Abstract and Introduction
The pathogenesis of acne is multifactorial and involves inflammation, bacterial dysbiosis, and androgen stimulation. Existing systemic therapies target hormonal pathways to mitigate acne lesions; however, their use is limited to the female population and associated with systemic adverse effects. Clascoterone is the first topical therapy to target the hormonal pathogenesis of acne approved to treat acne vulgaris. In two identical phase 3 trials, clascoterone showed favorable efficacy over placebo in treating acne, with higher treatment success and a greater reduction in acne lesions. Large scale trials are required to assess the efficacy of clascoterone against its comparators and in combination with existing acne therapies; however, results from the current phase 3 trials support the therapeutic value of clascoterone, suggesting that this novel topical androgen inhibitor represents a valuable addition to the catalogue of acne therapy.
Acne vulgaris is a common skin condition that impacts 85% of adolescents and young adults.[1,2] Acne prevalence decreases with age, yet many patients are burdened by acne throughout adulthood leading to known psychosocial impact and associated morbidity, including anxiety, depression, and low self-esteem.[3,4] The pathogenesis of acne is multifactorial and influenced by androgen stimulation, host microbiome, immune responses, genetics, and diet.[5–7] Androgens and other sebogenic hormones stimulate sebum production within the pilosebaceous unit, which enhances the proliferation and dysbiosis of Cutibacterium acnes (C. acnes) leading to inflammation and follicular hyperkeratinization (Figure 1). Acne onset is typically observed at adrenarche, and is rare in the prepubertal period when levels of sebogenic hormones are low. Associations also exist between acne and conditions with known androgen excess, such as polycystic ovarian syndrome (PCOS), congenital adrenal hyperplasia, and adrenal or ovarian tumors.[10–12]
Proposed mechanism of action for clascoterone in acne therapy.
Acne is an inflammatory condition of the pilosebaceous unit, driven by proliferation and dysbiosis of Cutibacterium acnes, follicular hyperkeratinization, inflammation due to innate and cellular immune responses, and increased sebum production by sebaceous glands.8 Circulating androgens are taken up by sebocytes (sebumproducing epithelial cells that reside within the sebaceous gland), and are converted to dihydrotestosterone (DHT) within the cytosol.24 DHT subsequently binds to androgen receptors, and the ligand-receptor complex dimerizes before translocating to the nucleus.25 Dimerized androgen receptors promote the transcription of genes involved in acne pathogenesis, including inflammatory cytokines and sebum.18 Clascoterone is postulated to competitively bind to androgen receptors at the site of application, competing with the endogenous ligand DHT and reducing downstream signalling cascades involved in acne pathogenesis.18 This ultimately reduces the production of sebum and release of proinflammatory cytokines implicated in acne lesions. The effects of clascoterone remain localized to site of application, due to the presence of esterases found in the skin and plasma.19
Common first-line acne therapies include topical retinoids, benzoyl peroxide, and topical or oral antibiotics. Combined oral contraceptives (containing estrogen and progesterone) and spironolactone effectively target the hormonal pathogenesis of acne. However, their use is limited to the female population and carries the potential risk of systemic adverse effects, such as thromboembolism or hyperkalemia.[15,16] Notably, there are no existing topical acne therapies that target hormonal factors involved in acne.
Skin Therapy Letter. 2022;27(1):1-3. © 2022 SkinCareGuide.com