Guidelines of care for the management of acne vulgaris.

BACKGROUND: Acne vulgaris commonly affects adults, adolescents, and preadolescents aged 9 years or older. OBJECTIVE: The objective of this study was to provide evidence-based recommendations for the management of acne. METHODS: A work group conducted a systematic review and applied the Grading of Recommendations, Assessment, Development, and Evaluation approach for assessing the certainty of evidence and formulating and grading recommendations. RESULTS: This guideline presents 18 evidence-based recommendations and 5 good practice statements. Strong recommendations are made for benzoyl peroxide, topical retinoids, topical antibiotics, and oral doxycycline. Oral isotretinoin is strongly recommended for acne that is severe, causing psychosocial burden or scarring, or failing standard oral or topical therapy. Conditional recommendations are made for topical clascoterone, salicylic acid, and azelaic acid, as well as for oral minocycline, sarecycline, combined oral contraceptive pills, and spironolactone. Combining topical therapies with multiple mechanisms of action, limiting systemic antibiotic use, combining systemic antibiotics with topical therapies, and adding intralesional corticosteroid injections for larger acne lesions are recommended as good practice statements. LIMITATIONS: Analysis is based on the best available evidence at the time of the systematic review. CONCLUSIONS: These guidelines provide evidence-based recommendations for the management of acne vulgaris.

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.

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.

Evaluation of in vitro Skin Permeation of Clascoterone From Clascoterone Topical Cream, 1% (w/w).

Winlevi® (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.

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.

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: 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.

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.

Open-label, long-term extension study to evaluate the safety of clascoterone (CB-03-01) cream, 1% twice daily, in patients with acne vulgaris.

BACKGROUND: Androgens foster acnegenic pathways. OBJECTIVE: To assess the long-term safety of an androgen receptor inhibitor, clascoterone cream, 1%, in patients who participated in phase 3 studies. METHODS: Clascoterone cream was applied twice daily for up to 9 months to the face or trunk, or both. Treatment-emergent adverse events (TEAEs) and local skin reactions were evaluated at months 1, 3, 6, and 9, and at any unscheduled visit(s). The statistical analysis was performed using SAS Windows 9.3 software (SAS Institute Inc, Cary, NC). RESULTS: The study screened and enrolled 609 individuals (n = 317 clascoterone, n = 292 vehicle from original studies), and 347 completed the study (n = 179 clascoterone, n = 168 vehicle). Overall, 110 patients (18.1%) experienced 191 TEAEs. The most frequently reported TEAE was nasopharyngitis (n = 20). A total of 19 test article-related TEAEs occurred in 14 patients; of these, 9 experienced 9 TEAEs leading to discontinuation. There were 7 serious TEAEs in 6 individuals, but none were treatment related. One serious TEAE led to study discontinuation. Overall, treatment-emergent local skin reactions occurred in 18.1% (110 of 607). The most frequent local skin reactions on the face and trunk were erythema, scaling/dryness, and pruritus, and most were trace/minimal or mild in severity. LIMITATIONS: Long-term efficacy was not a primary end point. CONCLUSION: A low frequency of TEAEs over 9 months of clascoterone treatment was observed.

Game Changer in Acne Treatment.

Of the four primary pathogenic factors that drive acne vulgaris—androgen excess, increased sebum production, faulty keratinization, and overgrowth of C. acnes—androgen excess has been the most elusive therapeutic target. Oral contraceptive pills (OCPs) have direct effect on circulating hormones, but their potential use is limited to a subset of women. As such, a sizable portion of the population affected by acne vulgaris cannot even consider treatment with OCPs. While these systemic agents are generally associated with a low risk profile and have a history of safe and effective use, they are not entirely risk-free. Indirect androgen modulation through the use of spironolactone has become increasingly popular.

Cortexolone 17α-Propionate (Clascoterone) is an Androgen Receptor Antagonist in Dermal Papilla Cells In Vitro

Cortexolone 17α-propionate (clascoterone) is a novel androgen antagonist that is currently being analyzed in a large phase 2 clinical trial for the topical treatment of androgenetic alopecia (AGA). While the pathogenesis of AGA is still debated, the consensus is that AGA is an androgen-dependent hair disorder with strong genetic links, and that the testosterone metabolite, dihydrotestosterone (DHT), plays a causal role in its development. DHT binds to the androgen receptor (AR) in scalp dermal papilla cells (DPC) to induce AR-mediated transcription of genes that contribute to AGA in genetically predisposed individuals. Several studies have established that clascoterone is a potent antiandrogen that is well tolerated and has selective topical activity. The study described herein elucidates a potential mechanism of clascoterone in AGA. Clascoterone was found to inhibit AR-regulated transcription in a reporter cell line with similar efficacy to the 5α-reductase inhibitor, finasteride. More importantly, when compared with another direct AR antagonist, enzalutamide, clascoterone was significantly better at inhibiting IL-6 synthesis from DHT-stimulated primary cultures of human scalp DPC. Therefore, clascoterone may be an excellent candidate to be the first topical antiandrogen for treating AGA. J Drugs Dermatol. 2019;18(2):197-201.

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

Androgens play a key role in acne pathogenesis in both males and females. Clascoterone (CB-03-01, Cortexolone 17α propionate) cream is a topical anti-androgen under investigation for the treatment of acne. The results from a phase 2b dose escalating study are discussed. Methods: Primary objective: to compare the safety and efficacy of topical creams containing clascoterone 0.1% (twice daily [BID]), 0.5% (BID), or 1% (daily [QD] or BID) versus vehicle (QD or BID) in male and female subjects ≥12 years with facial acne vulgaris. Efficacy was assessed by: Investigator's Global Assessment (IGA)--the overall severity of acne using a five-point scale (from 0=clear to 4=severe); inflammatory and non-inflammatory acne lesion counts (ALC); and subject satisfaction with treatment--subjects assessed overall treatment satisfaction using a 4-point scale. Safety assessments: local and systemic adverse events (AEs), physical examination/vital signs, laboratory tests, local skin reactions (LSRs), and electrocardiograms (ECGs). Treatment success required a score of "clear" or "almost clear" (IGA score of 0 or 1) and a two or more-grade improvement from baseline. Results: 363 subjects (N=72, 0.1% BID; N=76, 0.5% BID; N=70, 1% QD; N=70, 1% BID; and N=75, vehicle QD or BID) enrolled. 304 subjects (83.7%) completed the study. Intention to Treat (ITT) population: 196/363 (54.0%) females; 167/363 46.0%) males; (257/363 (70.2%) were white; average age=19.7 years. Demographic and baseline characteristics were similar across all groups. Treatment success at week 12 were highest for the 1% BID (6/70, 8.6%) and 0.1% BID (6/72, 8.3%) groups versus vehicle (2/75, 2.7%). Absolute change in inflammatory (P=0.0431) and non-inflammatory (P=0.0303) lesions was statistically significant among the treatment groups. The median change from baseline at week 12 in inflammatory and non-inflammatory lesions was greatest in the 1% BID group -13.5 and -17.5, respectively. Similar results were observed for the secondary efficacy endpoints whereby the highest success rate and greatest reduction in lesion counts from baseline to week 12 occurred with 1% BID. 93/363 subjects (25.6%) reported ≥1 AEs; total number of AEs=123 with 2 probably/possibly related to treatment (N=1, 1% QD group). Subjects with ≥1AEs: 0.1% BID=25.0%, 0.5% BID=38.2%, 1% QD=22.9%, 1% BID=18.6%, and vehicle=22.7%. AEs were mostly mild in severity and similar across all groups. Most AEs (93/121 76.8%) resolved by the end of the study. Erythema was the most prevalent LSR; 36.8% had at least minimal erythema at some point during the study. Conclusions: All clascoterone cream concentrations were well tolerated with no clinically relevant safety issues noted. Clascoterone 1% BID treatment had the most favorable results and was selected as the best candidate for further clinical study and development. Two Phase 3 investigations of clascoterone topical cream, 1% for the treatment of moderate-to-severe acne vulgaris in individuals ≥9 years recently concluded. J Drugs Dermatol. 2019;18(6):570-575.

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

Clascoterone (cortexolone 17α-propionate, CB-03-01) 1% cream, a topical, androgen receptor (AR) inhibitor under investigation for the treatment of acne vulgaris, is rapidly metabolized to cortexolone in human plasma. The primary objectives of this study were to determine the pharmacokinetic (PK) properties and adrenal suppression potential of clascoterone topical cream, 1% in subjects with acne vulgaris. Study Design: This study was an open-label, multicenter study in 42 subjects ≥12 years of age with moderate-to-severe acne (Grade 3-4 on the Investigator's Global Assessment [IGA]), on the face, chest and/or back. Cohort 1(>18 years of age) and Cohort 2 (12-18 years of age) applied clascoterone topical cream, 1% twice daily (BID) for 14 days. Primary safety endpoints included hypothalamic-pituitary-adrenal (HPA) axis response to cosyntropin via a Cosyntropin Stimulation Test (CST) upon screening (day 1) and at day 14 (HPA axis suppression was defined as a post-stimulation serum cortisol level <18 µg/dL at day 14); and PK evaluation including concentration-time profiles of clascoterone and cortexolone in plasma­PK parameters were determined using "non-compartmental" analysis. Secondary safety endpoints included clinical laboratory testing, local and systemic adverse events (AEs), physical examination/vital signs, and electrocardiogram (ECG). Results: 42 subjects (Cohort 1=20, Cohort 2= 22) enrolled. Cohort 1 was comprised of 15 females (15/20, 75%) and 5 males (5/20, 25%), non-Hispanic/Latino (20/20, 100%), mean age is 24.4 years. Cohort 2 was comprised of 12 females (12/22, 54.5%) and 10 males (10/22, 45.5%), non-Hispanic/Latino (21/22, 95.5%), and mean age is 15.6 years. Three subjects (3/42,7%), 1 adult and 2 adolescents, demonstrated an abnormal HPA axis response with post-stimulation serum cortisol levels ranging from 14.9 to 17.7 µg/dL at day 14. All returned to normal HPA axis function, four weeks after day 14. None showed clinical evidence of adrenal suppression. Clascoterone plasma concentrations achieved PK steady-state by day 5. Clascoterone systemic exposure was similar between both cohorts. At steady-state, plasma concentrations increased ~1.8 to 2.1 fold versus first dose with mean (coefficient of variation [CV] %) maximum plasma concentrations of 4.4 ng/mL (67%) and 4.6 ng/mL (103%) in Cohort 1 and Cohort 2, respectively. Cortexolone plasma concentrations trended below the lower limit of quantitation (0.5 ng/mL) in both cohorts. Local skin reactions (LSRs) were mostly mild, with only one moderate case of pruritus. There were nine AEs categorized as follows: definitely related (N=2), probably related (N=4), unlikely/not related (N=3), to clascoterone. Conclusion: This study demonstrates the safety and tolerability of clascoterone topical cream, 1% in adolescents and adults with acne vulgaris treated BID for 14 consecutive days. J Drugs Dermatol. 2019;18(6):563-568.

Cortexolone 17α-propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist that Inhibits Production of Lipids and Inflammatory Cytokines from Sebocytes In Vitro

Cortexolone 17α-propionate (clascoterone) is a novel topical androgen antagonist that is being analyzed for its ability to treat acne. The pathogenesis of acne is attributed to multiple factors, including altered sebum production, inflammatory processes, dysregulation of the hormone microenvironment, and the proliferation of the skin commensal bacteria, Propionibacterium acnes (P. acnes). Androgens induce the proliferation and differentiation of sebocytes, (cells that comprise the sebaceous gland), help regulate the synthesis of the lipids that are incorporated into sebum and stimulate the production of cytokines that are found in inflammatory acne lesions. Several studies have established that clascoterone is a potent antiandrogen that is well tolerated and has selective topical activity. Its potency as an acne therapeutic is currently being analyzed in a large phase 3 clinical trial. The study described herein elucidates for the first time the mechanism of action of clascoterone. Clascoterone was found to bind the androgen receptor (AR) with high affinity in vitro, inhibit AR-regulated transcription in a reporter cell line, and antagonize androgen-regulated lipid and inflammatory cytokine production in a dose-dependent manner in human primary sebocytes. In particular, when compared to another AR antagonist, spironolactone, clascoterone was significantly better at inhibiting inflammatory cytokine synthesis from sebocytes. Therefore, clascoterone may be an excellent candidate to be the first topical antiandrogen to treat acne. J Drugs Dermatol. 2019;18(5):412-418.

Gas Chromatography-Mass Spectrometry Analysis of Urinary Steroid Metabolomics for Detection of Early Signs of Adrenal Neoplasm Malignancy in Patients with Cushing's Syndrome.

The metabolomics of urinary steroids was studied by gas chromatography-mass spectrometry in 25 patients with Cushing's syndrome without malignant potential and in 12 patients with malignant potential of adrenal neoplasms (Weiss score 1-3). Patients with adrenocortical adenoma (N=24) constituted the control group. In patients with Cushing's syndrome and malignant potential, increased urinary excretion of 16-oxo-androstendiol, tetrahydro-11-deoxycortisol, and 16-hydroxypregnendiol, which had 100% specificity and sensitivity >90% for the diagnosis of malignant potential. Additionally, non-classical 5-ene-pregnenes (16-OHpregnenolone, 21-OH-pregnenolone, 3ß,16,20-pregnentriol, and 3ß,17,20-pregnentriol) were identified. The revealed changes in the metabolomics of steroids can be early signs of malignant potential in patients with Cushing's syndrome. In patients with malignant potential, three signs of reduced activity of 11ß-hydroxysteroid dehydrogenase type 2 were detected and in patients without malignant potential, one sign was found. In patients with and without malignant potential, three signs increased activity of 5ß-reductase were found.

The use of hormonal agents in the treatment of acne.

Hormones and androgens play an important role in the pathogenesis of acne. Multiple hormonal modulators are now available for the treatment of acne. The efficacies and side effects of currently available hormonal agents are reviewed here including the use of oral contraceptives, spironolactone, flutamide, cyproterone acetate, finasteride, and cortexolone 17α-propionate. Hormonal therapies are an efficacious treatment option for acne among females. With the growing need to reduce antibiotic exposures, hormonal therapies should be more widely studied and incorporated into acne treatment strategies.