madman
Super Moderator
Abstract
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 signaling 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.
Clascoterone (Winlevi®) cream 1%: Key points
*An androgen receptor inhibitor being developed by Cassiopea for the treatment of androgen-dependent skin disorders
*Received its first approval on 26 August 2020 in the USA
*Approved for the topical treatment of acne vulgaris
Introduction
Advances in the understanding of the pathogenesis of androgen-related diseases, such as acne vulgaris and androgenetic alopecia (male pattern hair loss), have led to the development of therapies targeting the synthesis of androgens or their binding to androgen receptors [1, 2]. 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 [3], the drug is believed to compete with the androgen dihydrotestosterone (DHT) for binding to androgen receptors in the sebaceous gland and dermal papilla cells in hair follicles to attenuate signaling necessary for acne pathogenesis [4, 5]. On 26 August 2020 [6], clascoterone cream 1% received its first approval in the USA for the topical treatment of acne vulgaris in patients 12 years of age and older [3]. It is recommended that after cleaning the affected area gently, clascoterone be applied as a thin uniform layer (≈ 1 g) twice daily in the morning and evening. Clinical studies of a different formulation of clascoterone (a solution containing a higher concentration of the drug) for androgenic alopecia are underway in Germany and the USA; clascoterone cream 1% is not approved for use in androgenic alopecia.
2 Scientific
Summary
2.1 Pharmacodynamics
Clascoterone (cortexolone 17α-propionate), an ester derivative of cortexolone, is a potent antiandrogen with selective topical activity [9]. In vitro studies showed that clascoterone binds to androgen receptors with high affinity and inhibits DHT-stimulated signaling [4]. Clascoterone dose-dependently inhibited DHT-induced lipid synthesis and inflammatory cytokine production in human primary sebocytes [4]. In hair follicle dermal papilla cells, clascoterone selectively inhibited androgen receptor-regulated pathways that impede hair follicle growth, without affecting the production and secretion of pro-follicle growth factors [5].
In preclinical studies, clascoterone exhibited strong topical antiandrogenic activity but was ineffective when administered subcutaneously [9]. The absence of systemic effects traditionally associated with oral antiandrogens/androgen receptor inhibitors (e.g. feminization of males, loss of libido), may be because of the fast hydrolysis of clascoterone by the liver or other tissues, indicating that topical administration of the drug is unlikely to have systemic antiandrogenic effects. Subcutaneous clascoterone was not associated with anti-anabolic effects, suggesting that topical administration of the drug should not be associated with an increased risk of skin atrophy. When compared to other antiandrogens, topical clascoterone was four times more potent than progesterone, three times more potent than flutamide, approximately two times more effective than finasteride, and approximately as active as cyproterone acetate [9].
As clascoterone is rapidly hydrolyzed to cortexolone, its use may be associated with adrenal suppression [10]. In adults (n=20) and adolescents (n=22) with acne vulgaris administered clascoterone cream 1% twice daily (mean dose ≈ 6 g twice daily or ≈ 4 g twice daily in younger, smaller subjects) for 2 weeks in an open-label, multicentre phase 2a study evaluating the potential for hypothalamic–pituitary–adrenal (HPA) axis suppression (as well as pharmacokinetics) (NCT01831960), one adult and two adolescent patients had evidence of HPA axis suppression on day 14, as indicated by 30-min post-stimulation serum cortisol level of≤18 μ/dL [3, 11]. All patients returned to normal HPA axis function at follow-up 4 weeks after the end of treatment [3, 11]. Elevated potassium levels have been observed in 5% of clascoterone-treated patients compared with 4% of vehicle-treated patients [3]. Clascoterone cream 1% at approximately two times the systemic exposure with the maximum dose did not prolong QT interval to a clinically significant extent [3].
2.2 Pharmacokinetics
2.3 Therapeutic Trials
2.3.1 Acne Vulgaris
2.3.2 Androgenetic Alopecia
2.4 Adverse Events
2.5 Ongoing Clinical Trials
Recruitment is underway in Germany for a phase 2, randomized, double-blind, multicentre, dose-ranging study (EudraCT2019-000950-78; CB03-01-35) to evaluate the efficacy and safety of clascoterone solution (5% and 7.5% twice daily) versus minoxidil solution (2% twice daily) and vehicle for the treatment of androgenetic alopecia in females [17]. The 6-month study plans to enroll ≈ 280 female subjects aged 18–55 years with mild to moderate androgenetic alopecia; the co-primary endpoints are changed from baseline to month 6 in non-vellus TAHC, and HGA score at month 6 [17]. In July 2020, Cassiopea reported the submission of a special protocol assessment to the US FDA for a prospective phase 3 trial of clascoterone solution 7.5% for the treatment of androgenetic alopecia in males [18].
3 Current Status
On 26 Aug 2020 [6], clascoterone cream 1% received its first approval in the USA for the topical treatment of acne vulgaris in patients 12 years of age and older [3].
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 signaling 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.
Clascoterone (Winlevi®) cream 1%: Key points
*An androgen receptor inhibitor being developed by Cassiopea for the treatment of androgen-dependent skin disorders
*Received its first approval on 26 August 2020 in the USA
*Approved for the topical treatment of acne vulgaris
Introduction
Advances in the understanding of the pathogenesis of androgen-related diseases, such as acne vulgaris and androgenetic alopecia (male pattern hair loss), have led to the development of therapies targeting the synthesis of androgens or their binding to androgen receptors [1, 2]. 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 [3], the drug is believed to compete with the androgen dihydrotestosterone (DHT) for binding to androgen receptors in the sebaceous gland and dermal papilla cells in hair follicles to attenuate signaling necessary for acne pathogenesis [4, 5]. On 26 August 2020 [6], clascoterone cream 1% received its first approval in the USA for the topical treatment of acne vulgaris in patients 12 years of age and older [3]. It is recommended that after cleaning the affected area gently, clascoterone be applied as a thin uniform layer (≈ 1 g) twice daily in the morning and evening. Clinical studies of a different formulation of clascoterone (a solution containing a higher concentration of the drug) for androgenic alopecia are underway in Germany and the USA; clascoterone cream 1% is not approved for use in androgenic alopecia.
2 Scientific
Summary
2.1 Pharmacodynamics
Clascoterone (cortexolone 17α-propionate), an ester derivative of cortexolone, is a potent antiandrogen with selective topical activity [9]. In vitro studies showed that clascoterone binds to androgen receptors with high affinity and inhibits DHT-stimulated signaling [4]. Clascoterone dose-dependently inhibited DHT-induced lipid synthesis and inflammatory cytokine production in human primary sebocytes [4]. In hair follicle dermal papilla cells, clascoterone selectively inhibited androgen receptor-regulated pathways that impede hair follicle growth, without affecting the production and secretion of pro-follicle growth factors [5].
In preclinical studies, clascoterone exhibited strong topical antiandrogenic activity but was ineffective when administered subcutaneously [9]. The absence of systemic effects traditionally associated with oral antiandrogens/androgen receptor inhibitors (e.g. feminization of males, loss of libido), may be because of the fast hydrolysis of clascoterone by the liver or other tissues, indicating that topical administration of the drug is unlikely to have systemic antiandrogenic effects. Subcutaneous clascoterone was not associated with anti-anabolic effects, suggesting that topical administration of the drug should not be associated with an increased risk of skin atrophy. When compared to other antiandrogens, topical clascoterone was four times more potent than progesterone, three times more potent than flutamide, approximately two times more effective than finasteride, and approximately as active as cyproterone acetate [9].
As clascoterone is rapidly hydrolyzed to cortexolone, its use may be associated with adrenal suppression [10]. In adults (n=20) and adolescents (n=22) with acne vulgaris administered clascoterone cream 1% twice daily (mean dose ≈ 6 g twice daily or ≈ 4 g twice daily in younger, smaller subjects) for 2 weeks in an open-label, multicentre phase 2a study evaluating the potential for hypothalamic–pituitary–adrenal (HPA) axis suppression (as well as pharmacokinetics) (NCT01831960), one adult and two adolescent patients had evidence of HPA axis suppression on day 14, as indicated by 30-min post-stimulation serum cortisol level of≤18 μ/dL [3, 11]. All patients returned to normal HPA axis function at follow-up 4 weeks after the end of treatment [3, 11]. Elevated potassium levels have been observed in 5% of clascoterone-treated patients compared with 4% of vehicle-treated patients [3]. Clascoterone cream 1% at approximately two times the systemic exposure with the maximum dose did not prolong QT interval to a clinically significant extent [3].
2.2 Pharmacokinetics
2.3 Therapeutic Trials
2.3.1 Acne Vulgaris
2.3.2 Androgenetic Alopecia
2.4 Adverse Events
2.5 Ongoing Clinical Trials
Recruitment is underway in Germany for a phase 2, randomized, double-blind, multicentre, dose-ranging study (EudraCT2019-000950-78; CB03-01-35) to evaluate the efficacy and safety of clascoterone solution (5% and 7.5% twice daily) versus minoxidil solution (2% twice daily) and vehicle for the treatment of androgenetic alopecia in females [17]. The 6-month study plans to enroll ≈ 280 female subjects aged 18–55 years with mild to moderate androgenetic alopecia; the co-primary endpoints are changed from baseline to month 6 in non-vellus TAHC, and HGA score at month 6 [17]. In July 2020, Cassiopea reported the submission of a special protocol assessment to the US FDA for a prospective phase 3 trial of clascoterone solution 7.5% for the treatment of androgenetic alopecia in males [18].
3 Current Status
On 26 Aug 2020 [6], clascoterone cream 1% received its first approval in the USA for the topical treatment of acne vulgaris in patients 12 years of age and older [3].
