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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., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

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.

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., (© 2021 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

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.

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., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Acne is a common, multifactorial skin condition, and treatments with novel mechanisms have been elusive., Objective: To assess the safety and efficacy of clascoterone cream, 1%, a novel topical androgen receptor inhibitor, in 2 phase 3 randomized clinical trials (CB-03-01/25 and CB-03-01/26)., Design, Setting, and Participants: Two identical, multicenter, randomized, vehicle-controlled, double-blind, phase 3 studies conducted from November 2015 to April 2018 evaluated the efficacy and safety of use of clascoterone cream, 1%, in males and nonpregnant females 9 years and older with moderate or severe facial acne as scored on the Investigator's Global Assessment scale. Participants were enrolled if they had 30 to 75 inflammatory lesions and 30 to 100 noninflammatory lesions., Interventions: Patients were randomized to treatment with clascoterone cream, 1%, or vehicle cream and applied approximately 1 g to the whole face twice daily for 12 weeks., Main Outcomes and Measures: Treatment success was defined as an Investigator's Global Assessment score of 0 (clear) or 1 (almost clear), and a 2-grade or greater improvement from baseline and absolute change from baseline in noninflammatory and inflammatory lesion counts at week 12. Safety measures included adverse event frequency and severity., Results: A total of 1440 patients were randomzied in 2 studies. In CB-03-01/25, 353 participants were randomized to treatment with clascoterone cream, 1% (median [range] age, 18.0 [10-58] years; 221 [62.6%] female), and 355 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [9-50] years; 215 (60.6%) female); in CB-03-01/26, 369 participants were randomized to treatment with clascoterone cream, 1% (median [range] age, 18.0 [10-50] years; 243 [65.9%] female), and 363 participants were randomized to treatment with vehicle cream (median [range] age, 18.0 [range, 11-42] years; 221 [60.9%] female). At week 12, treatment success rates in CB-03-01/25 and CB-03-01/26 with clascoterone cream, 1%, were 18.4% (point estimate, 2.3; 95% CI, 1.4-3.8; P < .001) and 20.3% (point estimate, 3.7; 95% CI, 2.2-6.3; P < .001) vs 9.0% and 6.5% with vehicle, respectively. At week 12, in both CB-03-01/25 and CB-03-01/26, treatment with clascoterone cream, 1%, resulted in a significant reduction in absolute noninflammatory lesions from baseline to -19.4 (point estimate difference, -6.4; 95% CI, -10.3 to -2.6; P < .001) and -19.4 (point estimate difference, -8.6; 95% CI, -12.3 to -4.9; P < .001) vs -13.0 and -10.8 with vehicle, respectively, as well as a reduction in inflammatory lesions from baseline to -19.3 (point estimate difference, -3.8; 95% CI, -6.4 to -1.3; P < .001) and -20.0 (point estimate difference, -7.4; 95% CI, -9.8 to -5.1; P < .001) vs -15.5 and -12.6 with vehicle, respectively. Adverse events rates were low and mostly mild; the predominant local skin reaction was trace or mild erythema., Conclusions and Relevance: Use of clascoterone cream, 1%, for acne treatment appears to demonstrate favorable efficacy and safety with low adverse event rates., Trial Registration: ClinicalTrials.gov Identifiers: NCT02608450 and NCT02608476.

Of the four primary pathogenic factors that drive acne vulgaris&mdash;androgen excess, increased sebum production, faulty keratinization, and overgrowth of C. acnes&mdash;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.

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 plasma—PK 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.

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.

Purpose: The efficacy and toxicity of triamcinolone acetonide and other lipid formulae--calcium palmitate, cholesterol and 11-deoxycortisol--in the visualization of the prolapsed vitreous body in the anterior chamber after posterior capsule rupture were investigated in animal models., Methods: In porcine eyes, a suspension of calcium palmitate, cholesterol, triamcinolone acetonide and 11-deoxycortisol was injected into the anterior chamber after intentionally creating posterior capsule rupture. Following gentle irrigation and aspiration, the vitreous body prolapsed in the anterior chamber was removed using an anterior vitrectomy cutter. In phakic rabbit eyes, the side-effects of the reagents were assessed for biomicroscopic appearance, intraocular pressure (IOP) and corneal histology., Results: The suspension of calcium palmitate, cholesterol, triamcinolone acetonide and 11-deoxycortisol was effective in the visualization of the vitreous body prolapsed in the anterior chamber after posterior capsule rupture. When cholesterol and calcium palmitate were injected into the anterior chamber, they remained there; this induced a significant increase in IOP and corneal oedema. In contrast, most of the triamcinolone acetonide and 11-deoxycortisol that was injected into the anterior chamber had disappeared a day after the injection without affecting IOP or corneal endothelial density. When injected into the intravitreous cavity, triamcinolone led to a significant increase in IOP 2 and 4 weeks after the injection. However, calcium palmitate, cholesterol and 11-deoxycortisol injected into the vitreous cavity had no effect on IOP at 4 weeks., Conclusion: The suspension of triamcinolone acetonide and 11-deoxycortisol was effective in visualizing the vitreous body prolapsed in the anterior chamber after posterior capsule rupture. However, the amount of the reagent must be kept to a minimum to prevent the potential risk of ocular toxicities and postoperative late-onset ocular hypertension.

Behavioral, biochemical, and electrophysiological studies suggest that the trihydroxylated progestin steroid, 4-pregnen-17,20beta,21-triol-3-one (20beta-S) stimulates oocyte maturation and pheromone release in the Eurasian ruffe, a freshwater percid fish. Behavioral observations found that female ruffe undergoing oocyte maturation (OM) release a pheromonal cue that stimulates swimming activity and social interactions among conspecific males. Neither vitellogenic nor ovulated females released the cue. Pheromone production was directly associated with elevated plasma levels of 20beta-S in maturing female ruffe which in vitro incubation suggested to be a possible maturation-inducing hormone (MIH) in this species along with 4-pregnen-17,20beta-diol-3-one (17,20betaP). However, neither of these steroids appear to be the pheromone because electrophysiological and behavioral studies found them to lack olfactory (EOG) and behavioral activity. Instead, studies of the odor of steroid-injected fish suggest the pheromone is a metabolite of 20beta-S. In particular, inter-peritoneal injection of 20beta-S (but not 17,20betaP) consistently induced release of a urinary cue with strong behavioral activity. The pheromone may be a highly polar and novel metabolite because it could not be extracted using octadecylsilane resin (C18) which has proven effective for other teleost hormonal pheromones.

Few data are available on the reliability of measurements of adrenocortical and corticotroph hormones for use in clinical pharmacology. Two placebo controlled cross-over trials in 20 normal healthy male subjects offered the opportunity to perform three repeat samplings of adrenocortical and corticotroph hormones at 1 to 5 week intervals during the placebo periods. Measurements of baseline levels of plasma, salivary and urinary cortisol, plasma adrenocorticotroph hormone (ACTH), lipotrophic hormone (LPH), beta-endorphin, post tetracosactrin levels of plasma and salivary cortisol, post corticotrophin releasing hormone (CRH)-lysine vasopressine (LVP) levels of plasma cortisol, ACTH and LPH; and post metyrapone levels of plasma cortisol and 11-deoxycortisol (compound S), ACTH, LPH, beta-endorphin were performed in the same laboratory. The reliability of the measurements was estimated by computing the intraclass correlation coefficient (R) and by using Altman-Bland graphical method. The Rs of baseline parameters varied from 0.18 (for 08.00 h salivary cortisol) to 0.55 (for 08.00 h plasma cortisol and nocturnal urinary cortisol). In contrast, parameters obtained after direct stimulation or inhibition of the producing targets were much more reliable: Rs were above 0.80 for post tetracosactrin levels of plasma and salivary cortisol, post CRH-LVP levels of plasma ACTH and LPH. The Rs were below 0.50 for post metyrapone levels of plasma 11-deoxycortisol, ACTH, LPH and beta-endorphin. The interval between sampling did not affect R estimates. These data show that peak levels of plasma cortisol and ACTH after direct stimulation are highly reliable whereas baseline and main post-metyrapone levels are not.(ABSTRACT TRUNCATED AT 250 WORDS)

The localization in the mouse brain of corticosterone, the natural glucocorticoid in the mouse, and cortexolone, reported to be a glucocorticoid antagonist, was studied by autoradiography 30 min after in vivo administration of the tritiated compounds. After 3H-corticosterone (3HB) injection, radioactivity was preferentially concentrated in cell nuclei of several structures within the limbic system, and in nuclei of certain neurones of the cerebral cortex and medullar oblongata. This nuclear concentration was abolished after injection of 3H-corticosterone with an excess of unlabelled corticosterone. After 3H-cortexolone (3HS) injection, a diffuse radioactivity was observed throughout the brain. However, a higher concentration of grains was present in the ventral nucleus arcuatus and in the infundibulum. When excess unlabelled cortexolone was administered with 3H-cortexolone this preferential accumulation of grains was abolished. The accumulation of 3H-cortexolone in the medial basal hypothalamic region suggests that cortexolone concentrates preferentially in dexamethasone (DM) target regions, and in addition the autoradiographic results show that the cortexolone-receptor complex does not accumulate in the cell nucleus.

It has been shown that glucocorticoid receptor antagonist-cortexolone--increased anxiolytic action of diazepam in alcoholic rats. Neither diazepam (2 mg/kg), nor cortexolone (20 mg/kg) alone influenced voluntary ethanol consumption in alcoholic rats during 14 days of administration, however, combined administration of diazepam and cortexolone diminished ethanol consumption. Receptor and permissive mechanism of gluco- and antiglucocorticoid effect on the action of diazepam are being discussed.