INTRODUCTION
Acne vulgaris is a common, chronic skin disease characterized by open or closed comedones and inflammatory lesions.1 The pathogenesis of acne is multifactorial, and key factors include follicular hyperkeratinization, microbial colonization with Cutibacterium acnes, sebum production, innate and acquired immunity, diet, and genetic and nongenetic factors.1 Puberty is associated with an increase in androgen levels and sebum production, and these events correlate directly with the development of acne.2
Clascoterone cream 1% is an androgen receptor inhibitor indicated for the topical treatment of acne vulgaris in patients greater than or equal to 12 years of age at a recommended dosage of approximately 1 g applied twice daily.3 Clascoterone was found to be safe and effective in 2 identical Phase 3 trials with treatment for up to 12 weeks and a long-term extension trial with treatment for up to 9 months in patients greater than or equal to 9 years of age with facial acne vulgaris.4,5 In vitro, clascoterone inhibits the binding of dihydrotestosterone (DHT) to the androgen receptor and decreases DHT-stimulated production of sebum components and inflammatory cytokines.6,7
Steroids and steroidal molecules have the potential to interfere with the endogenous hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol secretion in a tightly controlled negative feedback loop.8,9 Prolonged adrenal suppression by steroid treatment can lead to atrophy of the adrenal glands and functional deficiency in the HPA axis, and failure of adequate preventative measures may lead to unnecessary morbidity and even death.8,9 Corticosteroid treatments such as dexamethasone and triamcinolone acetonide are associated with HPA axis suppression1,10; in contrast, treatment with the mineralocorticoid antagonist spironolactone can activate the HPA axis.11 In preclinical studies, clascoterone was rapidly
Clascoterone cream 1% is an androgen receptor inhibitor indicated for the topical treatment of acne vulgaris in patients greater than or equal to 12 years of age at a recommended dosage of approximately 1 g applied twice daily.3 Clascoterone was found to be safe and effective in 2 identical Phase 3 trials with treatment for up to 12 weeks and a long-term extension trial with treatment for up to 9 months in patients greater than or equal to 9 years of age with facial acne vulgaris.4,5 In vitro, clascoterone inhibits the binding of dihydrotestosterone (DHT) to the androgen receptor and decreases DHT-stimulated production of sebum components and inflammatory cytokines.6,7
Steroids and steroidal molecules have the potential to interfere with the endogenous hypothalamic-pituitary-adrenal (HPA) axis, which regulates cortisol secretion in a tightly controlled negative feedback loop.8,9 Prolonged adrenal suppression by steroid treatment can lead to atrophy of the adrenal glands and functional deficiency in the HPA axis, and failure of adequate preventative measures may lead to unnecessary morbidity and even death.8,9 Corticosteroid treatments such as dexamethasone and triamcinolone acetonide are associated with HPA axis suppression1,10; in contrast, treatment with the mineralocorticoid antagonist spironolactone can activate the HPA axis.11 In preclinical studies, clascoterone was rapidly
MATERIALS AND METHODS
Study Design
Study 1 (ClinicalTrials.gov NCT01831960; 171-7175-202) was an open-label, multicenter trial of clascoterone cream 1% in separate cohorts of adults and adolescent patients with acne vulgaris (Cohort 1 [greater than or equal to 18 years of age] and Cohort 2 [greater than or equal to 12 to <18 years of age]); the study was previously published, including an overall summary of HPA suppression data.13 Study 2 (clinicaltrials.gov NCT02720627; CB-03-01/28) was an open-label, multicenter trial of clascoterone cream 1% in adolescent patients 9 to <12 years of age with acne vulgaris. The study protocols, consent forms, participant recruitment materials, and other relevant documents were submitted to an institutional review board for review and approved prior to study initiation. The trials were conducted in accordance with Title v21 of the US Code of Federal Regulations, the International Conference on Harmonisation guidelines, current Good Clinical Practice principles, the Declaration of Helsinki, and local regulatory requirements. All patients and their parents or guardians provided written informed consent before enrollment.
Study Population
The eligibility criteria for Study 1 were previously described.13 Briefly, male and female patients with moderate-to-severe facial acne vulgaris (Investigator's Global Assessment [IGA] Grade 3 or 4) and obvious acne on the chest and/or back were eligible. Patients were enrolled in 2 separate cohorts: Cohort 1, including patients greater than or equal to 18 years of age, and Cohort 2, including patients greater than or equal to 12 to <18 years of age. For Study 2, male and female patients 9 to <12 years of age with moderate-to-severe facial acne vulgaris (IGA Grade 3 or 4) and obvious acne on the trunk (ie, shoulder, upper chest, and/or back) were eligible. Patients were excluded from either study if they were pregnant, lactating, or planning to become pregnant during the study; had a body mass index--for-age percentile >95% or >32.0 kg/m2 (Study 1, Cohort 1); had previously used systemic antibiotics within 2 weeks, topical anti-acne medication containing retinoids, or systemic spironolactone within 4 weeks, or systemic retinoid therapy within 3 months of baseline; or topical corticosteroids (including inhaled and intranasal corticosteroids) within 2 weeks or systemic corticosteroids (including intramuscular and intralesional injections) within 4 weeks of the cosyntropin stimulation test (CST).
Treatment
In Study 1, adult patients and adolescent patients with a body surface area >1.6 m2 applied 6 g of clascoterone cream 1% to their entire face, shoulders, upper chest, and upper back twice daily for 14 days. Patients <18 years of age with a body surface area less than or equal to 1.6 m2 applied 4 g of clascoterone cream 1% twice daily. In Study 2, patients applied 2 g of clascoterone cream 1% to their entire face and trunk twice daily for 14 days.
Assessments
In both studies, a CST was performed at baseline and again on day 14, within 1 hour of the same time of day as the baseline CST. Any patient with an abnormal CST result, defined as a serum cortisol level less than or equal to 18 mcg/dL 30 minutes post stimulation, at day 14 returned approximately 4 weeks later for a follow-up CST. The serum cortisol assays were analyzed at ACM Global Central Laboratory (Rochester, NY). All tubes of returned cream were weighed to determine the amount of test article used. Blood samples for pharmacokinetic analysis were collected at various time points, including pre-dose on day 14, and approximately 12 hours after the evening application on the prior day, in both studies. All plasma samples were frozen after collection and analyzed by MicroConstants (San Diego, CA). Local and systemic adverse events (AEs) were recorded throughout the study, and physical examination, vital signs, and electrocardiograms were performed at baseline and day 14.
Statistical Analyses
Individual patient-level data are provided, and no statistical analysis was performed.
RESULTS
Study Population
A total of 42 patients (Cohort 1, n = 20; Cohort 2, n = 22) were enrolled in Study 1; all completed the study and were evaluable for HPA suppression.13 A total of 27 patients were enrolled in Study 2; all completed the study, and 23 were evaluable for HPA suppression.
CST Results
Across both studies, 5 patients treated with clascoterone had an abnormal CST result at day 14: three from Study 1 and two from Study 2. These included 1 adult patient (Study 1, Cohort 1), 2 adolescent patients greater than or equal to 12 to <18 years of age (Study 1, Cohort 2), and 2 adolescent patients 9 to <12 years of age (Study 2). Baseline demographic and clinical characteristics of these
