Novel pharmacological approaches for the treatment of acne vulgaris.

Review

Novel pharmacological approaches for the treatment of acne vulgaris 1.

Introduction

2.

Agents that primarily target sebum production

3.

Agents that primarily

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normalize abnormal keratinization within the pilosebaceous unit 4.

Agents that primarily work by modulating P. acnes

5.

Agents that primarily work by modulating the inflammatory response

6.

Conclusion

7.

Expert opinion

Isabel Cristina Valente Duarte de Sousa Private Dermatology Practice, Mexico City, Mexico

Introduction: Acne vulgaris is the most common skin disease worldwide; yet, current treatment options, although effective, are associated with unwanted side effects, chronicity, relapses and recurrences. The adequate control of the four pathogenic mechanisms, involved in the appearance of acne lesions, is paramount to treatment success. Areas covered: The authors discuss and evaluate the pathogenic pathways related to the mechanisms of action of novel molecules, which are currently under investigation for the treatment of acne vulgaris. The manuscript is based on comprehensive searches made through PubMed, GoogleScholar and ClinicalTrial.gov, using different combination of key words, which include acne vulgaris, pathogenesis, treatment, sebogenesis and Propionibacterium acnes. Expert opinion: In the near future, more effective treatments with fewer side effects are expected. The use of topical antiandrogens, acetylcholine inhibitors and PPAR modulators seem to be promising options for controlling sebum production. Retinoic acid metabolism-blocking agents and IL-1a inhibitors have the potential to become legitimate alternative options to retinoid therapy in the management of infundibular dyskeratosis. Indeed, the authors believe that there will likely be a decline in the use of antibiotics for controlling P. acnes colonization and targeting the inflammation cascade. Keywords: acne vulgaris, antiandrogens, antimicrobial peptides, comedo, melanocortin receptor antagonist, monoclonal antibodies anti-IL-1a, PPARs, Propionibacterium acnes, retinoic acid metabolism-blocking agents, sebogenesis Expert Opin. Investig. Drugs [Early Online]

1.

Introduction

Acne vulgaris, a chronic inflammatory disease of the pilosebaceous unit [1], is the most common cutaneous disorder worldwide affecting up to 80% of adolescents [2] and up to 50% of adults [1]. Although the exact pathogenesis of acne is still being investigated, four major factors have been implicated with the appearance of acne lesions: i) altered sebum production; ii) abnormal keratinization within the pilosebaceous unit; iii) Propionibacterium acnes proliferation; and iv) perifollicular inflammation [1,3]. The current effective strategies of management recommended by the Global Alliance are directed toward one or more of these pathogenic causes and include topical and systemic antibiotics and retinoids, benzoyl peroxide (BPO), azelaic acid, salicylic acid and oral antiandrogens, depending on the severity of the disease [1]. However, because of unwanted side effects (irritation, bacterial resistance, systemic side effects) and chronicity [1], new treatments that target the different pathogenic mechanisms of acne with minimal side effects are desirable. The main objective of this paper is to review the current research being developed for the treatment of acne and to focus on novel molecules or approaches that differ 10.1517/13543784.2014.923401 © 2014 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

1

I. C. Valente Duarte de Sousa

One of the main factors in the pathogenesis of acne is excessive sebum production [4,5].

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Four major factors have been implicated in the appearance of acne lesions: i) altered sebum production; ii) abnormal keratinization within the pilosebaceous unit; iii) Propionibacterium acnes proliferation; and iv) perifollicular inflammation. Past knowledge on the pathogenesis of sebum production was sparse and was thought to be mainly a consequence of androgenic stimuli. However, recent findings have determined that other hormones such as a-melanocyte-stimulating hormone and IGF-1 also play a role. Skin sebogenesis is further controlled by acetylcholine, acetyl coenzyme A carboxylase and the presence of proinflammatory mediators, such as leukotriene B4, and their interaction with PPARs. These new findings have opened an array of possibilities for new treatment targets. Low levels of endogenous retinoic acid lead to abnormal keratinization within the follicular epithelium and consequently to comedo formation. Current treatment strategies to limit hyperkeratinization include exogenous administration of retinoids, which can cause side effects such as irritation, erythema, desquamation and dryness, among others. New treatment strategies are focused on increasing endogenous retinoic acid levels to limit side effects. Due to the growing concern over bacterial resistance, antibiotic use will decline over the next years and will be substituted with antimicrobial peptides and antioxidants. P. acnes population needs to be effectively controlled, because it has been associated with direct IL-1a, IL-b, TNF-a, metalloproteinase secretion, neutrophil migration and inflammation, which in turn is associated with scarring and sequels. More recently, the presence of IL-1a has also shown to be involved in comedo formation. Drugs that control IL-1a and IL-b secretion are currently being evaluated for the treatment of acne.

This box summarizes key points contained in the article.

from what is already established in current treatment guidelines. Therefore, a comprehensive review of the pathogenesis of acne or its treatment is beyond the scope of this paper; nevertheless, relevant pathogenic pathways are evaluated and discussed throughout the paper in relation to the mechanisms of action of these novel therapies.

Agents that primarily target sebum production (Table 1) 2.

Much has been discovered in sebaceous gland function in the past few years so it is no surprise that much research is being made on the pharmaceutical control of sebum production. Sebaceous glands play a central role in regulating diverse skin functions, but their principal function is to produce sebum, a lipid mixture of squalene, wax esters, triglycerides, cholesterol esters and free fatty acids, via the complete disintegration of its glandular cells (holocrine secretion) [2,3]. 2

Antiandrogens Androgens have been known to contribute to the onset and persistence of acne [6,7] by increasing sebum production through the activation of its androgen receptor (AR) located in the epithelial cells of sebaceous glands [7,8]. Interestingly, it has been noted that complete androgen-insensitive or castrated males do not develop acne due to a reduction in sebum production [9]. Although the exact mechanisms by which the interaction of androgen/AR regulates sebocyte activity in acne vulgaris are still unclear, it is thought to be through an increase in lipid synthesis, sebocyte proliferation and inflammation [7,10]. Sebaceous glands are known to contain type I and type III 5a-reductase [11,12], the enzymes that converts dehydroepiandrosterone and dehydroepiandrosterone sulfate into testosterone and its most potent active form dihydrotestosterone (DHT) [8,13]; thus the skin has the capacity of synthesizing its own testosterone and DHT either by metabolizing weaker circulating androgens into more potent ones by using 5-a reductase or by metabolizing cholesterol [8,13,14]. This capacity to locally produce DHT and testosterone aggravates sebum production and consequently acne lesions [7]. Interestingly, it has been noted that skin from acne patients have higher rates and amounts of testosterone and 5a-reductase than skin from healthy individuals [8,15]. Although the main mechanism of action of isotretinoin, an oral retinoid used in severe forms of acne, is the normalization of follicular dyskeratosis [1], it has also been shown to decrease AR levels in human skin, which might in part explain the reduction in sebum production observed in patients treated with isotretinoin [16]. ARs are also present in keratinocytes and their stimulation has shown to induce local TNF-a expression [17], contributing to the local inflammation observed in acne patients. Therefore, acne could be treated by either decreasing serum androgen levels or by inhibiting the action of androgens in the sebaceous glands [7]. Antiandrogen therapy is not a novel concept in the treatment of acne; however, due to their oral administration and consequent systemic side effects [18], antiandrogens are only recommended in the treatment of moderate-to-severe acne in female patients who have not responded to conventional therapy alone [1]. Antiandrogens for topical use are currently undergoing clinical trials and seem to offer a safe approach for controlling sebogenesis. 2.1

Cortexolone 17a-propionate (CB-03-01) Cortexolone 17a-propionate, also known as CB-03-01, is a new topical monoester of cortexolone [6,19], which exhibits potent antiandrogen activities [6]. Animal studies have determined that CB-03-01 displays stronger local antiandrogenic activity than other known 2.1.1

Expert Opin. Investig. Drugs (2014) 23(10)

Mechanism of action/advantages

Studies available

Year

Purpose of study

Clinical phase

Number of subjects enrolled

Study design

Antiandrogens The interaction between antiandrogens and the androgen receptor (AR) decreases lipid synthesis, sebocyte proliferation and inflammation [7,10] Cortexolone Topical application 2011 To establish the safety [6] Pilot study 77 Randomized, 17a propionate decreases lipid and efficacy of double-blind, synthesis locally cortexolone 17 a comparative study without any propionate 1% cream in versus placebo and androgenic systemic acne vulgaris applied to tretinoin side effects [19] the face once nightly for 8 weeks in comparison to placebo and to tretinoin 0.05% cream [20] 2013 To evaluate the adrenal Phase II 50 Interventional, suppression potential and single-group pharmacokinetic properassignment, ties of cortexolone 17a open-label study propionate 1.0% cream applied every 12 h for 2 weeks in subjects with acne [21] 2014 To evaluate the safety Phase II 360 Multicenter, and efficacy of randomized, cortexolone 17a double-blind, propionate cream applied vehicle-controlled to the face twice daily for and dose-escalating 12 weeks in the study treatment of acne vulgaris 2008 To evaluate the safety [25] Phase IIa 186 Multicenter, ASC-J9 cream Selectively promotes and efficacy of ASC-J9 randomized, the degradation of the cream at three different double-blind, AR [22-24], and thus exerts its concentrations (0.001%, placebo-controlled antiandrogenic effects 0.005%, 0.025%) study by inhibiting the applied twice daily for interaction of 12 weeks for the circulating androgens treatment of facial acne with their receptor vulgaris [26,27] 2012 To evaluate the safety and thus reducing Phase IIb 181 Multicenter, and efficacy of two sebaceous gland size randomized, different concentrations and sebum double-blind, of ASC-J9 cream (0.1 and production [17,25]

Examples

Table 1. Agents that primarily target sebum production.



No official results have been published

ASC-9 0.025%, was superior to placebo in changing the percentage of inflammatory lesion counts (-44.8 ± 35.6 vs -37.4 ± 41.0), respectively No serious adverse effects were reported

Ongoing study, no final results published

Cortexolone 17a propionate 1% cream was statistically better than placebo in reducing total lesion count (p = 0.0017), inflammatory lesion count (p = 0.0134) and Acne Severity Index (p = 0.0090), without any major side effects Ongoing study, no final results published

Main results

Novel pharmacological approaches for the treatment of acne vulgaris

3

4


2013

2013

[36-39]

[40-42]

Studies Year available

2012

Year

[10]

Studies available

Purpose of the study

0.025%) applied topically twice daily for 12 weeks for the treatment of acne To determine the effect of a daily topical application of NVN1000 0.5, 1.5 and 3 % gel on androgen-dependant hamsters flank glands for 28 days in comparison to vehicle alone To determine the safety and cutaneous tolerability of NVN1000 gel applied to the face twice daily for 2 weeks To compare the efficacy, tolerability and safety of NVN1000 gel 1 and 4% with vehicle gel twice daily in the treatment of acne

Purpose of study

Clinical phase

Phase II/III

Phase I

Preclinical study (animal model)

Clinical phase


153

30

Not applicable


Melanocortin receptor antagonists Antagonists of the melanocortin receptor 5 (MC5-R) inhibit sebocyte differentiation and reduce sebum production [4,5] JNJ 10229570 Decreases sebaceous 2011 To evaluate the safety [53] Phase I 18 gland’s size, and tolerability of a single production of topical application of JNJ sebaceous lipids and 10229570 1.2 and 3.6% the expression of the compared to placebo 2012 To evaluate the efficacy sebaceous differentia- [54] Phase II 400 and safety of a JNJ tion marker epithelial10229570-AAA topical membrane cream applied once daily antigen [48] for 12 consecutives weeks

Mechanism of action

Topical nitric oxide decreases skin androgen levels and reduces 5-a reductase activity, thus reducing sebocyte proliferation, sebum production and lipogenesis

NVN1000

Examples


Examples

Table 1. Agents that primarily target sebum production (continued).



Multicenter, double-blind, vehicle-controlled study

Main results

NVN is superior to placebo in reducing inflammatory and non-inflammatory lesion counts (p £ 0.05). It also decreased sebum production by 80%.


NVN1000 dose-dependently inhibited the growth of androgen-dependent hamster flank glands without evidence of systemic absorption

Main results

Randomized, double-blind, placebo-controlled study

Study design

Randomized, double-blind, multiple-dose, parallel-group study Multicenter, randomized, double-blinded, vehicle-controlled, parallel-group, three-arm study

Not applicable

vehicle-controlled study

Study design



Mechanism of action



Clinical phase

2006

To determine the clinical Phase I and histological effects of 1 and 5% EGCG solution applied topically to the face twice a day for 8 weeks in subjects with acne

Study design

35

Randomized, double-blind, vehicle-controlled study

Not applicable Not applicable

Not applicable Not applicable


EGCG significantly reduces size of sebaceous glands (p < 0.01), the mean number of sebocytes per gland (p < 0.05) and size of comedos (p < 0.001) EGCG inhibits cell proliferation and lipid synthesis in vitro (p < 0.001) EGCG decreases lipogenesis in human sebocytes by 55%, decreases inflammation and induces apoptosis of sebocytes Patients treated with EGCG solution showed a 79 -- 89% reduction in noninflammatory and inflammatory lesion counts after 8 weeks of treatment (p < 0.05) without any serious side effects

Main results

PPARs modulators PPARs are transcription factors that upregulate lipid synthesis. Leukotriene B4 (LTB4) is a ligand for PPAR, so by inhibiting its production, PPAR-mediated sebogenesis is controlled [2] 2003 To determine the effects Experimental Not applicable Not applicable Zileuton reduced neutral and Zileuton Zileuton is a of zileuton in human study polar lipids in SZ95 sebocytes 5-lipoxygenase (5-LOX) sebocytes in vitro (p < 0.001). Zileuton also inhibitor. reduces IL-6 release from Both 5-LOX, the SZ95 sebocytes (-42 ± 1%; enzyme responsible p < 0.001) for catalyzing the [76] 2003 To determine the effects Pilot study 10 Single-blinded Zileuton reduced the number conversion of of zileuton in patients of inflammatory lesions by arachidonic acid into with inflammatory acne 29% (p < 0.01), decreased LTB4, and PPAR are total sebum lipids and overexpressed in skin proinflammatory free fatty and sebaceous glands acids by 35% (p < 0.05) and of acne 22%, respectively and patients [66,77] thus providing logical diminished lipoperoxides by

[75]

IGF-1 inhibitors IGF-1 has been shown to stimulate androgen-induced lipogenesis and sebocyte proliferation [56,57,64] Epigallocatechin-3- Suppresses IGF-1-in2012 To examined the effects [65] Preclinical gallate (EGCG) duced lipogenesis and of EGCG on study cytokine expression in IGF-1-induced lipogenesis (animal sebocytes [65]. It also and inflammation in study, inhibits 5a-reductaseanimal models in vivo and in vitro 1 activity, and thus in human sebocytes model) limits in vitro dihydrotestosteronedependant sebum [74] 2006 To examined the effects Preclinical production [71] of EGCG on lipogenesis study and inflammation in (in vitro human sebocytes in vitro model)

Examples

Table 1. Agents that primarily target sebum production (continued).




5

6

support for the use of 5-LOX inhibitors to inhibit PPAR-mediated lipogenesis

Mechanism of action

[82]

[2]

2005

2003


Pilot study

Clinical phase

To test the safety and Phase II efficacy of zileuton in the treatment of facial acne

To determine the effects of zileuton in patients with inflammatory acne


90

10


Acetylcholine (ACH) inhibitors Ach increases lipid synthesis in a dose-dependent manner [91] 2012 To determine the safety, Phase II 72 ANT-1207 (Topical Botulinum toxin tolerance and efficacy of formulation of inhibits the ANT-1207 in the botulinum toxin) presynaptic release of treatment of acne Ach, which in turn reduces sebum production Acetyl coenzyme A carboxylase (ACC) inhibitors ACC is involved in the regulatory steps of sebaceous fatty acid biosynthesis resulting in de novo synthesis of lipids [95] 2014 To assess the safety and DRM01B Inhibitor of ACC Phase I 6 tolerability of DRM01B 7.5% topical gel applied for 1 week [96] 2014 To assess the safety, Phase II 100 tolerability and preliminary efficacy of 12-week application of DRM01B 7.5% topical gel

Examples

Table 1. Agents that primarily target sebum production (continued). Main results


Expected in June 2014

Expected in June 2014

Randomized, double-blind, vehicle-controlled study

Open-label

Randomized, vehicle-controlled, parallel-group study

26%. The degree of clinical improvement strongly correlated with the descent in total sebum lipids (p = 0.0009) and free fatty acids (p = 0.0003) Open-label, Zileuton decreased cohort study inflammatory and noninflammatory lesions by 71% (p = 0.007) and 36%, respectively. It also reduced the Acne Severity Index by 59% (p = 0.01) and suppressed total sebum lipid production by 65% (p = 0.038) after 12 weeks of treatment Randomized, Zileuton was effective in double-blind, reducing the number of placebo-controlled, inflammatory lesion by parallel-group, 41.6% (p = 0.025) multicenter study

Study design






antiandrogens such as progesterone, flutamide and finasteride without any systemic side effects. Although the mechanism through which topical CB-03-01 exhibits antiandrogenic effects has still not been completely elucidated, an interaction with the AR is proposed [19]. In 2011, Trifu et al. evaluated the safety and efficacy of CB-03-01 1% cream in acne vulgaris in comparison to placebo and to tretinoin 0.05% cream. A total of 77 male subjects were randomized to receive CB-03-01 1% cream, tretinoin 0.05% cream or placebo once nightly for 8 weeks. CB-03-01 1% cream was statistically better than placebo in reducing total lesion count (p = 0.0017), inflammatory lesion count (p = 0.0134) and Acne Severity Index (p = 0.0090), without any major side effects. Further, CB-03-01 1% cream showed a faster onset of all the abovementioned improvements and was clinically more effective than tretinoin 0.05% cream, although the results were not statistically significant [6]. Another study designed to evaluate the adrenal suppression potential and pharmacokinetic properties of 1.0% CB-03-01 cream applied every 12 h for 2 weeks in subjects with acne, was completed in November 2013. Approximately 50 males and females aged ‡ 12 years were enrolled in the study. No official results have been published yet, as this study is still ongoing [20]. The safety and efficacy of CB-03-01 cream in the treatment of acne vulgaris is currently being investigated in the USA in a Phase II, multicenter, randomized, double-blind, vehiclecontrolled and dose-escalating study. Approximately 360 males and females, aged ‡ 12 years, were included in the study and were instructed to apply either cortexolone cream at different concentrations or vehicle cream to the face twice daily for 12 weeks. The primary estimated completion date for this trial is March 2014 [21]. ASC-J9 cream ASC-J9 selectively promotes the degradation of the AR [2224] and thus exerts its antiandrogenic effects by inhibiting the interaction of circulating androgens with their receptor. A topical formulation of ASC-J9, ASC-J9 cream, has been shown to reduce sebaceous gland size and sebum production in animal studies [17] and in human subjects [25,26]. In 2008, a Phase IIa, multicenter, randomized, double-blind, placebocontrolled study to valuate the safety and efficacy of ASC-J9 cream at 3 different concentrations (0.001%, 0.005%, 0.025%) applied twice daily for 12 weeks for the treatment of facial acne vulgaris was completed. A total of 186 subjects were included in the study (76 female, 110 male, mean age 17.9 ± 5.2). ASC-9 0.025%, but not ASC-J9 0.005 and 0.001%, was superior to placebo in changing the percentage of inflammatory lesion counts from baseline to week 12 (-44.8 ± 35.6 vs -37.4 ± 41.0, respectively). Percentage of participants who showed improvement in the Investigator’s Global Assessment (IGA) scale was also superior in the group treated with ASC-J9 cream in comparison to placebo (60.8 vs 48.9%, respectively). No serious adverse effects were reported 2.1.2

in any of the ASC-J9 treatment groups; however, patients treated with ASC-J9 cream had an overall higher number of upper respiratory tract infections, nasopharyngitis and streptococcal infections reported in comparison to the placebo group [25]. Although, ASC-J9 clinically reduced inflammatory lesions compared to placebo and seemed to have a therapeutic benefit comparable to marketed acne drugs on inflammatory lesions, the study was not powered for statistical significance. AndroScience is, therefore, currently working on bolstering efficacy through a new formulation [27]. The Phase IIb trial that followed was a multicenter, randomized, double-blind, vehicle-controlled study in which the safety and efficacy of two different concentrations of ASC-J9 cream (0.1 and 0.025%) applied topically twice daily for 12 weeks for the treatment of acne were evaluated. A total of 181 male and female patients, aged ‡ 12 years old, were enrolled [26] and were randomized to receive either 0.1% ASC-J9 cream, 0.025% ASC-J9 cream or placebo (~ 60 participants per group) [27]. The study was completed in 2012; however the official results of this study have not been disclosed yet [26]. Nevertheless, ASC-J9 cream seemed to have a positive treatment response in patients with acne superior to treatment with vehicle alone. Patients treated with ASC-J9 cream showed a reduction in total, inflammatory, and noninflammatory lesion counts at weeks 2, 4, 8 and 12, as well as an improvement in the IGA score, which is indicative of ASC-J9 superiority to placebo in the treatment of acne. No systemic or local side effects were reported during the study, thus making ASC-J9 a drug with an adequate safety profile [27]. NVN1000 NVN1000, also called SB204, is a gel that releases nitric oxide (NO) when applied topically to the skin [10]. Animal studies have previously established that steroidogenesis is inhibited when concentrations of NO increase [28-30], due to inhibition of the conversion of cholesterol into steroid hormones [29], such as testosterone DHT [10]. By inhibiting CYP450 and reducing 5-a reductase activity [10,31,32], both of which can be found in sebocytes [13] and are required for independent skin steroidogenesis [8], NO is able to decrease skin androgen levels, thus reducing sebocyte proliferation, sebum production [10] and lipogenesis [33]. Thus, NO exerts its antiandrogenic effects by inhibiting the androgen-dependant sebum production pathway [10]. Considering that the skin from acne patients has higher rates and amounts of testosterone and 5a-reductase than the skin from healthy individuals [8,15], treatment with NO could potentially decrease androgen conversion and thus reduce sebum production [10]. Further, as a reactive free radical, NO exhibits antibacterial effects [34,35] by damaging the cell membrane and inhibiting cell function via oxidative and nitrosative stress [34], which reduces P. acnes proliferation [10]. It is also proposed that by 2.1.3


7



inhibiting sebum production, NO would altogether avoid abnormal P. acnes colonization [10]. In animal studies, NVN1000 has proven to inhibit sebaceous gland growth after 28 days of topical application without any systemic absorption, activity, side effects or toxicity [10], thus suggesting that it could be a potential new treatment for controlling sebum production. In humans, the tolerability, safety and efficacy of different concentrations (1%, 4%, 8%) of NVN1000 have also been evaluated in four Phase I clinical trials [36-39]. The last study, a randomized, double-blind, multiple-dose, parallel-group study to determine the safety and cutaneous tolerability of NVN1000 gel applied to the face twice daily for 2 weeks in 30 healthy male and female volunteers, was completed in June 2013 [39]. The effects of NVN1000 gel on P. acnes counts were also evaluated in this trial [39]. The results showed that SB204 gel reduced the colonization of P. acnes by 90% (p < 0.05) without any major side effects [40]. A Phase II/III multicenter, randomized, double-blinded, vehicle-controlled, parallel group, three-arm study, comparing the efficacy, tolerability and safety of two concentrations of NVN1000 gel (1 and 4%) with vehicle gel applied twice daily in the treatment of acne was completed last November 2013. A total of 153 patients, aged 12 -- 40 years, were enrolled in the study [41]. A total of 129 patients completed the 12-week study period [42]. The results showed that both concentrations of NVN1000 gel were superior to vehicle alone in reducing non-inflammatory and inflammatory lesions count as early as week 4 (p £ 0.05). By week 12, the median reduction for inflammatory lesions was 62% in the intent to treat population. Moreover, no serious adverse effects were reported and treatment with NVN1000 was as well tolerated as treatment with vehicle alone. It was also determined that NVN1000 is able to reduce sebum production by 80% in 12 weeks [42].

Melanocortin receptor antagonists Although the exact role that melanocortin receptor (MCR) plays in skin sebogenesis remains to be fully elucidated, some interesting findings have to come to light. Alpha-melanocyte-stimulating hormone (a-MSH) has been implicated in increased sebogenesis in rodents [43] via the stimulation of two receptor subtypes, the melanocortin receptor 1 (MC1-R) and the melanocortin receptor 5 (MC5-R), both of which are expressed in human sebocytes [44-49] MC1-R activity has been found to be more pronounced in the sebocytes of skin of acne patients than in the skin of healthy individuals, suggesting that it may be implicated with the pathogenesis of acne. MC1-R expression is upregulated by proinflammatory signals, which are also elevated in acne, which in turn also suggest that MC1-R may play a role in protecting the sebocytes from cytotoxic stimuli released during inflammation [50]. MCR-5 has been associated with sebum production and sebocyte differentiation [4]. 2.2

8

Chen et al. determined that after disruption of the murine MC5-R gene, a reduction in hair lipid content was observed [51]. Further, MC5-R-deficient mice exhibit a reduction in sebaceous lipids [4], which is consistent with previous findings that a-MSH acts as a sebothropic hormone [43,52] Studies in vitro have shown that antagonists of MC5-R inhibit sebocyte differentiation [4]. MC5-R antagonists are also capable of reducing sebum production in human skin transplanted onto immunodeficient mice [4], which suggest a role for MC5-R antagonists as potential sebum-suppressive agents [4] Eisinger et al. determined that JNJ 10229570, a MC1-R and MC5-R antagonist, decreases sebaceous gland’s size, production of sebaceous lipids and the expression of the sebaceous differentiation marker epithelial-membrane antigen in cultured primary human sebocytes. Further, a reduction in the hypercornification of the infundibulum is observed [48]. Two clinical trials have evaluated the role of JNJ 10229570 cream in the treatment of acne: i) a randomized, double-blind study to evaluate the safety and tolerability of a single topical application of JNJ 10229570-AAA cream at two different concentrations (1.2%, 3.6%) compared to placebo on 18 Japanese subjects with acne aged 25 -- 35 years [53]; and ii) a multicenter, double-blind, vehicle-controlled, Phase II study to evaluate the efficacy and safety of a JNJ 10229570-AAA topical cream applied once daily for 12 consecutives weeks in 400 male and female acne patients, aged ‡ 12 years [54]. Both studies have been completed but no official results have been published [53,54]. IGF-1 inhibitors IGF-1 has been recently implicated in the pathogenesis of acne. Interestingly, subjects with Laron syndrome, a congenital IGF-1 deficiency, do not develop acne [55]. IGF-1 has been shown to stimulate lipogenesis in human sebocytes [56,57] and induce keratinocyte proliferation in vitro and in vivo [58-63] Moreover, IGF-1 has been associated with increased androgen-induced lipogenesis and sebocyte proliferation [64], as well as with increased inflammatory cytokines production such as IL-1, IL-6 and IL-8 [65], known to be elevated in acne [3,66]. High serum IGF-1 levels directly correlate with the severity of acne [67,68] and the amount of facial sebum [69]. Further, skin from acne lesions present higher levels of IGF-1 and IGF-1 receptor (IGF-1R) than skin from healthy individuals [70]. Interestingly, IGF-1 and IGF-1R expression in keratinocytes can be stimulated by P. acnes [70]. Animal models have demonstrated that epigallocatechin3-gallate (EGCG), a major polyphenolic constituent in green tea, significantly reduces size of sebaceous glands (p < 0.01), the mean number of sebocytes per gland (p < 0.05) and size of comedos (p < 0.001), similar to all-trans-retinoic acid (RA) [65]. Further, EGCG dose-dependently inhibits cell proliferation and lipid synthesis in SZ95 sebocytes in vitro (p < 0.001) via inhibiting IGF-1 [65]. 2.3




EGCG has also shown to inhibit 5a-reductase-1 activity, and thus limit DHT-dependant sebum production [71]. Further, EGCG exerts antimicrobial activity against P. acnes and has proven to be clinically effective in the treatment of acne without any major side effects [65,72-74]. Further, EGCG has been shown to decrease lipogenesis in human SEB-1 sebocytes in vitro by 55%, to decrease inflammation through the inhibition of NF-kB and AP-1 pathways and to induce cytotoxicity of SEB-1 sebocytes via apoptosis [74]. A randomized, double-blind study to evaluate the effects of 1 or 5% EGCG solution applied twice daily to the face for 8 weeks in subjects with acne was completed in 2006 [75]. The study included 35 subjects, aged 15 -- 40 years (mean age 22.1), who showed significant improvement in acne lesions. Patients treated with EGCG solution showed a 79 -- 89% reduction in non-inflammatory and inflammatory lesion counts after 8 weeks of treatment (p < 0.05). No serious side effects were reported. Mild side effects such as erythema were present in only four patients. Further, immunohistochemical analysis of acne-affected skin before and after treatment showed a reduction in the expression of IL-8, sterol regulatory element-binding proteins type 1, phospho-c-Jun and NF-kB, which suggests that EGCG decreases the inflammatory response and increases apoptosis in acne lesions in vivo [74]. Zinc gluconate has also been shown to reduce the overexpression of IGF-1 and IGF-1R caused by P. acnes [69]. PPARs modulators Zileuton, an oral 5-lipoxygenase (5-LOX) inhibitor, has been shown to reduce the number of inflammatory lesions in moderate acne by downregulating IL-6 and leukotriene B4 (LTB4) and by temporarily inhibiting the synthesis of sebaceous lipids [76]. Zileuton inhibits sebum production in a manner similar to that of isotretinoin in a mechanism [2] thought to involve PPARs [76]. PPARs are ligand-activated transcription factors, highly expressed in human skin and other tissues [76], that have been shown to upregulate lipid synthesis and regulate cell proliferation, differentiation and apoptosis [2,77-79]. The three described isoforms of PPARs, PPAR-a, PPAR-b/d and PPAR-g are encoded in different genes and thus exhibit different ligand specificities, target genes, tissue distribution and biological roles [2,77,78,80]; however, all three have been implicated with increased lipogenesis [2,77,80]. PPAR-a mainly contributes to sebocyte activity through lipid and lipoprotein metabolism [2,80]. PPAR-b/d, the most abundantly expressed PPAR in human epidermis [81], has also been shown to enhance lipid synthesis and to upregulate keratinocyte differentiation, while limiting proliferation, reducing inflammation and accelerating skin barrier repair [77]. LTB4, a ligand for PPAR-a and a major player in the inflammation cascade, induces lysosomal release and IL production by neutrophils, increases neutrophil adherence and migration, promotes the generation of superoxide radicals, activates complement [2] and increases the synthesis of neutral 2.4

lipids [2,64]. Both 5-LOX, the enzyme responsible for catalyzing the first step in converting arachidonic acid into LTB4 [2,64], and PPAR are overexpressed in skin and sebaceous glands of acne patients [65,77], thus providing logical support for the use of 5-LOX inhibitors to downregulate expression of LTB4 in sebaceous gland [2], and thus inhibit PPAR-mediated lipogenesis. In a pilot study that included four female and six male subjects, zileuton was found to decrease acne severity by reducing the number of inflammatory lesions by 29% (p < 0.01), decreasing total sebum lipids and proinflammatory free fatty acids by 35% (p < 0.05) and 22%, respectively, and by diminishing lipoperoxides by 26% [76]. It is important to mention that the degree of clinical improvement and the decrease in inflammatory lesion count strongly correlates with the descent in total sebum lipids (p = 0.0009) and free fatty acids (p = 0.0003) [2,76]. A Phase II, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to determine the effects of zileuton on the count number of inflammatory and non-inflammatory lesions and on sebum production in patients with moderate-to-severe facial acne [82], showed that zileuton was effective in reducing the number of inflammatory lesion by 41.6% (p = 0.025) [2]. In another study, zileuton proved to significantly decrease inflammatory and non-inflammatory lesions by 71% (p = 0.007) and 36%, respectively, to reduce the Acne Severity Index by 59% (p = 0.01) and to suppress total sebum lipid production by 65% (p = 0.038) after 12 weeks of treatment. Zileuton also decreased free fatty acids and hydroperoxides levels in sebum [2]. Acetylcholine inhibitors Evidence for cholinergic signaling in sebaceous glands is still sparse. Sebaceous glands express acetylcholine (Ach) receptors [83] in a highly regulated manner, suggesting a role of Ach in sebum production, probably through promoting sebocyte differentiation [84]. Recently it was established that Ach increases lipid synthesis in a dose-dependent manner, in both cultured sebocytes and in healthy volunteers, probably due to its interaction with the Ach receptor a7 expressed in sebaceous glands [85]. Botulinum toxin inhibits the presynaptic release of Ach [86,87] and has recently been found to noticeably decrease sebum production, oily skin and pore size [85,88,89]. Further, topical anticholinergic agents (poldine methylmethosulfate) have also shown to reduce sebum production [90]. Thus, Ach inhibitors could offer a potential benefit in the treatment of acne. The safety and efficacy of a topical formulation of botulinum toxin type A (ANT-1207) was evaluated in 2012 in a Phase II, vehicle-controlled, double-blind, clinical study; however, the results have not been published yet [91]. 2.5

Acetyl coenzyme A carboxylase inhibitors Animal models have established that androgenic stimulation of sebaceous glands increases key enzymes involved in the 2.6


9



regulatory steps of sebaceous fatty acid biosynthesis, such as acetyl coenzyme A carboxylase (ACC) [92,93]. ACC catalyzes the conversion of acetyl-coenzyme A (CoA) into malonyl-CoA, which in turn is determinant of whether fatty acids are synthesized or oxidized [94]. ACC has two isoforms (ACC1 and ACC2) and although they both catalyze the conversion of acetyl-CoA into malonyl-CoA, the product of this reaction exerts different biological activities [94]. Both ACC1- and ACC2-mediated malonyl-CoA syntheses can result in de novo synthesis of lipids, but only ACC2 is capable of catalyzing malonyl-CoA involved in fatty acid oxidation. Further, inhibition of ACC has shown to significantly increase fatty acid oxidation and to reduce triglyceride synthesis [94]. Dermira, Inc. is currently recruiting male and female subjects, aged ‡ 18 years, to participate in a Phase I/II randomized, double-blind, parallel assignment clinical trail on the safety, tolerability and preliminary efficacy of the topical application of DRM01B (an inhibitor of the enzyme ACC [95]) gel on healthy subjects and in subjects with acne vulgaris. Phase I of this clinical trial involves an open-label study designed to assess the safety and tolerability of DRM01B 7.5% topical gel on six healthy volunteers who will be using the product for 1 week. If no major adverse effects are reported and if local tolerability is acceptable, the study will move on to Phase II, a randomized, vehiclecontrolled, parallel-group study that will assess the safety, tolerability and preliminary efficacy of 12-week application of DRM01B 7.5% topical gel in approximately 100 subjects with acne vulgaris. The estimated primary completion date of both studies is set for June 2014 [96].

3. Agents that primarily normalize abnormal keratinization within the pilosebaceous unit (Table 2) 3.1

Retinoic acid metabolism-blocking agents Talarozole

3.1.1

Talarozole, also called Rambazole or R115866, [97], is a selective azole derivative [98] that potently inhibits the CYP26, known to be involved in the metabolism of RA [99]. RA is involved in the keratinization process within the follicular epithelium and thus is also involved in comedo formation [100]. Rat studies have noted that high plasma levels of RA are associated with inhibition in keratinization [101]. The CYP450 isozyme system is involved in the breakdown of RA through oxidative metabolism [100]. Although several CYP isozymes are capable of initiating RA oxidation, CYP26 seems to be the isozyme that is more specific for RA breakdown [100]. The rational is that talarozole by inhibiting CYP26 increases the level of RA, allowing for normalization of desquamation of the follicular epithelium and thus reducing comedo formation [100]. 10

CYP26 inhibitors are capable of enhancing RA levels thus displaying retinoidal actions, such as inhibition of keratinization and induction of epidermal hyperplasia, among others [100]. A gel formulations containing 0.35 and 0.7% talarozole has been studied on human skin in a Phase I randomized trial performed with 16 healthy individuals, and it was determined that topical talarozole presents retinoic acid effects with less inflammation [102]. Topical talarozole has also been found to induce these retinoid-like effects even after a single topical application [98]. Taken together, these data suggest that CYP26 inhibitors could potentially presents an advantage over topical retinoids. As with retinoids, some concerns have also been raised with CYP inhibitors on the potential for mutagenesis [103,104]. In 2011, Stiefel, a GSK Company, completed a Phase II open--label, randomized, pilot trial to assess the safety and efficacy of 1 mg oral R115866 taken once daily for 12 weeks in the treatment of moderate-to-severe facial acne in 16 male patients, aged 16 -- 50 years. No results have been published for this study [97]. Monoclonal antibodies anti IL-1a Comedos or comedones, the primary lesion in acne, are a consequence of abnormal keratinization [105] and although the exact mechanisms underlying their formation remain unclear, IL-1a seems to play a role [106]. In vitro models of acne have determined that stimulation of the pilosebaceous infundibulum with IL-1a induced a hyperkeratinization response similar to that seen in comedos [107]. Further, this effect was reversed with the administration of IL-1 receptor antagonist (IL-1ra) [107]. Ingham et al. reported high levels of IL-1a in comedos extracted from acne patients [108]. The expression of IL-1a in acne seems to be controlled in part by the activation of Toll-like receptors (TLRs), which are major players of innate immunity [106]. TLRs recognize pathogen-associated molecular patterns (PAMPs), such as peptidoglycans (PGN) and lipopolysaccharide, that are present in Gram-positive and Gram-negative bacteria, respectively, and initiate the release of antibacterial factors (b-defensins and reactive oxygen species [ROS]) and proinflammatory mediators such as IL-1a [106]. The expression of TLR-2, one of the main TLRs present in keratinocytes and sebocytes [106], is increased in cultured epidermal keratinocytes exposed to P. acnes and in biopsies of lesional skin from acne patients [109]. Further studies in vitro showed that human epidermal keratinocytes release 46% more IL-1a on TLR stimulation with PGN, the PAMP present in P. acnes, compared to stimulation with vehicle alone (p < 0.05) [106]. Further, sebaceous glands maintained ex vivo exposed to PGN for 7 days, showed increased hyperkeratosis similar to that observed after IL-1a treatment, whereas sebaceous glands exposed to vehicle alone did not [106]. These data suggest that PAMPs not only exert an effect on keratinocytes and induce the release of IL-1a, but 3.2



Studies available

Year

Purpose of study

Clinical phase


Study design


2011

To assess the safety and efficacy of 1 mg oral talarozole taken once daily for 12 weeks in the treatment of moderate-to-severe facial acne Phase II

16

Open-label, randomized

Monoclonal antibodies anti-IL-1a High levels of IL-1a induce hyperkeratinization of the pilosebaceous infundibulum and thus stimulate comedo formation [105-108] RA-18C3 Monoclonal antibody [111] 2012 To determine the Phase II 7 Open-label, specific for IL-1a safety, pharmacokinetsingle-group ics and efficacy of assignment three injections of RA-18C3 administered subcutaneously on subjects with acne

[97]

Retinoic acid metabolism-blocking agents High levels of all-trans-retinoic acid (RA) are associated with normalization of desquamation of the follicular epithelium and thus reduction in comedo Talarozole Azole derivative that [102] 2009 To determine the Phase I 16 Open-label, inhibits the CYP26 in effect of topical randomized charge of RA breakdown, talarozole 0.35 and thus increasing RA serum 0.7% gel on retinoid levels biomarkers in normal skin

Examples

Table 2. Agents that primarily normalize abnormal keratinization within the pilosebaceous unit.


Inflammatory lesion count showed an average improvement of 35± 8% (median 34%, range 25 -- 48%) on day 42 and 44 ± 23% (median 42%, range 19 -- 71%) on day 56

formation [100] Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1, consistent with increased retinoic acid stimulation, without inducing skin inflammation No official results published yet

Main results


11



they also mediate their effects on sebaceous glands via TLRs [106]. Thus, P. acnes seems to activate the release of IL-1a via TLR-2 activation [110]. IL-1a, in turn, seems to play an important role not only in the development of inflammatory lesions but also in the development of comedos [106]. In 2012, a Phase II trial on the safety, pharmacokinetics and efficacy of a RA-18C3, a monoclonal antibody specific for IL-1a [111], to treat subjects with moderate-to-severe acne was concluded. Seven patients (five female, two male), aged 18 -- 30 years (median age 23), were treated with either 100 or 200 mg of RA-18C3, depending on weight, via subcutaneous injection on days 0, 21 and 42 for a total of three injections [111,112]. After three injections, the total facial inflammatory lesion count showed an average improvement of 35 ± 8% (median 34%, range 25 -- 48%) on day 42 and 44 ± 23% (median 42%, range 19 -- 71%) on day 56 [111]. 4. Agents that primarily work by modulating P. acnes (Table 3)

Antimicrobial peptides Antimicrobial peptides (AMPs), discovered in the 1980s, are considered to be a primitive mechanism of immunity and have been shown to have activity against an array of bacteria, mycobacteria, protozoa, fungi, yeasts and viruses [113,114]. They can also act as immunomodulators and enhance immunity [113]. AMPs can be produced by virtually all human cells in the presence of microbes [114]. Two of the most important AMPs are the defensins and the cathelicidins that are mainly produced by epithelial cells and neutrophils [114]. MBI 226, currently known as omiganan pentahydrochloride [115], is a topical cationic peptide [116] derived from the bovine AMP indolicidin [114] that is shown to have rapid (2 -- 6 h) in vitro microbicidal activity against a variety of Gram-positive and Gram-negative bacteria [113-115,117] by disrupting their cytoplasmic membranes and causing depolarization followed by cell death [117,118]. Hemolysis, a side effect of indolicidin, is not as common with omiganan pentahydrochloride [119], which is an important characteristic. Three Phase I studies have determined that omiganan pentahydrochloride solution is well tolerated and not systemically absorbed after topical administration [114,119]. In 2001, a Phase IIa, randomized, placebo-controlled, double-blind study to evaluate the safety and efficacy of MBI 226 2.5 and 5.0% solutions in the treatment of acne vulgaris was completed. The solution was applied topically on 75 male and female subjects, aged ‡ 13 years, with acne vulgaris [120]. After 6 weeks of treatment, patients treated with omiganan presented with a reduced count of comedos (25% reduction in the omiganan group compared to 10% reduction in the placebo group) and of papules and pustules (39% reduction in the omiganan group compared to 21% reduction in the placebo group). Also, according to the Physician’s Global Severity Assessment scores, 41% of patients treated 4.1

12

with omiganan presented good-to-excellent improvement in acne lesions compared to 32% of patients in the placebo group. Treatment with the 2.5% omiganan solution proved to be equal or superior to the 5% solution [114]. In 2003, a Phase II, randomized, vehicle-controlled, double-blind, multicenter clinical trial was completed to evaluate the safety and efficacy of MBI 226 1.25 and 2.5% acne solutions applied topically for 12 weeks on subjects with acne vulgaris. A total of 241 patients, aged 12 -- 45 years, were enrolled. Six weeks into the treatment, patients treated with the 2.5% omiganan pentahydrochloride solution showed statistically significant improvement of non-inflammatory and inflammatory lesion count [121]. Omiganan pentahydrochloride was able to reduce inflammatory lesions by 40% [119]. Antioxidants Vitamin C, a potent antioxidant and ROS scavenger [122], has shown to exert antimicrobial effects on P. acnes, to prevent up to 40% of ultraviolet A-induced sebum oxidation and to improve acne lesions in up to 76.9% of patients [123]. Woolery-Lloyd et al. recently conducted a randomized, double-blind, placebo-controlled trial to determine the efficacy of a twice-daily sodium L-ascorbyl-2-phosphate 5% lotion, a stable vitamin C derivative and potent antioxidant [124], for 12 weeks, in the treatment of acne vulgaris in subjects aged 18 -- 35 years [125]. It was determined that sodium L-ascorbyl-2-phosphate 5% lotion was superior to vehicle alone in reducing lesion counts, while having similar tolerability and adverse reactions frequency [124]. 4.2

Agents that primarily work by modulating the inflammatory response (Table 4)

5.

Phosphodiesterase inhibitors PDEs are known to degrade intracytoplasmic levels of cAMP. Low levels of cAMP lead to preferential expression of proinflammatory cytokines such as TNF-a, IL-1, IL-8, IL-12 and IL- 23 [126,127]. Therefore, agents that inhibit PDEs, and thus elevate cAMP, may play a role in chronic inflammatory diseases that have elevation of IL-1 and TNF-a, such as acne, rosacea and atopic dermatitis. Because PDE4 is the main cAMP-degrading isoenzyme [126], inhibiting PDE4 elevates cAMP levels and thus decreases the activity of proinflammatory cytokines [126]. Therefore, drugs such as apremilast, a small-molecule PDE4 inhibitor [128], could potentially play a role in acne treatment in the future. Apremilast has so far been proven effective in psoriasis and arthritic psoriasis [129]; however, it may have a role in other inflammatory diseases, such as acne, especially in women of child-bearing age in whom retinoids are best avoided [126]. An open-label, pilot study to determine the efficacy of 20 mg of apremilast taken orally twice a day for 12 weeks in the treatment of rosacea has already been completed, but results have not yet been published [130]. 5.1



Studies available

Year

Purpose of study


P. acnes: Propionibacterium acnes.

Antimicrobial peptides Antimicrobial peptides (AMPs) are primitive mechanism of immunity produced by epithelial which have activity against bacteria, amongst others [113,114] MBI 226 MBI 226 is a peptide 2000 To determine safety of [114,119] derived from the AMP topically applied MBI indolicidin that has rapid 226 in healthy volunteers microbicidal activity and patients with acne against Gram-positive and [114] 2001 To evaluate the safety Gram-negative bacteand efficacy of MBI 226 ria [113-117] 2.5 and 5.0% solutions applied topically for 6 weeks in the treatment of acne vulgaris [119,121] 2003 To evaluate the safety and efficacy of MBI 226 1.25 and 2.5% acne solutions applied topically for 12 weeks in subjects with acne vulgaris Antioxidants Antioxidants have shown to exert antimicrobial effects on P. acnes 2005 To determine the Vitamin C Vitamin C presents action [123] in vitro effect of against P. acnes and vitamin C on P. acnes prevent ultraviolet A (UVA)-induced sebum [123] 2005 To determine the effects oxidation [123] of vitamin C solution on UV-induced sebum oxidation [123] 2005 To determine the effect of a 5% vitamin C solution applied topically for 12 weeks on subjects with acne [124,125] 2010 To determine the efficacy of a twice-daily sodium L-ascorbyl-2- phosphate 5% lotion for 12 weeks in the treatment of acne

Examples

Table 3. Agents that primarily work by modulating P. acnes. Number of subjects enrolled

Study design

Main results

241

Not applicable

20

60

50

Experimental study (in vitro)

Pilot study

Pilot study

Phase II

75

Phase IIa

Phase II

71

Phase I

Randomized, double-blind, placebo-controlled trial

Open-label, placebo-controlled

Open-label

Not applicable

Randomized, vehicle-controlled, double-blind, multicenter clinical trial

Randomized, placebo-controlled double-blind study

Open-label

Vitamin C is superior to vehicle alone in reducing lesion counts, while having similar tolerability and adverse reactions frequency

76.9% of patients enrolled showed improvement in acne lesions without any major side effects

1% vitamin C solution has a strong antimicrobial effect with a log reduction of 5 after 8 h on P. acnes Vitamin C prevents the UVA-induced sebum oxidation up to 40%

Significant improvement (40% reduction) of non-inflammatory and inflammatory lesion count

Omiganan pentahydrochloride solution is well tolerated and not systemically absorbed after topical administration Reduced count of comedos (25%) and of papules and pustules (39%) in omiganan group in comparison to control group

cells and neutrophils that act as immunomodulators to enhance immunity and that

Clinical phase



13

14


Studies available

Year

Purpose of study

Clinical phase


Study design

Main results


P. acnes: Propionibacterium acnes.

PDE inhibitors PDE inhibitors limit the production of IL-1 and TNF-a present in inflammatory acne lesions [131] 2010 To determine the safety Apremilast PDE4 inhibitors limit the Phase II 3 Open label, Study terminated for lack and efficacy of 20 mg degradation of cAMP. High single-group of funding apremilast taken twice a levels of cAMP are associated assignment study day for 12 weeks in the with a decrease in levels of treatment of moderateproinflammatory cytokines to-severe acne Inhibitors of IL-1b-mediated inflammatory response P. acnes causes direct IL-1b secretion and thus stimulates inflammation. IL-1b is found to be overexpressed in acne correlating with disease activity and severity in correlation with disease development and severity [132,134,137] XOMA 052 Gevokizumab (XOMA 052) is a 2013 To determine whether [140] Phase II 127 Randomized, This study is currently humanized monoclonal gevokizumab is effective double-blind, active and no preliminary IgG2 antibody with high affinity in the treatment of placebo-controlled results have been and specificity to IL-1b. moderate-to-severe acne study published yet. Results are Inhibiting IL-1b increases vulgaris expected in 2014 IL-6 release, reduces TNF-a levels and decreases neutrophil migration, thus reducing acute inflammation in vivo [132,139] Vitamin D (VD) analogs VD analogues modulate TNFa and IL-8 and IL-6 expression, all of which are altered in acne lesions due to the presence of P. acnes [141,142] VD VD and its analogs have been [141] 2013 To determine changes in Experimental Not applicable Not applicable ELISA showed a decrease shown to decrease inflammatory inflammatory biomarkers study in the expression of IL-6, cytokine expression and to from cultured sebocytes (in vitro IL-8 and MMP-9, and a induce the expression of AMPs, after treatment with VD study) decreases in the such as b-defensin and expression of MMP-1 and cathelicidin. MMP-3, after treatment Further, some comedolytic with VD effects have been attributed to (10-6 M) [144] 2009 To test the effect of Calcipotriol Experimental Not applicable Not applicable some analogs Calcipotriol induces i the calcipotriol on the study expression of AMPs, such expression of AMPs in (in vitro as beta-defensin and human cultured study) cathelicidin LL-37, in keratinocytes cultured keratinocyte [146] 2006 To test the comedolytic Experimental Not applicable Not applicable Maxacalcitol has Maxacalcitol potential of a once-daily study (anicomedolytic action similar application of topical VD mal model) to tretinoin analog for 4 weeks in the rhino mouse [148] 2014 To study the effects of Calcipotriene Phase II/III 54 Randomized, Results are expected in twice daily application of double-blind, December 2014 topical VD cream for single-group 12 weeks in subjects with assignment study acne

Examples

Table 4. Agents that primarily work by modulating the inflammatory response.




In 2010, the University of North Carolina, Chapel Hill, in collaboration with Celgen Corp. started recruiting male and female patients, aged 18 -- 45 years, to participate in a study designed to determine the safety and efficacy of 20 mg apremilast taken twice a day for 12 weeks in the treatment of moderate--to-severe acne. However, the study was terminated before its completion due to lack of funding [131]. Inhibitors of IL-1b-mediated inflammatory response


5.2

IL-1b is a potent mediator of inflammatory responses, expressed by monocytes, macrophages, dendritic cells, B-lymphocytes, natural killer cells and epithelial cells [132,133], that is found to be overexpressed in several inflammatory and autoimmune diseases [134], in correlation with disease development and severity [132]. The secretion of active IL-1b requires cleavage and activation by caspase-1 [132,133]. Caspase-1 has been recently shown to be elevated in neutrophils in the presence of P. acnes, suggesting that P. acnes is capable of activating inflammation [135,136] by indirectly increasing IL-1b [135]. Further, P. acnes causes direct IL-b secretion in monocytic cells [137], which suggests that the perifollicular interaction of P. acnes with macrophages could induce secretion of IL-1b [137], and thus stimulate inflammation. Gevokizumab, also known as XOMA 052, is a humanized monoclonal IgG2 antibody that shows high affinity and specificity to IL-1b [132,138] Inhibition of IL-1b has shown to increase IL-6 release [132,139], reduce TNF-a levels and decrease neutrophil migration [139], thus reducing acute inflammation in vivo [132]. The potential use of gevokizumab to treat moderate-tosevere acne vulgaris is currently being studied in a Phase II, randomized, double-blind, placebo-controlled trial in which approximately 171 male and female subjects, aged ‡ 17 years, are subcutaneously administered either high-dose gevokizumab, low-dose gevokizumab or vehicle solution only on days 0, 28 and 56. Data based on the mean absolute change from baseline in inflammatory facial lesion and the proportion of subjects with successful treatment outcomes will be collected at day 84. This study is currently active and no preliminary results have been published yet [140]. Vitamin D analogs Abnormal colonization by P. acnes stimulates keratinocytes and sebocytes through TLR to produce proinflammatory cytokines and chemokines such as IL-1a, IL-1ra, IL-1b, IL-8, IL-12, TNF-a and MMP-9 [141,142]. Treatment of cultured sebocytes with vitamin D (VD) decreases expression of IL-6, IL-8 and MMP-9 [141,143]. Further, VD and its analog calcipotriol, have shown to regulate innate immunity by inducing the expression of AMPs, such as b-defensin and cathelicidin LL-37, in cultured keratinocytes [144,145]. It has also been noted that binding of VD to its receptor stimulates the proliferation, while inhibiting the 5.3

differentiation of sebocytes, thus decreasing lipid synthesis [141]. Some VD analogs have also shown to have comedolytic effects in animal models [146,147]. A Phase II/III, randomized, double--blind, single-group clinical trial to determine the efficacy of 1g calcipotriene cream applied twice daily in the treatment of acne in male and female patients aged ‡ 18 years is currently being conducted. This study is estimated to be completed in December 2014 [148].

6.

Conclusion

An ideal therapy in acne would target sebum production, comedo formation and P. acnes colonization and would modulate the inflammatory response associated with acne lesions. However, to date, no single treatment designed for acne targets all four pathogenic factors involved in the appearance of acne lesions; therefore, combination treatment is common [1,149]. As a chronic illness, acne characteristically presents with recurrences, relapses and psychological and social distress [1] that affect the patient’s quality of life [150], so new treatment strategies, which potentially are more effective and present with less side effects than current treatment options, are desirable. Topical retinoids, the current mainstay of therapy for mild and moderate acne [1], act by reducing dyskeratosis at the pilosebaceous unit [151] and thus they inhibit the formation of microcomedones and comedos [152] Further, they also have mild anti-inflammatory effects [1,151] However, they commonly cause skin irritation [149], which limits their use in some patients. Topical retinoic acid metabolism-blocking agents (RAMBAs), such as talarozole, which also normalize keratinization with the follicular units, present a new alternative to retinoid therapy with minimum local side effects [98,101]. The possible role of oral talarozole in the treatment of acne remains to be disclosed [97]; however, by increasing endogenous levels of RA [100] they could offer an alternative to oral isotretinoin. Oral isotretinoin, the most effective acne treatment developed to date [1] not only acts by reducing dyskeratosis in the pilosebaceous unit [151], but it also induces apoptosis of sebaceous glands, thus reducing sebum production [153]. Until recently, only isotretinoin and antiandrogen therapy had shown to modulate sebum production [74,154]. Nevertheless, new pathogenic findings relating to skin lipogenesis have opened a new array of possibilities in local lipid synthesis control. Future strategies mainly include: the downregulation of IGF-I signaling to reduce 5-a reductase 1-mediated sebum production and the inhibition of PPAR-mediated lipogenesis by downregulating the production of LTB4 [2]. Oral antiandrogen therapy for sebum control will be most likely be substituted by topical antiandrogens, such as cortexolone, topical NO and ASC-J9 cream, as they reduce sebum production with an apparent absence of systemic absorption and side effects [6,19,25], which makes them suitable to treat both male and female patients.


15



Topical and oral antibiotics are currently recommended for the treatment of mild, moderate and severe acne [1] because they target P. acnes colonization and the inflammation cascade [155]; however, due to the growing concerns on bacterial resistance [1], new non-antibiotic molecules that target these pathogenic factors are highly desirable. Due to its highly efficient bactericidal properties and lack of bacterial resistance, BPO is currently recommended for the treatment of acne instead of prolonged antibiotic use [1]; however, skin irritation is also an issue presented by many patients [149]. AMPs, such as omiganan pentahydrochloride, offer an alterative to antibiotics and BPO, as they exert antimicrobial actions [113,114,117,118] without any apparent side effects [114,119]. Further, omiganan pentahydrochloride reduces comedo count [114], and thus it attacks two of the pathogenic mechanisms involved in acne development. Topical vitamin C also exerts antimicrobial effects on P. acnes [122] and thus could be used in conjunction with current accepted treatments to limit antibiotic use. P. acnes is able to induce the expression of IL-1b [137], which in turn is associated with inflammatory acne lesions [133]; thus, molecules that target IL-1b, such as Gevokizumab, may play a role in nodular or conglobata cases of acne where inflammation is severe. The possible role of PDE4 inhibitors as modulator of proinflammatory cytokine expression in the management of acne remains to be determined, for they are associated with severe gastrointestinal side effects, with nausea being the most common [126]. Topical PDE4 inhibitors are already being developed [156] and could potentially be an option to limit inflammation in severe forms of acne with fewer side effects than their oral counterparts. VD analogs not only modulate the inflammatory response but also reduce sebogenesis [141] and comedo formation [146,147]; however, their future role in the management of acne remains to be seen [148]. 7.

Expert opinion

Acne is a seemingly simple but actually complex disease. Its pathogenesis is very convoluted and most mechanisms involved in its clinical course and severity remain unknown. Although we know that sebum production, dyskeratosis, P. acnes colonization and inflammation play a role, we still do not understand how these mechanisms interact with each other to determine patient outcome and response to treatment. There is also still a lot of information lacking regarding the potential for chronicity and/or relapses. This is in part because there was a previous lack of scientific interest in acne as a disease, and in part because it is impossible to recreate the acne model in a Petri dish or in an animal, so most studies focus only on one of the four pathogenic factors at a time, which limits the applicability of the data to human patients.

16

Before retinoids became available for the treatment of acne in 1972 [157], acne’s therapeutic regimen had been unchanged for years, with antibiotics being the mainstay of treatment. Since then, few first-in-class molecules have been developed, and new research has focused mainly on developing combination products, primarily of retinoids with antibiotics, that are not significantly different from the current monotherapies available. With the recent characterization of acne as a chronic disease, new interest in deciphering the molecular mechanisms responsible for acne lesions have peaked, which in turn has resulted in a spurt in research on the mechanisms involved in the appearance of acne lesions. One of the biggest void in the market is the current deficit of products that target sebogenesis, so it is no surprise that current researchers have focused their efforts in determining the mechanisms through which sebum is produced. Topical sebum modulators, such topical antiandrogens and PPAR modulators, will surely find a place in the treatment guidelines for patients with acne in the future. In fact, it could be hypothesized that by effectively controlling sebum production, P. acnes population would be normalized, which in turn would limit inflammation, eliminating the need for antibiotic use in acne. Current available treatments to control dyskeratosis, such as exogenous retinoids, are irritating, which limits their use in many patients, so research should focus on the development of molecular-based drugs that increase retinoic acid levels through selective inhibition of endogenous retinoid breakdown. Topical RAMBAs, for example, seem promising as retinoid substitutes. Although MCR antagonists, Ach inhibitors, ACC and monoclonal antibodies seem fascinating and promising as novel therapeutic strategies in the management of acne, they are still a long way from being available to clinician. The market is in urgent need of a blockbuster drug that ideally would target all of the pathogenic mechanisms involved in acne lesions without skin irritation and without systemic side effects. However, until this drug is developed, combination therapy will still be the foundation of acne treatment, so these new management modalities will most likely be incorporated into current treatment guidelines as to cover the most pathogenic factors possible for optimum disease control.

Declaration of interest IC Valente Duarte de Sousa has acted as a medical consultant for the More Pharma Corporation in the past. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.



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Affiliation Isabel Cristina Valente Duarte de Sousa1,2 MD 1 Private Dermatology Practice, Manzanas 44, Piso 5, Col. Tlacoquemecatl, Del. Benito Juarez, 03200 DF Me´xico, Mexico City, Mexico Tel: +5215510056226; E-mail: [email protected] 2 Hospital ABC Campus Santa Fe, Private Dermatology Practice, Av. Carlos Graef Fernańdez 154, Col. Tlaxcala Santa Fe, Delegacioń Cuajimalpa, Mexico City, 05300, Mexico

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