INTRODUCTION
Acne vulgaris, the eighth most prevalent disease globally,1,2 is a multifactorial skin condition characterized by the excess production of sebum, epithelial follicle hyperkeratinization, and inflammation.1-3 Clinical manifestations of acne can range from mild to severe depending on the number of comedones, papules, pustules, or nodules, which most commonly affect the face, chest, and/or back.3
The onset of acne is associated with the fluctuation of hormones - including androgens, estrogens, progesterone, insulin, andinsulin-like growth factor-1, adrenocorticotropic hormone,melanocortins, glucocorticoids, and growth hormone - andthus frequently begins at or before adrenarche or puberty.2,4,5 The principal drivers of acne pathogenesis are androgens suchas testosterone and dihydrotestosterone (DHT).4,5 Androgensbind to their receptors on sebaceous glands, sebocytes, and dermal papilla cells in the skin,2,6,7 and regulate the transcription of genes involved in acne pathogenesis, including inflammatory cytokines and factors driving sebaceous gland proliferation and sebum production.2,6,7 Serum dehydroepiandrosterone levels correlate with the presence of acne in prepubertal children and in adolescent girls (14-17 years of age) and with acne lesion counts in both male and female adults8-10; while DHT levels correlate positively with acne lesion counts in women (18-45 years of age).8
Topical 1% clascoterone cream (cortexolone 17α-propionate) is an androgen receptor inhibitor indicated for the topical treatment of acne in patients ≥12 years of age and is the first topical androgen receptor inhibitor approved by the US Food and Drug Administration (FDA) for acne treatment.3,11,12 In vitro studies have shown that by binding to the androgen receptor, clascoterone competes with DHT and inhibits sebum production and downstream proinflammatory signaling pathways in primary human sebocytes and hair follicle dermal papilla cells.13,14
The efficacy and safety of 1% clascoterone cream in patients with moderate-to-severe facial acne vulgaris (grade 3 or 4 on the Investigator Global Assessment [IGA] scale) were demonstrated in 2 identical phase 3 studies (CB-03-01/25 [NCT02608450] and CB-03-01/26 [NCT02608476]) that included a total of 1440 patients ≥9 years of age.2 The phase 3 clinical trial populations included only 19 patients aged ≥9 and <12 years, and clascoterone cream, 1% was subsequently approved in the United States for the treatment of acne vulgaris in patients ≥12 years of age. This paper presents post hoc pooled analyses of data from the 2 phase 3 randomized clinical trials on the efficacy and safety of 1% clascoterone cream after 12 weeks of treatment in 1421 patients ≥12 years of age.
The onset of acne is associated with the fluctuation of hormones - including androgens, estrogens, progesterone, insulin, andinsulin-like growth factor-1, adrenocorticotropic hormone,melanocortins, glucocorticoids, and growth hormone - andthus frequently begins at or before adrenarche or puberty.2,4,5 The principal drivers of acne pathogenesis are androgens suchas testosterone and dihydrotestosterone (DHT).4,5 Androgensbind to their receptors on sebaceous glands, sebocytes, and dermal papilla cells in the skin,2,6,7 and regulate the transcription of genes involved in acne pathogenesis, including inflammatory cytokines and factors driving sebaceous gland proliferation and sebum production.2,6,7 Serum dehydroepiandrosterone levels correlate with the presence of acne in prepubertal children and in adolescent girls (14-17 years of age) and with acne lesion counts in both male and female adults8-10; while DHT levels correlate positively with acne lesion counts in women (18-45 years of age).8
Topical 1% clascoterone cream (cortexolone 17α-propionate) is an androgen receptor inhibitor indicated for the topical treatment of acne in patients ≥12 years of age and is the first topical androgen receptor inhibitor approved by the US Food and Drug Administration (FDA) for acne treatment.3,11,12 In vitro studies have shown that by binding to the androgen receptor, clascoterone competes with DHT and inhibits sebum production and downstream proinflammatory signaling pathways in primary human sebocytes and hair follicle dermal papilla cells.13,14
The efficacy and safety of 1% clascoterone cream in patients with moderate-to-severe facial acne vulgaris (grade 3 or 4 on the Investigator Global Assessment [IGA] scale) were demonstrated in 2 identical phase 3 studies (CB-03-01/25 [NCT02608450] and CB-03-01/26 [NCT02608476]) that included a total of 1440 patients ≥9 years of age.2 The phase 3 clinical trial populations included only 19 patients aged ≥9 and <12 years, and clascoterone cream, 1% was subsequently approved in the United States for the treatment of acne vulgaris in patients ≥12 years of age. This paper presents post hoc pooled analyses of data from the 2 phase 3 randomized clinical trials on the efficacy and safety of 1% clascoterone cream after 12 weeks of treatment in 1421 patients ≥12 years of age.
MATERIALS AND METHODS
Study Design and Treatment
The study design and methods were previously published in detail.2 Briefly, both studies (CB-03-01/25 [NCT02608450] and CB-03-01/26 [NCT02608476]) were multicenter, randomized, double blind, and vehicle controlled.2 The CB-03-01/25 study was conducted from January 21, 2016, to April 11, 2018 and the CB-03-01/26 study was conducted from November 16, 2015, to February 21, 2018.2 Patients were randomized to apply 1% clascoterone cream or vehicle to the entire face twice daily for 12 weeks.2
Study Population
Male or non-pregnant female patients ≥9 years of age with a diagnosis of facial acne vulgaris and an IGA score of 3 or 4 (0 [clear] to 4 [severe] scale) were eligible for enrollment in 2 phase 3 studies; 722 patients were allocated to treatment with 1% clascoterone cream and 718 patients to vehicle. Only patients ≥12 years of age were included in this analysis (709 patients treated with 1% clascoterone cream and 712 treated with vehicle). Key exclusion criteria included the presence of >2 facial nodules, nodulocystic acne, or any skin pathology or condition that could interfere with the study. Use of topical or systemic anti-acne preparations (ie, over-the-counter acne cleansers or treatments, retinoids, corticosteroids, or antibiotics) within 2 to 4 weeks of the initiation of treatment and use of spironolactone within 8 weeks of treatment were also reasons for exclusion.
Assessments
Efficacy Assessments
The IGA was performed at each study visit (baseline and weeks 4, 8, and 12) using a 5-point scale (from 0 = clear to 4 = severe). Manual counting of noninflammatory lesions (NILCs) and inflammatory lesions (ILCs) was performed at each study visit (baseline and weeks 4, 8, and 12).2
Safety Assessments
Treatment-emergent adverse events (TEAEs) and local skin reactions (LSRs; edema, erythema/redness, pruritus, scaling/dryness, skin atrophy, stinging/burning, striae rubrae, and telangiectasia) were assessed at each study visit. TEAEs were summarized by treatment group and overall, and were classified using Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred terms. The number and proportion of patients with any TEAE and the number of TEAEs were listed by preferred term, seriousness, relationship to test article, and severity. LSRs including edema, erythema/redness, scaling/dryness, skin atrophy, striae rubrae, and telangiectasia were assessed by the investigators and recorded on a 5-point scale. Patients rated the severity of stinging/burning and pruritus on a 4-point scale.
Outcomes
In the phase 3 studies, the coprimary efficacy outcomes were the proportion of patients achieving "success" (defined as an IGA score of "clear" [score = 0] or "almost clear" [score = 1] with a ≥2-point reduction in IGA score from baseline) and absolute change from baseline (CFB) in NILCs and ILCs at week 12. The secondary efficacy outcomes were absolute CFB in total lesion counts (TLCs) at week 12 and percent CFB in TLCs, NILCs, and ILCs at week 12. Safety outcomes included TEAEs and LSRs scored by frequency and severity at every visit (baseline and weeks 4, 8, and 12).
Statistical Analysis
Efficacy endpoints were analyzed in the intention-to-treat set, which included all randomized patients; subgroup analyses, reported in this paper, included patients ages ≥12, excluding 19 patients aged ≥9 and <12 years.
