Adult Female Acne: Managing the Hormones.

Acne is a common inflammatory condition of the skin worldwide. The skin is an endocrine organ and hormones are a key pathogenic factor in all types of acne with a particularly important role in adult female acne pathogenesis and management. In females, we have the unique opportunity to manipulate hormones systemically to successfully manage acne and, more recently with the approval of clascoterone 1% cream, we can target the hormones topically in both genders. The intent of this paper is to provide physicians with an up-to-date clinically relevant review of the role of hormones in acne, the impact of currently available contraceptives and therapies available to target hormones in acne.

Hypothalamic-Pituitary-Adrenal Axis Response in Patients With Acne Vulgaris Treated With Clascoterone.

BACKGROUND: Clascoterone cream 1% is a topical androgen receptor inhibitor approved to treat acne vulgaris in patients =>12 years of age. This report provides details of patients who developed laboratory signs of hypothalamic-pituitary-adrenal (HPA) axis suppression without clinical signs of adrenal suppression during the clascoterone development program. METHODS: Two open-label, multicenter, Phase 2 trials evaluated HPA axis suppression in patients with moderate-to-severe acne vulgaris. Study 1 (NCT01831960) enrolled cohorts of adults =>18 years of age and adolescents =>12 to <18 years of age. Study 2 (NCT02720627) enrolled adolescents 9 to <12 years of age. Patients applied clascoterone twice daily at maximum-exposure dosages for 14 days. Adrenal suppression was evaluated via cosyntropin stimulation test (CST) at baseline and day 14. Patients with an abnormal CST result (serum cortisol level =<18 µg/dL) had a follow-up CST approximately 4 weeks later. Blood was collected for pharmacokinetic analysis. Other safety assessments included adverse events (AEs), physical examination/vital signs, and electrocardiography. RESULTS: Overall, 5/69 clascoterone-treated patients had an abnormal CST result on day 14, including 1/20 adults, 2/22 patients aged =>12 to <18 years, and 2/27 patients aged 9 to <12 years. All patients had normal cortisol levels at follow-up testing approximately 4 weeks later. No relationship was observed between abnormal CST results and clascoterone plasma concentrations or the amount of study drug applied. No clinically relevant AEs or clinically significant changes in safety measures were observed in patients with adrenal suppression. CONCLUSION: Clascoterone induced laboratory evidence of mild, reversible HPA axis suppression under maximum-use exposure. J Drugs Dermatol. 2024;23(6):433-437.     doi:10.36849/JDD.7997.

Steroids Used to Treat Acne Vulgaris: A Review of Efficacy, Safety, and Clinical Considerations.

Acne vulgaris is prevalent among adolescents and adults worldwide and can significantly impact patients' quality of life. Steroidal molecules, including oral and intralesional corticosteroids, combined oral contraceptives (COCs), oral spironolactone, and topical clascoterone, are an important part of the acne treatment armamentarium. The recommended use, mechanism of action, and available evidence supporting the use of steroids for acne treatment are reviewed, and differences in acne clinical presentation and treatment approaches based on patient characteristics relevant to the selection of an appropriate steroid are also discussed. Steroid-based approaches target the systemic or local hormones (ie, testosterone and androgens) and inflammation that contribute to acne pathogenesis. Oral corticosteroids are primarily used as a short-term adjunctive therapy early in treatment, whereas intralesional corticosteroid injections are used for individual acne lesions. COCs and oral spironolactone are limited to female patients who wish to avoid pregnancy. Topical clascoterone can be used by female and male patients 12 years of age and older. Patients' characteristics (including age and patients with darker skin color) and preferences for the route of administration can impact treatment response and adherence, respectively. Overall, healthcare providers must be aware of the differences among steroidal acne treatments and use shared decision-making to select the optimal therapy. J Drugs Dermatol. 2024;23(6):404-409.     doi:10.36849/JDD.7846.

The efficacy of Topical Clascoterone versus systematic spironolactone for treatment of acne vulgaris: A systematic review and network meta-analysis.

OBJECTIVES: This study aimed to evaluate the effectiveness of topical clascoterone (TC) compared to oral spironolactone for acne vulgaris treatment. METHODS: A computerized search through PubMed/MEDLINE, SCOPUS, and the Cochrane Library was conducted to find relevant papers. We used the "netmeta" and "meta" packages for network meta-analysis (NMA) in RStudio 1.2.5019 (2009-2019 RStudio, Inc.) to conduct all of our statistical tests. RESULTS: Seven articles (n = 2,006 patients) were included. The fixed-effect size showed that TC 1% bis in die (BID) showed potential effectiveness in reducing the inflammatory and non-inflammatory lesion count compared to placebo (Standardized mean difference, SMD = -0.27, 95% CI: -0.36 to -0.17) and (SMD = -0.31, 95% CI: -0.41 to -0.22), respectively. The random-effect size showed that TC 1% BID was significantly associated with a 12-week treatment success compared to placebo (Odds ratio, OR = 2.44, 95% CI: 1.12 to 5.30). Spironolactone 200 mg was associated with a significant reduction in total lesion count (SMD = -4.46, 95% CI: -5.60 to -3.32). CONCLUSION: TC appears to reduce both inflammatory and non-inflammatory lesion count and may lead to treatment success. Spironolactone at 200 mg showed potential effectiveness in terms of total lesion count reduction. These results suggest that both TC and Spironolactone could be beneficial in treating patients with acne vulgaris.

Topical Clascoterone for Acne Vulgaris.

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.

Topical Clascoterone: The First Novel Agent for Acne Vulgaris in 40 Years.

PURPOSE: Acne vulgaris is a ubiquitous condition in men and women starting in adolescence. It is often persistent and refractory to multiple treatment methods. Although multiple medications may be used on- or off-label for treatment, many adverse effects and risks exist with these treatments, and there has not been an agent with a novel mechanism of action introduced in 40 years. Clascoterone is a recently approved topical acne medication with the first novel mechanism of action since isotretinoin. The purpose of this article was to review the clinical data regarding the safety and efficacy of topical clascoterone for the treatment of acne vulgaris in male and female subjects aged >12 years. METHODS: A literature search of PubMed, EMBASE, and MEDLINE was conducted for clinical trials published between January 2014 and March 2021 in the English language using the key words Winlevi, clascoterone, and acne vulgaris. Articles were selected if they were related to the approval by the US Food and Drug Administration of clascoterone or provided novel data regarding this drug entity. FINDINGS: Two Phase III randomized controlled trials (NCT02608450 and NCT02608476) were ultimately selected, as these trials provided pivotal information to the US Food and Drug Administration for the approval of topical clascoterone. IMPLICATIONS: The findings of this review show that topical clascoterone is likely an effective and safe option for the treatment of acne vulgaris. It offers efficacy rates similar to those of current medications through a novel mechanism of action. Its place in therapy remains unclear, but it might be placed ahead of other androgen receptor antagonists such as spironolactone due to its avoidance of systemic side effects.

Clascoterone: a new topical anti-androgen for acne management.

Clascoterone is an androgen receptor inhibitor which has been approved by the United States Food and Drug Administration for the topical treatment of acne vulgaris in patients 12 years of age and older. It competes with androgens, especially dihydrotestosterone, for androgen-receptor binding and limits their binding, thus inhibiting downstream signaling of pathways involved in the pathogenesis of acne. It inhibits androgen receptor-regulated gene transcription, and antagonizes lipid and inflammatory cytokine production in a dose-dependent manner in human primary sebocytes. Clascoterone is commercially available as 1% (10 mg/g) cream. Adverse effects of topical clascoterone are mild and infrequent, and are mostly limited to local skin reactions. Long-term safety studies have shown an absence of systemic antiandrogenic effects like reduced libido or feminization in male participants. Clascoterone seems a promising topical drug with a novel mechanism of action that could be added to the armamentarium of therapies for acne.

A Phase 1 Study to Investigate the Effects of Cortexolone 17α-Propionate, Also Known as Clascoterone, on the QT Interval Using the Meal Effect to Demonstrate ECG Assay Sensitivity.

Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.

Androgens and acne: perspectives on clascoterone, the first topical androgen receptor antagonist.

Introduction: Increased circulating androgens are key to the multifactorial pathogenesis of acne. Clascoterone is the first topical androgen antagonist developed to treat acne in both male and female patients and the first such agent to receive U.S. Food and Drug Administration (FDA) approval for treatment of acne. Androgens directly stimulate sebaceous gland growth and increased sebum production, creating a nourishing medium in which anaerobic Cutibacterium acnes (C. acnes) bacteria flourish. Androgens may directly contribute to inflammation in the sebaceous gland.Areas covered: In this review, the author assesses clascoterone's potential role in the management of acne. With a 4-ring backbone identical to dihydrotestosterone (DHT) and spironolactone, topically applied clascoterone binds androgen receptors (ARs) in the sebaceous glands and hair follicles, interfering with the pathogenesis of acne and reducing acne lesions with no reported systemic effects.Expert opinion: Phase III study results confirmed the safety and efficacy of topical clascoterone for acne, with considerable reductions in absolute non-inflammatory and inflammatory lesion counts at week 12. The approval of a first-in-class topical androgen antagonist is indeed a 'game-changer' for acne management. This topical agent is expected to be quickly adopted in clinical practice, likely within combination regiments, yet to be formally evaluated.

Clascoterone: A Novel Topical Androgen Receptor Inhibitor for the Treatment of Acne.

OBJECTIVE: To review the efficacy and safety of clascoterone 1% cream for the treatment of acne vulgaris in patients 12 years of age and older. DATA SOURCES: A literature search through PubMed, MEDLINE, and ClinicalTrials.gov was conducted using the following keywords: clascoterone, cream, acne, and CB-03-01. Articles published between 2004 and 2020 were included in this review. STUDY SELECTION AND DATA EXTRACTION: Preclinical and clinical studies describing the efficacy and safety of topical clascoterone cream were included. DATA SYNTHESIS: Early preclinical studies demonstrated that clascoterone exhibits local antiandrogenic effects without any systemic effects. Phase 2 and 3 trials demonstrated a statistically significant reduction in inflammatory and noninflammatory lesions and mild erythema with clascoterone use. Long-term studies confirmed the favorable safety profile of the drug in subjects for up to 9 months of use, with erythema being the most common treatment-emergent local skin reaction. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Pharmacological treatment options for acne vulgaris include topical and systemic agents. Systemic antiandrogen medications are associated with adverse effects and should be avoided in pregnancy and male patients. Clascoterone is a novel topical antiandrogen drug with no systemic adverse effects. This drug provides prescribers with an appealing treatment option for male and female patients 12 years of age and older, who are not candidates for systemic drugs because of contraindications or adverse effects or who have failed other topical therapies. CONCLUSION: Clascoterone, a novel topical androgen receptor inhibitor, is a safe and effective treatment option for patients with acne vulgaris.

Clascoterone: How the Novel Androgen Receptor Inhibitor Fits Into the Acne Treatment Paradigm.

Many patients with acne remain unsatisfied with results from the various topical treatments available and often do not improve, because of poor adherence. Even if topical clascoterone, a safe and effective treatment, were more potent than existing topicals, it could face the same poor adherence hurdle as existing treatments. Real-life efficacy will likely not reflect trial results because, for several reasons, adherence is better in trials than in real-life practice. Although topical clascoterone may be exciting initially for its promise to improve acne outcomes, the long-term place in therapy may be another topical option that minimally enhances patients' treatment outcomes.

Clascoterone cream (1%) topical androgen receptor inhibitor for the treatment of acne in patients 12 years and older.

INTRODUCTION: The efficacy of clascoterone cream was demonstrated in two phase three vehicle-controlled clinical trials that enrolled over 1,400 subjects. Its safety profile allowed it to be approved for treating patients as young as 12 years old. During clinical trials, the occurrence of local skin reactions (edema, erythema, pruritus, dryness) was similar to treatment with vehicle alone. AREAS COVERED: All publications describing the clinical development of clascoterone cream (cortexolone 17α-propionate) are reviewed and discussed in relation to with existing topical and systemic therapies for acne vulgaris. EXPERT OPINION: Clascoterone 1% cream is a novel first-in-class topical androgen receptor inhibitor for the treatment of acne vulgaris. Topical clascoterone 1% cream represents the first new type of therapy for acne treatment in almost 40 years and may become first-line therapy.

Efficacy and safety of topical clascoterone cream for treatment of acne vulgaris: A systematic review and meta-analysis of randomized placebo-controlled trials.

To systematically and meta-analytically pool evidence from randomized placebo-controlled trials that examined the efficacy and safety of topical clascoterone cream in patients with acne vulgaris. Four databases were screened from inception to 10 October 2020. Included studies were assessed for risk of bias. Efficacy outcomes included investigator's global assessment (IGA) treatment success and absolute change in inflammatory lesion counts (ILCs) and noninflammatory lesion counts (NILCs). Safety outcomes included the proportion of patients with any treatment-emergent adverse event (TEAE) as well as incidence of any TEAE, serious adverse events (AEs), AEs related to study drug, AEs leading to study drug discontinuation, nasopharyngitis, headache, oropharyngeal pain, and vomiting. Dichotomous data were analyzed using the risk ratio (RR) and 95% confidence interval (95% CI) whereas continuous data were analyzed using the mean difference (MD) and 95% CI. Review Manager Software version 5.4.1 was used for statistical analysis. Five clinical trials, comprising 2457 patients (1357 and 1100 patients received clascoterone and placebo, respectively) were included. Studies revealed an overall low risk of bias. Clascoterone significantly increased IGA success rates (RR = 2.87, 95% CI [2.11, 3.89], P < .001) and decreased NILCs (MD = -5.64, 95% CI [-8.41, -2.87], P < .01) without substantially impacting the ILCs (MD = -1.82, 95% CI [-5.06, 1.43], P = .27). No significant differences were noted between both groups for all safety outcomes, except for nasopharyngitis which was significantly lower in the clascoterone group (RR = 0.47, 95% CI [0.27, 0.83], P = .01). Topical clascorterone cream is safe and effective in the treatment of acne vulgaris.

Clascoterone: First Approval.

Clascoterone (Winlevi®) is an androgen receptor inhibitor being developed as a topical cream and solution by Cassiopea (a spin-out company of Cosmo Pharmaceuticals) for the treatment of androgen-dependent skin disorders, including androgenetic alopecia and acne vulgaris. Although the exact mechanism of action of clascoterone for the topical treatment of acne vulgaris is unknown, the drug is believed to compete with the androgen dihydrotestosterone for binding to androgen receptors in the sebaceous gland and hair follicles to attenuate signalling necessary for acne pathogenesis. In August 2020, clascoterone cream 1% received its first approval in the USA for the topical treatment of acne vulgaris in patients 12 years of age or older. Clinical studies of a different formulation of clascoterone (a solution containing a higher concentration of the drug) for the treatment of androgenetic alopecia are underway in Germany and the USA. This article summarizes the milestones in the development of clascoterone leading to this first approval for the topical treatment of acne vulgaris.