Selection of Nemolizumab Clinical Dosage for Atopic Dermatitis.

Nemolizumab is a monoclonal antibody directed against the interleukin-31 receptor A subunit, which is involved in the pathogenesis of pruritus and inflammation in atopic dermatitis (AD). Clinical trial results were combined with population PK (popPK) and pharmacokinetic/ pharmacodynamic (PK/PD) models to optimize nemolizumab dosing. Phase 1 and 2a clinical studies indicated that weight-based nemolizumab dosing reduced pruritus in patients with moderate-to-severe AD with good safety and tolerability even at the highest dose (3 mg/kg single dose and 2 mg/kg multiple doses). Nemolizumab PK profile was characterized by a slow absorption with peak serum concentrations reached 4.5-9.2 days post-dose, and a long terminal half-life ranging from 12.6 to 16.5 days. A change from weight-based dosing to flat dose was supported by an additional phase 2b study sponsored by Galderma. Flat dosing provides several practical advantages, including ease of preparation for self- or auto-injection and reduced chance of dosing errors. Doses of 10, 30, and 90 mg were selected based on popPK and PK/PD simulations to result in nemolizumab serum concentrations sufficient to achieve efficacy. Loading doses were administrated at the 2 lower doses in order to achieve target systemic concentrations from the first injection. The efficacy of Nemolizumab in improving cutaneous signs of inflammation and pruritus in AD and its safety profile, combined with popPK and PK/PD analyses, supported selection of the flat-dose regimen of 30 mg (with a 60 mg loading dose) given every 4 weeks subcutaneously for 16 weeks in the phase 3 ARCADIA studies sponsored by Galderma. J Drugs Dermatol. 2023;22(10):1017-1020 doi:10.36849/JDD.7437R1.

Clinical Pharmacology and Safety of Trifarotene, a First-in-Class RARγ-Selective Topical Retinoid.

Trifarotene is a new drug with retinoic acid receptor activity and selectivity for retinoic acid receptor-γ. The reported studies aimed at assessing the clinical pharmacology and safety of trifarotene. The clinical pharmacology of topical trifarotene up to 100 µg/g was extensively investigated through 2 maximal usage pharmacokinetic trials (MUsT) conducted in adult (≥18 years) and pediatric patients (9-17 years) with moderate to severe acne and two studies conducted in healthy volunteers: 1 thorough QTC study and 1 drug-drug interaction study with concomitantly administered oral levonorgestrel (0.15 mg)/ethinyl estradiol (0.03 mg). Safety assessments included adverse event reporting and assessment of erythema, scaling, dryness, and stinging/burning using a scale from 0 = none to 4 = severe, as well as the evaluation of the systemic safety of trifarotene through routine laboratory testing. Systemic absorption of trifarotene was generally unquantifiable in the target population, especially when applied at 50 µg/g. QTC investigations did not show any risk of cardiovascular health issues; trifarotene did not reduce the systemic exposure to oral contraceptives such as levonorgestrel/ethinyl estradiol. Safety analyses did not show local or systemic safety concerns with trifarotene up 100 µg/g, a dose twice as high as the intended market dose. Results showed that trifarotene 50 µg/g cream is well tolerated and safe, even when applied under maximized conditions in adults and pediatric acne patients presenting with severe acne. Daily use of trifarotene 50 µg/g cream was not associated with cardiovascular effects and did not result in drug-drug interaction in women of childbearing potential using oral contraception.

Randomized phase 3 evaluation of trifarotene 50 µg/g cream treatment of moderate facial and truncal acne.

BACKGROUND: Acne vulgaris often affects the face, shoulders, chest, and back, but treatment of nonfacial acne has not been rigorously studied. OBJECTIVES: Assess the safety and efficacy of trifarotene 50 µg/g cream, a novel topical retinoid, in moderate facial and truncal acne. METHODS: Two phase III double-blind, randomized, vehicle-controlled, 12-week studies of once-daily trifarotene cream versus vehicle in subjects aged 9 years or older. The primary end points were rate of success on the face, as determined by the Investigator's Global Assessment (clear or almost clear and ≥2-grade improvement), and absolute change from baseline in inflammatory and noninflammatory counts from baseline to week 12. The secondary end points were rate of success on the trunk (clear or almost clear and ≥2-grade improvement) and absolute change in truncal inflammatory and noninflammatory counts from baseline to week 12. Safety was assessed through adverse events, local tolerability, vital signs, and routine laboratory testing results. RESULTS: In both studies, at week 12 the facial success rates according to the Investigator's Global Assessment and truncal Physician's Global Assessment and change in inflammatory and noninflammatory lesion counts (both absolute and percentage) were all highly significant (P < .001) in favor of trifarotene when compared with the vehicle. LIMITATIONS: Adjunctive topical or systemic treatments were not studied. CONCLUSION: These studies demonstrate that trifarotene appears to be safe, effective, and well tolerated in treatment of both facial and truncal acne.

Treatment of 2,453 acne vulgaris patients aged 12-17 years with the fixed-dose adapalene-benzoyl peroxide combination topical gel: efficacy and safety.

Acne vulgaris is a common disease in adolescents, and early treatment may minimize its physical and psychological effects. A fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5% (adapalene-BPO) is efficacious and safe in the treatment of acne patients aged 12 years or older, as demonstrated in three randomized and controlled studies. The current study is a subgroup analysis of the efficacy and safety of adapalene-BPO among 2,453 patients aged 12-17 years. After 12 weeks of treatment, significantly more patients in the adapalene-BPO group were "clear" or "almost clear" (30.9%, P < 0.001) compared to the monotherapies and vehicle. The percentage reduction from baseline in total, inflammatory and non-inflammatory lesions was 56, 63 and 54.5 percent in the adapalene-BPO group, respectively, significantly higher than in the monotherapy groups and vehicle (all P < 0.001). Significantly earlier onset of effect was observed at week 1. Adapalene-BPO was also well tolerated, with the mean scores of dryness, erythema, scaling and stinging/burning less than 1 (mild) at all study visits. Overall, the adapalene-BPO combination gel provides significantly greater and synergistic efficacy and a fast onset of action compared to the monotherapies and vehicle in young acne patients aged 12-17 years.

Adapalene 0.1% lotion in the treatment of acne vulgaris: results from two placebo-controlled, multicenter, randomized double-blind, clinical studies.

BACKGROUND: Acne vulgaris is a common chronic skin disease affecting roughly 15 percent of the general population and up to 85 percent of adolescents and young adults. Adapalene, a synthetic naphthoic acid derivative with retinoid activity, has demonstrated good clinical efficacy in the treatment of acne if used with full compliance. OBJECTIVES: To evaluate the efficacy and assess safety of a new adapalene formulation, adapalene 0.1% lotion, versus the lotion vehicle in subjects with acne vulgaris. METHODS: Subjects were randomized to receive either adapalene 0.1% lotion or its vehicle once daily for 12 weeks in two multicenter, randomized, vehicle-controlled, double-blind, parallel group studies. Efficacy was evaluated using two co-primary endpoints: Investigator Global Assessment (IGA) of success rate (defined as the proportion of subjects who achieved at least a two point reduction, on a 5-point scale, from baseline to week 12 in IGA score); and the absolute change from baseline to week 12 in total, inflammatory and non-inflammatory lesions. Signs of local skin irritation and routine clinical safety parameters were evaluated throughout both studies. RESULTS: In total, 2,141 subjects were included in the two studies: 1,068 patients received adapalene 0.1 percent lotion and 1073 received the vehicle. In both studies, adapalene 0.1% lotion was shown to be significantly more effective than its vehicle in improvement in the IGA success rate. Adapalene 0.1% lotion was also significantly superior to its vehicle in all three lesion reduction measures: total, inflammatory and non-inflammatory. Reports of application site skin irritation in the adapalene 0.1% lotion treatment group were transient and mild or moderate in severity, with only a few being severe. Additionally, according to patient surveys, the lotion formulation was found to be easily spreadable, easily absorbed and pleasant to use. CONCLUSION: Adapalene 0.1% lotion used once a day for 12 weeks is effective and well tolerated in the treatment of acne vulgaris.

A North American study of adapalene-benzoyl peroxide combination gel in the treatment of acne.

A fixed-dose combination gel with adapalene 0.1% and benzoyl peroxide (BPO) 2.5% recently has been developed for the treatment of acne vulgaris. In this multicenter, randomized, double-blind, parallel-group, active- and vehicle-controlled study conducted at 60 centers in the United States, Puerto Rico, and Canada, we assessed the efficacy and safety of adapalene-BPO combination gel in comparison with adapalene and BPO monotherapies as well as the gel vehicle. Participants with moderate facial acne vulgaris (rated 3 on the 5-point investigator global assessment of acne severity scale) were recruited and randomized to receive once-daily treatment with adapalene-BPO combination gel, adapalene monotherapy, BPO monotherapy, or gel vehicle for 12 weeks. They were assessed for success rate (the percentage of participants with investigator global assessment of acne severity rated clear or almost clear) and percentage change in inflammatory lesion (IL), noninflammatory lesion (NIL), and total lesion counts. Of the 1668 participants enrolled, 1429 (85.7%) completed the study. At study end point, adapalene-BPO combination gel showed a significantly higher success rate (P < or = .006) and a greater percentage reduction in all acne lesion counts (P < or = .017) compared with the other treatment groups. A significant early treatment effect of adapalene-BPO combination gel at week 1 compared with adapalene monotherapy and vehicle also was observed for all lesion count reductions (P<.001). The safety of adapalene-BPO combination gel was comparable with adapalene and BPO monotherapies and vehicle. In a large clinical trial, the adapalene-BPO fixed-dose combination gel has shown superiority in efficacy compared with adapalene and BPO monotherapies and vehicle, with an early onset of efficacy and a good safety profile.

Long-term safety and efficacy study of adapalene 0.3% gel.

The efficacy and safety of adapalene 0.1% gel in the treatment of acne vulgaris has been demonstrated in multiple controlled clinical trials. A higher concentration formulation, adapalene 0.3% gel, has been developed to provide a broader range of treatment options for acne management. Phase 3 clinical studies have demonstrated the superior efficacy of adapalene 0.3% gel compared to adapalene 0.1% gel and its vehicle at the end of a 12-week treatment period. The goal of this study was to evaluate the long-term safety of adapalene 0.3% gel in subjects treated once daily for 52 weeks, with a secondary objective to evaluate long-term efficacy. Subjects 12 years of age or older (N=551) with acne vulgaris participated in a multicenter, open-label study of the long-term (up to 52 weeks) efficacy and safety of once-daily applications of adapalene 0.3% gel. Of those enrolled, 167 subjects completed 12 months of treatment. Expected signs and symptoms of local cutaneous irritation (erythema, dryness, scaling, and stinging/burning) were mostly mild or moderate, with mean tolerability scores below 1 (mild) at all time points for the parameters assessed. Treatment-related, dermatologic adverse events were experienced by 21% of subjects and dry skin, skin discomfort, and scaling were reported by 10.5%, 8.3% and 3.3% of subjects, respectively. Most of the adverse events reported occurred in the first quarter of treatment. Adverse events were mostly mild to moderate in severity. Subjects treated with adapalene 0.3% gel for 52 weeks achieved a >75% median reduction in total, inflammatory, and noninflammatory lesions in this open-label study by the end of the treatment period. Adapalene 0.3% gel was safe and effective in the long-term (up to 1 year) treatment of subjects with acne vulgaris.

Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment of acne vulgaris.

BACKGROUND: A unique, once-daily, fixed-dose combination gel with adapalene 0.1% and benzoyl peroxide (BP) 2.5% has been developed for the treatment of acne vulgaris. OBJECTIVE: To evaluate the long-term (up to 12 months) safety and efficacy of the adapalene 0.1%/BP 2.5% fixed-dose combination gel for the treatment of acne vulgaris. METHODS: A total of 452 subjects were enrolled in this 12-month study and received adapalene/BP once daily. Evaluations included lesion count reduction, subject's assessment of acne, adverse events, and cutaneous tolerability. RESULTS: Adverse events were mild to moderate, occurred early in the study, and decreased thereafter. Discontinuations due to adverse events were low (2.0%) and no subjects discontinued due to lack of efficacy. Early and sustained reductions in inflammatory and noninflammatory lesions were observed, with clinically significant lesion reductions as early as week 1. CONCLUSIONS: These findings are consistent with previous clinical findings and support the use of a once-daily adapalene/BP fixed-dose combination as a safe and effective treatment in the long-term management of acne.

Calcitriol 3 microg/g ointment in the management of mild to moderate plaque type psoriasis: results from 2 placebo-controlled, multicenter, randomized double-blind, clinical studies.

BACKGROUND: Psoriasis is a chronic skin disorder affecting approximately 2% of the US population. Psoriasis may occur anywhere on the body with initial presentation usually seen between 15 and 30 years of age. Calcitriol 3 microg/g ointment has demonstrated good clinical efficacy as well as topical and systemic safety when used to treat psoriasis. OBJECTIVES: To confirm the efficacy and safety of calcitriol 3 microg/g ointment versus its vehicle in the treatment of subjects with mild to moderate chronic plaque psoriasis. METHODS: Suitable subjects were randomized to receive either calcitriol 3 microg/g ointment or its vehicle twice daily for up to 8 weeks in 2 multicenter, randomized, vehicle-controlled, double-blind parallel group studies. Efficacy was evaluated through a Global Severity Score dichotomized in success (clear and minimal) or failure. Erythema, plaque elevation, scaling and dermatologic sum score (sum of the scores for erythema, plaque elevation, and scaling), pruritus, and global improvement were also assessed. Routine safety and clinical laboratory parameters, including calcium homeostasis, were evaluated throughout the study. RESULTS: In total, 839 subjects were included in the 2 studies: 419 patients received calcitriol 3 microg/g ointment and 420 received the vehicle. In both studies, calcitriol 3 microg/g ointment was shown to be significantly more effective than its vehicle, with onset of therapeutic effect seen as early as week 2 and sustained at all subsequent visits. Calcitriol 3 microg/g ointment demonstrated good systemic and local safety profile comparable to its vehicle with no effect on calcium homeostasis. CONCLUSION: Calcitriol 3 microg/g ointment applied for 8 weeks is effective and safe in the treatment of mild to moderate psoriasis.

Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study.

BACKGROUND: A fixed-dose combination gel with adapalene 0.1% and benzoyl peroxide (BPO) 2.5% has been developed for the once-daily treatment of acne. OBJECTIVE: To evaluate the efficacy and safety of adapalene 0.1% -BPO 2.5% fixed combination gel (adapalene-BPO) for the treatment of acne. METHODS: A total of 517 subjects were randomized in a double-blind controlled trial to receive either adapalene-BPO, adapalene, BPO, or vehicle for 12 weeks (2:2:2:1 randomization). Evaluation included success rate (subjects "clear" or "almost clear"), lesion count, cutaneous tolerability, and adverse events. RESULTS: The fixed-dose combination gel of adapalene and BPO was significantly more effective than corresponding monotherapies, with significant differences in total lesion counts observed as early as 1 week. Adverse event frequency and cutaneous tolerability profile for adapalene-BPO were similar to adapalene monotherapy. LIMITATIONS: These data were generated in a controlled trial. Results obtained in clinical practice could differ. CONCLUSIONS: The fixed-dose combination of adapalene and BPO provides significantly greater efficacy for the treatment of acne vulgaris as early as week 1 relative to monotherapies, with a comparable safety profile to adapalene.

Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial.

BACKGROUND: A new 0.3% gel formulation of adapalene has been developed. OBJECTIVE: We sought to provide evidence of the superiority of adapalene gel 0.3% over adapalene gel 0.1% and gel vehicle in the treatment of acne. METHODS: A total of 653 patients were randomized to receive adapalene gel 0.3%, adapalene gel 0.1%, or vehicle once daily for 12 weeks (2:2:1 randomization). Analysis for efficacy was conducted on correlated repeated measurements at weeks 8 and 12 using Generalized Estimating Equation methodology. RESULTS: Adapalene gel 0.3% was significantly superior to adapalene gel 0.1% and vehicle in success rate, total lesion count, and inflammatory lesion count. A consistent, dose-dependent effect was demonstrated for all efficacy measures. Signs and symptoms were mostly mild to moderate and transient in nature. LIMITATIONS: Adjunctive topical or oral agents and their impact on acne were not studied in this trial. CONCLUSIONS: Adapalene gel 0.3% was effective and well tolerated in the treatment of acne.

The efficacy and safety of adapalene gel 0.3% in the treatment of acne vulgaris: A randomized, multicenter, investigator-blinded, controlled comparison study versus adapalene gel 0.1% and vehicle.

A randomized, multicenter, investigator-blinded, active- and vehicle-controlled study was conducted to evaluate the efficacy and safety of adapalene gel 0.3% versus adapalene gel 0.1% and the corresponding gel vehicle. Subjects were assigned randomly to receive either adapalene gel 0.3%, adapalene gel 0.1%, or vehicle once daily for 12 weeks. A total of 214 subjects with moderate to moderately severe acne vulgaris were enrolled, and 85% of subjects completed the study. Adapalene gel 0.3% was significantly superior to adapalene gel 0.1% in total and noninflammatory lesion counts and in global severity score (P < .05 for all). A concentration-dependent increase in clinical benefit for all efficacy assessments was observed. As expected, there were also statistically significant differences in all efficacy parameters in the adapalene gel 0.3% group relative to the vehicle group (P < .001 for all). Treatment-related adverse events were mostly mild-to-moderate and similar between active groups. The results of this study show that adapalene gel 0.3% was superior to adapalene gel 0.1% and vehicle in the treatment of moderate to moderately severe acne while retaining a similar safety and tolerability profile to adapalene 0.1% gel.

Pimecrolimus cream 1%: a potential new treatment for chronic hand dermatitis.

A multicenter, randomized, vehicle-controlled, 3-week study was conducted in patients with chronic hand dermatitis (HD) of various etiologies and locations to identify subgroups particularly responsive to twice-daily application of pimecrolimus cream 1% with overnight occlusion. A total of 294 patients were randomized to the study. By the final visit on day 22, there was a trend toward greater clearance in patients who received pimecrolimus than in those treated with vehicle cream. An analysis of treatment success by various stratification factors was performed, and it was found that palmar involvement had notable impact on response (P = .033). Patients in the pimecrolimus group continued to improve throughout the study; however, in the vehicle group, improvement plateaued after 15 days. Pimecrolimus was well tolerated, with a low rate of application-site reactions such as burning. Pimecrolimus cream 1%, when used twice daily with overnight occlusion, may be of benefit in the management of chronic HD.

An experimental ointment formulation of pimecrolimus is effective in psoriasis without occlusion.

Pimecrolimus (Elidel, SDZ ASM 981), a new macrolactam ascomycin derivative, was highly effective in treating plaque-type psoriasis when applied under Finn-chamber occlusion. A two-centre, randomized, double-blind, vehicle- and positive-controlled within-patient study was therefore conducted in 23 adult psoriasis patients. Pimecrolimus 1% was applied, twice daily, in an experimental ointment formulation, along with the corresponding vehicle, 0.005% calcipotriol ointment and 0.05% clobetasol-17-propionate ointment to test sites without occlusion for 21 days. Erythema, induration and scaling (score: 0 [absent] to 4 [severe]) were evaluated. The total sign score was defined as the sum of the erythema, induration and scaling scores (range 0-12). Pimecrolimus 1% ointment was significantly (p = 0.03) more effective than the corresponding vehicle, with an improvement in total sign score of 51.4% compared with 36.7% for the corresponding vehicle. Improvements with calcipotriol and clobetasol-17-propionate were 71.5% and 88.3%, respectively. No local or systemic drug-related side effects were observed in the study. We conclude that pimecrolimus 1% in the experimental ointment formulation was significantly more effective than its corresponding vehicle, but less effective than calcipotriol and clobetasol ointment. This is the first study reporting a significant therapeutic effect of pimecrolimus in an ointment formulation applied without occlusion to psoriatic plaques.

Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.

OBJECTIVE: Pimecrolimus cream (SDZ ASM 981), a nonsteroid inhibitor of inflammatory cytokines, is effective in atopic dermatitis (AD). We assessed whether early treatment of AD signs/symptoms with pimecrolimus could influence long-term outcome by preventing disease flares. METHODS: Early intervention with pimecrolimus was compared with a conventional AD treatment strategy (ie, emollients and topical corticosteroids). In this 1-year, controlled, double-blind study, 713 AD patients (2-17 years) were randomized 2:1 to a pimecrolimus-based or conventional regimen. Both groups used emollients for dry skin. Early AD signs/symptoms were treated with pimecrolimus cream or, in the conventional treatment group, vehicle to prevent progression to flares. If flares occurred, moderately potent topical corticosteroids were mandated. The primary efficacy endpoint was ranked flares at 6 months. Safety was monitored clinically, and a skin recall-antigen test was performed at study completion. RESULTS: BASELINE CHARACTERISTICS OF THE PATIENTS: The mean age for both groups was approximately 8 years, and the majority of patients had moderate disease at baseline. PATIENT FOLLOW-UP AND EXPOSURE TO STUDY MEDICATION: The mean duration of follow-up (+/-standard error) was 303.7 (+/-5.30) days in the pimecrolimus group and 235.2 (+/-9.40) days in the control group. The discontinuation rate was significantly higher in the control group than in the pimecrolimus group (51.5% vs 31.6% at 12 months), and proportionately more patients with severe or very severe disease discontinued in the control group. The main reason for the higher discontinuation rate in the control group was unsatisfactory therapeutic effect (30.4% vs 12.4%). This resulted in a substantially higher mean number of study medication treatment days in the pimecrolimus group compared with the control group: 211.9 (69.8% of study days) versus 156.0 (66.3% of study days). Of those patients who completed 12 months on study, 14.2% and 7.0% of patients in the pimecrolimus and vehicle groups, respectively, used study medication continuously. EFFICACY: Patients in the pimecrolimus group experienced significantly fewer AD flares than those in the control group, according to the primary efficacy analysis on ranked flares of AD (Van Elteren test). The proportion of patients who completed 6 or 12 months with no flares was approximately twice as high in the pimecrolimus group compared with control (61.0% vs 34.2% at 6 months; 50.8% vs 28.3% at 12 months). Fewer flares were observed in the pimecrolimus group regardless of baseline disease severity, so even severe patients derived benefit from the treatment. The analysis of time to first flare showed that treatment with pimecrolimus was associated with a significantly longer flare-free period (log- rank test). Covariate analysis indicated a statistically significant effect on time to first flare of baseline Eczema Area and Severity Index score, and whether patients had "severe" or "very severe" disease at baseline according to the Investigators' Global Assessment, although patients in all baseline disease severity subgroups benefited from treatment. Age had no significant effect. Fewer patients in the pimecrolimus group required topical corticosteroid therapy compared with control (35.0% vs 62.9% at 6 months; 42.6% vs 68.4% at 12 months), and patients in the pimecrolimus group spent fewer days on topical corticosteroid therapy (57.4% vs 31.6% [pimecrolimus vs control, respectively] spent 0 days on topical corticosteroid therapy, 17.1% vs 27.5% 1-14 days, and 25.5% vs 41.0% >14 days over the 12 months of the study). This steroid-sparing effect of pimecrolimus was evident despite pimecrolimus-treated patients being on study longer than patients in the control group. The average proportion of study days spent on second-line corticosteroids was 4.08% in the pimecrolimus group and 9.10% in the control group. Analysis of Eczema Area and Severity Index over time showed significantly lower median scores, thus indicating better disease control in the pimecrolimus group compared with the control group. Similar results were obtained from analysis of the Investigators' Global Assessment (not shown). The treatment groups were well balanced with respect to the number of patients using antihistamines during the study (57.2% vs 62.9%, pimecrolimus vs control, respectively). SAFETY: There were no appreciable differences between treatment groups in the overall incidence of adverse events. The most frequent adverse events were common childhood infections and ailments, including nasopharyngitis, headache, and cough. The incidence of suspected drug-related adverse events was not significantly different in the pimecrolimus group (24.7% vs 18.7%--pimecrolimus vs control), and the incidence of serious adverse events was low (8.3% vs 5.2%--pimecrolimus vs control). Life-table analysis of incidence of adverse events revealed no significant differences between the treatment groups, except for cough. Local tolerability was good in both treatment groups. The most common application site reaction reported was sensation of burning (10.5% vs 9.3%--pimecrolimus vs control). There were no major differences between treatment groups in the duration or severity of application site reactions, most of which were mild-to-moderate and transient, occurring within the first week of treatment. Skin infections were reported in both groups. There were no between-group differences in the life-table analysis of time to first occurrence of bacterial skin infections nor in the adjusted incidence of bacterial skin infections. Although there were no significant differences between treatment groups in the incidence of individual viral skin infections, the incidence of grouped viral skin infections (12.4% vs 6.3%--pimecrolimus vs control) showed a slightly higher incidence in the pimecrolimus group. Laboratory values and vital signs showed no significant between-group differences. There were no significant differences between treatment groups in response to recall antigens in those patients who remained on study for 12 months. CONCLUSIONS: Treatment of early AD signs/symptoms with pimecrolimus was effective in preventing progression to flares in more than half the patients, reducing or eliminating the need for topical corticosteroids. The benefits were consistently seen at 6 months across important disease severity subgroups and with respect to the various predefined efficacy endpoints. Furthermore, these benefits were sustained for 12 months, providing evidence that long-term treatment with pimecrolimus leads to better control of AD. Treatment with pimecrolimus was well tolerated and was not associated with clinically relevant adverse events compared with the conventional treatment group. The results reported here offer the prospect of effective long-term management of AD with reduced need for topical corticosteroids.

Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents.

BACKGROUND: The ascomycin derivative pimecrolimus (ASM 981) is a cell-selective cytokine inhibitor, specifically developed for the treatment of inflammatory skin diseases. OBJECTIVE: When applied topically, pimecrolimus cream 1% has shown promise as a treatment for inflammatory skin conditions, including atopic dermatitis (AD) in children and adults, allergic contact dermatitis, and chronic contact irritant hand dermatitis in adults. METHODS: In two independent 6-week, randomized, multicenter studies of identical design, the efficacy and safety of pimecrolimus cream 1% in children with predominantly moderate AD were compared with vehicle. Pooled data from a total of 403 patients were used in the analysis. The primary efficacy parameter was the Investigator's Global Assessment (IGA) score. Secondary parameters included Eczema Area and Severity Index (EASI) and severity of pruritus scores. Subjects were also asked to assess their disease control as uncontrolled, limited, good, or complete. RESULTS: Significant therapeutic benefits relative to vehicle were observed in the pimecrolimus-treated group at the first efficacy assessment, 8 days after initial application of the study medication (eg, relief of pruritus). At each subsequent postbaseline visit, pimecrolimus-treated patients showed significant improvement relative to controls in all efficacy measures. The medication was well tolerated. CONCLUSION: Pimecrolimus cream 1% appears to be a safe and effective alternative to currently used therapies for AD.