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Improvement of psoriasis after antibiotic therapy with cefuroxime axetil
P3357 AN2728 preclinical studies demonstrate an acceptable safety profile for the topical treatment of psoriasis and atopic dermatitis Irwin Heyman, Anacor Pharmaceuticals, Inc, Palo Alto, CA, United States; Emily Ip, PhD, Anacor Pharmaceuticals, Inc, Palo Alto, CA, United States; Kirk Maples, PhD, Anacor Pharmaceuticals, Inc, Palo Alto, CA, United States; Liang Liu, MD, Anacor Pharmaceuticals, Inc, Palo Alto, CA, United States
P3359
AN2728 (5-(4-cyanophenoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole) is a broad spectrum antiinflammatory compound currently in development for the topical treatment of plaque psoriasis and atopic dermatitis. AN2728 is a novel boroncontaining compound which inhibits the release of tumor necrosis factor-alfa (TNFa), interleukin (IL)-12, IL-23, and other cytokines. AN2728 (1 M) was classified as a low potency hERG-channel blocker, minimizing concerns over cardiovascular safety. AN2728 demonstrated no mutagenic activity in the presence or absence of Aroclor-induced S9 liver fraction in the bacterial reverse mutation assay. AN2728 demonstrated no clastogenic activity in the in vitro mammalian chromosome aberration assay in the presence or absence of S9 activation using human peripheral blood lymphocytes and did not induce a significant increase in the incidence of micronucleated polychromatic erythrocytes in the rat micronucleus assays at oral doses up to 2000 mg/kg. Following oral administration of 10, 30, and 100 mg/kg to shrews, dose-responsive emetic effect was observed. The no observed effect level (NOEL) was 10 mg/kg, and was associated with significant plasma exposure. Following oral administration of 10, 30, and 100 mg/kg to ferrets, no emetic episodes were observed in any dose group. In the mouse local lymph node assay, AN2728 as a 1%, 5%, and 10% solution in acetone/ethanol (50:50, vol/vol) did not demonstrate skin sensitizing activity. AN2728 was administered by oral gavage to Sprague-Dawley rats at dosages of 50, 150, 400, and 1000 mg/kg/day for 28 consecutive days with a 14-day recovery period (high dose and vehicle). Mortality and clinical signs were observed in males (only) while hematology, clinical signs, and liver weight changes were observed in females dosed at 1000 mg/kg/day. The NOEL in males was 150 mg/kg/day and in females were 400 mg/kg/day. Go¨ttingen minipigs were dosed by dermal application once daily for up to 28 days with AN2728 cream B at concentrations of vehicle, 0.3%, 2%, and 5% with a 14-day recovery period (high dose and vehicle). Varying degrees of erythema/edema were present primarily in the 2% and 5% concentrations, but no systemic toxicity was present at any dose level. The NOAEL for AN2728 cream B was 0.3% for dermal toxicity and 5% for systemic toxicity. These data suggest that AN2728 has an acceptable safety profile for the topical treatment of skin inflammatory diseases. Commercial support: None identified.
P3358 Efficacy and safety of topical INCB018424, a selective Janus kinase 1 & 2 (JAK1&2) inhibitor in psoriasis Naresh Punwani, MD, Incyte Corporation, Wilmington, DE, United States; Alice Gottlieb, MD, PhD, Tufts-New England Medical Center, Boston, MA, United States; Jay Birnbaum, PhD, Jay E. Birnbaum Consulting, Montville, NJ, United States; William Williams, MD, Incyte Corporation, Wilmington, DE, United States Background: Janus kinases (JAKs) mediate signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis. INCB018424, a small gamma molecule of psoriasis, including interleukin (IL)-12, IL-23, and interferon (IFN) inhibitor of the JAK family of kinases with preferential activity for JAK1 and JAK2, is being developed as a topical treatment for psoriasis. Objectives: To characterize the clinical safety, efficacy, and impact on markers of dermal inflammation and pharmacokinetics of topical INCB018424 in patients with active, stable plaque psoriasis. Methods: Two 28-day studies were performed: (1) a double-blind, within-patient comparison of the safety, tolerability, and efficacy of INCB018424 cream versus vehicle and active comparators; and (2) an open-label evaluation of the safety, tolerability, efficacy, and PK of INCB018424 cream applied to patients with increasing body surface area involvement (2-7% and 8-13% BSA, completed; 1420% BSA, ongoing). Skin biopsies were performed at baseline and day 28 in some patients. Clinical, laboratory, and electrocardiographic assessments were performed at least weekly in both studies.
P3360 Improvement of psoriasis after antibiotic therapy with cefuroxime axetil Malgorzata Olszewska, Department of Dermatology, Warsaw Medical University, Warsaw, Poland; Adriana Rakowska, MD, Department of Dermatology, CSK MSWiA, Warsaw, Poland; Irena Walecka, MD, PhD, MBA, Department of Dermatology, CSK MSWiA, Warsaw, Poland; Lidia Rudnicka, MD, PhD, Department of Dermatology, CSK MSWiA, Warsaw, Poland
Results: Study 1: reductions in mean lesion scores were 53% for 1% cream QD versus 32% for vehicle (P # .05); 54% for 1.5% cream BID versus 27% for vehicle (P # .05); 46% for 1.5% cream BID versus 40% for calcipotriene; 58% for 1.5% cream BID versus 44% for betamethasone diproprionate. Study 2: safety and efficacy were demonstrated with the 1.5% cream BID at 2% to 13% BSA. Improvements in lesion thickness, erythema, scaling, and reduction in treated lesion area were observed in comparison to the untreated lesions. Mean lesion scores for treated areas decreased by 55% to 61% while untreated lesions showed a mean change of 14% to 21%. Mean total area decreased by 59% for treated lesions as compared to a decrease of 3% for untreated lesions. Efficacy was seen as early as 1 week following study drug application in some patients. Adverse events were mild in intensity and most judged to be unrelated to study medication. Plasma concentrations of INCB018424 evaluated at steady state showed continued absorption over the dosing interval, but there was no correlation to the BSA treated. Transcriptome and qPCR analysis of skin biopsies indicate that a number of proinflammatory cytokines are down modulated by INCB018424, including markers of TH1 and TH17 pathways. Conclusion: Topical INCB018424 was safe, well tolerated, and effective and showed reduction in markers of dermal inflammation in the treatment of psoriasis.
Cefuroxime axetil, a prodrug of the cephalosporin cefuroxime, has broad spectrum antibacterial activity. Cefuroxime axetil has been suggested for the long-term therapy of localized scleroderma and subacute cutaneous lupus erythematosus because of its immunosuppressive and antiinflammatory activity. The aim of the study was to evaluate the efficacy of long-term cefuroxime axetil administration in psoriasis. The study included 15 patients with moderate to severe, active plaque psoriasis. Mean duration of the disease was 12.8 years (range, 0.5-23 yrs) and mean duration of the recent flare was 2.6 months (range, 0.5-5.0 mos). Four of the patients fulfilled additionally CASPAR criteria for psoriatic arthritis. None of the patients had symptoms of an active infection; however, in most cases the flare was triggered by a preceding infection of the upper respiratory tract. Cefuroxime axetil was applied according to the following scheme: 250 mg twice daily for 3 weeks, followed by 125 mg once daily for 9 weeks. The overall response rate, measured as achieving a reduction of 75% from baseline Psoriasis Area and Severity Index score (PASI75) was 26% after 4 weeks, 29% after 8 weeks, and 21% after 12 weeks. Now rebound phenomenon was observed; however, four patients with psoriatic arthritis and four patients with psoriasis required introduction of systemic antipsoriatic therapy. In all patients only recently developed skin lesions healed. Older plaques, especially on knees, elbows, and scalp remained unchanged. These results indicate that cefuroxime axetil therapy may serve as alternative or adjuvant intervention treatment of exacerbations in the course of psoriasis.
Commercial support: Sponsored by Incyte Corporation.
Commercial support: None identified.
AB176
J AM ACAD DERMATOL
MARCH 2009
P3359
AN2728 (5-(4-cyanophenoxy)-1-hydroxy-1,3-dihydro-2,1-benzoxaborole) is a broad spectrum antiinflammatory compound currently in development for the topical treatment of plaque psoriasis and atopic dermatitis. AN2728 is a novel boroncontaining compound which inhibits the release of tumor necrosis factor-alfa (TNFa), interleukin (IL)-12, IL-23, and other cytokines. AN2728 (1 M) was classified as a low potency hERG-channel blocker, minimizing concerns over cardiovascular safety. AN2728 demonstrated no mutagenic activity in the presence or absence of Aroclor-induced S9 liver fraction in the bacterial reverse mutation assay. AN2728 demonstrated no clastogenic activity in the in vitro mammalian chromosome aberration assay in the presence or absence of S9 activation using human peripheral blood lymphocytes and did not induce a significant increase in the incidence of micronucleated polychromatic erythrocytes in the rat micronucleus assays at oral doses up to 2000 mg/kg. Following oral administration of 10, 30, and 100 mg/kg to shrews, dose-responsive emetic effect was observed. The no observed effect level (NOEL) was 10 mg/kg, and was associated with significant plasma exposure. Following oral administration of 10, 30, and 100 mg/kg to ferrets, no emetic episodes were observed in any dose group. In the mouse local lymph node assay, AN2728 as a 1%, 5%, and 10% solution in acetone/ethanol (50:50, vol/vol) did not demonstrate skin sensitizing activity. AN2728 was administered by oral gavage to Sprague-Dawley rats at dosages of 50, 150, 400, and 1000 mg/kg/day for 28 consecutive days with a 14-day recovery period (high dose and vehicle). Mortality and clinical signs were observed in males (only) while hematology, clinical signs, and liver weight changes were observed in females dosed at 1000 mg/kg/day. The NOEL in males was 150 mg/kg/day and in females were 400 mg/kg/day. Go¨ttingen minipigs were dosed by dermal application once daily for up to 28 days with AN2728 cream B at concentrations of vehicle, 0.3%, 2%, and 5% with a 14-day recovery period (high dose and vehicle). Varying degrees of erythema/edema were present primarily in the 2% and 5% concentrations, but no systemic toxicity was present at any dose level. The NOAEL for AN2728 cream B was 0.3% for dermal toxicity and 5% for systemic toxicity. These data suggest that AN2728 has an acceptable safety profile for the topical treatment of skin inflammatory diseases. Commercial support: None identified.
P3358 Efficacy and safety of topical INCB018424, a selective Janus kinase 1 & 2 (JAK1&2) inhibitor in psoriasis Naresh Punwani, MD, Incyte Corporation, Wilmington, DE, United States; Alice Gottlieb, MD, PhD, Tufts-New England Medical Center, Boston, MA, United States; Jay Birnbaum, PhD, Jay E. Birnbaum Consulting, Montville, NJ, United States; William Williams, MD, Incyte Corporation, Wilmington, DE, United States Background: Janus kinases (JAKs) mediate signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis. INCB018424, a small gamma molecule of psoriasis, including interleukin (IL)-12, IL-23, and interferon (IFN) inhibitor of the JAK family of kinases with preferential activity for JAK1 and JAK2, is being developed as a topical treatment for psoriasis. Objectives: To characterize the clinical safety, efficacy, and impact on markers of dermal inflammation and pharmacokinetics of topical INCB018424 in patients with active, stable plaque psoriasis. Methods: Two 28-day studies were performed: (1) a double-blind, within-patient comparison of the safety, tolerability, and efficacy of INCB018424 cream versus vehicle and active comparators; and (2) an open-label evaluation of the safety, tolerability, efficacy, and PK of INCB018424 cream applied to patients with increasing body surface area involvement (2-7% and 8-13% BSA, completed; 1420% BSA, ongoing). Skin biopsies were performed at baseline and day 28 in some patients. Clinical, laboratory, and electrocardiographic assessments were performed at least weekly in both studies.
P3360 Improvement of psoriasis after antibiotic therapy with cefuroxime axetil Malgorzata Olszewska, Department of Dermatology, Warsaw Medical University, Warsaw, Poland; Adriana Rakowska, MD, Department of Dermatology, CSK MSWiA, Warsaw, Poland; Irena Walecka, MD, PhD, MBA, Department of Dermatology, CSK MSWiA, Warsaw, Poland; Lidia Rudnicka, MD, PhD, Department of Dermatology, CSK MSWiA, Warsaw, Poland
Results: Study 1: reductions in mean lesion scores were 53% for 1% cream QD versus 32% for vehicle (P # .05); 54% for 1.5% cream BID versus 27% for vehicle (P # .05); 46% for 1.5% cream BID versus 40% for calcipotriene; 58% for 1.5% cream BID versus 44% for betamethasone diproprionate. Study 2: safety and efficacy were demonstrated with the 1.5% cream BID at 2% to 13% BSA. Improvements in lesion thickness, erythema, scaling, and reduction in treated lesion area were observed in comparison to the untreated lesions. Mean lesion scores for treated areas decreased by 55% to 61% while untreated lesions showed a mean change of 14% to 21%. Mean total area decreased by 59% for treated lesions as compared to a decrease of 3% for untreated lesions. Efficacy was seen as early as 1 week following study drug application in some patients. Adverse events were mild in intensity and most judged to be unrelated to study medication. Plasma concentrations of INCB018424 evaluated at steady state showed continued absorption over the dosing interval, but there was no correlation to the BSA treated. Transcriptome and qPCR analysis of skin biopsies indicate that a number of proinflammatory cytokines are down modulated by INCB018424, including markers of TH1 and TH17 pathways. Conclusion: Topical INCB018424 was safe, well tolerated, and effective and showed reduction in markers of dermal inflammation in the treatment of psoriasis.
Cefuroxime axetil, a prodrug of the cephalosporin cefuroxime, has broad spectrum antibacterial activity. Cefuroxime axetil has been suggested for the long-term therapy of localized scleroderma and subacute cutaneous lupus erythematosus because of its immunosuppressive and antiinflammatory activity. The aim of the study was to evaluate the efficacy of long-term cefuroxime axetil administration in psoriasis. The study included 15 patients with moderate to severe, active plaque psoriasis. Mean duration of the disease was 12.8 years (range, 0.5-23 yrs) and mean duration of the recent flare was 2.6 months (range, 0.5-5.0 mos). Four of the patients fulfilled additionally CASPAR criteria for psoriatic arthritis. None of the patients had symptoms of an active infection; however, in most cases the flare was triggered by a preceding infection of the upper respiratory tract. Cefuroxime axetil was applied according to the following scheme: 250 mg twice daily for 3 weeks, followed by 125 mg once daily for 9 weeks. The overall response rate, measured as achieving a reduction of 75% from baseline Psoriasis Area and Severity Index score (PASI75) was 26% after 4 weeks, 29% after 8 weeks, and 21% after 12 weeks. Now rebound phenomenon was observed; however, four patients with psoriatic arthritis and four patients with psoriasis required introduction of systemic antipsoriatic therapy. In all patients only recently developed skin lesions healed. Older plaques, especially on knees, elbows, and scalp remained unchanged. These results indicate that cefuroxime axetil therapy may serve as alternative or adjuvant intervention treatment of exacerbations in the course of psoriasis.
Commercial support: Sponsored by Incyte Corporation.
Commercial support: None identified.
AB176
J AM ACAD DERMATOL
MARCH 2009