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Androgen Receptor Inhibitors in the Treatment of Acne Vulgaris: Efficacy and Safety Profiles of Clascoterone 1% Cream (2022)
Carol Sanchez, Jonette Keri
Abstract
The purpose of this narrative review is to provide a summary of the clinical trials on the efficacy and safety of clascoterone 1% cream (Winlevi) to grant providers an understanding of which patients will benefit most from this novel topical antiandrogen medication. Clascoterone 1% cream (Winlevi) offers a new and exciting treatment approach for a difficult and common skin condition such as acne vulgaris. This topical androgen antagonist is the first of its kind but will hopefully provoke investigations into other androgen receptor antagonists with similar or better efficacy.
Introduction
Acne vulgaris is an inflammatory skin condition that typically affects teens and adolescents, although it can expand to affect other age groups.1 There are several pathophysiologic pathways in the emergence of acne vulgaris. These pathways involve follicular hyperkeratinization, overactive sebaceous glands, Cutibacterium acnes colonization, and inflammation. Therefore, the role of current acne treatments is to target these specific pathogenic factors.
Anti-androgen medications target overactive sebaceous glands, leading to a reduction in sebum secretion rate.2 Physicians have long been using hormonal agents with anti-androgen effects to treat acne vulgaris. The most commonly prescribed medications are combined oral contraceptives (COCs) and spironolactone. COCs were first introduced in the 1960s for contraceptive use. It was not until 1997 that the first COC, Ortho Tri-cyclen, was approved for acne vulgaris.3 Since then, there have been three more COCs approved by the FDA. These include Estrostep (approved in 2001), Yaz (approved in 2007), and Beyaz (approved in 2010).3 The estrogen in the FDA-approved medications is Ethinyl estradiol. Progestins in the formulations for COCs approved for acne differ but include norgestimate, norethindrone acetate, and drospirenone.3 COCs alter acne lesions through disparate pathways. The anti-androgenic effect of COCs is mainly through estrogen’s testosterone synthesis inhibition mechanism.4 However, progestins in birth control also have a function in anti-androgenic effects through antagonistic mechanisms.4 First, COCs, primarily through estrogen, increase the levels of sex-hormone binding globulin, which leads to a decrease in free testosterone available for receptors. Simultaneously, luteinizing hormone inhibition leads to decreased production of testosterone.5 In addition, COCs inhibit the enzyme 5-alpha-reductase, which is responsible for the conversion of testosterone into dihydrotestosterone (DHT). COCs have also been proposed to block testosterone and DHT binding to their corresponding receptors, thus limiting their androgenetic effects on the skin.6
There has been a wide range of clinical trials to assess the efficacy of COCs for acne. Most of these trials showed evidence of reduced acne lesion count in patients on COCs. In trials in which acne lesion count was not reduced, researchers still established an effect on sebum production. COCs were associated with a significant reduction in sebum production in the face.4 Despite significant efficacy in treating acne, COCs carry a more extensive side effect profile than topical therapies. For instance, although infrequent, COCs confer a cardiovascular risk, especially in patients with higher baseline risk. This cardiovascular risk increases with the length of contraceptive use.4 Another uncommon risk to acknowledge when counseling patients for treatment is cancer risk, specifically breast cancer, which remains controversial.4 More commonly, patients report headaches, menstrual irregularities, and mood lability after initiation of COCs.7
Apart from COCs, spironolactone is a different therapeutic agent used for its anti-androgenic properties. However, it has not received United States Food and Drug Administration (FDA) approval for acne and thus is used off-label. According to the American Academy of Dermatology (AAD), it is considered an alternative treatment in all cases of acne vulgaris from mild to severe.8 Dating back to the 1980s, prospective studies on oral spironolactone have shown statistically significant efficacy against acne vulgaris in women.8–11 Although studies have shown efficacy in spironolactone for acne, they have been small in sample size. A recent retrospective study of 110 patients concluded that spironolactone therapy provided patients with improvement in their acne.11 Similar to COCs, the systemic exposure of oral anti-androgens poses risks for potential side effects. Common side effects are menstrual irregularities, dizziness, breast enlargement, and nausea. Less common side effects associated with spironolactone include hyperkalemia and estrogen-sensitive cancers. However, cancer development has not been well-established in humans and instead has been shown in animal studies.8 Many of the risks conferred by hormonal agents arise from their systemic exposure. In addition, male patients do not tolerate associated gynecomastia when taking spironolactone for acne.12
On the contrary, systemic exposure can be limited through the use of topical applications. They reduce the risk for potential side effects, although they have sometimes been considered less efficacious in more severe cases of acne vulgaris.13
Topical spironolactone has been postulated for use in acne vulgaris. In one small single-blinded study, topical spironolactone 2% solution was shown to significantly reduce comedones count compared to no effect on comedones by clindamycin.14 Additionally, compared to clindamycin, the topical application of spironolactone resulted in a more significant reduction in patients’ Acne Severity Index (ASI). Similar results have been achieved in other clinical trials.15,16
Another way to target the increased levels of DHT in acne pathogenesis is through inhibition of 5-alpha-reductase, the enzyme responsible for peripherally converting testosterone to DHT.16 Finasteride is a 5-alpha-reductase inhibitor that is mainly used in benign prostatic hyperplasia (BPH) and male pattern hair loss. However, there have been studies examining its use for acne vulgaris. For example, in one clinical trial done on hyperandrogenic women with moderate-severe acne, finasteride was beneficial for decreasing Cook Score (an acne severity index that uses photographs to document acne severity and is scored from 0–8), although less beneficial than other anti-androgens such as flutamide.17 In a more recent prospective study, the efficacy of finasteride was compared to montelukast for moderate acne in women. The study results showed that finasteride is more efficacious in treating moderate acne than montelukast. Specifically, at the end of the study period (12 weeks), 88% of patients on finasteride had near-total clarity of their acne compared to 76% of patients in the montelukast group. For patient satisfaction, the finasteride group reported 80% satisfaction at the end of the 12 weeks, whereas the montelukast group had a 66.7% satisfaction rate.16
A novel topical antiandrogens for use in acne vulgaris is Cortexolone 17α-propionate (Clascoterone or CB-03-01). Clascoterone 1% cream (Winlevi) is a steroidal topical androgen receptor inhibitor hypothesized to work through competitive inhibition of DHT receptors within the sebaceous glands and hair follicles.7,15 The structure of clascoterone resembles other hormonal agents used for acne vulgaris (Figure 1). The primary metabolite of clascoterone is cortexolone or 11-deoxycortisol, an inactive form.18 In regards to excretion, clascoterone is hypothesized to be hydrolyzed in the skin’s epidermis upon topical application. During in vitro studies, clascoterone 1% cream (Winlevi) was significantly more efficacious in inhibiting inflammatory cytokine production from sebocytes than spironolactone.1 Clascoterone 1% cream (Winlevi) was approved for male and female patients, 12 years and older, by the United States FDA on August 27, 2020.7,15 This novel treatment provides physicians with more options when treating such common skin conditions such as acne. It gives practitioners an anti-androgen treatment, which can be used in males without systemic side effects. Notably, there are no human studies on clascoterone 1% cream (Winlevi) use during pregnancy and breastfeeding.
However, animal studies conducted on rats showed organ malformations when subcutaneous doses of 8 to 39 times the recommended dose for humans were used.19
*With more options in acne treatment, it is imperative that prescribing physicians understand the populations and outcomes in which this drug was studied. Therefore, the objective of this narrative review is to provide a summary of the clinical trials on the efficacy and safety of clascoterone 1% cream (Winlevi) to grant providers an understanding of which patients will benefit most from this novel topical anti-androgen medication.
*Experimental Studies
*Clinical Trials
Conclusion
In conclusion, clascoterone 1% cream (Winlevi) offers a new and exciting treatment approach for a difficult and common skin condition such as acne vulgaris. Not only do clinical trials show efficacy for a reduction in total acne lesion counts, but it also has a significantly tolerable safety profile even at nine months of treatment. At this time, this topical androgen antagonist is the first of its kind but will hopefully provoke investigations into other androgen receptor antagonists with similar or better efficacy.
Carol Sanchez, Jonette Keri
Abstract
The purpose of this narrative review is to provide a summary of the clinical trials on the efficacy and safety of clascoterone 1% cream (Winlevi) to grant providers an understanding of which patients will benefit most from this novel topical antiandrogen medication. Clascoterone 1% cream (Winlevi) offers a new and exciting treatment approach for a difficult and common skin condition such as acne vulgaris. This topical androgen antagonist is the first of its kind but will hopefully provoke investigations into other androgen receptor antagonists with similar or better efficacy.
Introduction
Acne vulgaris is an inflammatory skin condition that typically affects teens and adolescents, although it can expand to affect other age groups.1 There are several pathophysiologic pathways in the emergence of acne vulgaris. These pathways involve follicular hyperkeratinization, overactive sebaceous glands, Cutibacterium acnes colonization, and inflammation. Therefore, the role of current acne treatments is to target these specific pathogenic factors.
Anti-androgen medications target overactive sebaceous glands, leading to a reduction in sebum secretion rate.2 Physicians have long been using hormonal agents with anti-androgen effects to treat acne vulgaris. The most commonly prescribed medications are combined oral contraceptives (COCs) and spironolactone. COCs were first introduced in the 1960s for contraceptive use. It was not until 1997 that the first COC, Ortho Tri-cyclen, was approved for acne vulgaris.3 Since then, there have been three more COCs approved by the FDA. These include Estrostep (approved in 2001), Yaz (approved in 2007), and Beyaz (approved in 2010).3 The estrogen in the FDA-approved medications is Ethinyl estradiol. Progestins in the formulations for COCs approved for acne differ but include norgestimate, norethindrone acetate, and drospirenone.3 COCs alter acne lesions through disparate pathways. The anti-androgenic effect of COCs is mainly through estrogen’s testosterone synthesis inhibition mechanism.4 However, progestins in birth control also have a function in anti-androgenic effects through antagonistic mechanisms.4 First, COCs, primarily through estrogen, increase the levels of sex-hormone binding globulin, which leads to a decrease in free testosterone available for receptors. Simultaneously, luteinizing hormone inhibition leads to decreased production of testosterone.5 In addition, COCs inhibit the enzyme 5-alpha-reductase, which is responsible for the conversion of testosterone into dihydrotestosterone (DHT). COCs have also been proposed to block testosterone and DHT binding to their corresponding receptors, thus limiting their androgenetic effects on the skin.6
There has been a wide range of clinical trials to assess the efficacy of COCs for acne. Most of these trials showed evidence of reduced acne lesion count in patients on COCs. In trials in which acne lesion count was not reduced, researchers still established an effect on sebum production. COCs were associated with a significant reduction in sebum production in the face.4 Despite significant efficacy in treating acne, COCs carry a more extensive side effect profile than topical therapies. For instance, although infrequent, COCs confer a cardiovascular risk, especially in patients with higher baseline risk. This cardiovascular risk increases with the length of contraceptive use.4 Another uncommon risk to acknowledge when counseling patients for treatment is cancer risk, specifically breast cancer, which remains controversial.4 More commonly, patients report headaches, menstrual irregularities, and mood lability after initiation of COCs.7
Apart from COCs, spironolactone is a different therapeutic agent used for its anti-androgenic properties. However, it has not received United States Food and Drug Administration (FDA) approval for acne and thus is used off-label. According to the American Academy of Dermatology (AAD), it is considered an alternative treatment in all cases of acne vulgaris from mild to severe.8 Dating back to the 1980s, prospective studies on oral spironolactone have shown statistically significant efficacy against acne vulgaris in women.8–11 Although studies have shown efficacy in spironolactone for acne, they have been small in sample size. A recent retrospective study of 110 patients concluded that spironolactone therapy provided patients with improvement in their acne.11 Similar to COCs, the systemic exposure of oral anti-androgens poses risks for potential side effects. Common side effects are menstrual irregularities, dizziness, breast enlargement, and nausea. Less common side effects associated with spironolactone include hyperkalemia and estrogen-sensitive cancers. However, cancer development has not been well-established in humans and instead has been shown in animal studies.8 Many of the risks conferred by hormonal agents arise from their systemic exposure. In addition, male patients do not tolerate associated gynecomastia when taking spironolactone for acne.12
On the contrary, systemic exposure can be limited through the use of topical applications. They reduce the risk for potential side effects, although they have sometimes been considered less efficacious in more severe cases of acne vulgaris.13
Topical spironolactone has been postulated for use in acne vulgaris. In one small single-blinded study, topical spironolactone 2% solution was shown to significantly reduce comedones count compared to no effect on comedones by clindamycin.14 Additionally, compared to clindamycin, the topical application of spironolactone resulted in a more significant reduction in patients’ Acne Severity Index (ASI). Similar results have been achieved in other clinical trials.15,16
Another way to target the increased levels of DHT in acne pathogenesis is through inhibition of 5-alpha-reductase, the enzyme responsible for peripherally converting testosterone to DHT.16 Finasteride is a 5-alpha-reductase inhibitor that is mainly used in benign prostatic hyperplasia (BPH) and male pattern hair loss. However, there have been studies examining its use for acne vulgaris. For example, in one clinical trial done on hyperandrogenic women with moderate-severe acne, finasteride was beneficial for decreasing Cook Score (an acne severity index that uses photographs to document acne severity and is scored from 0–8), although less beneficial than other anti-androgens such as flutamide.17 In a more recent prospective study, the efficacy of finasteride was compared to montelukast for moderate acne in women. The study results showed that finasteride is more efficacious in treating moderate acne than montelukast. Specifically, at the end of the study period (12 weeks), 88% of patients on finasteride had near-total clarity of their acne compared to 76% of patients in the montelukast group. For patient satisfaction, the finasteride group reported 80% satisfaction at the end of the 12 weeks, whereas the montelukast group had a 66.7% satisfaction rate.16
A novel topical antiandrogens for use in acne vulgaris is Cortexolone 17α-propionate (Clascoterone or CB-03-01). Clascoterone 1% cream (Winlevi) is a steroidal topical androgen receptor inhibitor hypothesized to work through competitive inhibition of DHT receptors within the sebaceous glands and hair follicles.7,15 The structure of clascoterone resembles other hormonal agents used for acne vulgaris (Figure 1). The primary metabolite of clascoterone is cortexolone or 11-deoxycortisol, an inactive form.18 In regards to excretion, clascoterone is hypothesized to be hydrolyzed in the skin’s epidermis upon topical application. During in vitro studies, clascoterone 1% cream (Winlevi) was significantly more efficacious in inhibiting inflammatory cytokine production from sebocytes than spironolactone.1 Clascoterone 1% cream (Winlevi) was approved for male and female patients, 12 years and older, by the United States FDA on August 27, 2020.7,15 This novel treatment provides physicians with more options when treating such common skin conditions such as acne. It gives practitioners an anti-androgen treatment, which can be used in males without systemic side effects. Notably, there are no human studies on clascoterone 1% cream (Winlevi) use during pregnancy and breastfeeding.
However, animal studies conducted on rats showed organ malformations when subcutaneous doses of 8 to 39 times the recommended dose for humans were used.19
*With more options in acne treatment, it is imperative that prescribing physicians understand the populations and outcomes in which this drug was studied. Therefore, the objective of this narrative review is to provide a summary of the clinical trials on the efficacy and safety of clascoterone 1% cream (Winlevi) to grant providers an understanding of which patients will benefit most from this novel topical anti-androgen medication.
*Experimental Studies
*Clinical Trials
Conclusion
In conclusion, clascoterone 1% cream (Winlevi) offers a new and exciting treatment approach for a difficult and common skin condition such as acne vulgaris. Not only do clinical trials show efficacy for a reduction in total acne lesion counts, but it also has a significantly tolerable safety profile even at nine months of treatment. At this time, this topical androgen antagonist is the first of its kind but will hopefully provoke investigations into other androgen receptor antagonists with similar or better efficacy.
