Clascoterone Is a Novel Androgen Receptor Antagonist That Inhibits Production of Lipids and Inflammatory Cytokines From Sebocytes in Vitro

Journal of Drugs in Dermatology

TAKE-HOME MESSAGE

• In this in vitro study, cortexolone 17α-propionate (clascoterone) bound to androgen receptors with high affinity, antagonized testosterone-stimulated transcription activity, and inhibited DHT-induced lipid synthesis and inflammatory cytokine pathways in human sebocytes.

• Clascoterone demonstrated strong potential for becoming the first topical anti-androgen in the treatment of acne. Large phase III clinical trials, which are ongoing, may determine its potency in acne therapy.

– Caroline K. Crabtree, MD

Written by

 

 

Jerry K. L. Tan MD, FRCPC

The Advent of a Novel, Topical Acne Therapy Based on Sebocyte Inhibition, Clascoterone

Of the primary pathogenic factors in acne, namely follicular hyperkeratinization, inflammation, Cutibacterium acnes proliferation, and sebum hyperexcretion, topical therapies are available for all except the latter. This paper describes the in vitro effect of an androgen receptor antagonist, clascoterone, in inhibiting testosterone-stimulated production of pro-inflammatory mediators and lipids from human sebocytes.

Although the mechanism of action of drugs in dermatology is important, of primary relevance to patients and clinicians is the question—can it work and if so, how well? The recent history of topical acne drug development has been punctuated by excitement and innovation but fraught with challenges and failure in pivotal trials (eg, olumacostat glasaretil). This has not been the case for clascoterone. Can it work? Two phase III randomized controlled trials of clascoterone 1% cream (Winlevi® 1% cream, Cassiopea) vs vehicle involving just over 1400 patients with moderate to severe acne were completed in 2018. Both trials achieved primary and secondary endpoints of superiority vs vehicle in investigator global assessments (achievement of clear or almost clear and 2 grade reduction) and in reduction of inflammatory and comedonal acne lesion counts at 12 weeks of therapy, with tolerability and safety similar to vehicle.

The advent of a novel, topical agent based on sebocyte inhibition, a mechanism of action not previously addressed by topical acne medications, is finally here. How well does it work? The answer lays in future comparative clinical trials and clinical experience.

Abstract 

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.

Journal of Drugs in Dermatology

Cortexolone 17α-Propionate (Clascoterone) Is a Novel Androgen Receptor Antagonist That Inhibits Production of Lipids and Inflammatory Cytokines From Sebocytes In Vitro

J Drugs Dermatol 2019 May 01;18(5)412-418, C Rosette, FJ Agan, A Mazzetti, L Moro, M Gerloni 

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

Clinica Victoria en San Pedro: 4000-1054
Momentum Escazu: 2101-9574

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