New Directions in Acne Care Recent Developments and Therapeutic Advancements Continue to Improve Outcomes in the Management of This Common, Inflammatory Disease

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Acne&Rosacea New Directions in Acne Care Recent developments and therapeutic advancements continue to improve outcomes in the management of this common, inflammatory disease. BY LEON H. KIRCIK, MD

Over the past several years, an evolution has taken significantly greater rates of IGA Treatment Success (≥2 >> place both in our understanding of acne and our point reduction in IGA and score Clear (0) or Almost Clear approach to management of the disease. Especially in the (1)) at week 12 compared to vehicle. The study population realm of topical therapy, we have seen advancements that included both males and non-pregnant females with mixed can improve outcomes and lead to better patient experienc- acne (inflammatory and non-inflammatory lesions), nine es. Here’s a look at some of the latest findings with regards years of age or older, with baseline IGA score of 3 (moder- to management of acne patients. ate) or 4 (severe). Intent-to-treat analysis shows that active treatment was TOPICAL TREATMENT ADVANCES associated with greater mean total lesion reductions from Clascoterone. Dermatologists know well that the four baseline, compared to controls. Mean reductions from base- primary pathogenic factors that drive acne vulgaris are line in non-inflammatory lesions were 30.7 percent and 29.3 excess androgen, increased sebum production, faulty percent, respectively, for active treatment, compared to 21.9 keratinization, and overgrowth of C. acnes. Androgens percent and 15.8 percent, respectively, for controls. Mean contribute to the inflammation of acne both directly and reductions from baseline in inflammatory lesions were 44.8 indirectly. Studies show that the presence of circulat- percent and 47 percent, respectively, for active treatment, ing androgens in the follicles can directly promote local compared to 36.6 percent and 29.8 percent, respectively, for inflammatory responses.1 Additionally, androgens promote controls. sebum production. Excess sebum enables the overgrowth Treatment was well-tolerated, and only 13 treatment of C. acnes and subsequent accumulation of its inflamma- emergent adverse events (TEAE) were identified for clasco- tory by-products. terone cream 1%, in both studies. These included applica- Dermatologists now have access to a first-in-class topical tion site pain, oropharyngeal pain, application site dryness, androgen receptor antagonist that addresses androgens as a key driver of acne pathogenesis. Clascoterone cream 1% Dermatologists now have access to a first-in-class topical androgen receptor (Winlevi, Cassiopea) has been studied in the treatment of antagonist in clascoterone cream 1% (Winlevi, Cassiopea), which has been moderate to severe acne in individuals as young as age nine. studied in the treatment of moderate to severe acne in individuals as young as Importantly, it is appropriate for use by a vast majority of patients—regardless of gender—with no systemic effects age nine. Now available commercially for about a year, Amzeeq (minocycline) observed in users to date. topical foam 4%, from Foamix Pharmaceuticals, Ltd., is the first topical mino- Dermatologists are well-versed in the use of oral agents to cycline to be approved by the FDA for any condition. Still somewhat new to the modulate androgen excess in women; combined oral con- market is trifarotene cream 0.005% (Aklief, Galderma), the only topical retinoid traceptive pills and spironolactone are commonly employed. that selectively targets retinoic acid receptor (RAR) gamma, the most common Clascoterone shares a four-ring backbone identical to RAR found in the skin. Whereas the use of antibiotics, including the tetracycline dihydrotestosterone (DHT) and spironolactone. It com- class to which sarecycline (Seysara, Almirall) belongs, has a long history in petes with DHT to bind androgen receptors, thus blocking acne care, this newer tetracycline truly is unique in the class as a narrow spec- the effects of DHT by limiting or blocking transcription of trum antibiotic compared to minocycline and doxycycline. androgen responsive genes.2 Data from two Phase 3 trials suggest that topical clascoterone is effective in the management of acne vulgaris, with particularly promising results in reduction of inflammatory lesions. Treated patients achieved statistically thebottomline

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Taken together, the data and clinical experience increasingly suggest that topical minocycline foam may offer an “alternative to systemic antibiotics for some patients with moderate to severe acne. Controlled trials of combination regimens have yet to be published, but combining minocycline foam with a topical retinoid, and/or topical androgen antagonist, and benzoyl peroxide is expected to optimize treatment outcomes.”

application site erythema, application site hypertrichosis, and was four times more potent than tetracycline, eight acne, contact dermatitis, hair color changes, eye irritation, times more potent than clindamycin, and more than 32 peritonsillar abscess, headache, and application site hyper- times more potent than erythromycin against C. acnes.4 sensitivity. Importantly, no adverse events were suggestive of Development of a pharmaceutically active topical mino- systemic anti-androgen exposure. cycline formulation presented numerous challenges, and It is worth noting that clinical hyperandrogenism can be the unique foam vehicle formulation of Amzeeq has sev- observed in the absence of biochemical hyperandrogenism. eral characteristics that warrant focus. The hydrophobic In one study, while seven out of 10 women with acne had formulation has been shown to lower the melting temper- clinical hyperandrogenism, only 18 percent of these women ature of model human sebum below that of normal skin had confirmed chemical hyperandrogenism.3 Thus, a major- temperature, decreasing its viscosity. The foam was shown ity of women with acne may not require systemic androgen to deliver high concentrations of minocycline into the modulators and may be well-suited to management with sebaceous appendage, with minimal permeation beyond topical clascoterone. the dermal layer.5 Compared to oral administration of Because it acts locally with no evidence of systemic effects, minocycline, systemic exposure with topical minocycline clascoterone is a safe option for male patients. foam application was 730 to 765 times lower.6 With Winlevi now available clinically, prescribers will Taken together, the data and clinical experience increas- surely incorporate the agent into combination regimens, ingly suggest that topical minocycline foam may offer an although we have not yet seen combinations assessed in alternative to systemic antibiotics for some patients with controlled trials. Combination treatment is the norm in acne moderate to severe acne. Controlled trials of combination management today, and it seems reasonable to consider regimens have yet to be published, but combining minocy- using topical clascoterone along with benzoyl peroxide and/ cline foam with a topical retinoid, and/or topical androgen or a topical retinoid in order to target multiple aspects of antagonist, and benzoyl peroxide is expected to optimize acne pathogenesis. treatment outcomes.

Minocycline foam. Now available commercially for Trifarotene. Still somewhat new to the market is trifaro- about a year, Amzeeq (minocycline) topical foam 4%, from tene cream 0.005% (Aklief, Galderma) for the topical treat- Foamix Pharmaceuticals, Ltd., is approved for the treatment of acne. Aklief Cream is the only topical retinoid that ment of inflammatory lesions of non-nodular moderate to selectively targets retinoic acid receptor (RAR) gamma, the severe acne vulgaris in adults and pediatric patients nine most common RAR found in the skin. Clinical experience years of age and older. Formerly known as FMX101, it is has matched the positive results seen in the pivotal trials the first topical minocycline to be approved by the FDA for for the drug, with patients seeing marked reductions in any condition. both inflammatory and non-inflammatory acne lesions. In In clinical trials for acne, minocycline topical foam pivotal trials, use of topical trifarotene significantly reduced 4% met its primary end point of IGA treatment success inflammatory lesions as early as two weeks on the face and (defined as a score of 0 (“clear”) or 1 (“almost clear”) and four weeks on the back, shoulders, and chest, compared to at least a two-point decrease from baseline) and was well- vehicle. tolerated with no treatment-related serious adverse events Trifarotene is unique among topical acne treatments in reported. that the clinical trials looked specifically at efficacy of the In vitro data evaluating Amzeeq show a low rate of bac- drug for truncal acne. Data have suggested that truncal terial resistance. In vitro studies found that Amzeeq had acne may be an overlooked concern among many acne the lowest mean inhibitory concentration against C. acnes patients. In one analysis, about half of all patients who

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In keeping with best practices for acne care, sarecycline should be prescribed in conjunction with a topical retinoid as well “as topical antimicrobial agent, such as benzoyl peroxide. Topicals can be continued as maintenance therapy when the oral treatment is withdrawn.”

presented with acne vulgaris had involvement on the chest By week 12, 95 percent of subjects had at least a two-grade and/or back. Three-quarters of those with truncal acne improvement in IGA scores. Statistically significant reductions indicated they would be interested in treating truncal acne in inflammatory and non-inflammatory lesion counts were if they could, yet only about 25 percent of patients with seen beginning at week four and continuing through week 12. facial and truncal acne mentioned truncal involvement to By week four, 70 percent of patients had zero nodules.10 their dermatologist.7 MORE TO COME ORAL TREATMENTS Ongoing evolution in acne care is expected. One area Sarecycline. We continue to learn more about the role for to watch is the potential emergence of a cannabidiol oral sarecycline in the management of patients with acne (CBD)-based topical for acne vulgaris: BTX 1503 (Botanix vulgaris. Whereas the use of antibiotics, including the tetra- Pharmaceuticals). Phase 2 trials have been completed on cycline class to which sarecycline belongs, has a long history the agent, which may have effects on sebocytes, modulate in acne care, this newer tetracycline truly is unique in the keratinocyte proliferation, and confer anti-inflammatory class as a narrow spectrum antibiotic compared to minocy- and antibacterial effects. cline and doxycycline. Benzoyl peroxide currently is only available over the coun- As now reflected in the FDA-approved labeling for sare- ter, and adapalene 0.1%—a mainstay of topical acne treat- cycline, C. acnes strains display a low propensity for the ment for many years—has also become available over the development of resistance to the antibiotic. In trials, active counter. While newer retinoid formulations and fixed com- treatment with sarecycline was associated with significant bination formulations are thought to outperform adapalene reductions in inflammatory lesions as early as three weeks 0.1%, there may be a role for this accessible, cost-effective after start of treatment and was well tolerated.8 topical option for some patients. Data confirm that, like the other tetracyclines, sarecyline The use of energy-based devices may also increase. Strategies confers anti-inflammatory activity. In a rat model, sarecy- for device-based management were discussed in last month’s cline at a dose of 100mg/kg was shown to provide anti- edition, available online at PracticalDermatology.com. n inflammatory effects greater than those for doxycycline and minocycline; at 75mg/kg anti-inflammatory effects were Leon H. Kircik, MD is Clinical Associate Professor of comparable among the agents.9 Dermatology, Icahn School of Medicine at Mount Sinai, New In keeping with best practices for acne care, sarecycline York and at Indiana University Medical Center, Indianapolis, should be prescribed in conjunction with a topical retinoid as IN. He is Medical Director of Physicians Skin Care, PLLC, well as topical antimicrobial agent, such as benzoyl peroxide. DermResearch, PLLC, and Skin Sciences, PLLC in Louisville, KY. Topicals can be continued as maintenance therapy when the oral treatment is withdrawn. 1. Ju Q, Tao T, Hu T, Karadağ AS, Al-Khuzaei S, Chen W. Sex hormones and acne. Clin Dermatol. 2017 Mar - Apr;35(2):130-137. 2. Data on File. CB-03-01 2017. Cassiopea SpA. 3. Sardana K, Bansal P, Sharma LK, Garga UC, Vats G. A study comparing the clinical and hormonal profile of late onset and COMBINATION APPROACHES persistent acne in adult females. Int J Dermatol. 2020;59(4):428-433. 4. Zeichner J. An Update on the Use of Minocycline for the Treatment of Acne. Practical Dermatology 2020. 17(1):60-61. Given that acne is primarily an inflammatory disease, 5. Kircik L, Del Rosso JQ, Weiss JS, Stakias V, London A, Keynan R, Hazot Y, Elliott R, Stuart I. Formulation and Profile of FMX101 there was speculation that anti-inflammatory dose doxy- 4% Minocycline Topical Foam for the Treatment of Acne Vulgaris. J Clin Aesthet Dermatol. 2020 Apr;13(4):14-21. 6. Jones TM, Ellman H, deVries T. Pharmacokinetic Comparison of Once-Daily Topical Minocycline Foam 4% vs Oral Minocycline cycline (30mg immediate release and 10mg delayed release for Moderate-to-Severe Acne. J Drugs Dermatol. 2017 Oct 1;16(10):1022-1028. beads; Oracea, Galderma) would be effective for the dis- 7. Del Rosso JQ, Bikowski JB, Baum E, Smith J, Hawkes S, Benes V, Bhatia N. A closer look at truncal acne vulgaris: prevalence, ease. Sub-antimicrobial dose doxycycline is approved for severity, and clinical significance. J Drugs Dermatol. 2007 Jun;6(6):597-600. 8. Pariser DM, Green LJ, Lain EL,et al. Safety and Tolerability of Sarecycline for the Treatment of Acne Vulgaris: Results from a the treatment of rosacea with demonstrated efficacy, but Phase III, Multicenter, Open-Label Study and a Phase I Phototoxicity Study. J Clin Aesthet Dermatol. 2019 Nov;12(11):E53-E62. its effects in acne trials were not as robust as for rosacea, 9. Bunick CG, Keri J, Tanaka SK, Furey N, Damiani G, Johnson JL, Grada A. Antibacterial Mechanisms and Efficacy of Sarecycline in Animal Models of Infection and Inflammation. Antibiotics (Basel). 2021 Apr 15;10(4):439. and it is not generally considered an option for acne man- 10. Kircik LH. Anti-Inflammatory Dose Doxycycline Plus Adapalene 0.3% and Benzoyl Peroxide 2.5% Gel for Severe Acne. J Drugs agement. Dermatol. 2019 Sep 1;18(9):924-927.

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