New Developments in the Treatment of Acne Vulgaris

A paradigm shift in our understanding of acne over the last few years has allowed dermatologists to recognize this common skin condition as a fundamentally inflammatory disease. At the same time, we have been confronting the problem of antibiotic resistance and responding to the need to reduce dependence on systemic antibiotics for disease treatment. Though these developments have had major implications for patient care,¹ the pace of drug development for acne had been somewhat slow.

A new crop of drugs, either recently approved or currently in development, could provide worthwhile new treatment options for patients with acne. In addition to addressing the underlying inflammation of acne vulgaris, these novel drugs also support current guidelines of care for acne, which call for efforts to minimize the risk of developing antibiotic resistance.¹

Sarecycline

In October 2018, the FDA granted approval of sarecycline (Seysara), an oral medication indicated for patients with nonnodular moderate to severe acne. This novel tetracycline has a narrower spectrum of activity compared with other tetracyclines, and it also has reduced activity against enteric gram negative bacteria.² It is worthwhile to note that sarecycline is the first antibiotic approved only for a dermatologic indication in four decades.

Data from phase 3 clinical trials showed that sarecycline provided significant reductions in both inflammatory and noninflammatory lesions. At week 12, Investigator Global Assessment (IGA) success (≥2-point reduction in IGA and score Clear [0] or Almost Clear [1]) rates were 21.9% and 22.6% for active treatment, respectively, vs 10.5% and 15.3%, respectively, for controls.³ 

Topical Minocycline

There has long been interest in reducing dependence on oral minocycline, the most common antibiotic prescribed for acne treatment.⁴ Formulation of minocycline for topical application historically has proven difficult, even though it would be expected to offer optimum therapeutic benefit with fewer systemic effects. Amzeeq, a topical minocycline foam, represents a potential breakthrough in topical minocycline delivery. The FDA approved this innovative therapy in October 2019, making it the first topical minocycline to receive approval for any condition.⁵ It is expected to come to market in January 2020.

With application of topical minocycline, systemic minocycline exposure has been shown to be 730 to 765 times lower than with oral minocycline administration.⁶ There was no evidence of minocycline accumulation over 21 days of topical application. Topical minocycline foam 4% appears to be safe and well tolerated, with no serious treatment-emergent adverse events (TEAEs), treatment-related TEAEs, or TEAEs that led to treatment discontinuation.⁶

In the 12-week, phase 3, randomized studies of topical minocycline vs foam vehicle for acne, active treatment was associated with a significantly greater reduction in both inflammatory and noninflammatory lesions.⁷

In a recent phase 3 study,⁸ patients (n=1507) with moderate to severe acne vulgaris were randomized 1:1 to once-daily minocycline foam 4% or foam vehicle for 12 weeks. Patients receiving active treatment had statistically significantly greater absolute reductions in inflammatory and noninflammatory lesions from baseline (-16.93 and -18.80 vs -13.40 and -15.89, respectively). Of the study patients, 30.8% of those receiving the experimental treatment achieved IGA treatment success at week 12, compared with only 19.63% of those receiving vehicle.⁸

It is worth noting that a similar 1.5% minocycline foam formulation has shown benefit in trials for rosacea. In two phase 3 trials, active treatment was associated with statistically significant reductions in counts of inflammatory lesions of rosacea and significantly higher rates of IGA treatment success compared with vehicle foam.⁹

Overall, topical foam delivery represents a potentially useful option for the management of acne. Lesions are common on the face, where patients may prefer to apply a foam that leaves no residue or “heavy” feel on the skin. Those who wish to apply sunscreen and/or make-up over top of their medication may find it easy to do so after the foam “melts” into the skin. Additionally, a foam vehicle may be preferred over creams for application to large body areas, such as the chest or back. Since these areas may be hair-bearing, the foam may be particularly suited to use here.

Clascoterone

Cassiopea recently submitted a new drug application to the FDA for clascoterone cream 1%. Because of its role as an androgen inhibitor, it is hypothesized that clascoterone displaces androgen hormones from the androgen receptors located at the sebaceous gland and hair follicle. This action interrupts the cycle of physiologic events leading to acne formation. Since clascoterone is applied topically and acts locally on androgen receptors in the skin, there is no systemic exposure.

Topical clascoterone met its primary endpoints in two phase 3 trials, achieving statistically significantly greater rates of IGA treatment success at week 12.¹⁰ Of note, these study populations included both men and nonpregnant women, as young as 9 years of age, who had baseline IGA scores of 3 (moderate) or 4 (severe). In the two studies, active arms achieved 18.8% and 20.8% IGA success, respectively, in contrast to just 8.9% and 6.5%, respectively, for the vehicle arms. Further, both inflammatory and noninflammatory lesion count reductions were also statistically significant compared to vehicle at week 12. Similarly, low rates of TEAEs were reported in the active and vehicle arms of both studies. 

More to Come

Deeper in the pipeline is a topical cannabidiol (CBD) formulation for the management of acne vulgaris. In early phase testing, a topical gel formulation of CBD has been shown to be well tolerated in patients with moderate to severe acne.¹¹ CBD is distinct from tetrahydrocannabinol, the high-inducing compound in marijuana; the former has no psychotropic effects. 

 Vehicle innovations continue to provide better and more effective delivery of existing drugs or provide opportunities to deliver new compounds to the skin. If approved like topical minocycline foam, topical clascoterone will offer new options in the management of acne. 

The approval of sarecycline as the first new chemical entity approved for acne in several years has been welcome by dermatologists and may prove to be just the first in a series of new approvals for acne over the next several years. 

Clearly, acne remains an area ripe for innovation.

Dr Kircik is a clinical associate professor of dermatology at the Icahn School of Medicine at Mount Sinai in New York, NY, and at Indiana University Medical Center in Indianapolis. He is also the medical director of Physicians Skin Care, PLLC; DermResearch, PLLC; and Skin Sciences, PLLC, in Louisville, KY.

Disclosure: Dr Kircik has served as either an investigator, advisor, consultant, or speaker for Almirall, Botanix, Cassiopea, Foamix, Galderma, and MaynePharma.

References

1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-73.e33. doi:10.1016/j.jaad.2015.12.037

2. Leyden JJ, Sniukiene V, Berk DR, Kaoukohv A. Efficacy and safety of sarecycline, a novel, once-daily, narrow spectrum antibiotic for the treatment of moderate to severe facial acne vulgaris: results of a phase 2, dose-ranging study. J Drugs Dermatol. 2018;17(3):333-338.

3. Moore A, Green LJ, Bruce S, et al. Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris: results from two identically designed, phase 3, randomized, double-blind clinical trials. J Drugs Dermatol. 2018;17(9):987-996.

4. Lee YH, Liu G, Thiboutot DM, Leslie DL, Kirby JS. A retrospective analysis of the duration of oral antibiotic therapy for the treatment of acne among adolescents: investigating practice gaps and potential cost-savings. J Am Acad Dematol. 2014;71(1):70-76. doi:10.1016/j.jaad.2014.02.031

5. Foamix receives FDA approval of AMZEEQ™ topical minocycline treatment for millions of moderate to severe acne sufferers [news release]. Bridgewater, NJ: Foamix Pharmaceuticals Ltd; October 18, 2019. https://www.prnewswire.com/news-releases/foamix-receives-fda-approval-of-amzeeq-topical-minocycline-treatment-for-millions-of-moderate-to-severe-acne-sufferers-300941412.html. Accessed October 28, 2019.

6. Jones TM, Ellman H, deVries T. Pharmacokinetic comparison of once-daily topical minocycline foam 4% vs oral minocycline for moderate-to-severe acne. J Drugs Dermatol. 2017;16(10):1022-1028. 

7. Gold LS, Dhawan S, Weiss J, Draelos ZD, Ellman H, Stuart IA. A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: results of 2 randomized, double-blind, phase 3 studies. J Am Acad Dermatol. 2019;80(1):168-177. doi:10.1016/j.jaad.2018.08.020

8. Raoof TJ, Hooper D, Moore A, et al. Efficacy and safety of a novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: a phase 3 study [published online June 1, 2019]. J Am Acad Dermatol. 2019. doi:10.1016/j.jaad.2019.05.078

9. Gold LS, Del Rosso JQ, Bhatia ND, et al. Efficacy and safety of FMX103 (1.5% minocycline foam) in the treatment of moderate to severe papulopustular rosacea: results from two phase 3 randomized, multicenter, double blind, vehicle controlled studies. SKIN J Cutan Med. 2019;3(2):161. doi:10.25251/skin.3.2.1

10. Hebert A. Clascoterone topical cream, 1%: a novel, topical, local, selective androgen receptor antagonist: results from two phase 3 studies treating children and adult patients with facial acne vulgaris. Presented at: 2019 American Academy of Dermatology Annual Meeting; March 2, 2019; Washington, DC. 

11. Spleman L, Sinclair R, Freeman M, et al. The safety of topical cannabidiol (CBD) for the treatment of acne. J Invest Dermatol. 2018;138(5 suppl):S180. doi:10.1016/j.jid.2018.03.1074

A paradigm shift in our understanding of acne over the last few years has allowed dermatologists to recognize this common skin condition as a fundamentally inflammatory disease. At the same time, we have been confronting the problem of antibiotic resistance and responding to the need to reduce dependence on systemic antibiotics for disease treatment. Though these developments have had major implications for patient care,¹ the pace of drug development for acne had been somewhat slow.

A new crop of drugs, either recently approved or currently in development, could provide worthwhile new treatment options for patients with acne. In addition to addressing the underlying inflammation of acne vulgaris, these novel drugs also support current guidelines of care for acne, which call for efforts to minimize the risk of developing antibiotic resistance.¹

Sarecycline

In October 2018, the FDA granted approval of sarecycline (Seysara), an oral medication indicated for patients with nonnodular moderate to severe acne. This novel tetracycline has a narrower spectrum of activity compared with other tetracyclines, and it also has reduced activity against enteric gram negative bacteria.² It is worthwhile to note that sarecycline is the first antibiotic approved only for a dermatologic indication in four decades.

Data from phase 3 clinical trials showed that sarecycline provided significant reductions in both inflammatory and noninflammatory lesions. At week 12, Investigator Global Assessment (IGA) success (≥2-point reduction in IGA and score Clear [0] or Almost Clear [1]) rates were 21.9% and 22.6% for active treatment, respectively, vs 10.5% and 15.3%, respectively, for controls.³ 

Topical Minocycline

There has long been interest in reducing dependence on oral minocycline, the most common antibiotic prescribed for acne treatment.⁴ Formulation of minocycline for topical application historically has proven difficult, even though it would be expected to offer optimum therapeutic benefit with fewer systemic effects. Amzeeq, a topical minocycline foam, represents a potential breakthrough in topical minocycline delivery. The FDA approved this innovative therapy in October 2019, making it the first topical minocycline to receive approval for any condition.⁵ It is expected to come to market in January 2020.

With application of topical minocycline, systemic minocycline exposure has been shown to be 730 to 765 times lower than with oral minocycline administration.⁶ There was no evidence of minocycline accumulation over 21 days of topical application. Topical minocycline foam 4% appears to be safe and well tolerated, with no serious treatment-emergent adverse events (TEAEs), treatment-related TEAEs, or TEAEs that led to treatment discontinuation.⁶

In the 12-week, phase 3, randomized studies of topical minocycline vs foam vehicle for acne, active treatment was associated with a significantly greater reduction in both inflammatory and noninflammatory lesions.⁷

In a recent phase 3 study,⁸ patients (n=1507) with moderate to severe acne vulgaris were randomized 1:1 to once-daily minocycline foam 4% or foam vehicle for 12 weeks. Patients receiving active treatment had statistically significantly greater absolute reductions in inflammatory and noninflammatory lesions from baseline (-16.93 and -18.80 vs -13.40 and -15.89, respectively). Of the study patients, 30.8% of those receiving the experimental treatment achieved IGA treatment success at week 12, compared with only 19.63% of those receiving vehicle.⁸

It is worth noting that a similar 1.5% minocycline foam formulation has shown benefit in trials for rosacea. In two phase 3 trials, active treatment was associated with statistically significant reductions in counts of inflammatory lesions of rosacea and significantly higher rates of IGA treatment success compared with vehicle foam.⁹

Overall, topical foam delivery represents a potentially useful option for the management of acne. Lesions are common on the face, where patients may prefer to apply a foam that leaves no residue or “heavy” feel on the skin. Those who wish to apply sunscreen and/or make-up over top of their medication may find it easy to do so after the foam “melts” into the skin. Additionally, a foam vehicle may be preferred over creams for application to large body areas, such as the chest or back. Since these areas may be hair-bearing, the foam may be particularly suited to use here.

Clascoterone

Cassiopea recently submitted a new drug application to the FDA for clascoterone cream 1%. Because of its role as an androgen inhibitor, it is hypothesized that clascoterone displaces androgen hormones from the androgen receptors located at the sebaceous gland and hair follicle. This action interrupts the cycle of physiologic events leading to acne formation. Since clascoterone is applied topically and acts locally on androgen receptors in the skin, there is no systemic exposure.

Topical clascoterone met its primary endpoints in two phase 3 trials, achieving statistically significantly greater rates of IGA treatment success at week 12.¹⁰ Of note, these study populations included both men and nonpregnant women, as young as 9 years of age, who had baseline IGA scores of 3 (moderate) or 4 (severe). In the two studies, active arms achieved 18.8% and 20.8% IGA success, respectively, in contrast to just 8.9% and 6.5%, respectively, for the vehicle arms. Further, both inflammatory and noninflammatory lesion count reductions were also statistically significant compared to vehicle at week 12. Similarly, low rates of TEAEs were reported in the active and vehicle arms of both studies. 

More to Come

Deeper in the pipeline is a topical cannabidiol (CBD) formulation for the management of acne vulgaris. In early phase testing, a topical gel formulation of CBD has been shown to be well tolerated in patients with moderate to severe acne.¹¹ CBD is distinct from tetrahydrocannabinol, the high-inducing compound in marijuana; the former has no psychotropic effects. 

 Vehicle innovations continue to provide better and more effective delivery of existing drugs or provide opportunities to deliver new compounds to the skin. If approved like topical minocycline foam, topical clascoterone will offer new options in the management of acne. 

The approval of sarecycline as the first new chemical entity approved for acne in several years has been welcome by dermatologists and may prove to be just the first in a series of new approvals for acne over the next several years. 

Clearly, acne remains an area ripe for innovation.

Dr Kircik is a clinical associate professor of dermatology at the Icahn School of Medicine at Mount Sinai in New York, NY, and at Indiana University Medical Center in Indianapolis. He is also the medical director of Physicians Skin Care, PLLC; DermResearch, PLLC; and Skin Sciences, PLLC, in Louisville, KY.

Disclosure: Dr Kircik has served as either an investigator, advisor, consultant, or speaker for Almirall, Botanix, Cassiopea, Foamix, Galderma, and MaynePharma.

References

1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945-73.e33. doi:10.1016/j.jaad.2015.12.037

2. Leyden JJ, Sniukiene V, Berk DR, Kaoukohv A. Efficacy and safety of sarecycline, a novel, once-daily, narrow spectrum antibiotic for the treatment of moderate to severe facial acne vulgaris: results of a phase 2, dose-ranging study. J Drugs Dermatol. 2018;17(3):333-338.

3. Moore A, Green LJ, Bruce S, et al. Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris: results from two identically designed, phase 3, randomized, double-blind clinical trials. J Drugs Dermatol. 2018;17(9):987-996.

4. Lee YH, Liu G, Thiboutot DM, Leslie DL, Kirby JS. A retrospective analysis of the duration of oral antibiotic therapy for the treatment of acne among adolescents: investigating practice gaps and potential cost-savings. J Am Acad Dematol. 2014;71(1):70-76. doi:10.1016/j.jaad.2014.02.031

5. Foamix receives FDA approval of AMZEEQ™ topical minocycline treatment for millions of moderate to severe acne sufferers [news release]. Bridgewater, NJ: Foamix Pharmaceuticals Ltd; October 18, 2019. https://www.prnewswire.com/news-releases/foamix-receives-fda-approval-of-amzeeq-topical-minocycline-treatment-for-millions-of-moderate-to-severe-acne-sufferers-300941412.html. Accessed October 28, 2019.

6. Jones TM, Ellman H, deVries T. Pharmacokinetic comparison of once-daily topical minocycline foam 4% vs oral minocycline for moderate-to-severe acne. J Drugs Dermatol. 2017;16(10):1022-1028. 

7. Gold LS, Dhawan S, Weiss J, Draelos ZD, Ellman H, Stuart IA. A novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: results of 2 randomized, double-blind, phase 3 studies. J Am Acad Dermatol. 2019;80(1):168-177. doi:10.1016/j.jaad.2018.08.020

8. Raoof TJ, Hooper D, Moore A, et al. Efficacy and safety of a novel topical minocycline foam for the treatment of moderate-to-severe acne vulgaris: a phase 3 study [published online June 1, 2019]. J Am Acad Dermatol. 2019. doi:10.1016/j.jaad.2019.05.078

9. Gold LS, Del Rosso JQ, Bhatia ND, et al. Efficacy and safety of FMX103 (1.5% minocycline foam) in the treatment of moderate to severe papulopustular rosacea: results from two phase 3 randomized, multicenter, double blind, vehicle controlled studies. SKIN J Cutan Med. 2019;3(2):161. doi:10.25251/skin.3.2.1

10. Hebert A. Clascoterone topical cream, 1%: a novel, topical, local, selective androgen receptor antagonist: results from two phase 3 studies treating children and adult patients with facial acne vulgaris. Presented at: 2019 American Academy of Dermatology Annual Meeting; March 2, 2019; Washington, DC. 

11. Spleman L, Sinclair R, Freeman M, et al. The safety of topical cannabidiol (CBD) for the treatment of acne. J Invest Dermatol. 2018;138(5 suppl):S180. doi:10.1016/j.jid.2018.03.1074