madman
Super Moderator
ABSTRACT
Introduction: Increased circulating androgens are key to the multifactorial pathogenesis of acne. Clascoterone is the first topical androgen antagonist developed to treat acne in both male and female patients and the first such agent to receive U.S. Food and Drug Administration (FDA) approval for the treatment of acne. Androgens directly stimulate sebaceous gland growth and increased sebum production, creating a nourishing medium in which anaerobic Cutibacterium acnes (C. acnes) bacteria flourish. Androgens may directly contribute to inflammation in the sebaceous gland.
Areas covered: In this review, the author assesses clascoterone’s potential role in the management of acne. With a 4-ring backbone identical to dihydrotestosterone (DHT) and spironolactone, topically applied clascoterone binds androgen receptors (ARs) in the sebaceous glands and hair follicles, interfering with the pathogenesis of acne and reducing acne lesions with no reported systemic effects.
Expert opinion: Phase III study results confirmed the safety and efficacy of topical clascoterone for acne, with considerable reductions in absolute non-inflammatory and inflammatory lesion counts at week 12. The approval of a first-in-class topical androgen antagonist is indeed a ‘game-changer for acne management. This topical agent is expected to be quickly adopted in clinical practice, likely within combination regimens, yet to be formally evaluated.
1. Introduction
Only relatively recently has the dermatology community come to recognize acne as primarily an inflammatory disease[1]. Evidence shows that inflammation is at the heart of the disease, with inflammatory mediators evident in the precursor lesion of acne – the microcomedo, in the papules, pustules, and open and closed comedones of active acne, and even in resolving skin lesions and scars[2]. Cutibacterium acnes (C. acnes, formerly P. acnes) is shown to activate innate immunity via the expression of protease-activated receptors (PARs), tumor necrosis factor (TNF) α and toll-like receptors (TLRs), and the production of interferon (INF) γ, interleukins (IL-8, IL12, IL1), TNF, and matrix metalloproteinases (MMPs)[2].
This emergent recognition of the inflammatory nature of acne has fundamentally changed the way that we conceptualize the disease, but it does not replace the previously understood, multifactorial framework that has for decades underpinned our concept of the pathogenesis of acne. Rather, inflammation elegantly provides a key for understanding the interplay between androgens, hyperproliferation of keratinocytes, excess sebum production, and colonization by C. acnes. Acne treatment guidelines emphasize the inflammatory nature of the disease, recommending multimodal approaches to treatment to address the multifactorial pathogenesis of the disease and its inflammatory drivers[3].
In fact, topical therapies historically have been employed that address hyperkeratinization and/or provide antibacterial effects. These have proven effective for the management of acne for many patients. We have come to recognize that these therapies also often confer some degree of anti-inflammatory benefit.
However, topical approaches aimed at the androgenetic component of acne have not been successfully developed until now. Clascoterone or cortexolone 17α-propionate is a new chemical entity with direct anti-androgen effects. Clascoterone cream 1% (Winlevi, Cassiopea Pharmaceuticals) has recently been approved by the U. S. Food and Drug Administration (FDA) for the treatment of acne in patients 12 years of age and older. Although the precise mechanism of action of topical clascoterone has not been fully elucidated, the agent is shown to compete with androgens, specifically dihydrotestosterone (DHT), for binding to the androgen receptors within the sebaceous gland and hair follicles[4] (Figures 1). In two identical Phase III randomized trials, clascoterone cream, 1% was associated with greater treatment success compared to vehicle and with considerable reductions in absolute non-inflammatory and inflammatory lesion counts at week 12[5].
2. Assessing the role of androgens in acne
Nearly 30 years ago, acne expert and therapeutic pioneer, Dr. James Leyden co-wrote a paper that elegantly summarized the pathogenesis of acne, stating that it, ‘involves abnormal follicular hyperkeratosis and obstruction of the follicle, stimulation of sebaceous gland secretion by androgens, and the proliferation of Propionibacterium acnes, which promotes inflammation.’[6] While this statement reflects the long-established belief that is still held today, our understanding of inflammatory skin disease has become exponentially more sophisticated. It is established that increased circulating androgens directly stimulate the sebaceous glands to increase sebum production, creating a nourishing medium in which anaerobic C. acnes bacteria can flourish. The temporal onset of acne during adolescence is directly correlated to this increase in circulating androgens in peripubescent and pubescent males and females. Androgens, especially DHT, which exhibits potent androgenic activity, are shown to induce both sebaceous gland growth and increased sebum production [7].
*Evidence now suggests that, beyond stimulating sebum production and thus supporting subsequent C. acnes colonization, androgens may directly contribute to inflammation in the sebaceous gland. Sebocytes express functional androgen receptors (ARs), and androgens may stimulate lipogenic differentiation by these cells; this can lead to increases in both sebum production and in pro-inflammatory cytokine production by sebocytes[11].
A recent review article provides a comprehensive overview of the functions of androgens and ARs in the skin and their roles in the pathogenesis of certain skin diseases, especially acne[12]. The author directs readers to this article for greater insight. For the sake of the current discourse, it should be noted that the AR, a soluble molecule compartmentalized in the cytoplasm and complexed with specific heat shock proteins (HSPs), is able to bind with free DHT or testosterone. With this binding, the AR disassociates from the HSP complex and the AR-ligand transports to the nucleus. Within the nucleus, the AR can then elicit signaling cascades, including immune and inflammatory processes, that produce clinical effects[12].
Early evidence suggests that the effects of androgens may even be pertinent to the yet unsettled question of dietary mediated inflammatory influence on acne. Although it has been shown that diet may influence the synthesis of proinflammatory sebaceous lipids that may induce inflammation in the skin, research also has identified cell signaling pathways that may involve an interplay of androgens, insulin, insulin-like growth factor (IGF1), and high glycemic index diet in acne[13]
3. Historical strategies targeting androgens in acne
4. Clascoterone: a novel approach
Clascoterone is the first topical androgen antagonist developed to treat acne in both male and female patients and is the first such agent to receive FDA approval for the treatment of acne. Clascoterone’s chemical structure shares a 4-ring backbone identical to DHT and spironolactone.
Importantly, topically applied clascoterone has been shown to exert androgen binding effects in the androgen receptors only at the site of application in the skin with no systemic anti-androgen effect. When topically applied clascoterone binds ARs in the sebaceous glands and hair follicles, DHT binding is inhibited[4]. In Phase I/II studies, topical clascoterone demonstrated a safety profile similar to vehicle [19,20].
5. Conclusion
The dermatology community has long recognized that increased circulating androgens are one of the four key pathogenic features of acne. Androgens directly stimulate sebaceous gland growth and increased sebum production, creating a nourishing medium in which anaerobic Cutibacterium acnes (C. acnes) bacteria can flourish. However, topical therapeutic approaches aimed at modulating androgens have been elusive.
As a result of recent FDA approval, clascoterone is the first topical androgen antagonist developed to treat acne in both men and women. Studies document efficacy, favorable safety, and good tolerability. Clinicians are interested in identifying ideal combination strategies that combine clascoterone with existing topical treatments that target other pathogenic factors in acne. Early clinical experience has been positive, and there is anticipation in the dermatology community that this new agent will become a standard option for acne management.
6. Expert opinion
Several developments have shaped the acne treatment landscape in the past few years, producing new systemic and topical treatment options for an inflammatory skin disease that affects a majority of individuals at some point in their lifetime. However, the approval of a first-in-class topical androgen antagonist is indeed a ‘game-changer for acne management.
Androgen stimulation of the sebaceous gland is shown to mediate acne in multiple ways. Androgens can directly mediate enlargement of the gland and increase sebum production; excess, lipid-rich sebum is an ideal medium for the proliferation of C. acnes. Androgens appear to directly mediate inflammation in the sebaceous glands.
Of course, the notion of hormone modulation for the management of acne is not new, and there is a lengthy history of successful direct and indirect hormonal modulation used to manage acne in women. Nonetheless, these hormonally focused therapies generally have not been considered first-line interventions for acne – even in women[22]. Systemic antiandrogens and hormonal modulation are, indeed, effective for certain women with acne, however, concerns about systemic exposure limit utility in others[23]. No hormonal modulating agent has been adopted for use in men with acne, suggesting that roughly half of all patients with acne are not candidates for such therapies
As an androgen inhibitor, clascoterone is thought to displace androgen hormones, especially DHT, from the androgen receptors located at the sebaceous gland and hair follicle, thus inhibiting the cycle of physiologic events that leads to C. acnes proliferation and local inflammation in the skin. Clascoterone is applied topically and acts locally on androgen receptors in the skin, with no systemic exposure seen. Therefore, its use would be appropriate in both males and non-pregnant females. Results of one pilot study suggest that once-daily topical clascoterone was as or more effective than topical tretinoin with better tolerability[24]. Although clascoterone is approved for use in male patients, the notion of using a hormonal modulating treatment in men is something of a novel concept, and there may be hesitant to adopt it early on.
Similarly, the notion of ‘hormone modulating’ therapy in adolescents may not be readily understood or accepted by some patients and parents who fear potential impacts on developing youth. Topical clascoterone is not shown to induce systemic effects and is thought to act locally in the skin, suggesting that such concerns are not justified. Data from two Phase III trials confirm the safety and efficacy of topical clascoterone in patients as young as 9[5]. Of note, the product is indicated for use in those as young as age 12.
It may be noted that the efficacy of clascoterone in pivotal clinical trials compare favorably to the efficacy seen with topical retinoids, a mainstay of acne treatment. A recent systematic review finds that the Investigator Global Assessments for topical retinoids range from 24.1–28.8%. When a topical retinoid is combined with benzoyl peroxide, IGA improvement ranges from 26.1–34.9% at Week 12[25]. Studies have yet to investigate the benefit of topical retinoids and/or benzoyl peroxide used in combination with clascoterone, but it is reasonable to expect that combination therapy will yield greater improvement in acne than clascoterone alone.
Although elevated androgen levels are widely implicated in acne pathogenesis, there is evidence to suggest that significant androgen excess is not present in a certain percentage of patients with acne[26]. Additionally, acne severity has not been shown to correlate directly with acne severity[27].
With recent FDA approval, clascoterone is poised to become an essential component of the topical treatment regimen for many acne patients. The proposed tube size should last about 30–45 days with BID treatment (1 gram per treatment) of the face, supporting patient convenience and adherence. As with any first-in-class drug, patient education on the action and safety of the treatment may be especially important during early adoption.
Clascoterone has not been studied in combination with other commonly used topical treatments for acne and is approved only as monotherapy. However, there is no reason to believe that the agent cannot be safely used by patients who are also using established therapies like topical antibacterials and/or retinoids. Specific regimens for sequential application of topical treatments are sure to emerge.
*Of interest, topical clascoterone is currently under investigation for the treatment of androgenetic alopecia (AGA) in men.
Introduction: Increased circulating androgens are key to the multifactorial pathogenesis of acne. Clascoterone is the first topical androgen antagonist developed to treat acne in both male and female patients and the first such agent to receive U.S. Food and Drug Administration (FDA) approval for the treatment of acne. Androgens directly stimulate sebaceous gland growth and increased sebum production, creating a nourishing medium in which anaerobic Cutibacterium acnes (C. acnes) bacteria flourish. Androgens may directly contribute to inflammation in the sebaceous gland.
Areas covered: In this review, the author assesses clascoterone’s potential role in the management of acne. With a 4-ring backbone identical to dihydrotestosterone (DHT) and spironolactone, topically applied clascoterone binds androgen receptors (ARs) in the sebaceous glands and hair follicles, interfering with the pathogenesis of acne and reducing acne lesions with no reported systemic effects.
Expert opinion: Phase III study results confirmed the safety and efficacy of topical clascoterone for acne, with considerable reductions in absolute non-inflammatory and inflammatory lesion counts at week 12. The approval of a first-in-class topical androgen antagonist is indeed a ‘game-changer for acne management. This topical agent is expected to be quickly adopted in clinical practice, likely within combination regimens, yet to be formally evaluated.
1. Introduction
Only relatively recently has the dermatology community come to recognize acne as primarily an inflammatory disease[1]. Evidence shows that inflammation is at the heart of the disease, with inflammatory mediators evident in the precursor lesion of acne – the microcomedo, in the papules, pustules, and open and closed comedones of active acne, and even in resolving skin lesions and scars[2]. Cutibacterium acnes (C. acnes, formerly P. acnes) is shown to activate innate immunity via the expression of protease-activated receptors (PARs), tumor necrosis factor (TNF) α and toll-like receptors (TLRs), and the production of interferon (INF) γ, interleukins (IL-8, IL12, IL1), TNF, and matrix metalloproteinases (MMPs)[2].
This emergent recognition of the inflammatory nature of acne has fundamentally changed the way that we conceptualize the disease, but it does not replace the previously understood, multifactorial framework that has for decades underpinned our concept of the pathogenesis of acne. Rather, inflammation elegantly provides a key for understanding the interplay between androgens, hyperproliferation of keratinocytes, excess sebum production, and colonization by C. acnes. Acne treatment guidelines emphasize the inflammatory nature of the disease, recommending multimodal approaches to treatment to address the multifactorial pathogenesis of the disease and its inflammatory drivers[3].
In fact, topical therapies historically have been employed that address hyperkeratinization and/or provide antibacterial effects. These have proven effective for the management of acne for many patients. We have come to recognize that these therapies also often confer some degree of anti-inflammatory benefit.
However, topical approaches aimed at the androgenetic component of acne have not been successfully developed until now. Clascoterone or cortexolone 17α-propionate is a new chemical entity with direct anti-androgen effects. Clascoterone cream 1% (Winlevi, Cassiopea Pharmaceuticals) has recently been approved by the U. S. Food and Drug Administration (FDA) for the treatment of acne in patients 12 years of age and older. Although the precise mechanism of action of topical clascoterone has not been fully elucidated, the agent is shown to compete with androgens, specifically dihydrotestosterone (DHT), for binding to the androgen receptors within the sebaceous gland and hair follicles[4] (Figures 1). In two identical Phase III randomized trials, clascoterone cream, 1% was associated with greater treatment success compared to vehicle and with considerable reductions in absolute non-inflammatory and inflammatory lesion counts at week 12[5].
2. Assessing the role of androgens in acne
Nearly 30 years ago, acne expert and therapeutic pioneer, Dr. James Leyden co-wrote a paper that elegantly summarized the pathogenesis of acne, stating that it, ‘involves abnormal follicular hyperkeratosis and obstruction of the follicle, stimulation of sebaceous gland secretion by androgens, and the proliferation of Propionibacterium acnes, which promotes inflammation.’[6] While this statement reflects the long-established belief that is still held today, our understanding of inflammatory skin disease has become exponentially more sophisticated. It is established that increased circulating androgens directly stimulate the sebaceous glands to increase sebum production, creating a nourishing medium in which anaerobic C. acnes bacteria can flourish. The temporal onset of acne during adolescence is directly correlated to this increase in circulating androgens in peripubescent and pubescent males and females. Androgens, especially DHT, which exhibits potent androgenic activity, are shown to induce both sebaceous gland growth and increased sebum production [7].
*Evidence now suggests that, beyond stimulating sebum production and thus supporting subsequent C. acnes colonization, androgens may directly contribute to inflammation in the sebaceous gland. Sebocytes express functional androgen receptors (ARs), and androgens may stimulate lipogenic differentiation by these cells; this can lead to increases in both sebum production and in pro-inflammatory cytokine production by sebocytes[11].
A recent review article provides a comprehensive overview of the functions of androgens and ARs in the skin and their roles in the pathogenesis of certain skin diseases, especially acne[12]. The author directs readers to this article for greater insight. For the sake of the current discourse, it should be noted that the AR, a soluble molecule compartmentalized in the cytoplasm and complexed with specific heat shock proteins (HSPs), is able to bind with free DHT or testosterone. With this binding, the AR disassociates from the HSP complex and the AR-ligand transports to the nucleus. Within the nucleus, the AR can then elicit signaling cascades, including immune and inflammatory processes, that produce clinical effects[12].
Early evidence suggests that the effects of androgens may even be pertinent to the yet unsettled question of dietary mediated inflammatory influence on acne. Although it has been shown that diet may influence the synthesis of proinflammatory sebaceous lipids that may induce inflammation in the skin, research also has identified cell signaling pathways that may involve an interplay of androgens, insulin, insulin-like growth factor (IGF1), and high glycemic index diet in acne[13]
3. Historical strategies targeting androgens in acne
4. Clascoterone: a novel approach
Clascoterone is the first topical androgen antagonist developed to treat acne in both male and female patients and is the first such agent to receive FDA approval for the treatment of acne. Clascoterone’s chemical structure shares a 4-ring backbone identical to DHT and spironolactone.
Importantly, topically applied clascoterone has been shown to exert androgen binding effects in the androgen receptors only at the site of application in the skin with no systemic anti-androgen effect. When topically applied clascoterone binds ARs in the sebaceous glands and hair follicles, DHT binding is inhibited[4]. In Phase I/II studies, topical clascoterone demonstrated a safety profile similar to vehicle [19,20].
5. Conclusion
The dermatology community has long recognized that increased circulating androgens are one of the four key pathogenic features of acne. Androgens directly stimulate sebaceous gland growth and increased sebum production, creating a nourishing medium in which anaerobic Cutibacterium acnes (C. acnes) bacteria can flourish. However, topical therapeutic approaches aimed at modulating androgens have been elusive.
As a result of recent FDA approval, clascoterone is the first topical androgen antagonist developed to treat acne in both men and women. Studies document efficacy, favorable safety, and good tolerability. Clinicians are interested in identifying ideal combination strategies that combine clascoterone with existing topical treatments that target other pathogenic factors in acne. Early clinical experience has been positive, and there is anticipation in the dermatology community that this new agent will become a standard option for acne management.
6. Expert opinion
Several developments have shaped the acne treatment landscape in the past few years, producing new systemic and topical treatment options for an inflammatory skin disease that affects a majority of individuals at some point in their lifetime. However, the approval of a first-in-class topical androgen antagonist is indeed a ‘game-changer for acne management.
Androgen stimulation of the sebaceous gland is shown to mediate acne in multiple ways. Androgens can directly mediate enlargement of the gland and increase sebum production; excess, lipid-rich sebum is an ideal medium for the proliferation of C. acnes. Androgens appear to directly mediate inflammation in the sebaceous glands.
Of course, the notion of hormone modulation for the management of acne is not new, and there is a lengthy history of successful direct and indirect hormonal modulation used to manage acne in women. Nonetheless, these hormonally focused therapies generally have not been considered first-line interventions for acne – even in women[22]. Systemic antiandrogens and hormonal modulation are, indeed, effective for certain women with acne, however, concerns about systemic exposure limit utility in others[23]. No hormonal modulating agent has been adopted for use in men with acne, suggesting that roughly half of all patients with acne are not candidates for such therapies
As an androgen inhibitor, clascoterone is thought to displace androgen hormones, especially DHT, from the androgen receptors located at the sebaceous gland and hair follicle, thus inhibiting the cycle of physiologic events that leads to C. acnes proliferation and local inflammation in the skin. Clascoterone is applied topically and acts locally on androgen receptors in the skin, with no systemic exposure seen. Therefore, its use would be appropriate in both males and non-pregnant females. Results of one pilot study suggest that once-daily topical clascoterone was as or more effective than topical tretinoin with better tolerability[24]. Although clascoterone is approved for use in male patients, the notion of using a hormonal modulating treatment in men is something of a novel concept, and there may be hesitant to adopt it early on.
Similarly, the notion of ‘hormone modulating’ therapy in adolescents may not be readily understood or accepted by some patients and parents who fear potential impacts on developing youth. Topical clascoterone is not shown to induce systemic effects and is thought to act locally in the skin, suggesting that such concerns are not justified. Data from two Phase III trials confirm the safety and efficacy of topical clascoterone in patients as young as 9[5]. Of note, the product is indicated for use in those as young as age 12.
It may be noted that the efficacy of clascoterone in pivotal clinical trials compare favorably to the efficacy seen with topical retinoids, a mainstay of acne treatment. A recent systematic review finds that the Investigator Global Assessments for topical retinoids range from 24.1–28.8%. When a topical retinoid is combined with benzoyl peroxide, IGA improvement ranges from 26.1–34.9% at Week 12[25]. Studies have yet to investigate the benefit of topical retinoids and/or benzoyl peroxide used in combination with clascoterone, but it is reasonable to expect that combination therapy will yield greater improvement in acne than clascoterone alone.
Although elevated androgen levels are widely implicated in acne pathogenesis, there is evidence to suggest that significant androgen excess is not present in a certain percentage of patients with acne[26]. Additionally, acne severity has not been shown to correlate directly with acne severity[27].
With recent FDA approval, clascoterone is poised to become an essential component of the topical treatment regimen for many acne patients. The proposed tube size should last about 30–45 days with BID treatment (1 gram per treatment) of the face, supporting patient convenience and adherence. As with any first-in-class drug, patient education on the action and safety of the treatment may be especially important during early adoption.
Clascoterone has not been studied in combination with other commonly used topical treatments for acne and is approved only as monotherapy. However, there is no reason to believe that the agent cannot be safely used by patients who are also using established therapies like topical antibacterials and/or retinoids. Specific regimens for sequential application of topical treatments are sure to emerge.
*Of interest, topical clascoterone is currently under investigation for the treatment of androgenetic alopecia (AGA) in men.
Last edited:
