PracticalDermatology

It is sometimes easy to forget that in the not too distant past, successful acne treatment in the US relied heavily on oral antibiotics, acne was considered a disease with both “inflammatory” and “non-inflammatory” manifestations, and it was pigeon-holed as a disease of adolescence. Today, of course, dermatologists know that acne is at its root an inflammatory disease that, while it typically presents in adolescence, can persist through adulthood. We also have significantly reduced our dependence on oral antibiotics and implemented strategies intended to diminish the risk of contributing to antibiotic resistance.¹

Although our knowledge of acne developed at a rapid pace over the past decade or so, the therapeutic landscape remained relatively unchanged. That is quickly changing with a number of recent approvals and several new agents in development. Here’s a look at new and emerging treatments.

Sarecycline

The approval of sarecycline (Seysara, Almirall) late in 2018 (it hit the market in early 2019) heralded a new era in acne drug approvals. Sarecycline is a novel tetracycline and was the first topical antibiotic approved for a dermatologic indication in more than 40 years. It has a narrower spectrum of activity compared to other tetracyclines and has reduced activity against enteric Gram-negative bacteria.²

Among patients aged nine years or older with moderate to severe acne vulgaris who received sarecycline once daily for up to 40 weeks, there were low rates of TEAEs, with nasopharyngitis, upper-respiratory-tract infection, headache, and nausea being the only TEAEs reported by two percent or more of patients.³

Data from Phase 3 clinical trials show that sarecycline provided significant reductions in both inflammatory and non-inflammatory 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 percent and 22.6 percent for active treatment, respectively, versus 10.5 percent and 15.3 percent, respectively, for controls.⁴

Topical Minocycline

Last fall, the FDA approved Amzeeq (minocycline) topical foam 4%, from Foamix Pharmaceuticals for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in adults and pediatric patients 9 years of age and older. Formerly known as FMX101, it is the first topical minocycline to be approved by the FDA for any condition. Systemic minocycline has been the most commonly prescribed oral antibiotic for acne.⁵

Topical minocycline foam 4% is associated with dramatic reduction of systemic minocycline exposure compared to oral administration, and there was no evidence of minocycline accumulation over 21 days of topical application.⁶

In the 12-week Phase 3 randomized studies of minocycline foam 4%, active treatment was associated with a significantly greater reduction in both inflammatory and non-inflammatory active lesions, compared to foam vehicle.^7,8 Subjects receiving active treatment had a greater rate of treatment success based on Investigator’s Global Assessment (P < .0001) versus the foam vehicle group at week 12.⁸

A 1.5% minocycline foam formulation has shown benefit in trials for rosacea. In 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 to vehicle foam.⁹

Still in development is a topical minocycline formulation developed by BioPharmX. BPX-01 uses a novel, patented HyantX delivery system, which stabilizes and solubilizes hydrophilic molecules in an anhydrous, biphasic gel. In a 12-week randomized, double-blind, vehicle-controlled, dose-ranging Phase 2b clinical trial, 25 percent of the intent-to-treat (ITT) population achieved a two-grade reduction to clear or almost clear. Interestingly, female patients had higher rates of success, relative to the overall ITT population.

Clascoterone

Now under review at the FDA is clascoterone (Winlevi) 1% cream (Cassiopea). Clascoterone is a topically delivered androgen inhibitor that is thought to displace androgen hormones from the androgen receptors located at the sebaceous gland and hair follicle. Clascoterone acts locally on androgen receptors in the skin with no evidence of systemic exposure.

In two Phase 3 trials recently published, topical clascoterone met it primary endpoints.¹⁰ Treated patients achieved statistically significantly greater rates of IGA Treatment Success (≥2 point reduction in IGA and score Clear (0) or Almost Clear (1)) at week 12, compared to controls. Treated subjects had treatment success rates of 16.1 percent and 18.7 percent, respectively, compared to 7 percent and 4.7 percent for vehicle, respectively. Active treatment subjects had reductions in non-inflammatory lesions of 30.7 percent and 29.3 percent, respectively, compared to 21.9 percent and 15.8 percent, respectively, for controls. Mean reductions from baseline in inflammatory lesions were 44.8 percent and 47 percent, respectively, for active treatment, compared to 36.6 percent and 29.8 percent, respectively, for controls.

Rates of treatment-emergent adverse events (TEAE) were low and similar in the active and placebo groups in both studies.

Trifarotene

The first new topical retinoid approved for acne since the 1990s, trifarotene (Aklief Cream 0.005%, Galderma) selectively targets retinoic acid receptor (RAR) gamma, the most common RAR found in the skin. Of note, the clinical trials for trifarotene included assessments of facial (forehead, cheeks, nose, and chin) and truncal (chest, shoulders, and back) acne.

In two randomized, multicenter, parallel group, double-blind, vehicle-controlled, 12-week Phase 3 clinical trials involving 2,420 patients, once-daily Aklief Cream significantly reduced inflammatory lesions as early as two weeks on the face and four weeks on the back, shoulders and chest compared to vehicle (p<0.05).

Tazarotene Lotion

Arazlo (tazarotene, Ortho Dermatologics) Lotion, 0.045% has been approved for the topical treatment of acne vulgaris in patients nine years of age and older, the first tazarotene acne treatment available in a lotion form. In a head-to-head study, Arazlo demonstrated similar efficacy as tazarotene cream 0.1% with about half the adverse events yet with less than half of the percentage of active tazarotene. The most frequent adverse events reported with Arazlo (≥1%) were application site pain, dryness, exfoliation, erythema, and pruritus.

In Phase 3 trials, tazarotene 0.045% lotion demonstrated statistically significant superiority to vehicle in reducing inflammatory and noninflammatory lesion counts at week 12. Mean percent reductions in inflammatory and noninflammatory lesions were 55.5 percent and 51.4 percent in Study 1 (versus vehicle: 45.7 percent and 41.5 percent, respectively) and 59.5 percent and 60 percent in Study 2 (versus vehicle: 49 percent and 41.6 percent, respectively) with tazarotene 0.1% cream at week 12. Treatment success was achieved by 25.5 percent (Study 1) and 29.6 percent (Study 2) of subjects treated with tazarotene 0.045% lotion.

Among subject treated with tazarotene, improvements in quality-of-life domain scores were consistently greater with tazarotene.¹¹

1. Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May;74(5):945-73.

2. Leyden JJ, Sniukiene V, Berk DR, Kaoukhov 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 Mar 1;17(3):333-338.

3. Pariser DM, Green LJ, Lain EL, Schmitz C, Chinigo AS, McNamee B, Berk DR. Safety and Tolerability of Sarecycline for the Treatment of Acne Vulgaris: Results from a Phase III, Multicenter, Open-Label Study and a Phase I

Phototoxicity Study. J Clin Aesthet Dermatol. 2019 Nov;12(11):E53-E62.

4. Moore A, Green LJ, Bruce S, Sadick N, Tschen E, Werschler P, Cook-Bolden FE, Dhawan SS, Forsha D, Gold MH, Guenthner S, Kempers SE, Kircik LH, Parish JL, Rendon MI, Rich P, Stein-Gold L, Tyring SK, Weiss RA, Nasir A, Schmitz C, Boodhoo TI, Kaoukhov A, Berk DR. 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 Sep 1;17(9):987-996.

5. . 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. Journal of the American Academy of Dermatology. 2014;71(1):70–76.

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 Oct 1;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 Jan;80(1):168-177.

8. Raoof TJ, Hooper D, Moore A, Zaiac M, Sullivan T, Kircik L, Lain E, Jankicevic J, Stuart I. Efficacy and safety of a novel topical minocycline foam for the treatment of moderate to severe acne vulgaris: A phase 3 study. J Am Acad Dermatol. 2020 Apr;82(4):832-837.

9.. Poster presented at the 2019 Winter Clinical Dermatology Conference, HI; January 18-23, 2019; 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; Linda Stein Gold, MD, James Q. Del Rosso, DO, Neal D. Bhatia, MD, Deirdre Hooper, MD, Walter Nahm, MD, PhD, Iain Stuart, PhD.

10. Hebert A, Thiboutot D, Stein Gold L, Cartwright M, Gerloni M, Fragasso E, Mazzetti A. Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne: Two Phase 3 Randomized Clinical Trials. JAMA

Dermatol. 2020 Apr 22.

11. Tanghetti EA, Werschler WP, Lain T, Guenin E, Martin G, Pillai R. Tazarotene 0.045% Lotion for Once-Daily Treatment of Moderate-to-Severe Acne Vulgaris: Results from Two Phase 3 Trials. J Drugs Dermatol. 2020 Jan 1;19(1):70-77.