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Figure 2. Psoriasis of the KneeThis patient experienced75% reduction in PsoriasisArea and Severity Indexscore after 4 weeks’ treatmentwith 60 mg oralpimecrolimus. Top photois at baseline; bottomphoto shows day 28.Source: Rappersberger K, et al.Pimecrolimus identifies a commongenomic anti-inflammatory profile,is clinically highly effective in psoriasisand is well tolerated. J InvestDermatol. 2002:119;876-887.Used with permission.plasma flow. There was no effect onglucose tolerance and no seriousadverse events. The one notable sideeffect was a transient feeling ofwarmth by patients after taking thedrug. Pharmacokinetic assessmentsfound that pimecrolimus was rapidlyabsorbed; a steady state of pimecrolimuswas reached after 5 to 10days, C MAX , and area under thecurve from 0 to 24 hours was 54.5ng/mL, at steady state and 589.9ng/mL, respectively, at steady state atthe highest dose. There was no psoriasisrebound observed.Novel Oral AntiinflammatorySubject of 12-WeekPsoriasis StudyBased on these encouragingresults, two international, multicenterdose-finding studies werelaunched, one testing oral pimecrolimusfor psoriasis and one foratopic dermatitis. 6The psoriasis study was a randomized,double-blind, placebo-con-trolled, parallel-group dose-findingstudy in 142 otherwise healthypatients (in particular, without anyhypertension, hyperlipidemia, or diabetes)with moderate to severe psoriasis.The study consisted of four arms:placebo, 10 mg, 20 mg, and 30 mgpimecrolimus twice daily. A 12-weekdouble-blind phase was followed by a12-week posttreatment follow-upphase. The primary efficacy end pointwas week 7. Efficacy was assessed viaPASI score, Investigator’s GlobalAssessment (IGA), and subject assessment.Safety was evaluated with laboratorytests and other tests similar tothose in the Rappersberger study butalso included a skin allergy test.An evaluation of participant discontinuationsshowed that twice asmany patients taking the placebodropped out as did patients on activemedication. Unsatisfactory therapeuticeffect was the reason mostcommonly cited.In looking at efficacy end points,a summary of PASI results showed:• Reductions in both mean andmedian percentage change frombaseline, indicating a clear doseresponserelationship (Figure 3).• The primary end point, week 7mean reduction in PASI scores,was highly significant for both 20-mg and 30-mg twice-daily groups(P
Safety Analysis of Pooled ResultsThe safety results of the 12-weektreatment phases of both the psoriasisand the atopic dermatitis trials werepooled for analysis, thus covering theoutcomes of a total of 243 patients. 6Only two serious adverse events werereported, both of which occurred inthe placebo group. Among sideeffects reported, headache was themost common complaint in all fourpatient groups (including placebo),but it did not show a clear dose relationship.Patients receiving the higherdoses of pimecrolimus reported thetransient feeling of warmth thatRappersberger and colleagues hadnoted in their study. Nausea and gastrointestinalupset also were reportedin the active medication group andappeared to show a dose-responseeffect. Infections appeared to beincreased in the 30-mg twice-dailygroup. Most of the infectionsoccurred in patients with atopic dermatitis,not psoriasis, and most infectionsseemed to be in the form of folliculitis,furuncles, and related skininfections.Particular attention was paid toblood glucose and renal function inthe safety analysis, as the pancreasand kidneys were identified astarget organs in preclinical studies.Investigators found that mean serumcreatinine levels remained fairly consistentthroughout the duration ofboth studies.One patient in the placebo groupand three patients in the 30-mgtwice-daily group exhibited a ≥30%increase in serum creatinine levelsover the 12-week treatment period.This is in contrast to approximately20% of patients taking oralcyclosporine who experienced a≥30% increase in serum creatininelevels in the same time frame.(However, it should be noted thatthe cyclosporine studies includedpatients with hypertension and othercomorbid illnesses.) There was nomodification of oral blood glucosetolerance in any treatment group.The hypertension evaluationshowed that pimecrolimus appearedto have no effect on blood pressure.Skin allergy testing showed thatimmune response to bacterial andfungal antigens remained intact duringpimecrolimus treatment.In summary, the safety findings forthe two trials showed that oral pimecrolimushas a good safety profile.ConclusionIt is hoped that the promisingresults of these early trials will pavethe way for larger phase III trialswith patients more representative ofthe general population. Psoriasis hasa considerable degree of comorbidityassociated with it, and oral pimecrolimusshould be tested in patientswith controlled hypertension, hyperlipidemia,diabetes, and similar conditionsif it is to be compared withoral cyclosporine. Long-term dataare needed to test safety and efficacyafter 1 year or more of treatment.Pediatric trials and psoriatic arthritistrials are also called for to seewhether these special populationscan benefit from this medication.References1. Lebwohl M, Ellis C, Gottlieb A, et al.Cyclosporin consensus conference:With emphasis on the treatment ofpsoriasis. J Am Acad Dermatol.1998;39:464-465.2. Lebwohl M, Ali S. Treatment of psoriasis.Part 2: Systemic therapies. J AmAcad Dermatol. 2001;45:649-651.3. Rappersberger K, Meingassner JG,Fialla R, et al. Clearing of psoriasis byFigure 4. Atopic Dermatitisof the NeckAdult male at baseline, top,and one week after completionof a 12-week study of oralpimecrolimus for atopic dermatitis.Photo courtesy Klaus Wolff, MD, FRCP,University of Vienna, Austriaa novel immunosuppressive macrolide.J Invest Dermatol. 1996;106:701-710.4. Mrowietz U, Graeber M, BräutigamM, et al. The novel ascomycin derivativeSDZ ASM 981 is effective for psoriasiswhen used topically underocclusion. Br J Dermatol. 1998;139:992-996.5. Rappersberger K, Komar M, EbelinME, et al. Pimecrolimus identifies acommon genomic anti-inflammatoryprofile, is clinically highly effective inpsoriasis and is well tolerated. J InvestDermatol. 2002;119;876-887.6. Data on file, Novartis PharmaceuticalsCorp., East Hanover, NJ.New Strategies in the Management of Inflammatory Skin Diseases 15
Page 1 and 2: A SUPPLEMENT TOSkin & Allergy News
Page 3 and 4: AccreditationThe SKIN & ALLERGY NEW
Page 5 and 6: mal Langerhans’ cells, and dysreg
Page 7 and 8: Practical Treatments for Atopic Der
Page 9 and 10: cataracts, and other complications.
Page 11 and 12: “not at all effective” for thei
Page 13: Potential Oral Treatment forPsorias

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