PracticalDermatology

Over the past several years, an evolution has taken place both in our understanding of acne and our approach to management of the disease. Especially in the realm of topical therapy, we have seen advancements that can improve outcomes and lead to better patient experiences. Here’s a look at some of the latest findings with regards to management of acne patients.

Topical Treatment Advances

Clascoterone. Dermatologists know well that the four primary pathogenic factors that drive acne vulgaris are excess androgen, increased sebum production, faulty keratinization, and overgrowth of C. acnes. Androgens contribute to the inflammation of acne both directly and indirectly. Studies show that the presence of circulating androgens in the follicles can directly promote local inflammatory responses.¹ Additionally, androgens promote sebum production. Excess sebum enables the overgrowth of C. acnes and subsequent accumulation of its inflammatory by-products.

Dermatologists now have access to a first-in-class topical androgen receptor antagonist that addresses androgens as a key driver of acne pathogenesis. Clascoterone cream 1% (Winlevi, Cassiopea) has been studied in the treatment of moderate to severe acne in individuals as young as age nine. Importantly, it is appropriate for use by a vast majority of patients—regardless of gender—with no systemic effects observed in users to date.

Dermatologists are well-versed in the use of oral agents to modulate androgen excess in women; combined oral contraceptive pills and spironolactone are commonly employed. Clascoterone shares a four-ring backbone identical to dihydrotestosterone (DHT) and spironolactone. It competes with DHT to bind androgen receptors, thus blocking the effects of DHT by limiting or blocking transcription of 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 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 vehicle. The study population included both males and non-pregnant females with mixed acne (inflammatory and non-inflammatory lesions), nine years of age or older, with baseline IGA score of 3 (moderate) or 4 (severe).

Intent-to-treat analysis shows that active treatment was associated with greater mean total lesion reductions from baseline, compared to controls. Mean reductions from baseline in non-inflammatory lesions were 30.7 percent and 29.3 percent, respectively, for active treatment, 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.

Treatment was well-tolerated, and only 13 treatment emergent adverse events (TEAE) were identified for clascoterone cream 1%, in both studies. These included application site pain, oropharyngeal pain, application site dryness, application site erythema, application site hypertrichosis, acne, contact dermatitis, hair color changes, eye irritation, peritonsillar abscess, headache, and application site hypersensitivity. Importantly, no adverse events were suggestive of systemic anti-androgen exposure.

It is worth noting that clinical hyperandrogenism can be observed in the absence of biochemical hyperandrogenism. In one study, while seven out of 10 women with acne had clinical hyperandrogenism, only 18 percent of these women had confirmed chemical hyperandrogenism.³ Thus, a majority of women with acne may not require systemic androgen modulators and may be well-suited to management with topical clascoterone.

Because it acts locally with no evidence of systemic effects, clascoterone is a safe option for male patients.

With Winlevi now available clinically, prescribers will surely incorporate the agent into combination regimens, although we have not yet seen combinations assessed in controlled trials. Combination treatment is the norm in acne management today, and it seems reasonable to consider using topical clascoterone along with benzoyl peroxide and/or a topical retinoid in order to target multiple aspects of acne pathogenesis.

Minocycline foam. Now available commercially for about a year, Amzeeq (minocycline) topical foam 4%, from Foamix Pharmaceuticals, Ltd., is approved for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in adults and pediatric patients nine years of age and older. Formerly known as FMX101, it is the first topical minocycline to be approved by the FDA for any condition.

In clinical trials for acne, minocycline topical foam 4% met its primary end point of IGA treatment success (defined as a score of 0 (“clear”) or 1 (“almost clear”) and at least a two-point decrease from baseline) and was well-tolerated with no treatment-related serious adverse events reported.

In vitro data evaluating Amzeeq show a low rate of bacterial resistance. In vitro studies found that Amzeeq had the lowest mean inhibitory concentration against C. acnes and was four times more potent than tetracycline, eight times more potent than clindamycin, and more than 32 times more potent than erythromycin against C. acnes.⁴

Development of a pharmaceutically active topical minocycline formulation presented numerous challenges, and the unique foam vehicle formulation of Amzeeq has several characteristics that warrant focus. The hydrophobic formulation has been shown to lower the melting temperature of model human sebum below that of normal skin temperature, decreasing its viscosity. The foam was shown to deliver high concentrations of minocycline into the sebaceous appendage, with minimal permeation beyond the dermal layer.⁵ Compared to oral administration of minocycline, systemic exposure with topical minocycline foam application was 730 to 765 times lower.⁶

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.

Trifarotene. Still somewhat new to the market is trifarotene cream 0.005% (Aklief, Galderma) for the topical treatment of acne. Aklief Cream is the only topical retinoid that selectively targets retinoic acid receptor (RAR) gamma, the most common RAR found in the skin. Clinical experience has matched the positive results seen in the pivotal trials for the drug, with patients seeing marked reductions in both inflammatory and non-inflammatory acne lesions. In pivotal trials, use of topical trifarotene significantly reduced inflammatory lesions as early as two weeks on the face and four weeks on the back, shoulders, and chest, compared to vehicle.

Trifarotene is unique among topical acne treatments in that the clinical trials looked specifically at efficacy of the drug for truncal acne. Data have suggested that truncal acne may be an overlooked concern among many acne patients. In one analysis, about half of all patients who presented with acne vulgaris had involvement on the chest and/or back. Three-quarters of those with truncal acne indicated they would be interested in treating truncal acne if they could, yet only about 25 percent of patients with facial and truncal acne mentioned truncal involvement to their dermatologist.⁷

Oral Treatments

Sarecycline. We continue to learn more about the role for oral sarecycline in the management of patients with acne vulgaris. Whereas the use of antibiotics, including the tetracycline class to which sarecycline belongs, has a long history in acne care, this newer tetracycline truly is unique in the class as a narrow spectrum antibiotic compared to minocycline and doxycycline.

As now reflected in the FDA-approved labeling for sarecycline, C. acnes strains display a low propensity for the development of resistance to the antibiotic. In trials, active treatment with sarecycline was associated with significant reductions in inflammatory lesions as early as three weeks after start of treatment and was well tolerated.⁸

Data confirm that, like the other tetracyclines, sarecyline confers anti-inflammatory activity. In a rat model, sarecycline at a dose of 100mg/kg was shown to provide anti-inflammatory effects greater than those for doxycycline and minocycline; at 75mg/kg anti-inflammatory effects were comparable among the agents.⁹

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.

Combination Approaches

Given that acne is primarily an inflammatory disease, there was speculation that anti-inflammatory dose doxycycline (30mg immediate release and 10mg delayed release beads; Oracea, Galderma) would be effective for the disease. Sub-antimicrobial dose doxycycline is approved for the treatment of rosacea with demonstrated efficacy, but its effects in acne trials were not as robust as for rosacea, and it is not generally considered an option for acne management.

By week 12, 95 percent of subjects had at least a two-grade improvement in IGA scores. Statistically significant reductions in inflammatory and non-inflammatory lesion counts were seen beginning at week four and continuing through week 12. By week four, 70 percent of patients had zero nodules.¹⁰

More to Come

Ongoing evolution in acne care is expected. One area to watch is the potential emergence of a cannabidiol (CBD)-based topical for acne vulgaris: BTX 1503 (Botanix Pharmaceuticals). Phase 2 trials have been completed on the agent, which may have effects on sebocytes, modulate keratinocyte proliferation, and confer anti-inflammatory and antibacterial effects.

Benzoyl peroxide currently is only available over the counter, and adapalene 0.1%—a mainstay of topical acne treatment for many years—has also become available over the counter. While newer retinoid formulations and fixed combination formulations are thought to outperform adapalene 0.1%, there may be a role for this accessible, cost-effective topical option for some patients.

The use of energy-based devices may also increase. Strategies for device-based management were discussed in last month’s edition, available online at PracticalDermatology.com.

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 persistent acne in adult females. Int J Dermatol. 2020;59(4):428-433.

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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 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 for Moderate-to-Severe Acne. J Drugs Dermatol. 2017 Oct 1;16(10):1022-1028.

7. Del Rosso JQ, Bikowski JB, Baum E, Smith J, Hawkes S, Benes V, Bhatia N. A closer look at truncal acne vulgaris: prevalence, 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 Phase III, Multicenter, Open-Label Study and a Phase I Phototoxicity Study. J Clin Aesthet Dermatol. 2019 Nov;12(11):E53-E62.

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.

10. Kircik LH. Anti-Inflammatory Dose Doxycycline Plus Adapalene 0.3% and Benzoyl Peroxide 2.5% Gel for Severe Acne. J Drugs Dermatol. 2019 Sep 1;18(9):924-927.