Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
Conflict of interest:
The authors have no conflicts of interest to declare.
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, clascoterone, androgen inhibitor, topical 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 hyperkeratinization8 (Figure 1). Acne onset is typically observed at adrenarche, and is rare in the prepubertal period when levels of sebogenic hormones are low.9 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
Common first-line acne therapies include topical retinoids, benzoyl peroxide, and topical or oral antibiotics.13 Combined oral contraceptives (containing estrogen and progesterone) and spironolactone effectively target the hormonal pathogenesis of acne.14 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.
Novel Therapy for Acne Vulgaris
In August 2020, the US FDA approved clascoterone 1% cream as a novel therapy for the treatment of acne vulgaris in individuals aged 12 or older. Two identical randomized phase 3 trials (n=708 and n=732) demonstrated that clascoterone 1% cream showed favorable efficacy compared to vehicle cream at achieving treatment success for acne vulgaris with minimal side effects.17
Mechanism of Action
Clascoterone (cortexolone 17a-propionate) is a novel topical androgen receptor inhibitor. Clascoterone competitively binds to the androgen receptor with high affinity, competing with the endogenous ligand dihydrotestosterone (DHT) at the site of application18 (Figure 1). In vitro studies revealed that clascoterone decreases the downstream signaling events from androgen receptors, thereby reducing the transcription of androgenregulated genes and downstream lipid and proinflammatory cytokine production.18 Ultimately, this decreases sebum production and inflammation of the pilosebaceous unit.18 Esterases present in the skin and plasma hydrolyze clascoterone into its inactive parent form (cortexolone), resulting in a localized effect of clascoterone to the site of topical application and minimizing systemic antiandrogenic effects.19 Small dosefinding phase 2a studies showed that steady-state plasma concentrations of clascoterone were achieved by day 5 at 4.5 ng/mL, which was an approximate two-fold increase compared with the first dose.20 Plasma concentrations of cortexolone (the inactive metabolite of clascoterone) were undetectable (<0.5 ng/mL).
Initial pilot studies demonstrated that 1% topical clascoterone cream was more effective than placebo cream at reducing the total number of acne lesions, inflammatory lesions and acne severity.21 The small pilot study also suggested that clascoterone was similar or more clinically effective than its comparator, 0.05% tretinoin cream.21 Phase 2 studies revealed that clascoterone 0.1%, 0.5% and 1% cream were safe and welltolerated in male and female adolescent and adult populations, with application of clascoterone 1% twice daily showing the most favorable clinical results.20,22
The efficacy and safety of clascoterone 1% cream was further assessed in two identical randomized placebo-controlled double-blind phase 3 studies in patients over the age of 9 with moderate to severe facial acne (ClinicalTrials.gov Identifiers: NCT02608450 and NCT02608476).17 Subjects enrolled in the study had between 30-75 inflammatory acne lesions and 30-100 non-inflammatory acne lesions. Subjects were excluded if they expressed 2 or more facial nodules on assessment.
Severity of patient acne was scored using the 5-point category Investigator’s Global Assessment (IGA) scale (0=clear, 1=trace, 2=mild, 3=moderate, 4=severe). Composite treatment success was defined as a ≥2 point reduction in IGA score from baseline, and a score of 0 (clear) or 1 (almost clear) at 12 weeks. Three coprimary efficacy endpoints assessed during the trial included: (1) proportion of subjects that achieved treatment success at 12 weeks, and absolute change in number of (2) non-inflammatory and (3) inflammatory acne lesions at week 12 of the study. Secondary endpoints addressed changes in total lesion count, including percentage and absolute changes in lesion number from baseline at 12 weeks.
A total of 1440 subjects were randomized 1:1 to receive clascoterone 1% cream (n=722) or vehicle (n=718) in two identical multicentre trials (n=708, n=732). Approximately 1 gram of clascoterone or vehicle cream was applied to the whole face twice daily for 12 weeks. The subjects included male and non-pregnant female patients, with a median age of 18 years (range 9-58 years) and a slight female predominance (60.6%-65.9% female across all groups). The main phototypes were Fitzpatrick types II, III, and IV, with the majority of subjects being White (>83%) with lesser representation of Black, Asian or other races.
At 12 weeks, subjects assigned to the clascoterone groups achieved significantly more treatment success compared to vehicle controls. In the clascoterone groups, 18.4% (trial 1) and 20.3% (trial 2) obtained treatment success at week 12, compared to only 9.0% (trial 1) and 6.5% (trial 2) of vehicle groups (p<0.001 for both trials). There was also a significant reduction in the absolute number of inflammatory (trial 1, p=0.003; trial 2, p<0.001) and non-inflammatory acne lesions (p<0.001 for both trials) in the clascoterone group compared to vehicle at week 12. As a result, both phase 3 trials met the three coprimary efficacy endpoints. Secondary endpoints, including percentage change in total, inflammatory and non-inflammatory lesion counts from baseline, also favored clascoterone treatment over vehicle in both trials (percentage change in total lesion count: trial 1 p=0.001, trial 2 p<0.001; inflammatory lesion count: trial 1 p=0.005, trial 2 p<0.001; non-inflammatory lesion count: trial 1 p=0.009, trial 2 p<0.001).
In the phase 3 trials, clascoterone was well-tolerated and maintained a safety profile similar to vehicle.17 The most common local skin reactions were erythema (11.3%-13.1% clascoterone, 14.8%-15.7% vehicle), xerosis (8.8%-12.2% clascoterone, 7.6%-13% vehicle), and local pruritus (5.1%-5.4% clascoterone, 5.2%-6.0% vehicle); while the most common treatment emergent adverse events included nasopharyngitis (1.4% clascoterone, 2.7% vehicle), oropharyngeal pain (0.06% clascoterone, 0.04% vehicle) and headache (0.08% clascoterone, 0.06% vehicle). No electrocardiogram changes or systemic adverse effects were observed in the phase 3 trials. Most reported adverse events were mild in severity, and 76.8% had resolved by conclusion of the study.22 Notably, topical clascoterone did not demonstrate side effects associated with systemic spironolactone use, such as hyperkalemia, abnormal uterine bleeding, hypotension, and renal disturbance.23 In the phase 2a dose-finding study, 7% of subjects (3/42) exhibited an abnormal hypothalamic-pituitary-adrenal (HPA) axis response with elevated serum cortisol levels on day 14 of the study (range 14.9-17.7 μg/dL).20 Follow-up 4 weeks after study conclusion revealed normal cortisol concentrations without evidence of adrenal suppression. In the phase 3 studies, no symptoms of adrenal suppression were observed.17 It should be noted that no studies were performed to assess the long-term safety of clascoterone use, or the safety of clascoterone use in combination with other existing anti-acne therapies (topical or systemic).
Clascoterone 1% cream represents a novel and promising therapeutic agent in the management of acne vulgaris for individuals ≥12 years of age. Evidence surrounding its use demonstrates that clascoterone is an efficacious treatment with a reassuring safety profile, where the most common side effects include erythema, xerosis, and pruritus.17 Notably, this topical agent was not observed to have significant systemic effects seen with systemic anti-androgenic agents. No evidence exists regarding the safety of clascoterone use during pregnancy or lactation, or its efficacy in combination with or compared to existing topical and systemic acne therapies. Indeed, a previous small study (n=77) indicated that clascoterone 1% cream had similar, if not better, efficacy than its comparator tretinoin 0.05% cream,21 yet these findings remain to be substantiated in larger scale trials. Further studies on the long-term safety and efficacy of clascoterone in combination with other therapies are warranted, and subgroup analyses may help guide the clinical utility of clascoterone in specific patient populations.
- Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2163-96.
- Lynn DD, Umari T, Dunnick CA, et al. The epidemiology of acne vulgaris in late adolescence. Adolesc Health Med Ther. 2016 7:13-25.
- Rocha MA, Bagatin E. Adult-onset acne: prevalence, impact, and management challenges. Clin Cosmet Investig Dermatol. 2018 11:59-69.
- Karimkhani C, Dellavalle RP, Coffeng LE, et al. Global skin disease morbidity and mortality: an update from the Global Burden of Disease Study 2013. JAMA Dermatol. 2017 May 1;153(5):406-12.
- Rocha MA, Bagatin E. Skin barrier and microbiome in acne. Arch Dermatol Res. 2018 Apr;310(3):181-5.
- O’Neill AM, Gallo RL. Host-microbiome interactions and recent progress into understanding the biology of acne vulgaris. Microbiome. 2018 Oct 2;6(1):177.
- Woo TE, Sibley CD. The emerging utility of the cutaneous microbiome in the treatment of acne and atopic dermatitis. J Am Acad Dermatol. 2020 Jan;82(1):222-8.
- Tan JKL, Stein Gold LF, Alexis AF, et al. Current concepts in acne pathogenesis: pathways to inflammation. Semin Cutan Med Surg. 2018 Jun;37(3S):S60-S2.
- Admani S, Barrio VR. Evaluation and treatment of acne from infancy to preadolescence. Dermatol Ther. 2013 Nov-Dec;26(6):462-6.
- Franik G, Bizon A, Wloch S, et al. Hormonal and metabolic aspects of acne vulgaris in women with polycystic ovary syndrome. Eur Rev Med Pharmacol Sci. 2018 Jul;22(14):4411-8.
- Novello L, Speiser PW. Premature adrenarche. Pediatr Ann. 2018 Jan 1;47(1):e7-e11.
- Bienenfeld A, Azarchi S, Lo Sicco K, et al. Androgens in women: androgenmediated skin disease and patient evaluation. J Am Acad Dermatol. 2019 Jun;80(6):1497-506.
- Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May;74(5):945-73 e33.
- Elsaie ML. Hormonal treatment of acne vulgaris: an update. Clin Cosmet Investig Dermatol. 2016 9:241-8.
- Charny JW, Choi JK, James WD. Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. Int J Womens Dermatol. 2017 Jun;3(2):111-5.
- Slopien R, Milewska E, Rynio P, et al. Use of oral contraceptives for management of acne vulgaris and hirsutism in women of reproductive and late reproductive age. Prz Menopauzalny. 2018 Mar;17(1):1-4.
- Hebert A, Thiboutot D, Stein Gold L, et al. Efficacy and safety of topical clascoterone cream, 1%, for treatment in patients with facial acne: two phase 3 randomized clinical trials. JAMA Dermatol. 2020 Jun 1;156(6):621-30.
- Rosette C, Rosette N, Mazzetti A, et al. Cortexolone 17alpha-propionate (clascoterone) is an androgen receptor antagonist in dermal papilla cells in vitro. J Drugs Dermatol. 2019 Feb 1;18(2):197-201.
- Ferraboschi P, Legnani L, Celasco G, et al. A full conformational characterization of antiandrogen cortexolone-17α-propionate and related compounds through theoretical calculations and nuclear magnetic resonance spectroscopy. MedChemComm. 2014 Apr 4;5(7):904-14.
- Mazzetti A, Moro L, Gerloni M, et al. Pharmacokinetic profile, safety, and tolerability of clascoterone (cortexolone 17-alpha propionate, CB-03-01) topical cream, 1% in subjects with acne vulgaris: an open-label phase 2a study. J Drugs Dermatol. 2019 Jun 1;18(6):563.
- Trifu V, Tiplica GS, Naumescu E, et al. Cortexolone 17alpha-propionate 1% cream, a new potent antiandrogen for topical treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0.05% cream. Br J Dermatol. 2011 Jul;165(1):177-83.
- Mazzetti A, Moro L, Gerloni M, et al. A phase 2b, randomized, double-blind vehicle controlled, dose escalation study evaluating clascoterone 0.1%, 0.5%, and 1% topical cream in subjects with facial acne. J Drugs Dermatol. 2019 Jun 1;18(6):570.
- Trivedi MK, Shinkai K, Murase JE. A Review of hormone-based therapies to treat adult acne vulgaris in women. Int J Womens Dermatol. 2017 Mar;3(1):44-52.
- Moradi Tuchayi S, Makrantonaki E, Ganceviciene R, et al. Acne vulgaris. Nat Rev Dis Primers. 2015 Sep 17;1:15029.
- Tan MH, Li J, Xu HE, et al. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin. 2015 Jan;36(1):3-23.