Clascoterone

10 In August 2020, the FDA approved Clascoterone (Winlevi®, Cassiopea, Italy) [9]. It is a first-in-class topical acne treatment, a steroidal anti-androgen and anti-inflammatory. It binds to the androgen receptor with higher affinity than dihydrotestosterone [8]. The complex supresses the transcription of genes involved in both sebum and inflammatory cytokine production [10-12].

11 Clascoterone 1% topical cream was effective and safe as treatment for acne [13-15]. Based on a meta-analysis, Alkhodaidi et al. confirmed a high level of efficacy and safety of Clascoterone [16]. Using the Investigator Global Assessment (IGA), it significantly increased success rates (risk ratio = 2.87, 95% CI [2.11, 3.89], p<0.001) and decreased the non-inflammatory lesion count (mean difference = -5.64, 95% CI [-8.41, -2.87], p<0.01) with no significant impact on the inflammatory lesion count (mean difference = -1.82, 95% CI [-5.06, 1.43], p = 0.27) when compared to the vehicle.

Lidose-isotretinoin

12 Oral isotretinoin has been the standard in severe nodular acne care for almost 40 years [17, 18].

13 In 2014, a novel isotretinoin formulation utilising Lidose technology (Absorica^TM, Sun Pharmaceutical Industries Limited, USA) was approved by the FDA and is also available in Europe.

14 Lidose-isotretinoin (LI) contains pre-solubilized isotretinoin in a lipid matrix. It improves the bioavailability of isotretinoin through greater gastrointestinal absorption [19, 20]. Its gastrointestinal absorption depends less on the amount and/or type of food intake than that for traditional isotretinoin. This allows patients to achieve similar therapeutic outcomes, even when taken in an unfed state, and to reduce the inconvenience of consistently maintaining a correct diet [21].

15 In 2019, a novel formulation based on advanced micronisation technology was made available. This physically reduces the size of the drug molecule, resulting in twice as high absorption levels of isotretinoin after fasting. In the fed state, similar plasma levels to those of standard LI with a 20% lower dose and consistent serum isotretinoin levels, irrespective of gastrointestinal contents, were observed. By eliminating the food effect seen with traditional oral isotretinoin, this novel formulation has the potential to improve patient adherence and long-term patient outcomes [20, 22]. Clinical trials remain to be conducted.

Trifarotene

16 Topical trifarotene (Aklief^®, Galderma Laboratories, Switzerland) is a first-in-class, fourth-generation drug for the topical treatment of acne. Trifarotene received its approval in the USA and Europe as topical treatment for acne on the face and trunk in patients ≥ nine years of age in 2019 [23, 24].

17 Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARβ, and is active in keratinocytes. Trifarotene at 0&middot;01% is highly comedolytic and possesses excellent anti-inflammatory properties. Gene expression studies indicated potent activation of epidermal differentiation, proliferation, the stress response and retinoic acid metabolism, as well as novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, and in human skin after four weeks of topical application [25].

18 Two Phase III double-blinded, randomized, vehicle-controlled, 12-week studies of once-daily trifarotene cream versus vehicle in subjects ≥nine years showed that facial success rates, according to the IGA and truncal Physician's Global Assessment and change in inflammatory and noninflammatory lesion counts (both absolute and percentage), were all significant (p<0.001) in favour of Trifarotene when compared with the vehicle after 12 weeks of treatment [26]. Trifarotene was shown to be safe, well tolerated, and effective for moderate facial and truncal acne over 52 weeks [27].

Tretinoin

19 Tretinoin, a topical retinoid, has been prescribed for more than 40 years. However, its use is associated with skin dryness, erythema and sometimes dermatitis [28, 29]. The initial formulation contained alcohol, potentially partially responsible for irritation, and later formulations incorporated Tretinoin encapsulated in sponge-like, porous, polymorphic microspheres, delivering the drug gradually, thus resulting in an improved safety profile and drug stability [30].

20 Tretinoin 0.05% lotion (Altreno^TM, Ortho Dermatologics) contains a polymeric honeycomb matrix that provides a uniform distribution of both active and hydrating ingredients. It reduces trans-epidermal water loss and significantly (p<0.001) reduces both inflammatory and non-inflammatory lesions compared to vehicle as early as Week 4 and Week 8, respectively [31].

21 As with other retinoids, a dose-dependent potential to cause irritation has been a major concern with Tretinoin. The lotion formulation was very well tolerated, with an incidence of less than 4% for dryness, stinging, burning, pain, and erythema, respectively [32].

22 This formulation has yet not received market approval.

Tazarotene

23 A novel lotion formulation was approved by the FDA for tazarotene 0.045% (Arazlo^TM, Bausch Health Companies Inc., Canada) in 2019. This lotion uses less than half the concentration of 0.1% tazarotene in a polymeric emulsion [33].

24 The oil-in-water emulsion structure allows for a more uniform release and increased absorption of tazarotene, while being better tolerated [34]. It is more effective, with a slightly greater benefit in female rather than male patients and better tolerated than previous tazarotene formulations [33-35].

Sarecycline

26 Sarecycline (Seysara^TM, Almirall, Spain) is the most recent tetracycline derivative. It was approved by the FDA in October 2018 [4, 38]. It is indicated in patients ≥nine years with moderate-to-severe acne. For oral minocycline, dosing is once-daily, weight-dependant and may be taken with or without food [39].

27 Sarecycline exhibits the same inhibitory effect on protein synthesis as all tetracycline derivatives. However, it is considered a narrow-spectrum antibiotic which may reduce the risk of developing antibiotic resistance [40-42]. C. acnes was shown to be associated with a low tendency of developing resistance to Sarecycline, but with no clinically confirmed relevance [41]. It was four- to eight-fold less active against other bacterial inhabitants of healthy human skin [41].

28 The IGA with Sarecycline, after 12 weeks of treatment, reached 22%, versus up to 15% with the placebo (p<0.005). Onset of efficacy for inflammatory lesions occurred by the first visit (Week 3), with a mean percentage reduction in inflammatory lesions at Week 12 with Sarecycline of up to 52%, versus -35% with the placebo (p<0.0001). Onset of efficacy regarding the absolute reduction of noninflammatory lesion count was reached at Week 6 (p< 0.05) and Week 9 (p<0.01) [43]. Observed adverse events with Sarecycline were similar to those reported for other tetracyclines [39].

Minocycline

29 In October 2019, the FDA approved topical Minocyline at 4% (Amzeeq^TM, Foamix Pharmaceuticals, NJ, United States). It is a hydrophobic, topical foam to treat moderate-to-severe acne in patients aged ≥nine years. It maintains the anti-inflammatory and antibiotic activities of Minocycline while minimizing potentially serious systemic adverse events commonly associated with oral delivery [44, 45].

30 Oral minocycline was shown to maintain a good resistance profile for isolates of C. acnes. Clinical testing showed that when applied once daily, it significantly improved both inflammatory and non-inflammatory lesions compared to its vehicle. Its use over 52 weeks provided additional benefit. The product was well tolerated. Cutaneous adverse events were rare [46-49].

Hyaluronic acid

31 Hyaluronic acid (HA) is the major glycosaminoglycan in the extracellular matrix and is involved in several functions in skin cells. Human skin sebaceous glands in vivo and sebocytes in vitro express the HA-binding receptor, CD44. Moreover, HA downregulates lipid synthesis in a dose-dependent manner and significantly decreases sebum production, indicating that HA may be an effective candidate to treat acne [50].

Cannabidiol

32 The endocannabinoid system (ECS) is involved in several pathophysiological diseases such as cancer, cardiovascular, neurodegenerative and skin diseases [51]. All ECS components are found in the skin, confirming its role in healthy and diseased skin and general homeostasis [52, 53].

33 The anti-inflammatory properties of some cannabinoids, particularly cannabidiol (CBD), suggest that it may be beneficial against dermatological inflammatory disease [54]. In addition to anti-inflammatory effects, cannabinoids were shown to interact with the ECS components of the skin to produce antipruritic, anti-aging, anti-cancer, and anti-nociceptive effects [55, 56].

34 CBD is sebostatic, inhibits the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppresses sebocyte proliferation via the activation of transient receptor potential vanilloid-4 (TRPV4) ion channels. Moreover, CBD has anti-inflammatory properties. Thus, CBD may be a promising candidate in the armamentarium for the treatment of different dermatoses, including acne [55, 57-60].

Insulin-like growth factor

35 Diet is considered to be potentially one factor that influences acne [61]. While an increasing amount of evidence seems to demonstrate the relationship between diet and acne, with insulin-like-growth factor (IGF)-1 potentially affecting the production of androgens and sebaceous lipogenesis as well as the formation of comedones, the effect of sebocytes has not yet been sufficiently confirmed clinically [62, 63]. Further research on the role of IGF-1 in acne remains to be carried out [64].

Modulators of the skin microbiota

39 Acne treatment with topical antibiotics as monotherapy has led to antibacterial resistance, while the use of systemic antibiotics is associated with changes in the composition and diversity of skin microbiota, especially C. acnes, which correlates with acne severity [78]. Thus, preserving natural resources and mechanisms of the skin ecosystem is essential. A novel approach based on these principles, named ecobiology, has recently emerged; the skin is considered as a constantly evolving ecosystem which hosts human and microbial cells that interact together with their environment [79].

40 Respecting this ecosystem has led to the notion of skin microbiome modulation, which has become a new field of investigation, and several approaches have been reported in the literature [80].

41 New treatment options that may help the disturbed microbiome to recover and allow the healthy microbiome to maintain its homeostasis may certainly play a future role in dermatology [81].

Vaccines

42 The idea of a vaccine against C. acnes emerged about 15 years ago [82, 83]. In one study, mice were immunized with Christie-Atkins-Munch-Peterson (CAMP) factor 2 that produced neutralizing antibodies which efficiently reduced C. acnes-induced ear swelling and production of macrophage-inflammatory protein-2. The passive neutralisation of CAMP factor increased immunity, eliminating C. acnes at the infection site, without influencing bacterial growth at other locations [84].

43 More recently, Wang et al. confirmed that the secreted virulence factor, CAMP 2, from C. acnes promotes inflammatory responses. Its pro-inflammatory property may be inhibited by antibodies to CAMP 2, suggesting this factor to be a candidate target in acne vaccination [85].

44 To date, clinical evidence of the efficacy of a vaccine against C. acnes is still lacking and proper clinical research has to be conducted to confirm its benefit in the systemic treatment of acne.

Bacteriophages

45 Bacteriophages are viruses that infect bacteria [86]. They are essential members of the human microbiome [87-90]. Little is known about bacteriophage interaction with the skin microbiota and their distribution depends on their host organisms [88].

46 There is some evidence to support phage therapy for skin infections. Although C. acnes bacteriophages have been isolated and characterized, only a few in vitro studies have tested the ability of bacteriophages to eliminate C. acnes. Moreover, no clinical study has been conducted to investigate the benefit of bacteriophage therapy for acne [86]. Some in vitro research has shown that BX001 phages kill C. acnes in a biofilm and penetrate sebum [91]. Other research in mice has shown that treatment with the bacteriophage, TCUCAP1, from the skin of healthy volunteers reduced C. acnes-induced skin inflammation and inflammatory lesions [92].

Probiotics

47 There is increasing evidence that the gut microbiome is involved in modulating systemic inflammation and disease. Moreover, oral probiotics modulate the intestinal microbiome and have demonstrated efficacy in the treatment of atopic dermatitis, acne and rosacea. Therefore, exogenous application of probiotics to the skin may also promote a positive bacterial balance to mitigate or potentially eliminate pathological conditions [93].

48 As an example, a study conducted by Paetzold et al. showed that after sequential applications of a donor microbiome, the recipient microbiome became likened to that of the donor during the first week after implantation. The authors observed greater engraftment using a multi-strain donor solution with recipient skin rich in C. acnes subtype H1 and Leifsonia [94].

49 Several other studies have shown that topical and oral probiotics impact the human skin microbiota by rebalancing metagenomic elements [95-97].

Anti-microbial peptides

50 Designed antimicrobial peptides (dAMPs) are synthesized peptides that are analogues of naturally occurring AMPs, which provide the first line of defence against invading pathogens in all multicellular organisms [98-100]. dAMPs, also known as host defence peptides, possess direct antibiotic activities in addition to modulating immune responses [98]. They act as antimicrobial agents by electrostatically interacting and selectively perturbing the barrier function of the bacterial membrane. This membrane is rich in anionic phospholipids and negatively charged lipopolysaccharides, in contrast to mammalian cells that are predominantly composed of zwitterionic phospholipids [101]. The remarkable targeting and direct disruption of the bacterial membrane makes bacterial resistance less likely [98].

51 In an in vitro assay, several dAMP sequences were screened for bactericidal effectiveness against antibiotic-resistant C. acnes clinical isolates [102]. Five different peptides exhibited potent in vitro antibacterial activity. A topical application of 5 mg/mL RP556 (0.5%) eliminated infection. The authors hypothesized that if these preclinical results are translated clinically, dAMPs may be considered a topical monotherapy to treat recalcitrant acne.