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Comparison of two vehicle-controlled trials of imiquimod 5% cream for the treatment of external genital warts
s210
ESDR I JSID I SID Abstracts
1255
1258
DOUBLE-BLD\ID HYDROCORTISON-CONTROLLED TACROLIMUS OINTME?;T FOR ATOPIC DERMATITIS Cwsren G”@.esell.Thomas lung. Kriatn” Retch. Volk:r
CORTICOSTEROID INDUCED SKIN ATROPHY AND BARRIER IMPAIP.MENT MONITORED WITH NON-INVASIVE METHODS Ludeer KolL&. Tmcv Stoudemaver’. and Albert M. Klinmag. ‘S.K.I.N. Inc., Conslwhocken, PA,’ Paul-Gason-Utma Skin Research Center, AG, Hamburg, Germany, ?Jniversity of Pennsylvania, Philadelphia, PA Ski atmphy is the most common adverse effects of steroid treatment. In this study we focused an the effect of clotetawl propionate (Ternovate cream 0.05%) on the epidermis and tlx strahun comama barrier fuwtian of the v&r forearm. We treated subjects twice daily for 4 weeks acd monitored skin changes with several non-invasive methods: 1. Confocal k&w micmscopy for epidennal changes 2. Ultrasound for skin thickness 3. Replicas for mici-otopography 4. Detergent scrubs for comeocyte analysis 5. Evapmimeter for TWL 6. Cyanoacrykde biopsies for ceramide analysis Ultmsound shaved thinning of the skii as early as otx week of treatmznt; confocal laser micmxopy revealed a thinning of the epidermis and a decrease in kwatinocyte size. Silflo-replica analysis showed a flattening ofthe surface. Comeacyte analysis showed a decrease of the mean w~mwcyte size. TWL increased during treatment, indicating an @aired barrier. Lipid content of the we c0nclude that our methods are stmtum comelull deawed after treament. sensitive enough to nxmitor various steroid induced skin changes.
lunehanr. Mattias Bohn’ and Chnsune Neumann Departl”e”, ofDerma,o,ogy and ‘Pharmacy oftbe Universi~ ofGo”,“gen, Germany Tacrolimus (FK506) is a” ~mm”“~s”ppressa”t drug show” to be efXecovcL” Ihs 1opLc~ reatment of ample dermatius (AD, up 10 now. “0 data ilre “vailable on the eficacy of wcr”lim”s in companso” to ” standard tre3tme”t of AD, fie toputl corucorreroids Therefore, we wad sevenpahents &fen”% from severe, longstanoing AD (age 22 to 36 yrs) wth tacrohmur (0 1%) antment a” one body hti and hydrocoruson (3%) on the other hod? half The appbcauon w”s double-bhnd. The axa of treatment d,d not exceed 20 % of the whole bwiv surface Irule of “mesi The veh,c!e of tacrolmms and hydrocottlco” was idenucnl The frequency of ointment “pphcatio” ,ras ior 2 “mes dally over three weeks The treated areas included face. neck and forearms Chmcai documentation ~85 performed weekly by a modified SCOIWD
score Bcsxder
patients had a diary for daly estmuuon of plunlur I” the affected areas and their rmpressm” of diseaseactivq Atler tiee weeks of treatment. all pwents showed r15nlflcanr improvement I” both tacrolim”s and hydrcarusan Vested nress I” SIX of rhe we” pauents. there was no chm~l difference between tacmhmus and hydrocorusoninduced mqrovement of the affected skin. These results coriclawd por”LAy w”h “w s”b,ecwe pammeters pmnt”s and es”maua” of diseaseacuwty I” one pat~cnt. t”cm!~“~us omtment WQ clearly superior to bydrocortiso”. The difference of the ciirucal score war about 30%. The only side effect of tacralimus LIcatment was the semauo” of burmng i” two pauents. We conclude that the effect of short-term treaunent wuh tlcralimus (0 i%) ol”nne”t IS comparable to hydxxoruson 3% in most AD pnuenis whereas a subgroup might profit from this therapy to a greater extent.
Beiersdorf
1256
1259
EXPRESSION OF CYTOCHROME P450 ISOENZYMES IN DIFFEF COMPARTMENTS OF m HUMAN SKIN. J. M. Baron. G Z&Klaawa& Sieben A. Ritbben. I’. K. Iupwt H. F. hferk, Dapartmaa of a&adogyand?rMtituteof PhwacolqyandToxioology, UnivunityHos&lRWTBAacbnAoobeqGemuny Cytxbmnx P450 (CYP) iwmzyme6 metabdiEe various mdogacw acd cmgenw small mc4Bxlarwigbtnzrqwd8Mdanimol~intheaxidatiooafmMyadogemuscmnpounds ~.blthepreMnt sucbasaiwicacidorxen&icaicaiwludingdnw,mt@nsaad 8twlywcwaaedtoagenrthedi&w@inCYPexpreasionin&isolatedfmntioup compartmadsoffhehvmansidn.RT-PCRwasusedasa~mmodfatbe~~of c(piJocozymcxpnasicnin~tagetalls.RT-PCR-regulemnmn6mEedafterwardsby meansofNcut&mbl~immwblot,inrmunodliningmhicatal~aa~ays.Knatiwcytes derived &,m the human q&&a revealed an cxpzwaon of CYP IAI, lBl.2B1,2B6,2El and3A.Antigenpresmtb@ceUsswbasmonocytesandmanopbaen:~tbC wmtitutive mrpresrion OFCYP lB1,2B6,2El and &owed tbo e.xp!ession of CYP IA1 and 3A3/4~~incubafioowimlmownCYPinhran,Similarnsultswesetoundin
COMPARISON
OF TWO VEHICLE-CONTROLLED
TRIALS
OF IMIQUTMOD
5%
CREAM FOR THE TREATMENT OF EXTERNAL GENITAL WARTS K. Bcutt,et+ L. Edward& M. Owe&T.F+> and Study Group, ‘Solarm Dennatolo$y Associates, Vallejo, CA, USA; Carolinas Medical Center, Charlotte, NC, USA; 3M Pharmaceuticals, bniquimod (IQ) is an immune
St. Paul, MN, USA response modifier which stimulates
the production
of
interferon-a and other cytokines. Two multi-center, double-blind, vehicle-controlled, parallel group trials compared IQ 5% and vehicle. In the first trial, 209 patients (123 male, 86 female) were treated 3 times/week, and in the second trial, 189 patients (105 male, 84 female) were treated daily. Data from a treatment-f;ulures analysis (excludes non-compliant patients) are reported. In both studies, patxnts were treated for up to 16 weeks or until complete wart clearance. Patients with complete wart clearance entered a 12.week treatment-free follow-up period. Complete wart clearance in the first trial was seen in 56% of IQ 5% patients and 14% of vehicle patients (p~O.0001). In the second trial, 71% of IQ 5% patients and 4% ofvehicle patients had wart clearance @cO.OoOl). Clearance rates were higher in women than in men. In the first trial, 13% of IQ 5% patients and 10% of vehicle patients had a wart recurrence during follow-up. Recurrence rates were also low in the second trial: 19% of IQ 5% patients and 0% of vehicle patients. Local skin reactions associated with IQ occurred in both studies, but were more common and of greater severity with daily dosing. There were no statishcally significant differences among treatment groups for systemic adverse events. Both the 3 times/week and daily dosing regimens of IQ 5% cream were safe and effective with acceptable clearance rates and low recurrence rates.
1257 ORAL SDZ ASM 981 INHIBITS PRURITIC ERYTHEMATOUS RASH IN HYPOMAGNESEMIC HAIRLESS RATS. G. Ncckcrmann. A. Bavandi. I.G. Mlemaassncr, Novarus Forschungsinsbtut, Vienna, Austria SDZ ASM 981, a new ascomycin macrolactam derivative, has been shown to inhibit in vitro the release of preformed and newly synthesized pro-inflammatory mediators from immunologically stimulated rat basophdic leukemia cells, serving as a model for human mast cells. We, therefore, studied the anti-inflammatory effect of SDZ ASM 981 in hairless tats maintained on a magnesium-deficient diet. These tats develop histaminemia and a pruritic erythematous rash, probably via mast cell activation, and they also exhibit increased blood levels of nitric oxide. Diseased animals were treated orally either with SDZ ASM 981 at 4 and 12.5 &kg/day OI with the vehicle for three days (d 1,2, 3) and observed until d 4 01 d 8. SDZ ASM 981 at 4 &kg bad only a marginal activity. In contrast, SDZ ASM 981 at 12.5 &kg almost completely teheved ptuntus and rash from d 2 until d 4, but symptoms reappeared thereafter and lasted until d 8. At d 4 histamine and nitric oxide compared to controls. were significantly reduced by 40 and 24%, respectively, Histomorphometric analysis of pmnal ~ectmns revealed a marked decrease in degranulated mast cells (58 YS 81% in controls) and a clear reduction of inflammatory lesmns. At d 8 (5 days after the last treatment and after symptoms had reappeared) all parameters suppressed at d 4 were equal to controls, a phenomenon observed also with dexamethasone by other groups in this model. In conclusion, the anti-mflammatory effects observed with SDZ ASM 981 in hypomagncscmic tats can be mterpreted as a consequence of the inhibition of mast cell activation and suggest that SDZ ASM 981 has a therapeutic potential for the oral treatment of skin drseascs in which mast cells play a role.
1260 T.4RGETmG cmFOR IMMUNOTHERAPY: RESULTS OFAPHASE 1TRIAL WITH A LF*-3llgG FeFUSION PROTEIN. Damel Madaw. Paul Norman, Gerard Maieau. Steve” Knox. Gunther Winkler. Steohen MacLellan. Lvn” Sanori. Maw Coonev. Wcmcr Meier. Paula Hh-hma”. and Mark Roeee B&e”, Inc., Cambridge. MA 02142 and UMDSG”y’s Hospital, Land”“. UK. BG9273, a recombinant 115 kD dlmenc glywsylated protein which consists of tie first extracellular
has been
do-” of human WA-3 fused to the hinge and CH2 and CH3 syuences of human ,gG, designed to modulate immune responses through interaction with the CD2 receptor. BG9273 cwnpetitively inhibits the binding of CD? cells to LFA-3* cells. Based upon the in vitro effects of BG9273 on T cell function and its therapeutic potential BSa” immunosuppressweagent, tolerabihty. pharmacakinellcs. and biologic activity of BG9273 were evaluated in a blmded, single i”~ave”ws dare, placebo-controlled. dose-escalation study af hcalrhy volunteers. Seven dose groups (0.005 mgkg. 0.01 m&, 0.02 mpntp, 0.W m&g, 0.10 mg/kg, 0.15 m&, and 0.225 mgnig) with SIX subjects per group were enrolled. BG97.73 was well tolerated wtb n” saws adverse events reported. Elimination half life was - 9 days. A tIMsie”t (less *a” 7 day, red”c”on from premfwon in the absolute “umber of peripheral lymphofyten was observed in alI subjects wb” received 869273. This red”f”on was noted I” total, CD?‘, CD4+, and CD8’ lymphocytes but not in CDIP’ lymphocytes The degree and duration of redmtm” from baseline levels conelated directly with the dose of BG9273. A greater reductm” m CDT cells wiul memory,effector phenotypes (CD4+CD45RO+ and CDS?CD45ROC) than with naive phenotypes (CD4*-CD4SRA’ and CDS’.CD45RA? was observed Sclectivily for CD45RO* cells over CD45RA’ cells may be related to increased expression of CD2 whrch was &served by ““w cytomehic analysis. k Maxim”rn Re*uctio” from Baseline CD4*-CD45RO*
80%
1 crM*-cD4IRA* 1 CDt?.CD45RO* 1 CD8’-cxMsRA* 43% I 96% I 488 I
Snilar changes in per&ml lymphocyte subsets were ““ted I” two Phase lb& multidose studier in patlena with chronic plaque psoriasis. Thus, because tolerabdity, PK profile, and selectivity for memory/effecter T cells, BG9273 has potential BSa therapeutic imm”“omod”l”tor in psoriasis.
of its
ESDR I JSID I SID Abstracts
1255
1258
DOUBLE-BLD\ID HYDROCORTISON-CONTROLLED TACROLIMUS OINTME?;T FOR ATOPIC DERMATITIS Cwsren G”@.esell.Thomas lung. Kriatn” Retch. Volk:r
CORTICOSTEROID INDUCED SKIN ATROPHY AND BARRIER IMPAIP.MENT MONITORED WITH NON-INVASIVE METHODS Ludeer KolL&. Tmcv Stoudemaver’. and Albert M. Klinmag. ‘S.K.I.N. Inc., Conslwhocken, PA,’ Paul-Gason-Utma Skin Research Center, AG, Hamburg, Germany, ?Jniversity of Pennsylvania, Philadelphia, PA Ski atmphy is the most common adverse effects of steroid treatment. In this study we focused an the effect of clotetawl propionate (Ternovate cream 0.05%) on the epidermis and tlx strahun comama barrier fuwtian of the v&r forearm. We treated subjects twice daily for 4 weeks acd monitored skin changes with several non-invasive methods: 1. Confocal k&w micmscopy for epidennal changes 2. Ultrasound for skin thickness 3. Replicas for mici-otopography 4. Detergent scrubs for comeocyte analysis 5. Evapmimeter for TWL 6. Cyanoacrykde biopsies for ceramide analysis Ultmsound shaved thinning of the skii as early as otx week of treatmznt; confocal laser micmxopy revealed a thinning of the epidermis and a decrease in kwatinocyte size. Silflo-replica analysis showed a flattening ofthe surface. Comeacyte analysis showed a decrease of the mean w~mwcyte size. TWL increased during treatment, indicating an @aired barrier. Lipid content of the we c0nclude that our methods are stmtum comelull deawed after treament. sensitive enough to nxmitor various steroid induced skin changes.
lunehanr. Mattias Bohn’ and Chnsune Neumann Departl”e”, ofDerma,o,ogy and ‘Pharmacy oftbe Universi~ ofGo”,“gen, Germany Tacrolimus (FK506) is a” ~mm”“~s”ppressa”t drug show” to be efXecovcL” Ihs 1opLc~ reatment of ample dermatius (AD, up 10 now. “0 data ilre “vailable on the eficacy of wcr”lim”s in companso” to ” standard tre3tme”t of AD, fie toputl corucorreroids Therefore, we wad sevenpahents &fen”% from severe, longstanoing AD (age 22 to 36 yrs) wth tacrohmur (0 1%) antment a” one body hti and hydrocoruson (3%) on the other hod? half The appbcauon w”s double-bhnd. The axa of treatment d,d not exceed 20 % of the whole bwiv surface Irule of “mesi The veh,c!e of tacrolmms and hydrocottlco” was idenucnl The frequency of ointment “pphcatio” ,ras ior 2 “mes dally over three weeks The treated areas included face. neck and forearms Chmcai documentation ~85 performed weekly by a modified SCOIWD
score Bcsxder
patients had a diary for daly estmuuon of plunlur I” the affected areas and their rmpressm” of diseaseactivq Atler tiee weeks of treatment. all pwents showed r15nlflcanr improvement I” both tacrolim”s and hydrcarusan Vested nress I” SIX of rhe we” pauents. there was no chm~l difference between tacmhmus and hydrocorusoninduced mqrovement of the affected skin. These results coriclawd por”LAy w”h “w s”b,ecwe pammeters pmnt”s and es”maua” of diseaseacuwty I” one pat~cnt. t”cm!~“~us omtment WQ clearly superior to bydrocortiso”. The difference of the ciirucal score war about 30%. The only side effect of tacralimus LIcatment was the semauo” of burmng i” two pauents. We conclude that the effect of short-term treaunent wuh tlcralimus (0 i%) ol”nne”t IS comparable to hydxxoruson 3% in most AD pnuenis whereas a subgroup might profit from this therapy to a greater extent.
Beiersdorf
1256
1259
EXPRESSION OF CYTOCHROME P450 ISOENZYMES IN DIFFEF COMPARTMENTS OF m HUMAN SKIN. J. M. Baron. G Z&Klaawa& Sieben A. Ritbben. I’. K. Iupwt H. F. hferk, Dapartmaa of a&adogyand?rMtituteof PhwacolqyandToxioology, UnivunityHos&lRWTBAacbnAoobeqGemuny Cytxbmnx P450 (CYP) iwmzyme6 metabdiEe various mdogacw acd cmgenw small mc4Bxlarwigbtnzrqwd8Mdanimol~intheaxidatiooafmMyadogemuscmnpounds ~.blthepreMnt sucbasaiwicacidorxen&icaicaiwludingdnw,mt@nsaad 8twlywcwaaedtoagenrthedi&w@inCYPexpreasionin&isolatedfmntioup compartmadsoffhehvmansidn.RT-PCRwasusedasa~mmodfatbe~~of c(piJocozymcxpnasicnin~tagetalls.RT-PCR-regulemnmn6mEedafterwardsby meansofNcut&mbl~immwblot,inrmunodliningmhicatal~aa~ays.Knatiwcytes derived &,m the human q&&a revealed an cxpzwaon of CYP IAI, lBl.2B1,2B6,2El and3A.Antigenpresmtb@ceUsswbasmonocytesandmanopbaen:~tbC wmtitutive mrpresrion OFCYP lB1,2B6,2El and &owed tbo e.xp!ession of CYP IA1 and 3A3/4~~incubafioowimlmownCYPinhran,Similarnsultswesetoundin
COMPARISON
OF TWO VEHICLE-CONTROLLED
TRIALS
OF IMIQUTMOD
5%
CREAM FOR THE TREATMENT OF EXTERNAL GENITAL WARTS K. Bcutt,et+ L. Edward& M. Owe&T.F+> and Study Group, ‘Solarm Dennatolo$y Associates, Vallejo, CA, USA; Carolinas Medical Center, Charlotte, NC, USA; 3M Pharmaceuticals, bniquimod (IQ) is an immune
St. Paul, MN, USA response modifier which stimulates
the production
of
interferon-a and other cytokines. Two multi-center, double-blind, vehicle-controlled, parallel group trials compared IQ 5% and vehicle. In the first trial, 209 patients (123 male, 86 female) were treated 3 times/week, and in the second trial, 189 patients (105 male, 84 female) were treated daily. Data from a treatment-f;ulures analysis (excludes non-compliant patients) are reported. In both studies, patxnts were treated for up to 16 weeks or until complete wart clearance. Patients with complete wart clearance entered a 12.week treatment-free follow-up period. Complete wart clearance in the first trial was seen in 56% of IQ 5% patients and 14% of vehicle patients (p~O.0001). In the second trial, 71% of IQ 5% patients and 4% ofvehicle patients had wart clearance @cO.OoOl). Clearance rates were higher in women than in men. In the first trial, 13% of IQ 5% patients and 10% of vehicle patients had a wart recurrence during follow-up. Recurrence rates were also low in the second trial: 19% of IQ 5% patients and 0% of vehicle patients. Local skin reactions associated with IQ occurred in both studies, but were more common and of greater severity with daily dosing. There were no statishcally significant differences among treatment groups for systemic adverse events. Both the 3 times/week and daily dosing regimens of IQ 5% cream were safe and effective with acceptable clearance rates and low recurrence rates.
1257 ORAL SDZ ASM 981 INHIBITS PRURITIC ERYTHEMATOUS RASH IN HYPOMAGNESEMIC HAIRLESS RATS. G. Ncckcrmann. A. Bavandi. I.G. Mlemaassncr, Novarus Forschungsinsbtut, Vienna, Austria SDZ ASM 981, a new ascomycin macrolactam derivative, has been shown to inhibit in vitro the release of preformed and newly synthesized pro-inflammatory mediators from immunologically stimulated rat basophdic leukemia cells, serving as a model for human mast cells. We, therefore, studied the anti-inflammatory effect of SDZ ASM 981 in hairless tats maintained on a magnesium-deficient diet. These tats develop histaminemia and a pruritic erythematous rash, probably via mast cell activation, and they also exhibit increased blood levels of nitric oxide. Diseased animals were treated orally either with SDZ ASM 981 at 4 and 12.5 &kg/day OI with the vehicle for three days (d 1,2, 3) and observed until d 4 01 d 8. SDZ ASM 981 at 4 &kg bad only a marginal activity. In contrast, SDZ ASM 981 at 12.5 &kg almost completely teheved ptuntus and rash from d 2 until d 4, but symptoms reappeared thereafter and lasted until d 8. At d 4 histamine and nitric oxide compared to controls. were significantly reduced by 40 and 24%, respectively, Histomorphometric analysis of pmnal ~ectmns revealed a marked decrease in degranulated mast cells (58 YS 81% in controls) and a clear reduction of inflammatory lesmns. At d 8 (5 days after the last treatment and after symptoms had reappeared) all parameters suppressed at d 4 were equal to controls, a phenomenon observed also with dexamethasone by other groups in this model. In conclusion, the anti-mflammatory effects observed with SDZ ASM 981 in hypomagncscmic tats can be mterpreted as a consequence of the inhibition of mast cell activation and suggest that SDZ ASM 981 has a therapeutic potential for the oral treatment of skin drseascs in which mast cells play a role.
1260 T.4RGETmG cmFOR IMMUNOTHERAPY: RESULTS OFAPHASE 1TRIAL WITH A LF*-3llgG FeFUSION PROTEIN. Damel Madaw. Paul Norman, Gerard Maieau. Steve” Knox. Gunther Winkler. Steohen MacLellan. Lvn” Sanori. Maw Coonev. Wcmcr Meier. Paula Hh-hma”. and Mark Roeee B&e”, Inc., Cambridge. MA 02142 and UMDSG”y’s Hospital, Land”“. UK. BG9273, a recombinant 115 kD dlmenc glywsylated protein which consists of tie first extracellular
has been
do-” of human WA-3 fused to the hinge and CH2 and CH3 syuences of human ,gG, designed to modulate immune responses through interaction with the CD2 receptor. BG9273 cwnpetitively inhibits the binding of CD? cells to LFA-3* cells. Based upon the in vitro effects of BG9273 on T cell function and its therapeutic potential BSa” immunosuppressweagent, tolerabihty. pharmacakinellcs. and biologic activity of BG9273 were evaluated in a blmded, single i”~ave”ws dare, placebo-controlled. dose-escalation study af hcalrhy volunteers. Seven dose groups (0.005 mgkg. 0.01 m&, 0.02 mpntp, 0.W m&g, 0.10 mg/kg, 0.15 m&, and 0.225 mgnig) with SIX subjects per group were enrolled. BG97.73 was well tolerated wtb n” saws adverse events reported. Elimination half life was - 9 days. A tIMsie”t (less *a” 7 day, red”c”on from premfwon in the absolute “umber of peripheral lymphofyten was observed in alI subjects wb” received 869273. This red”f”on was noted I” total, CD?‘, CD4+, and CD8’ lymphocytes but not in CDIP’ lymphocytes The degree and duration of redmtm” from baseline levels conelated directly with the dose of BG9273. A greater reductm” m CDT cells wiul memory,effector phenotypes (CD4+CD45RO+ and CDS?CD45ROC) than with naive phenotypes (CD4*-CD4SRA’ and CDS’.CD45RA? was observed Sclectivily for CD45RO* cells over CD45RA’ cells may be related to increased expression of CD2 whrch was &served by ““w cytomehic analysis. k Maxim”rn Re*uctio” from Baseline CD4*-CD45RO*
80%
1 crM*-cD4IRA* 1 CDt?.CD45RO* 1 CD8’-cxMsRA* 43% I 96% I 488 I
Snilar changes in per&ml lymphocyte subsets were ““ted I” two Phase lb& multidose studier in patlena with chronic plaque psoriasis. Thus, because tolerabdity, PK profile, and selectivity for memory/effecter T cells, BG9273 has potential BSa therapeutic imm”“omod”l”tor in psoriasis.
of its