Pimecrolimus 1% Cream for the Treatment of Atopic Dermatitis

K. Wolff, MD, FRCP
Department of Dermatology, Medical University of Vienna, Vienna General Hospital, Vienna, Austria

ABSTRACT

Atopic dermatitis is a highly pruritic inflammatory disorder of the skin characterized by onset in infancy or childhood and a chronically relapsing course. Mainstay treatments are emollients and topical corticosteroids, but the latter are limited by side-effects from longterm use. Pimecrolimus is an ascomycin macrolactam derivative and a calcineurin inhibitor that targets T-cell activation but does not inhibit antigen-presenting cells in the skin. In multiple clinical trials comprising more than 19,000 patients, pimecrolimus cream has been shown to be very effective in suppressing atopic dermatitis and to have an excellent safety profile. This has also been shown in long-term studies (>2 years) and by postmarketing experience.

Key Words: atopic dermatitis, calcineurin inhibitor, pimecrolimus

Atopic Dermatitis (AD)

AD is a highly pruritic inflammatory disorder that is characterized by childhood onset and that usually assumes a chronically relapsing course.¹ The incidence of AD has increased in recent years with a prevalence of 7%-21% in school-age children, but it is also common in adolescents and adults.¹ Immunologic abnormalities play a fundamental role in the development of the disease, but environmental factors such as Staphylococcus aureus, dust-mites, or pollens contribute to the onset and exacerbation of AD. In response to antigens, levels of circulating IgE antibodies increase, giving rise to excessive T-cell activation. This in turn leads to an overproduction of cytokines, thus initiating and sustaining dermal inflammation.1
Levels of natural defense proteins such as cathelicidins and defensins are significantly decreased in the skin of AD patients. The essential features of AD are dry skin, pruritus, and eczema with an acute, subacute, or chronic relapsing course. The mainstay of the treatment of AD is the use of emollients, as well as topical corticosteroids. In more severe cases, phototherapy, photochemotherapy, and the use of immunosuppressants is used.1 Although undoubtedly effective, corticosteroids have been limited by side-effects, such as skin atrophy and even systemic effects, including hypothalamic-pituitaryadrenal axis suppression and growth inhibition.
In the past, therefore, the therapeutic armamentarium available for AD clearly indicated the need for the development of anti-inflammatory compounds that are both effective and not limited by side-effects, making them suitable for prolonged use in a chronic skin disease that greatly reduces the quality of life.

Pimecrolimus

Pimecrolimus, an ascomycin macrolactam derivative, is a calcineurin inhibitor that binds with high affinity to the cytosolic receptor macrophilin-12, inhibiting the calcium-dependent phosphatase calcineurin, an enzyme required for the dephosphorylation of the cytosolic form of the nuclear factor of the activated T cell (NF-AT).²
It thus targets Tcell activation and proliferation by blocking the release of both TH1 and TH2 cytokines such as IF-g, IL-2, -4, -5, and -10.³ It also prevents the production of TNF-a and the release of proinflammatory mediators such as histamine, hexosaminidase, and tryptase from activated mast cells.3 It does not have general antiproliferative activity on keratinocytes, endothelial cells, and fibroblasts, and in contrast to corticosteroids, it does not affect the differentiation, maturation, functions, and viability of human dendritic cells.⁴ As shown in mice, topical pimecrolimus does not affect epidermal Langerhans cells or antigen-presenting cells that play a key role in the local immunosurveillance.⁵ A recent study confirmed that for the treatment of AD, betamethasone, but not pimecrolimus, results in the depletion of Langerhans cells. Both drugs significantly reduce T cells in skin biopsies, demonstrating a more selective mode of action of pimecrolimus vs. corticosteroids.⁶

In animal models of skin inflammation pimecrolimus is highly active after both topical and systemic application and its effects differ considerably from those of corticosteroids, cyclosporin and tacrolimus.⁷ Although pimecrolimus combines high anti-inflammatory activity in the skin, it has a low potential to impair systemic immune reactions, and topical application in humans is not associated with the atrophogenic side-effects observed with corticosteroids.7 Pimecrolimus blood levels remain consistently low after repeated topical application and no clinically relevant drug-related systemic adverse events have been reported among the patients treated in clinical trials so far.⁷ Pimecrolimus is approved as a 1% cream (Elidel™, Novartis) in 83 countries and has been given approval by both the US FDA and Health Canada for the short-term (acute) and long-term intermittent treatment of AD.

Clinical Trials

The efficacy of topical pimecrolimus has been established in clinical studies in adults, children, and infants in both short-term treatment and long-term management.⁷ In an initial double-blind, right and left arm comparison proof of concept study in adults with AD, pimecrolimus proved to be more effective than the vehicle. Patients receiving pimecrolimus twice daily achieved a mean Atopic Dermatitis Severity Index (ADSI) reduction at the endpoint of 71.9% compared with 10.3% in the vehicle group. A significant therapeutic effect was already being observed by day 2. In a multicenter dose finding study comparing the efficacy of 0.05%-1% pimecrolimus in adults with mild-to-severe AD, a clear dose-effect relationship was seen.8 Two hundred sixty patients were randomized to receive pimecrolimus at concentrations of 0.05%, 0.2%, 0.6%, or 1%, a vehicle, or 0.1% betametasone 17-valerate cream b.i.d. for up to 3 weeks. Using the Eczema Area and Severity Index (EASI), no therapeutic effect was observed with 0.05% pimecrolimus, but all other concentrations of pimecrolimus cream proved to be significantly superior to the vehicle.⁹ Efficacy was clearly dose-dependent with 1.0% pimecrolimus cream showing the greatest efficacy and a 47% median reduction of EASI from baseline. A significant reduction of the pruritus score from baseline was demonstrated for 1% pimecrolimus cream over the other concentrations and this was subsequently selected for further studies.

Short-term efficacy of pimecrolimus in acute flares of AD was studied in children and adolescents (aged 1-17 years), and in infants (aged 3-23 months).^9,10 A design was used whereby the initial double-blind, vehicle-controlled phase patients were randomized 2:1 to be treated with pimecrolimus or vehicle twice daily for 6 weeks. This was then followed by a 20-week open-label phase where all patients received pimecrolimus twice daily. Treatment success was assessed by the Investigators’ Global Assessment (IGA) and EASI scores.

Two studies in children and adolescents were pooled and a total of 403 patients (1-17 years of age), with a baseline IGA score of 2 or 3 and AD affecting at least 5% of the total body surface area, were randomized to receive pimecrolimus (n=267) or vehicle (n=136). The results revealed a significantly higher efficacy for pimecrolimus than vehicle. Significantly more pimecrolimus-treated patients had an IGA of 0 or 1 on day 8 compared with the vehicle-treated patients (p< 0.01), and thereafter, the proportion of pimecrolimus-treated patients who experienced treatment success increased continuously over time until the end of the double-blind phase.⁷ This was also reflected by the assessment of the EASI score. Pimecrolimus was particularly effective in the head and neck area, and a significant relief from pruritus was observed within the first week of pimecrolimus treatment (p < 0.001).

In the subsequent 20-week, open-label phase, the therapeutic effect was maintained in the pimecrolimus group and a rapid overall improvement was noted in the patients previously treated with the vehicle alone. Using the Parents’ Index of Quality of Life in Atopic Dermatitis (PIQoL-AD), a significant improvement was found in patients younger than 8 years of age. An identical study performed in infants (3-23 months) showed similar results.⁷ In a total of 186 patients with an IGA score of 2 or 3, 89% of patients in the pimecrolimus group completed the study compared with 52% in the vehicle group, and at the end of the 6-week double-blind phase, 54.5% of the pimecrolimus-treated patients were almost clear compared with 23.8% in the vehicle group(p < 0.001). After 6 weeks of treatment, a greater than 80% median reduction of EASI was observed and was maintained during the following 20-week open-label period. Again, change from vehicle to pimecrolimus in the open-label extension resulted in a rapid and profound improvement of EASI in the patients previously treated with vehicle alone.

Population	Pimecrolimus Group	Control Group
Infants ( < 2 years)	70	70
Children (2-17 years)	66	38
Adults (>18 years)	49	22
Table 1: Proportion of patients not requiring topical corticosteroids

Long-Term Treatment

Three multicenter, double-blind controlled studies in infants, children, and adults compared the efficacy and safety of pimecrolimus with conventional treatment based on the reactive use of corticosteroids.7 Patients were randomized to receive either pimecrolimus or control treatment, and in both groups emollients were used for general skin care throughout the studies. At the first appearance of signs or symptoms of AD, patients received either pimecrolimus or vehicle twice daily until complete remission was achieved. When the disease was not adequately controlled by this treatment, a moderately potent topical corticosteroid was provided as “rescue” medication after which the study medication was resumed. Endpoints measured were the number of flares requiring topical corticosteroids within a period of 6 months (in all studies) and within 12 months in the infant- and children-only studies. In infants treated with pimecrolimus, 68% remained without a single corticosteroid-requiring flare for 6 months, compared with 30% of patients in the control group. In all three studies the percentage of patients completing 6 months without flare was significantly higher in the pimecrolimus group than in the controls (p < 0.001).

About twice as many patients remained flare-free in the pimecrolimus group after 1 year of treatment compared with the group receiving conventional therapy.6 Superior control of AD by the treatment employing pimecrolimus was particularly obvious when the number of days requiring corticosteroid treatment was compared with conventional treatment. The proportion of patients requiring corticosteroids was significantly reduced in all age groups (Table 1).

In the adult study, the severity of pruritus decreased significantly in the pimecrolimus group compared with the control group as early as 48 hours after beginning treatment (p < 0.001).7

In conclusion, pimecrolimus has proven highly effective in reducing the signs and symptoms of AD in long-term clinical trials, and this has been observed in infants, children, and adults. Significant improvement can be seen after the first few days of treatment and in longterm studies pimecrolimus demonstrated the ability to prevent disease progression and to reduce flares as measured by a reduction of the necessity of employing “rescue” corticosteroid treatment.

In clinical practice more than 5 million patients have been treated since December 2001. Of these, roughly 2.7 million patients were younger than 10 years of age. The average pimecrolimus usage was 1.6g/day used intermittently, 45 days/year.¹¹

Pharmacokinetics

Pimecrolimus levels in the blood were measured after treatment with 1% pimecrolimus cream twice daily for up to 1 year in adults, infants and children.⁷ A review published in 2004 identified several openlabel, noncontrolled, pharmacokinetic studies of adult patients with moderate-to-severe AD who were treated with pimecrolimus cream on all affected areas for 3 weeks, and had blood concentrations below the level of detection (level of quantitation [LoQ]=0.5ng/ml) in 78% of 444 samples evaluated; the highest concentration observed was 1.4ng/ml.7

In another study where 44 patients with moderate-tosevere AD were treated for up to 1 year, 13 patients completed 1 year in the study. A total of 98% of the 918 concentrations measured remained below the LoQ of 0.5ng/ml and the highest concentration observed was 0.8ng/ml without drug accumulation.7

Children and infants

• aged 1-4 years with an affected body surface area
• (BSA) of 23%-69%
• aged 4 months-14 years old with a BSA of 21%-80%
• aged <23 months with a BSA of 10%- 92%,

who were all treated with pimecrolimus, showed blood concentrations of pimecrolimus below 2ng/ml in 99% of readings. Only 10 out of 75 patients had measurable AUCs, ranging from 11-39ng*h/ml. Even in patients with large affected areas (70%-92%), the blood concentrations were between < 0.1-1.8ng/ml and were thus consistently low. No drug accumulation was observed in any of the patients, including patients treated with pimecrolimus for up to 1 year. These data show that topical treatment of AD with pimecrolimus leads to a minimal systemic exposure irrespective of the extent of the body area treated. It should also be noted that the single highest AUC ever measured (38ng*h/ml) is approx. 14 times less than the minimal AUC needed to treat psoriasis with the oral formulation of pimecrolimus and 27 times less than the NOAEL (No Observed Adverse Effect Level) in rodents, suggesting a comfortable safety profile.¹²

Tolerability and Safety

There is a large safety database available for topical pimecrolimus from more than 19,000 patients treated in clinical studies since 1996. This includes ~3,000 infants (3-23 months) and more than 7,000 children aged 2-17 years who have been treated with topical pimecrolimus in clinical trials for up to 2 years.11

Systemic Side-Effects

No clinically relevant systemic side-effects have been noted in AD patients treated with pimecrolimus cream in clinical trials to date.7 This is in line with the observation that treatment of AD patients with pimecrolimus leads to minimal or negligible systemic exposure even in patients with large body surface areas affected as discussed above. A study involving 251 infants randomized to topical pimecrolimus or vehicle for 1 year showed no significant difference between groups in the incidence of adverse effects.⁷ More importantly, in a recently published study comparing the adverse event profile in infants after 1 and 2 years of pimecrolimus long-term management, the overall incidence of adverse events decreased over time,¹³ suggesting no impact on the developing immune system in infants.

Application-site Reactions

The most frequently reported application-site reaction is a sensation described as burning or a feeling of warmth, which has occurred in about 15% of adults and in 7% of pediatric patients. These sensations are transient and usually resolve after a few days of treatment. Other application-site reactions are irritation, erythema, and pruritus, which were generally observed early in treatment and were mild and of short duration. There was no significant difference between the pimecrolimus and control groups.⁷

Skin Infections

Topical treatment with 1% pimecrolimus cream is not associated with an increase in skin infections as compared with corticosteroids or vehicle. The incidence of fungal and viral infections was not increased significantly with pimecrolimus. In the clinical pivotal program, only one case of virologically proven eczema herpeticum was observed in a patient on pimecrolimus. The incidence of clinically diagnosed eczema herpeticum (i.e., nonvirologically proven) was 0.5 in 1,000 control-treated subjects compared with 1 in 1,000 pimecrolimus-treated patients, but the difference was not significant. Postregistration studies do, however, show an increased, albeit small, risk of viral skin infections, mostly herpes simplex, in pimecrolimus-treated children as compared with vehicle-treated patients. The relative risk for all viral skin infections vs. vehicle is 1.6 and for herpes simplex specifically, 2.2. Of note, in a 1-year, randomized controlled trial of pimecrolimus vs. topical corticosteroids (n=658), the incidence of herpes simplex was similar in both groups (topical corticosteroids: 5.5%, pimecrolimus 6%).¹⁴

Systemic Infections

No overall differences in the incidence of systemic infections between pimecrolimus cream-treated and control groups was observed in all analyses. The few imbalances were equally distributed between the pimecrolimus and the vehicle groups.¹² Phototoxicity and Photocarcinogenicity According to the European Summary of Product Characteristics, pimecrolimus has shown no phototoxicity or photocarcinogenicity in standard animal models.

Delayed-Type Hypersensitivity

The response of skin to recall antigens was tested after 1 year of treatment with pimecrolimus or conventional treatment in order to evaluate the effect of pimecrolimus on delayed-type hypersensitivity. No significant differences were observed between the two treatment groups using a range of common bacterial and fungal antigens. This seems to indicate that topical pimecrolimus does not impair the skin immunosurveillance of the patient.⁷

Vaccination Response

Topical pimecrolimus treatment has no effect on the vaccination response in infants and children. Protective antibody titer levels to rubella, measles, diphtheria, and tetanus in pimecrolimus-treated pediatric patients were not different from the range in the general population.¹⁵

Malignancies

Clinical studies show no evidence of increased risk of malignancies in patients treated with pimecrolimus. As of January 2005, seven cases of malignancies were reported in clinical trials, two of which occurred among the ~19,000 patients using pimecrolimus and five of which occurred within the ~4,000 control patients. The malignancies occurring in the pimecrolimus-treated patients were one squamous cell carcinoma (65-yearold female) and one case of colon cancer (male, 47- years) whereas the malignancies occurring in the control groups were one each of gastric carcinoma (male, 67-years), melanoma (male, 64 years), histiocytosis X (male, 5 years), leukemia (female, 5 months), and one thyroid cancer (female, 65 years). Continuous reporting on malignancies outside clinical trials up to March 2005 showed 17 patients with malignancies. These were five patients with skin tumors (one basal cell carcinoma, two squamous cell carcinomas, and two “skin carcinomas”), 10 patients with lymphoma (three < 3 years, two aged 40- 49, and five aged >50), one myelodysplastic syndrome, and one breast cancer. Stratifying these cases according to age, type of cancer, and the incidence of spontaneous occurrence of these cancers in the normal population shows that the incidence of the reported malignancies is far below the expected number of cases in the general population. No causality between pimecrolimus use and the occurrence of malignancy can be established. This issue has also been evaluated by an independent expert committee, which found no causality between spontaneous reports of lymphoma and pimecrolimus.¹⁶

Summary on Safety

There is no clinical evidence for increased risk of malignancies after the use of pimecrolimus cream, and there is no evidence for systemic immunosuppression by topical pimecrolimus. These facts become particularly evident when considering the immunocompetence and infection rates in children having received pimecrolimus. These outcomes are also improbable on the basis of pharmacokinetic considerations.

Black Box Warning Label

Earlier this year, the US FDA announced that it was considering adding a black box warning label on pimecrolimus (and also on tacrolimus) based on a recommendation of its Pediatric Advisory Committee because of a potential risk of cancer. At the time of writing no black box warning had been issued. This concern of the FDA is based on the postmarketing spontaneous reports on cancers discussed above, the theoretical concerns of carcinogenicity by immunosuppression, and a cynomolgus monkey study with an oral formulation of pimecrolimus which demonstrated an occurrence of transient lymphomas in the lowest dose, which was >30 times higher than the highest AUC in humans after application of the cream formulation. The American Academy of Dermatology expressed disappointment about this action, “despite the fact that there is no data that proves that proper topical use of pimecrolimus (and tacrolimus) is dangerous in people.”17 Similarly, the ISDI (Inflammatory Skin Disease Institute) has expressed disappointment with the decision and presented testimonies regarding this issue.18 The topical Calcineurin Inhibitor Task Force of the ACAAI and AAAI19 have stated that “none of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus (or tacrolimus) in AD indicate or suggest a causal relationship” and concluded “that there was no clear-cut link between pimecrolimus (or tacrolimus) and increased risk of lymphoma”; also, they state that “there is no evidence of systemic immune suppression from topical pimecrolimus (or tacrolimus) as measured by response to childhood immunization and delayed hypersensitivity.” Further, they say that “the topical Calcineurin Inhibitor Task Force of ACAAI and AAAI concludes that based on current data the riskbenefit ratio of topical pimecrolimus (and tacrolimus) are similar to most conventional therapies for the treatment of chronic relapsing eczema.” A number of organizations in the US and in Europe share this view, and the general question is why the FDA decided to take this step despite the fact that current data provide no basis for suggesting an increase in the risk of neoplasia. In the opinion of many experts with whom I have spoken, there is no unequivocal answer to this question.

It is an opinion that I share. It seems that the FDA has decided to exercise particular caution in the use of topical calcineurin inhibitors outside the approved indications and therefore wants to limit the practice of off-label use. Many believe, and I share this view, that the FDA is acting prematurely. As a personal note I would like to add that I have not been deterred by the black box warning from a continued use of pimecrolimus, and neither have my patients or their parents. Long-term studies designed to look into this issue are either planned or are already ongoing.

References

1. Data on file with Novartis as of March 15, 2005, URL: http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4089s2_02_02_Novartis%20Core%20Safety%20(CS).pdf.
2. Stuetz A, Grassberger M, Meingassner JG. Pimecrolimus (Elidel®, SDZ ASM 981) – preclinical pharmacologic profile and skin selectivity. Semin Cutan Med Surg 20(4):233-41 (2001 Dec).
3. Hultsch T, Müller KD, Meingassner JG, Grassberger M, Schopf RE, Knop J. Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent manner. Arch Dermatol Res 290(9):501-7 (1998 Sep).
4. Kalthoff FS, Chung J, Musser P, Stuetz A. Pimecrolimus does not affect the differentiation, maturation and function of human monocyte-derived dendritic cells, in contrast to corticosteroids. Clin Exp Immunol 133(3):350-9 (2003 Sep).
5. Meingassner JG, Kowalsky E, Schwendinger H, Elbe-Burger A, Stütz A. Pimecrolimus does not affect Langerhans cells in murine epidermis. Br J Dermatol 149(4):853-7 (2003 Oct).
6. Hoetzenecker W, Ecker R, Kopp T, Stütz A, Stingl G, Elbe-Bürger A. Pimecrolimus leads to an apoptosisinduced depletion of T cells but not Langerhans cells in patients with atopic dermatitis. J Allergy Clin Immunol, 115(6):1276-83 (2005 Jun).
7. Wolff K, Stuetz A. Pimecrolimus for the treatment of inflammatory skin disease. Expert Opin Pharmacother 5(3):643-5 (2004 Mar).
8. Van Leent EJM, Gräber M, Thurston M, Wagenaar A, Spuls PI, Bos JD. Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol 134(7):805-9 (1998 Jul).
9. Luger T, Van Leent EJM, Graeber M, et al. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 144(4):788-94 (2001 Apr).
10. Ho V, Gupta A, Kaufmann R, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr 142(2):155-62 (2003 Feb).
11. Eichenfield LF, Lucky AW, Boguneiwicz M, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 46(4):495-504 (2002 Apr).
12. Rappersberger K, Komar M, Ebelin ME, et al. Pimecrolimus identifies a common genomic antiinflammatory profile, is clinically highly effective in psoriasis and is well tolerated. J Invest Dermatol 119(4):876-87 (2002 Oct).
13. Papp KA, Werfel T, Fölster-Holst R, et al. Long-term control of atopic dermatitis with pimecrolimus cream 1% in infants and young children: a 2-year study. J Am Acad Dermatol 52(2):240-6 (2005 Feb).
14. Wahn U, Bos JD, Goodfield M, et al. Efficacy and safety of pimecrolimus cream in the longterm management of atopic dermatitis in children. Pediatrics 110(1 Pt 1):e2 (2002 Jul).
15. Papp KA, Breuer K, Meurer M, et al. Long-term treatment of atopic dermatitis with pimecrolimus cream 1% in infants does not interfere with the development of protective antibodies after vaccination. J Am Acad Dermatol 52(2):247-53 (2005 Feb).
16. Drug Regulatory Affairs Briefing Document of the FDA Pediatric Advisory Committee Meeting. Elidel® (pimecrolimus) Cream 1% NDA 21-302 (2005 February 15). URL: http://www.fda.gov/ohrms/dockets/ac/05/brief ing/2005-4089b2_ 03_04_Elidel%20Novartis%20Brief ing%20 Bookredacted.pdf.
17. American Academy of Dermatology issues statement in response to FDA decision related to two eczema medications. Press Release (2005 Mar 10). URL: http://www.aad.org/public/News/NewsReleases/fda_decision.htm.
18. Inflammatory Skin Disease Institute. FDA announces it is adding a Black Box Warning Label. Press Release. Current News. URL: http://www.isdionline.org/current.htm.
19. Calcineurin Task Force Final Report. URL: http://www.acaai.org/NR/rdonlyres/32BE405B-3 F 3 B - 4 B 1 2 - A 3 8 6 - 8 E 1 1 2 D 2 4 4 8 5 D / 0 / CalcineurinTaskForceFinalReport.pdf.

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