Acne, the most common skin disease, affects 50 million Americans each year.1 The condition is highly visible on the face and other exposed areas and disproportionately affects people during adolescence and young adulthood, when they are developing socially and are highly image-conscious.
More than $3 billion is spent annually in the United States on acne treatment,2 much of it on therapies that are only marginally and/or temporarily effective. That spending reflects the condition’s significant physical and psychological morbidity, which includes permanent scarring, poor self-image, depression, and anxiety.3 These conditions provide significant opportunity for development of new treatments, and pharma is responding with new options that show promising potential.
In 2016, the American Academy of Dermatology (AAD) issued new guidelines for treatment of acne in adolescents and adults, endorsing the long-standing practice of combining 2 or more topical and systemic remedies.4
Existing Treatments
Here’s a look at currently prescribed treatments.
Topical Therapy
Topical therapy includes benzoyl peroxide (BP), retinoids, and—less commonly—topical antibiotics. Topical retinoids, which lack the teratogenicity of oral retinoids, are the most commonly prescribed topical acne drugs and are especially effective in treating comedonal acne. BP, used alone or in combination with other topical or oral medications, has antimicrobial, anticomedogenic, antikeratolytic, and anti-inflammatory properties.
In 2016, topical 7.5% dapsone gel (Aczone) was FDA approved to treat patients 12 and older (and for several years prior prescribed, at lower strength, exclusively to adult female patients).5 In a 12-week, double-blind study, patients using dapsone 7.5% once daily showed a more than 50% reduction in inflammatory lesions and a greater than 40% reduction in noninflammatory lesions, though much of this effect was attributed to the vehicle—a common occurrence in acne studies.6
Antibiotics
When oral antibiotics are used to treat moderate to severe acne, the AAD recommends concurrent use of topical therapy to reduce patients’ likelihood of developing antimicrobial resistance, which has become an increasing problem. Antibiotics in the tetracycline class—including minocycline and doxycycline—are the most commonly prescribed, providing anti-inflammatory properties in addition to fighting bacteria.
Isotretinoin
Oral isotretinoin, the most effective treatment for severe nodulocystic acne, inhibits sebaceous gland differentiation and sebum production. About 60% of patients given a 5-month course are permanently cured of their acne—never requiring further treatment. However, to avoid the high risk of birth defects, women must take care to prevent pregnancy while taking this drug, and patients who take isotretinoin—and all physicians who prescribe it—must enroll in iPLEDGE, a federally administered risk management program developed to eliminate fetal exposure.
In 2013, a new formulation of the drug, isotretinoin-Lidose, was introduced with the goal of reducing bioavailability differences during fed and fasted states. Less dependent on the presence of fat in the gut for absorption, isotretinoin-Lidose has high levels of absorption even when patients are in a fasting stage, with no difference in safety or efficacy.7 In an open-label, single-dose, 4-treatment crossover study, the drug was found bioequivalent to isotretinoin under fed conditions but delivered twice as much isotretinoin and twice as much 4-oxoisotrentinoin when administered after an overnight fast.8
Hormonal Therapies
Some women see their acne improve with the use of certain oral contraceptives such as ethinyl estradiol and norgestimate (Ortho Tri-Cyclen), norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets (Estrostep), and drospirenone/ethinyl estradiol (Yaz), which reduce sebum production. These drugs, along with the diuretic spironolactone, provide an opportunity to reduce use of antibiotics, both oral and topical. A Cochrane meta-analysis of randomized, controlled trials comparing the efficacy of antibiotics and oral contraceptives in managing acne found that, while antibiotics may be superior at 3 months, oral contraceptives are equivalent at 6 months in reducing acne lesions and may represent an alternative to antibiotics for long-term treatment.9
However, contraceptives that are effective in acne are estrogenic, and the potential for disease improvement must be balanced with the attendant risks of this approach, including thromboembolism. The same caution applies to spironolactone, whose use as an acne treatment has recently increased. In the past, the risk of hyperkalemia and the need for potassium monitoring might have deterred physicians from prescribing this medication, but a recent retrospective review in young, healthy women taking the drug found no increased risk of hyperkalemia vs the general population.7 Nevertheless, patients on other medications that can increase potassium or who eat high amounts of potassium-containing foods should be educated and monitored.
Laser Treatments and Chemical Peels
Limited data has shown that these therapies may improve acne, but AAD guidelines do not recommend such procedures for routine acne management.
New and Emerging Treatments
Topical Adapalene/BP
Combining retinoids, antibiotics, and/or BP into a single topical product has become increasingly popular over the past decade. While topical treatments are not thought to be very effective against severe acne, recent research on patients with severe inflammatory outbreaks suggests that once-daily use of a combination topical gel of adapalene 0.3% and BP 2.5% (Epiduo Forte) may be an effective option.
In a 12-week, phase 3, multicenter, randomized, double-blind study, one-third of patients treated with the combination topical gel achieved clear or almost clear skin compared with only 11% of patients treated with the vehicle. Treated patients also experienced a 68% reduction in inflammatory lesion count compared with 37% with the vehicle.10
Micronized BP/Lipohydroxy Acid (LHA)
The combination of BP 5.5% with LHA 0.04% (Effaclar Duo) can penetrate the pilosebaceous unit. LHA is a derivative of salicylic acid, which contains a long-chain fatty acid that makes the molecule lipophilic and more readily penetrable into intercellular spaces.
Data demonstrates the efficacy of BP 5.5%/LHA 0.04% as monotherapy and in conjunction with a topical prescription retinoid. An unpublished 10-day trial of BP 5.5%/LHA 0.04% monotherapy showed significant mean reductions in papules and pustules, along with open and closed comedones. In a separate study, combination therapy with BP 5.5%/LHA 0.04% and tretinoin 0.025% was shown as effective as combination therapy with prescription BP 5%/clindamycin 1% gel and tretinoin 0.025% in reducing inflammatory and noninflammatory acne lesions.11
Article continues on page 2
Cortexolone 17a-propionate
In a pilot study of 77 men with facial acne, this topical antiandrogen was shown to decrease acne lesions over placebo and tretinoin 0.05% cream.12 Cortexolone 17a-propionate is now in phase 3 clinical trials in the United States and Europe.
Topical Minocycline
FMX-101 is a topical minocycline foam being studied for acne. Early clinical data shows that application of minocycline 4% foam directly to the epidermis reduces inflammatory and noninflammatory lesions by up to 70% at 12 weeks.13 However, the drug did not meet its co-primary endpoints in 1 of 2 phase 3 trials. A third phase 3 study with a larger number of patients will soon be initiated.
Sebum Reduction
Recently there has been a shift toward inhibiting sebum production, rather than eliminating Propionibacterium acnes, as a drug development strategy for acne. Excessive sebum production, the nutrient source of P acnes, is a key to the pathogenesis of acne and the inhibition of sebum production predicts therapy outcomes.
Acetyl Coenzyme A Carboxylase Inhibitor
This prodrug of 5-tetradecyloxy-2-furoic-acid (TOFA) inhibits synthesis of sebum lipids in vitro and reduces sebaceous gland size in the hamster ear model. In an early phase study, this compound reduced lesion counts by 64% compared with 46% for the vehicle.14 Topical TOFA is now in phase 3 studies of acne as a sebosuppressive agent.
Melanocortin-1 and -5 Receptor Antagonists
The melanocortin-1 and -5 receptors (MC1R and MC5R) are expressed in the sebaceous glands. A dual MC1R and MC5R antagonist has been shown to inhibit sebocyte differentiation in vitro and to reduce sebum production in human skin transplanted onto immunodeficient mice.15 Thus far, melanocortin antagonists have not displayed clinical efficacy in treatment of acne.
Nitric Oxide in a Nanotechnology Vehicle
Nitric oxide-releasing nanoparticles have been shown to inhibit the inflammatory cascade stimulated by P acnes with minimal toxicity to keratinocytes. In a phase 2 study, this compound was shown to decrease sebum, and phase 3 studies were just completed.14 The co-primary endpoints of lesion count reduction and Investigator’s Global Assessment success were met in 1 phase 3 acne trial, but not in the other.
A Promising Outlook
The potential physical and emotional sequelae of acne are compelling reasons to implement early and efficient therapy. An improved understanding of the pathogenesis of acne is driving the rapid evolution of new therapies that improve patients’ quality of life while promoting responsible use of antibiotics. New and emerging prescription and over-the-counter topical treatments offer new drug targets, sebosuppressive approaches, improved active-drug penetration, and potentially better outcomes than traditional acne therapies.
Dr Welgus is medical director of dermatology at Premier Research in Durham, NC.
Disclosure: The author reports no relevant financial relationships.
References
1. Bickers DR, Kim HW, Margolis D, et al; American Academy of Dermatology Association; Society for Investigative Dermatology. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-500.
2. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol. 2013;168(3):474-485.
3. Strauss JS, Krowchuk DP, Leyden JJ, et al; American Academy of Dermatology/American Academy of Dermatology Association. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56(4):651-653.
4. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):943-973.e33.
5. Aczone (dapsone topic gel) 5 percent. FDA website. https://wayback.archive-it.org/7993/20170406125054/https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm458053.htm. Accessed August 26, 2017.
6. Allergan announces FDA Approval of ACZONE® (dapsone) gel, 7.5% for treatment of acne vulgaris [news release]. Dublin, Ireland: Allergan plc; February 26, 2016. https://www.allergan.com/news/news/thomson-reuters/allergan-announces-fda-approval-of-aczone-dapsone. Accessed August 26, 2017.
7. Plovanich J, Weng QY, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. 2015;151(9):941-944.
8. Webster GF, Leyden JJ, Gross JA. Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-lidose) and the innovator isotretinoin formulation: a randomized, four-treatment, crossover study. J Am Acad Dermatol. 2013;69(5):762-767.
9. Koo EB, Petersen TD, Kimball AB. Meta-analysis comparing efficacy of antibiotics versus oral contraceptives in acne vulgaris. J Am Acad Dermatol. 2014;71(3):450-459.
10. Epiduo Forte [package insert]. Fort Worth, TX: Galderma Laboratories, LP. 2015.
11. Baldwin H. Effaclar Duo: an effective, widely available OTC acne therapy. Clin Insights. 2012;2:1-2.
12. Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G. Cortexolone 17a-proprionate cream, a new potent antiandrogen for the topic treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0.05% cream. Br J Dermatol. 2011;165(1):177-183.
13. FMX 101 for moderate-to-severe acne. Foamix Pharmaceuticals website. https://www.foamix.co.il/lead.asp?nodeID=549. Accessed August 26, 2017.
14. Hilton L. New and emerging treatment options for acne. Dermatology Times. April 12, 2016. https://dermatologytimes.modernmedicine.com/dermatology-times/news/new-and-emergingtreatment-options-acne?page=1,0. Accessed August 26, 2017.
15. Li WH, Li, Z, Seiberg M. Melanocortin-1 and -5 receptors as targets for acne therapy. https://www.researchgate.net/publication/287271872_Melanocortin-1_and_-5_receptors_as_targets_ for_acne_therapy. Accessed August 26, 2017.
Acne, the most common skin disease, affects 50 million Americans each year.1 The condition is highly visible on the face and other exposed areas and disproportionately affects people during adolescence and young adulthood, when they are developing socially and are highly image-conscious.
More than $3 billion is spent annually in the United States on acne treatment,2 much of it on therapies that are only marginally and/or temporarily effective. That spending reflects the condition’s significant physical and psychological morbidity, which includes permanent scarring, poor self-image, depression, and anxiety.3 These conditions provide significant opportunity for development of new treatments, and pharma is responding with new options that show promising potential.
In 2016, the American Academy of Dermatology (AAD) issued new guidelines for treatment of acne in adolescents and adults, endorsing the long-standing practice of combining 2 or more topical and systemic remedies.4
Existing Treatments
Here’s a look at currently prescribed treatments.
Topical Therapy
Topical therapy includes benzoyl peroxide (BP), retinoids, and—less commonly—topical antibiotics. Topical retinoids, which lack the teratogenicity of oral retinoids, are the most commonly prescribed topical acne drugs and are especially effective in treating comedonal acne. BP, used alone or in combination with other topical or oral medications, has antimicrobial, anticomedogenic, antikeratolytic, and anti-inflammatory properties.
In 2016, topical 7.5% dapsone gel (Aczone) was FDA approved to treat patients 12 and older (and for several years prior prescribed, at lower strength, exclusively to adult female patients).5 In a 12-week, double-blind study, patients using dapsone 7.5% once daily showed a more than 50% reduction in inflammatory lesions and a greater than 40% reduction in noninflammatory lesions, though much of this effect was attributed to the vehicle—a common occurrence in acne studies.6
Antibiotics
When oral antibiotics are used to treat moderate to severe acne, the AAD recommends concurrent use of topical therapy to reduce patients’ likelihood of developing antimicrobial resistance, which has become an increasing problem. Antibiotics in the tetracycline class—including minocycline and doxycycline—are the most commonly prescribed, providing anti-inflammatory properties in addition to fighting bacteria.
Isotretinoin
Oral isotretinoin, the most effective treatment for severe nodulocystic acne, inhibits sebaceous gland differentiation and sebum production. About 60% of patients given a 5-month course are permanently cured of their acne—never requiring further treatment. However, to avoid the high risk of birth defects, women must take care to prevent pregnancy while taking this drug, and patients who take isotretinoin—and all physicians who prescribe it—must enroll in iPLEDGE, a federally administered risk management program developed to eliminate fetal exposure.
In 2013, a new formulation of the drug, isotretinoin-Lidose, was introduced with the goal of reducing bioavailability differences during fed and fasted states. Less dependent on the presence of fat in the gut for absorption, isotretinoin-Lidose has high levels of absorption even when patients are in a fasting stage, with no difference in safety or efficacy.7 In an open-label, single-dose, 4-treatment crossover study, the drug was found bioequivalent to isotretinoin under fed conditions but delivered twice as much isotretinoin and twice as much 4-oxoisotrentinoin when administered after an overnight fast.8
Hormonal Therapies
Some women see their acne improve with the use of certain oral contraceptives such as ethinyl estradiol and norgestimate (Ortho Tri-Cyclen), norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets (Estrostep), and drospirenone/ethinyl estradiol (Yaz), which reduce sebum production. These drugs, along with the diuretic spironolactone, provide an opportunity to reduce use of antibiotics, both oral and topical. A Cochrane meta-analysis of randomized, controlled trials comparing the efficacy of antibiotics and oral contraceptives in managing acne found that, while antibiotics may be superior at 3 months, oral contraceptives are equivalent at 6 months in reducing acne lesions and may represent an alternative to antibiotics for long-term treatment.9
However, contraceptives that are effective in acne are estrogenic, and the potential for disease improvement must be balanced with the attendant risks of this approach, including thromboembolism. The same caution applies to spironolactone, whose use as an acne treatment has recently increased. In the past, the risk of hyperkalemia and the need for potassium monitoring might have deterred physicians from prescribing this medication, but a recent retrospective review in young, healthy women taking the drug found no increased risk of hyperkalemia vs the general population.7 Nevertheless, patients on other medications that can increase potassium or who eat high amounts of potassium-containing foods should be educated and monitored.
Laser Treatments and Chemical Peels
Limited data has shown that these therapies may improve acne, but AAD guidelines do not recommend such procedures for routine acne management.
New and Emerging Treatments
Topical Adapalene/BP
Combining retinoids, antibiotics, and/or BP into a single topical product has become increasingly popular over the past decade. While topical treatments are not thought to be very effective against severe acne, recent research on patients with severe inflammatory outbreaks suggests that once-daily use of a combination topical gel of adapalene 0.3% and BP 2.5% (Epiduo Forte) may be an effective option.
In a 12-week, phase 3, multicenter, randomized, double-blind study, one-third of patients treated with the combination topical gel achieved clear or almost clear skin compared with only 11% of patients treated with the vehicle. Treated patients also experienced a 68% reduction in inflammatory lesion count compared with 37% with the vehicle.10
Micronized BP/Lipohydroxy Acid (LHA)
The combination of BP 5.5% with LHA 0.04% (Effaclar Duo) can penetrate the pilosebaceous unit. LHA is a derivative of salicylic acid, which contains a long-chain fatty acid that makes the molecule lipophilic and more readily penetrable into intercellular spaces.
Data demonstrates the efficacy of BP 5.5%/LHA 0.04% as monotherapy and in conjunction with a topical prescription retinoid. An unpublished 10-day trial of BP 5.5%/LHA 0.04% monotherapy showed significant mean reductions in papules and pustules, along with open and closed comedones. In a separate study, combination therapy with BP 5.5%/LHA 0.04% and tretinoin 0.025% was shown as effective as combination therapy with prescription BP 5%/clindamycin 1% gel and tretinoin 0.025% in reducing inflammatory and noninflammatory acne lesions.11
Article continues on page 2
Cortexolone 17a-propionate
In a pilot study of 77 men with facial acne, this topical antiandrogen was shown to decrease acne lesions over placebo and tretinoin 0.05% cream.12 Cortexolone 17a-propionate is now in phase 3 clinical trials in the United States and Europe.
Topical Minocycline
FMX-101 is a topical minocycline foam being studied for acne. Early clinical data shows that application of minocycline 4% foam directly to the epidermis reduces inflammatory and noninflammatory lesions by up to 70% at 12 weeks.13 However, the drug did not meet its co-primary endpoints in 1 of 2 phase 3 trials. A third phase 3 study with a larger number of patients will soon be initiated.
Sebum Reduction
Recently there has been a shift toward inhibiting sebum production, rather than eliminating Propionibacterium acnes, as a drug development strategy for acne. Excessive sebum production, the nutrient source of P acnes, is a key to the pathogenesis of acne and the inhibition of sebum production predicts therapy outcomes.
Acetyl Coenzyme A Carboxylase Inhibitor
This prodrug of 5-tetradecyloxy-2-furoic-acid (TOFA) inhibits synthesis of sebum lipids in vitro and reduces sebaceous gland size in the hamster ear model. In an early phase study, this compound reduced lesion counts by 64% compared with 46% for the vehicle.14 Topical TOFA is now in phase 3 studies of acne as a sebosuppressive agent.
Melanocortin-1 and -5 Receptor Antagonists
The melanocortin-1 and -5 receptors (MC1R and MC5R) are expressed in the sebaceous glands. A dual MC1R and MC5R antagonist has been shown to inhibit sebocyte differentiation in vitro and to reduce sebum production in human skin transplanted onto immunodeficient mice.15 Thus far, melanocortin antagonists have not displayed clinical efficacy in treatment of acne.
Nitric Oxide in a Nanotechnology Vehicle
Nitric oxide-releasing nanoparticles have been shown to inhibit the inflammatory cascade stimulated by P acnes with minimal toxicity to keratinocytes. In a phase 2 study, this compound was shown to decrease sebum, and phase 3 studies were just completed.14 The co-primary endpoints of lesion count reduction and Investigator’s Global Assessment success were met in 1 phase 3 acne trial, but not in the other.
A Promising Outlook
The potential physical and emotional sequelae of acne are compelling reasons to implement early and efficient therapy. An improved understanding of the pathogenesis of acne is driving the rapid evolution of new therapies that improve patients’ quality of life while promoting responsible use of antibiotics. New and emerging prescription and over-the-counter topical treatments offer new drug targets, sebosuppressive approaches, improved active-drug penetration, and potentially better outcomes than traditional acne therapies.
Dr Welgus is medical director of dermatology at Premier Research in Durham, NC.
Disclosure: The author reports no relevant financial relationships.
References
1. Bickers DR, Kim HW, Margolis D, et al; American Academy of Dermatology Association; Society for Investigative Dermatology. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-500.
2. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol. 2013;168(3):474-485.
3. Strauss JS, Krowchuk DP, Leyden JJ, et al; American Academy of Dermatology/American Academy of Dermatology Association. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56(4):651-653.
4. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):943-973.e33.
5. Aczone (dapsone topic gel) 5 percent. FDA website. https://wayback.archive-it.org/7993/20170406125054/https://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm458053.htm. Accessed August 26, 2017.
6. Allergan announces FDA Approval of ACZONE® (dapsone) gel, 7.5% for treatment of acne vulgaris [news release]. Dublin, Ireland: Allergan plc; February 26, 2016. https://www.allergan.com/news/news/thomson-reuters/allergan-announces-fda-approval-of-aczone-dapsone. Accessed August 26, 2017.
7. Plovanich J, Weng QY, Mostaghimi A. Low usefulness of potassium monitoring among healthy young women taking spironolactone for acne. JAMA Dermatol. 2015;151(9):941-944.
8. Webster GF, Leyden JJ, Gross JA. Comparative pharmacokinetic profiles of a novel isotretinoin formulation (isotretinoin-lidose) and the innovator isotretinoin formulation: a randomized, four-treatment, crossover study. J Am Acad Dermatol. 2013;69(5):762-767.
9. Koo EB, Petersen TD, Kimball AB. Meta-analysis comparing efficacy of antibiotics versus oral contraceptives in acne vulgaris. J Am Acad Dermatol. 2014;71(3):450-459.
10. Epiduo Forte [package insert]. Fort Worth, TX: Galderma Laboratories, LP. 2015.
11. Baldwin H. Effaclar Duo: an effective, widely available OTC acne therapy. Clin Insights. 2012;2:1-2.
12. Trifu V, Tiplica GS, Naumescu E, Zalupca L, Moro L, Celasco G. Cortexolone 17a-proprionate cream, a new potent antiandrogen for the topic treatment of acne vulgaris. A pilot randomized, double-blind comparative study vs. placebo and tretinoin 0.05% cream. Br J Dermatol. 2011;165(1):177-183.
13. FMX 101 for moderate-to-severe acne. Foamix Pharmaceuticals website. https://www.foamix.co.il/lead.asp?nodeID=549. Accessed August 26, 2017.
14. Hilton L. New and emerging treatment options for acne. Dermatology Times. April 12, 2016. https://dermatologytimes.modernmedicine.com/dermatology-times/news/new-and-emergingtreatment-options-acne?page=1,0. Accessed August 26, 2017.
15. Li WH, Li, Z, Seiberg M. Melanocortin-1 and -5 receptors as targets for acne therapy. https://www.researchgate.net/publication/287271872_Melanocortin-1_and_-5_receptors_as_targets_ for_acne_therapy. Accessed August 26, 2017.
Acne, the most common skin disease, affects 50 million Americans each year.1 The condition is highly visible on the face and other exposed areas and disproportionately affects people during adolescence and young adulthood, when they are developing socially and are highly image-conscious.
More than $3 billion is spent annually in the United States on acne treatment,2 much of it on therapies that are only marginally and/or temporarily effective. That spending reflects the condition’s significant physical and psychological morbidity, which includes permanent scarring, poor self-image, depression, and anxiety.3 These conditions provide significant opportunity for development of new treatments, and pharma is responding with new options that show promising potential.
In 2016, the American Academy of Dermatology (AAD) issued new guidelines for treatment of acne in adolescents and adults, endorsing the long-standing practice of combining 2 or more topical and systemic remedies.4
Existing Treatments
Here’s a look at currently prescribed treatments.
Topical Therapy
Topical therapy includes benzoyl peroxide (BP), retinoids, and—less commonly—topical antibiotics. Topical retinoids, which lack the teratogenicity of oral retinoids, are the most commonly prescribed topical acne drugs and are especially effective in treating comedonal acne. BP, used alone or in combination with other topical or oral medications, has antimicrobial, anticomedogenic, antikeratolytic, and anti-inflammatory properties.
In 2016, topical 7.5% dapsone gel (Aczone) was FDA approved to treat patients 12 and older (and for several years prior prescribed, at lower strength, exclusively to adult female patients).5 In a 12-week, double-blind study, patients using dapsone 7.5% once daily showed a more than 50% reduction in inflammatory lesions and a greater than 40% reduction in noninflammatory lesions, though much of this effect was attributed to the vehicle—a common occurrence in acne studies.6
Antibiotics
When oral antibiotics are used to treat moderate to severe acne, the AAD recommends concurrent use of topical therapy to reduce patients’ likelihood of developing antimicrobial resistance, which has become an increasing problem. Antibiotics in the tetracycline class—including minocycline and doxycycline—are the most commonly prescribed, providing anti-inflammatory properties in addition to fighting bacteria.
Isotretinoin
Oral isotretinoin, the most effective treatment for severe nodulocystic acne, inhibits sebaceous gland differentiation and sebum production. About 60% of patients given a 5-month course are permanently cured of their acne—never requiring further treatment. However, to avoid the high risk of birth defects, women must take care to prevent pregnancy while taking this drug, and patients who take isotretinoin—and all physicians who prescribe it—must enroll in iPLEDGE, a federally administered risk management program developed to eliminate fetal exposure.
In 2013, a new formulation of the drug, isotretinoin-Lidose, was introduced with the goal of reducing bioavailability differences during fed and fasted states. Less dependent on the presence of fat in the gut for absorption, isotretinoin-Lidose has high levels of absorption even when patients are in a fasting stage, with no difference in safety or efficacy.7 In an open-label, single-dose, 4-treatment crossover study, the drug was found bioequivalent to isotretinoin under fed conditions but delivered twice as much isotretinoin and twice as much 4-oxoisotrentinoin when administered after an overnight fast.8
Hormonal Therapies
Some women see their acne improve with the use of certain oral contraceptives such as ethinyl estradiol and norgestimate (Ortho Tri-Cyclen), norethindrone acetate and ethinyl estradiol tablets and ferrous fumarate tablets (Estrostep), and drospirenone/ethinyl estradiol (Yaz), which reduce sebum production. These drugs, along with the diuretic spironolactone, provide an opportunity to reduce use of antibiotics, both oral and topical. A Cochrane meta-analysis of randomized, controlled trials comparing the efficacy of antibiotics and oral contraceptives in managing acne found that, while antibiotics may be superior at 3 months, oral contraceptives are equivalent at 6 months in reducing acne lesions and may represent an alternative to antibiotics for long-term treatment.9
However, contraceptives that are effective in acne are estrogenic, and the potential for disease improvement must be balanced with the attendant risks of this approach, including thromboembolism. The same caution applies to spironolactone, whose use as an acne treatment has recently increased. In the past, the risk of hyperkalemia and the need for potassium monitoring might have deterred physicians from prescribing this medication, but a recent retrospective review in young, healthy women taking the drug found no increased risk of hyperkalemia vs the general population.7 Nevertheless, patients on other medications that can increase potassium or who eat high amounts of potassium-containing foods should be educated and monitored.
Laser Treatments and Chemical Peels
Limited data has shown that these therapies may improve acne, but AAD guidelines do not recommend such procedures for routine acne management.
New and Emerging Treatments
Topical Adapalene/BP
Combining retinoids, antibiotics, and/or BP into a single topical product has become increasingly popular over the past decade. While topical treatments are not thought to be very effective against severe acne, recent research on patients with severe inflammatory outbreaks suggests that once-daily use of a combination topical gel of adapalene 0.3% and BP 2.5% (Epiduo Forte) may be an effective option.
In a 12-week, phase 3, multicenter, randomized, double-blind study, one-third of patients treated with the combination topical gel achieved clear or almost clear skin compared with only 11% of patients treated with the vehicle. Treated patients also experienced a 68% reduction in inflammatory lesion count compared with 37% with the vehicle.10
Micronized BP/Lipohydroxy Acid (LHA)
The combination of BP 5.5% with LHA 0.04% (Effaclar Duo) can penetrate the pilosebaceous unit. LHA is a derivative of salicylic acid, which contains a long-chain fatty acid that makes the molecule lipophilic and more readily penetrable into intercellular spaces.
Data demonstrates the efficacy of BP 5.5%/LHA 0.04% as monotherapy and in conjunction with a topical prescription retinoid. An unpublished 10-day trial of BP 5.5%/LHA 0.04% monotherapy showed significant mean reductions in papules and pustules, along with open and closed comedones. In a separate study, combination therapy with BP 5.5%/LHA 0.04% and tretinoin 0.025% was shown as effective as combination therapy with prescription BP 5%/clindamycin 1% gel and tretinoin 0.025% in reducing inflammatory and noninflammatory acne lesions.11
Article continues on page 2
Cortexolone 17a-propionate
In a pilot study of 77 men with facial acne, this topical antiandrogen was shown to decrease acne lesions over placebo and tretinoin 0.05% cream.12 Cortexolone 17a-propionate is now in phase 3 clinical trials in the United States and Europe.
Topical Minocycline
FMX-101 is a topical minocycline foam being studied for acne. Early clinical data shows that application of minocycline 4% foam directly to the epidermis reduces inflammatory and noninflammatory lesions by up to 70% at 12 weeks.13 However, the drug did not meet its co-primary endpoints in 1 of 2 phase 3 trials. A third phase 3 study with a larger number of patients will soon be initiated.
Sebum Reduction
Recently there has been a shift toward inhibiting sebum production, rather than eliminating Propionibacterium acnes, as a drug development strategy for acne. Excessive sebum production, the nutrient source of P acnes, is a key to the pathogenesis of acne and the inhibition of sebum production predicts therapy outcomes.
Acetyl Coenzyme A Carboxylase Inhibitor
This prodrug of 5-tetradecyloxy-2-furoic-acid (TOFA) inhibits synthesis of sebum lipids in vitro and reduces sebaceous gland size in the hamster ear model. In an early phase study, this compound reduced lesion counts by 64% compared with 46% for the vehicle.14 Topical TOFA is now in phase 3 studies of acne as a sebosuppressive agent.
Melanocortin-1 and -5 Receptor Antagonists
The melanocortin-1 and -5 receptors (MC1R and MC5R) are expressed in the sebaceous glands. A dual MC1R and MC5R antagonist has been shown to inhibit sebocyte differentiation in vitro and to reduce sebum production in human skin transplanted onto immunodeficient mice.15 Thus far, melanocortin antagonists have not displayed clinical efficacy in treatment of acne.
Nitric Oxide in a Nanotechnology Vehicle
Nitric oxide-releasing nanoparticles have been shown to inhibit the inflammatory cascade stimulated by P acnes with minimal toxicity to keratinocytes. In a phase 2 study, this compound was shown to decrease sebum, and phase 3 studies were just completed.14 The co-primary endpoints of lesion count reduction and Investigator’s Global Assessment success were met in 1 phase 3 acne trial, but not in the other.
A Promising Outlook
The potential physical and emotional sequelae of acne are compelling reasons to implement early and efficient therapy. An improved understanding of the pathogenesis of acne is driving the rapid evolution of new therapies that improve patients’ quality of life while promoting responsible use of antibiotics. New and emerging prescription and over-the-counter topical treatments offer new drug targets, sebosuppressive approaches, improved active-drug penetration, and potentially better outcomes than traditional acne therapies.
Dr Welgus is medical director of dermatology at Premier Research in Durham, NC.
Disclosure: The author reports no relevant financial relationships.
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