Topical retinoids are a staple first-line treatment option cited in the American Academy of Dermatology’s most recent guidelines for the care of patients with acne, yet they are likely underused in today’s clinical practice.

Dr. Emmy Graber

Dr. Emmy Graber

A study of prescribing practices from 2012 to 2014 indicated that dermatologists prescribed retinoids for just 58.8% of acne cases, while nondermatologists prescribed them for only 32.4% of cases. “If the guidelines are telling us that we should use topical retinoids for almost all of our acne patients, why are we using them for half of the patients?” Emmy Graber, MD, MBA, asked during MedscapeLive’s annual Las Vegas Dermatology Seminar. “We have a lot of options today for topical retinoids,” she added, noting that, in the past few years, trifarotene cream 0.005% and new formulations of tazarotene lotion (0.045%) and tretinoin lotion (0.05%) have become available.

According to Dr. Graber, president of The Dermatology Institute of Boston, tazarotene has been considered the most efficacious topical retinoid but is generally the least well tolerated, while adapalene has often been considered to be one of the better-tolerated topical retinoids. “This is a broad generalization,” she said. “One should also take into account the concentration and formulation of the retinoid. Cutaneous adverse events increase in severity as the concentration increases regardless of the vehicle.” There are no studies comparing trifarotene with other topical retinoids, she added.

In two phase 2, double-blind, vehicle-controlled studies (PERFECT 1 and PERFECT 2), researchers randomized more than 2,400 patients with moderate facial or truncal acne to receive trifarotene cream or a vehicle for 12 weeks. The mean percent change from baseline in facial inflammatory lesions in the trifarotene-treated group was –54.4% and –66.2% in PERFECT 1, and PERFECT 2, respectively, while the mean percent change from baseline in facial noninflammatory lesions was –49.7% and –57.7%, respectively.

In addition, the mean percent change from baseline in truncal inflammatory lesions in the trifarotene-treated groups was –57.4% and –65.4%, respectively, while the mean percent change from baseline in truncal noninflammatory lesions was –49.1% and –55.2%, respectively.

The choice of vehicle may affect absorption of topical retinoids, and some formulations may increase skin hydration and decrease transepidermal water loss, “which is a good thing,” Dr. Graber said. “Also, vehicles aim to slow drug delivery over time while also making sure that the drug penetrates into the pilosebaceous unit.”

One recent advance is the honeycomb-like polymeric emulsion technology found in tretinoin 0.05% lotion and tazarotene 0.045% lotion. These formulations contain droplets of the tretinoin and tazarotene embedded in a honeycomb matrix with hydrating agents. “I think this is exciting and could enhance our patient compliance and tolerability,” she said. Another unique feature about these two products, especially the tretinoin product, is the very small particle size with this new formulation. “It’s small enough that it can penetrate down into the pilosebaceous unit,” which is different than with older formulations, in which the tretinoin “largely just sat on the surface of the skin and didn’t penetrate into the pilosebaceous unit.” In addition, she said, “there’s only 9% degradation of the tretinoin in UV light, compared to 72% degradation of standard tretinoin 0.025% gel, and with the new tretinoin formulation, there’s no degradation when used with benzoyl peroxide.”

Another new topical retinoid to consider is a fixed-dose combination of encapsulated benzoyl peroxide 3% and encapsulated tretinoin 0.1% cream (Twyneo), which was approved by the Food and Drug Administration in July 2021 for the treatment of acne in adults and children aged 9 years and older. “Typically, benzoyl peroxide and tretinoin cannot be mixed in the same tube to stability issues,” she said. “Here, each product is individually encapsulated in a silica shell so that they can be applied together.”

The approval was supported by positive results from two phase 3, randomized, double-blind, vehicle-controlled, multicenter studies (NCT03761784 and NCT03761810), in which Twyneo demonstrated efficacy and a favorable tolerability profile in patients aged 9 years and older with facial acne.

Another topical treatment option, dapsone, is now FDA approved for ages 9 and up, expanded from its initial indication for ages 12 and up. The new indication is based on a phase 4, multicenter, open-label study in which acne patients aged 9-11 years applied dapsone 7.5% gel once daily to the face and acne-affected areas on the upper chest, upper back, and shoulders for 12 weeks. After 12 weeks, facial acne was clear or almost clear in about 47% of patients. “Inflammatory, noninflammatory, and total lesions decreased from baseline, but there was a greater reduction in noninflammatory lesions, so if you have a very young patient with acne, now you can consider dapsone gel,” Dr. Graber said.

In August 2020, clascoterone cream became the first topical androgen receptor inhibitor approved for the treatment of acne in patients 12 years of age and older. It is a drug believed to address sebum and inflammation directly in the sebaceous gland and is structurally similar to dihydrotestosterone and spironolactone.

“This is a completely new drug category in acne,” she said. “Unlike all oral antiandrogen therapies, clascoterone cream can be used in both males and females with acne. It’s the first acne drug to have a new mechanism of action in almost 40 years, since isotretinoin was approved in 1982.”

In vitro, she continued, clascoterone competes with dihydrotestosterone for binding to the androgen receptor, inhibiting downstream signaling and leading to inhibited sebum production, reduced secretion of inflammatory cytokines, and inhibition of inflammatory pathways. Two phase 3 studies that led to its approval involved 1,440 patients with moderate to severe facial acne aged 9-58 years. The cream was applied twice a day for 12 weeks and treatment adherence was approximately 90%. The researchers found that clascoterone cream was significantly more effective than vehicle cream at achieving Investigator’s Global Assessment scores of 0 (clear) or 1 (almost clear), the definition of treatment success in the study, and reducing noninflammatory lesion and inflammatory lesion counts at week 12. “There were no safety issues noted during these studies, and clascoterone cream was well tolerated,” Dr. Graber said.

Dr. Graber disclosed that she is a consultant/adviser for Digital Diagnostics, Almirall, Hovione, Keratin Biosciences, La Roche Posay, Ortho Dermatologics, Sebacia, Sol-Gel, Verrica, and WebMD. She is also a research investigator for Hovione, Ortho Dermatologics, Sebacia, and she receives royalties from Wolters Kluwer Health.

MedscapeLive and this news organization are owned by the same parent company.

Commentary by Lawrence W. Eichenfield, MD

Acne vulgaris remains an issue of tremendous importance to preteens, teens, and young adults, with approximately 85% of individuals aged 12-24 being affected. Expanding options for topical treatments may help bring effective disease control. Dr. Graber pointed out that historically, pediatricians and other primary care practitioners utilize topical retinoids less often for acne care as compared with dermatologists or guidelines recommendations (either the AAP’s or AAD’s). There are now expanded options, including over-the-counter retinoids (adapalene 0.1% gel), generic and trade brand topical tretinoin products, prescription adapalene medications, older and recently approved tazarotene products, and a newer type of topical retinoid, trifarotene. Novel formulations and emulsion technology, as well as retinoid developed in combination products, give more options in patients down to 9 years of age. A novel topical anti-androgen, clascoterone, is in its own category, as the first topical “hormonal agent,” allowing hormonal therapy to be used for males as well as females (aged 12 years and up). A recent review in JAMA (2021 Nov 23;326[20]:2055-67) incorporates many of these newer medications into management suggestions, emphasizing that first-line therapies are topical retinoids, benzoyl peroxide, azelaic acid, or combinations of topicals, whereas in more severe disease, oral antibiotics such as doxycycline or minocycline, hormonal therapies such as combination oral conceptive agents or spironolactone, or isotretinoin are most effective.

Dr. Eichenfield is chief of pediatric and adolescent dermatology at Rady Children's Hospital-San Diego. He is vice chair of the department of dermatology and professor of dermatology and pediatrics at the University of California, San Diego. He disclosed that he has served as an investigator and/or consultant to AbbVie, Lilly, Pfizer, Regeneron, Sanofi-Genzyme, and Verrica.

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This article was updated 6/18/22.