from Novartis provide new treatment options. These agents are already “making a dramatic change,” says Dr. Kress. They work extremely well as maintenance therapies, he says, after initial treatment with topical steroids. Emmanuel Loucas, M.D., Advanced Dermatology, Manhattan and Long Island, NY, looks for these two drugs to be used in multiple skin conditions. They include alopecia areata, graft versus host disease, lichen planus, pyoderma gangrenosum, sarcoidosis and vitiligo. Acne and Rosacea Unlike psoriasis, no new blockbuster treatments promise treatment of acne in the near term. But treatments for rosacea are another story. Azelaic acid gel 15% (Finacea) was approved early this month for the treatment of the inflammatory papules and pustules caused by mild to moderate rosacea. Finacea is the first new therapy for rosacea in more than a decade. Berlex will launch its drug in the first quarter of this year. A study for a systemic treatment for rosacea is also underway. Last summer, CollaGenex Pharmaceuticals began Phase III clinical trials with its doxycycline hyclate tablets, 20 mg (Periostat). Galderma also launched a daily cleanser, sodium sulfacetamide 10%, sulfur 5% (Rosanil), which is meant to complement topical rosacea therapy. For acne, advances involve the way medications are combined, says Dr. Feldman. Recognition is growing, he says, that topical retinoids can help not only comedones but also inflammatory lesions. Clinicians may use retinoids with topical and oral antibiotics to treat different types of acne. Allergan’s oral tazarotene (Tazorac) offers a shorter half-life compared to Roche’s isotretinoin (Accutane), says Dr. Leonardi. Because of concerns about pregnancy and possibly depression when administering retinoids, any drug that works in the same fashion but offers a shorter half-life would represent an advance, he says. In addition, Stiefel Labs just launched its new product to treat inflammatory acne. Clindamycin, 1% - benzoyl peroxide, 5% (Duac Topical Gel) is approved for once-a-day dosing. Currently, trials are underway on topical dapsone gel, says Dr. Weinberg, also assistant clinical professor of dermatology at Columbia University College of Physicians and Surgeons, New York. Anecdotal evidence indicates that the antibiotic has an effect. Photodynamic therapy (PDT) is another area that holds promise. It involves administering a topical photosensitizing agent and then subjecting the area to a blue light. Doing so causes the release of free oxygen radicals, which can destroy the organism Propionibacterium acnes. Some methods involve high-intensity blue light without the photosensitizing agent. Actinic Keratosis Already approved for genital warts, 3M’s topical immunomodulator imiquimod (Aldara) cream 5% is the most exciting treatment for actinic keratoses, says Dr. Weinberg. Phase III trials are nearing completion, and researchers are studying several dose regimens, he says. (The literature also indicates that the drug is successful for nodular and superficial basal cell carcinoma and Bowen’s disease, he says.) Diclofenac sodium (Solaraze gel 3%) from Bioglan Pharma, Inc. is another effective approach. In theory, this NSAID inhibits the cyclooxygenase pathway, which leads to decreased prostaglandin synthesis. One benefit of this therapy is that patient compliance tends to be better, says Dr. Loucas. It’s much less irritating than traditional 5-fluorouracil medications. That means patients are more likely to apply Solaraze gel for longer periods of time. Recently approved by the FDA, Solaraze represents a “nice breakthrough,” he says. Carac (Dermik Laboratories), a diluted form of 5-fluorouracil, can also be of benefit. Clinicians are also using PDT for actinic keratoses. Non-Melanoma Clinicians are also studying Aldara to treat skin cancers, particularly basal cell carcinoma, says Dr. Loucas. Several studies, he says, showed complete resolution of skin cancer after 12 to 20 weeks of treatment. Extending the PDT trend, Novartis Ophthalmics and QLT Inc. have announced the start of patient enrollment in two Phase III clinical trials using PDT with verteporfin for the treatment of multiple basal cell carcinomas. A Phase II trial demonstrated preliminary safety and efficacy of verteporfin at three light doses in patients with non-melanoma skin cancer with multiple lesions. The group of patients that was exposed to the highest light dose had the best response rate. In this group, 98% of the assessed tumors showed a complete clinical response following 6 months of initial treatment. Melanoma For melanoma, current research focuses on vaccines to help broaden the immune attack against the disease. Researchers are looking at three ways to deliver antigen genes to the patient: into the blood using plasmid DNA; retrovirus; and adenovirus, says Dr. Loucas. Immunization, he notes, will likely require a combination of these three delivery systems. Future development of vaccines, says Dr. Weinberg, may offer a better alternative than interferon or interleukin as adjuvant therapy for advanced disease. More Potential Advances Besides drugs for these major conditions, other agents hold out hope for dermatology patients: • Thalidomide for pyoderma gangrenosum and refractory aphthous ulcers in the mouth. • Resiquimod (3M), a relative of imiquimod, for genital herpes. • In addition, although it’s not new, hydrocortisone buteprate 0.1% (Pandel) for psoriasis and atopic dermatitis will be relaunched in 2003 by CollaGenex. Gene Therapy for the Future Though biologic therapies and other advances are likely to transform dermatologists’ prescribing patterns in the near term, gene therapy holds the promise for long-range changes. Right now, gene therapy is in the “infant stage,” says Dr. Lebwohl. Genetics is “always just over the horizon,” says Datamonitor’s Mr. Pang. While some rare genetic defects produce skin diseases, most dermatology conditions are multifactorial, says Joseph Fowler, Jr., M.D., clinical professor of dermatology at the University of Louisville. That means genetic therapy may be most beneficial, he says, for a small group of patients with those genetic diseases. Beyond Dermatology Drugs in development today may have far-reaching effects in other areas. “The dermatology market,” says the Datamonitor report, “represents an effective route to other autoimmune diseases. Dermatological disorders provide a prototypic model for other autoimmune diseases, in terms of disease pathogenesis, and serve as an ideal proof-of-concept model since drug effectiveness can be easily assessed via changes in skin appearance. This will greatly increase the market potential for new biologics in development for the treatment of dermatological disorders.”
