Journal of Dermatological Treatment

ISSN: 0954-6634 (Print) 1471-1753 (Online) Journal homepage: https://www.tandfonline.com/loi/ijdt20

Acne vulgaris: new evidence in pathogenesis and

future modalities of treatment

Neirita Hazarika

To cite this article: Neirita Hazarika (2019): Acne vulgaris: new evidence in pathogenesis
and future modalities of treatment, Journal of Dermatological Treatment, DOI:
10.1080/09546634.2019.1654075

To link to this article: https://doi.org/10.1080/09546634.2019.1654075

Accepted author version posted online: 08

Aug 2019.

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 Title Page

Title of the article: Acne vulgaris: new evidence in pathogenesis and future modalities of

treatment

 Author details and Affiliation:

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Dr Neirita Hazarika

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Associate Professor, Department of Dermatology,

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All India Institute of Medical Sciences, Rishikesh, India

Email: neiritahazarika@yahoo.com
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 Corresponding author:
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Dr Neirita Hazarika
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Associate Professor, Department of Dermatology,

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All India Institute of Medical Sciences, Rishikesh, India

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Email: neiritahazarika@yahoo.com
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 Key-words: Acne vulgaris, Propionibacterium acnes, biofilm, diet, future therapy.

Abstract:

Acne vulgaris, a common and chronic disorder of the pilosebaceous unit, affects upto 85% of

adolescent and young adults. While a lot is already known about acne and its treatment, still the

gaps in our understanding of acne remains. This article will review the emerging evidence in the

complex pathogenesis of acne and provide an overview of the potential future therapy in

management of acne vulgaris.

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Key Messages

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What is known?

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Propionibacterium acnes targeted therapy has been the mainstay in the management of acne till

now.
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What is new?
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Sebocyte activity is controlled via a range of cellular pathways and hormones in addition to
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androgens. This has opened an array of therapeutic options to be available for treating acne in the
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near future.
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Introduction:

According to the Global Burden of Disease (GBD) study, acne vulgaris affects ~85% of young

adults’ aged 12–25 years.1 The pathogenesis of acne is multifactorial. Traditionally, four distinct

processes were believed to play critical roles: increased sebum production, alteration of

keratinization processes leading to comedone formation, follicular colonization by

Propionibacterium acnes (P.acnes) and inflammatory mediators around pilosebaceous unit

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(PSU). The main objective of this review is to highlight the emerging evidence in the complex

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pathogenesis of acne vulgaris and provide an overview of the novel molecules being evaluated

for treatment of acne, with a short focus into relevant pathogenic pathways in relation to

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mechanisms of action of these novel therapies.

Methods
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Literature searches were conducted in PubMed and National Institutes of Health ongoing trials

register (www.clinicaltrials.gov) in April 2019 using both Medical Subject Headings (MESH)
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terms and search phrases: “acne vulgaris”, “acne vulgaris pathogenesis”, “Propionibacterium
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acnes’’, “acne vulgaris diet’, “acne vulgaris biofilm”, “acne vulgaris treatment”. The search was

limited to all articles in English published since 2008. Bibliography of included publications
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were manually searched for additional studies. Few publications prior to 2008 relevant to this
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review were also included. Only ongoing trials involving new molecules as drugs, not

commercially available for use, were included. Trials with medical devices and trials on acne

scarring were excluded as they were beyond the scope of this review. This review used data that

are publicly available and is not primary research. Therefore, approval by an institutional review

board is not required.

Emerging evidence in pathogenesis

Current research on genome-wide associations with severe acne has identified six gene loci:

11q13.1, 5q11.2, 11p11.2, 1q41, 1q24.2 and 8q24. These loci are involved in androgen

metabolism, inflammation processes and scar formation.2-4 A marked increase of Tumor

Necrosis Factor (TNF) gene transcripts was observed in acne lesions.5 Also, a meta-analysis

suggests that the -308 G/A polymorphism in the TNF gene contributes to acne risk in

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Caucasians.6 Insulin‑ like growth factor-1 (IGF‑ 1) polymorphism also has recently been shown

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to predispose Turkish individuals to acne.7

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There has been recent focus on the epidermal permeability barrier and sebum of untreated skin of

people with acne. Within acne lesions, there is an increase in filaggrin expression in follicular
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keratinocytes. P.acnes has been shown to increase filaggrin expression in cultured keratinocytes.
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The hypothesis proposed is that, a reduced ability to express filaggrin due to null mutation in the

filaggrin gene, correlates directly with a lesser ability to form acne lesions.8 There is need for
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more studies to validate this hypothesis. Acne patients was shown to have significantly reduced
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free sphingosine and total ceramides in their stratum corneum, which correlates with impairment
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of the stratum corneum permeability barrier.9 In males with acne, the sebum quantity was 59-
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percent higher, squalene was increased approximately two-fold, and free fatty acids were
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decreased.10 Also, acne-prone individuals have a higher amount of lobules per sebaceous gland

and the overall size of the follicles is increased.11

Recent work suggests that the formation of sebocytes is regulated by several molecular pathways

(e.g. Lef-1, Blimp1, Wnt, C-myc) and that sebocyte activity is controlled via a range of cellular

pathways and hormones in addition to androgens including, for example, peroxisome

proliferator-activated receptors, substance P receptors, α-melanocyte-stimulating hormone,

insulin-like growth factor, corticotropin-releasing hormone, vitamin D and ectopeptidases.11

The role of insulin‑ like growth factor 1 (IGF‑ 1) in the pathogenesis of acne have been

extensively studied. Deplewski and Rosenfield pointed out that not serum androgens but serum

IGF-1 levels correlate with the clinical manifestation of acne.12 IGF-1 is a potent inducer of

gonadal testosterone and adrenal dehydroepiandrosterone (DHEA) synthesis and also, promotes

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the intracutaneous conversion of testosterone to dihydrotestosterone (DHT) by enhancing 5α-

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reductase activity.13 Androgen receptor (AR) activation requires two major stimuli: 1) binding of

its hormone ligand (androgen) and 2) depression of its inhibitory nuclear coregulator Forkhead

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box protein O1 (FoxO1). Ligand-mediated activation of AR depends on androgen binding
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affinity, highest exhibited by DHT, which is ten times higher than testosterone. Once converted,

DHT has the capability of activating its intranuclear receptor AR, regulated by FoxO1. FoxO1 in
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turn is inhibited by the protein kinase Akt, a downstream target associated with insulin- and IGF-
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1-receptor activation. Therefore transient rises of insulin and IGF-1 occurring during the normal
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course of puberty inhibit FoxO1 regulation and allow the activated AR to trigger a chain of
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metabolic events, which lead to an excess production of keratinocytes and sebum.14 The
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proliferating ductal lining cells unable to escape the infundibulum of the PSU form a plug,

compromise the availability of diffusible oxygen to cells below, providing an ideal, anoxic
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environment for P. acnes to grow.

P. acnes and biofilm formation

The role of P. acnes in the pathogenesis of acne, however, remains controversial. Conflicting

opinions arise from the fact that P. acnes is a dominant member of the normal cutaneous flora,

while few studies have shown that it induces inflammatory responses in skin parenchymal cells
and immune cells. Utilizing more refined DNA-based typing methods, recently it was found that

P. acnes consists of phylogenetically distinct cluster groups with various pathogenic

characteristics, including differing abilities to elicit inflammation and differing secretome

profiles. This evidence may suggest that while some P. acnes strains may play an aetiological

role in acne, others are associated with health.15

Jahns et al. demonstrated extensive P. acnes biofilms in the sebaceous follicles of patients with

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acne. They did not find any qualitative differences between P. acnes biofilms in acne and

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controls, indicating that phenotypic, rather than genetic, changes associated with biofilm

formation may account for the pathogenic role of P. acnes.16 Biofilm formation substantially

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increases P. acnes virulence, associated with enhanced expression of exogenous P. acnes
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triglyceride lipase that increases sebum concentrations of free palmitate and oleate. Free oleic

acid increases P. acnes adherence and growth.13 Abundance of sebum-derived free palmitate
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together with P. acnes-derived danger-associated molecular patterns (DAMPs) stimulates innate
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immunity, inflammasome activation in neutrophils, and interleukin-1β (IL-1β)-signalling. IL-1β

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finally orchestrates follicular and perifollicular inflammation with Th17 cell differentiation and
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IL-17-mediated local keratinocyte hyperproliferation.13 P. acnes also induces follicular

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keratinocytes to release IL-1α leading to keratinocyte proliferation and comedone formation.17

Pawin H et al have proposed that P. acnes itself may act as a superantigen, activating cells to
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proliferate and to accumulate.18 P. acnes also induces the expression of TLR-2 on keratinocytes

and the secretion of pro-inflammatory cytokines and matrix metalloproteinase-9 (MMP-9).19

MMP-9 enhances follicular rupture, as does invasion of CD4 cells, which further spreads

inflammation through the dermis.20

Furthermore P. acnes release chemotactic factors, which firstly recruit CD4-lymphocytes, and

later neutrophils and monocytes to the affected area. Activation of Toll-like receptor 2 (TLR-2)

on monocytes by P. acnes induces the production of interleukin (IL)-8 which subsequently leads

to the recruitment of neutrophils into the PSU.21-22 P. acnes also interacts with antimicrobial

peptides and protease-activated receptors.20 One of the most important aspect of P. acnes

biofilm is that it acts as a protective physical barrier, limiting effective anti‑ microbial

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concentrations within the biofilm. It further promotes antibiotic resistance of the colonies by

production of certain proteins.23

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Diet and acne

High glycaemic index foods, including glucose, white bread, white rice, and chocolate, stimulate
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the release of insulin which then activates the Akt signalling pathway directly through its
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receptor and indirectly through the production of IGF-1 and its receptor. The protein kinase Akt

then phosphorylate FoxO1, and inactivate it. FoxO1 deactivation in turn leads to gene
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transcription that drives the proliferation of keratinocytes in the PSU.14

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The protein, mechanistic target of rapamycin complex 1 (mTORC1) control lipogenesis and
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protein synthesis that drive sebaceous activity and ductal plugging, respectively. mTORC1 has

recently been recognized to play a major role in diet-induced acne. Insulin, IGF-1, essential
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branched-chain amino acid leucine (found in dairy milk and whey, meat and egg), and

glutamine, cause full activation of mTORC1 signaling. On the other hand FoxO1 and FoxO3 are

negative regulators of the nutrient-sensitive kinase mTORC1. Cow milk is also known to contain

anabolic androgen precursors of DHT, including 5a-pregnanedoine, 5a-pregnan-3B-ol-20-one,

5a-androstene-3B, 17B-diol, 5a-androstanedoin, and 5a-androstan-3B-ol-17-one.14

Adiponectin is an adipocyte-derived hormone that inhibits proinflammatory cytokines and

induces anti-inflammatory ones, down-regulates adhesion molecule expression, suppresses toll-

like receptors and their ligands, and increases insulin sensitivity. It inhibits mTORC1 activity by

activating 5’adenosine monophosphate (AMP)-activated protein kinase. Dietary glycaemic index

and glycaemic load have been shown to be inversely associated with adiponectin concentrations.

Hypoadiponectinemia associated with a high-glycaemic-index/-load diet may augment the

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inflammatory response in patients with acne. In a study done on 50 acne patients and 36 healthy

controls, glycemic index and glycemic load levels were significantly higher (P = .022 and P =

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.001, respectively) and serum adiponectin levels were significantly lower (P = .015) in patients

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with acne than in controls. There was an inverse correlation between serum adiponectin
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concentration and glycemic index (P = .049, r = _0.212). Also, the glycemic index values were

significantly higher in patients with moderate and severe acne than in patients with mild acne,
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and positively correlated with disease severity.24
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A look into the future in acne management.

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New knowledge into the complex pathogenesis of acne have opened an array of possibilities for
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new treatment targets. Due to the growing concern over bacterial resistance, antibiotic use in
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treatment of acne will decline over the next years and will be substituted with antimicrobial
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peptides, bacteriophages, agents decreasing sebum, monoclonal antibodies and various novel

pharmacological agents including vaccines against P. Acnes..

Agents decreasing sebum production (Table 1)

1. Via action on androgen-dependant sebum production pathway

Clinical trial on topical cortexolone 17a-propionate 1% cream or CB-03-01, a synthetic, steroidal

antiandrogen, which act by inhibiting the interaction of circulating androgens with their receptor

is underway (NCT02682264).25 Use of topical ASC-J9 cream in acne , a synthetic androgen

receptor degradation enhancer, has also been evaluated (NCT00525499).26 NVN1000 gel or

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SB204, releases nitric oxide (NO) when applied topically and inhibits the androgen-dependant

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sebum production pathway.27 Safety of use of NVN1000 gel in acne has been evaluated in trial

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(NCT01844752).28 Epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent in

green tea, inhibit 5a-reductase-1 activity.29 It also inhibits cell proliferation and lipid synthesis in
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sebocytes in vitro via inhibiting IGF-1 mediated androgen-induced lipogenesis.30 A study on the
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use of EGCG in acne was undertaken (NCT01687556).31

2. Via action on α-Melanocyte- Stimulating Hormone (α-MSH)

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Alpha-melanocyte- stimulating hormone (α-MSH) cause increased sebogenesis in rodents via the
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stimulation of the melanocortin receptor 1 (MC1-R) and the melanocortin receptor 5 (MC5-R),
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also expressed in human sebocytes. JNJ 0229570, a MC1-R and MC5-R antagonist, decreases

sebaceous gland’s size and production of sebaceous lipids in cultured primary human
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sebocytes.32 and its use has been evaluated in a trial (NCT01492647).33

3. Peroxisome proliferator activated receptor (PPAR) modulators

PPARs are ligand-activated transcription factors that upregulate lipid synthesis. Certain

leukotrienes are potent PPAR ligands, such as leukotriene B4 (LTB4). LTB4 is considered to be

a major player in the development of tissue inflammation. Synthesis of LTB4 is controlled by the
enzyme 5-lipoxygenase (5-LOX). Zileuton, an oral 5-LOX inhibitor downregulate expression of

LTB4 in sebaceous gland, and inhibit PPAR-mediated lipogenesis,34 and underwent a clinical

trial for safety and efficacy in acne (NCT00098358).35 The results of a phase 2 study (2016–

000540-33), with the PPAR-γ modulator, N-Acetyl-GED- 0507–34-LEVO, in 1% and 2% gel in

acne are awaited.36 Acebilustat (CTX-4430), a leukotriene A4 hydrolase inhibitor, is also under

investigation (NCT02385760) in patients with moderate to severe acne.37

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4. Acetylcholine (Ach) inhibitors

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Ach increases lipid synthesis by its interaction with the Ach receptor α7, expressed in sebaceous

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glands.38 Botulinum toxin inhibits the presynaptic release of Ach and has recently been found to

noticeably decrease sebum production, oily skin and pore size.39 A topical formulation of
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botulinum toxin was tested in trial (NCT01293552).40
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5. Acetyl coenzyme A carboxylase inhibitors
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Androgenic stimulation of sebaceous glands increases key enzymes involved in the regulatory
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steps of sebaceous fatty acid biosynthesis, such as acetyl coenzyme A carboxylase (ACC).32
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Topical DRM01B, an inhibitor of enzyme ACC, is under trial (NCT03127956).41

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6 .Lupeol
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Lupeol is an alchoholic, pentacyclic triterpene, obtained from the hexane extract of Solanum

melongena L., a medicinal plant from Solanum species. Lupeol strongly suppressed lipogenesis

by modulating the ‘IGF-1R/phosphatidylinositide 3 kinase/Akt/sterol response element–binding

protein-1 (SREBP-1)’ signaling pathway in SEB-1 sebocytes, and reduced inflammation by

suppressing the NF-κB pathway in SEB-1 sebocytes and HaCaT keratinocytes.42

 7. 5α-reductase inhibitors

Finasteride has preferential selectivity for enzyme 5α-reductase type 2. A clinical trial

(NCT02502669) was undertaken to evaluate the efficacy and safety of once weekly, high-dose

oral finasteride (23.5 and 33.5 mg) for the treatment of severe nodulocystic acne in males.43

However, there is no rationale for acne treatment with finasteride in female patients.

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Agents that primarily normalize abnormal keratinization within PSU (Table 2)

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1. Talarozole (Rambazole / R115866)

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It is a selective azole derivative that inhibits the CYP26 isoenzyme, involved in the metabolism

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of retinoic acid (RA). By inhibiting CYP26, it enhances the intracellular endogenous levels of
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all-trans-retinoic acid, allowing for normalization of desquamation of the epithelium, and thus

may decrease comedo formation in acne.44 In a study by Verfaille CJ et al, oral R115866 1 mg
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once daily for 12 weeks in patients with moderate to severe facial acne vulgaris was shown to be

efficacious and well tolerated, requiring further investigation.45

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2. Monoclonal antibody against interleukin 1α (IL-1α)

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P. acnes activate the release of IL-1α via Toll like recepter-2 activation. In vitro models of acne
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have determined that stimulation of the pilosebaceous infundibulum with IL-1α induce a
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hyperkeratinization response similar to that seen in comedones.46 RA-18C3 is a human

monoclonal antibody specific for IL-1α. A phase 2 trial of RA-18C3 in moderate to severe acne

vulgaris, is under way.47

Agents acting on P.acnes (Table 3)

1. Newer antibiotics

Pentobra: Tobramycin is conjugated to a short 12AA peptide to form composite molecule,

Pentobra. Pentobra combines the potent ribosomal activity of aminoglycosides with the bacteria-

selective membrane-permeabilizing abilities of antimicrobial peptides (AMPs) and demonstrated

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potent and selective killing of P. acnes along with suppression of some P. acnes-induced

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chemokines.48

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Sarecycline is a new, once-daily, tetracycline-class antibiotic. In a multicenter, phase 2, dose-

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ranging study (NCT02320149), the efficacy and safety of oral sarecycline as once-daily, narrow
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spectrum antibiotic for the treatment of moderate to severe facial acne vulgaris was evaluated

with satisfactory results.49

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Zolav© is a p-carboethoxy-tristyrylbenzene derivative that interact with novel mechanosensitive

ion channel of large conductance (MscL) and inhibit bacterial growth.50 At a final concentration
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of 50 µg/mL, Zolav© is effective in reducing the P. acnes burden in a mouse intradermal

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infection model.51
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NAI: Bacterial elongation factor Tu (EF-Tu) and EF-Ts are interacting proteins involved in

polypeptide chain elongation in protein biosynthesis.52 NAI, a semi-synthetic thiopeptide, is a

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peptide elongation factor Tu inhibitor, and highly selective against P. acne, and is currently

under evaluation as a 3% gel for acne.36

 2. Agents acting on P. acnes biofilm

Rifampicin alone and in combination, against planktonic and biofilm of P. acnes was evaluated

by Tafin et al, in an in vitro and in a foreign-body infection model.53 Rifampicin may be used in

the future as an anti-acne agent.

Next Science Acne Gel (NAG) is a topical gel containing salicylic acid which causes biofilm

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matrix degradation. Extracellular polysaccharide (EPS) polymers encapsulate bio- films,

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protecting P. acnes from conventional treatments. NAG contains a chelating agent and buffer

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which remove ionic bonds between the EPS to disrupt the network. Also, it contains isopropyl

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alcohol and surfactant which solubilize EPS, allowing salicylic acid to effectively reach P. acnes.

Because the EPS is removed, the minimum monograph concentration of salicylic acid (0.5%) in
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NAG is highly effective, with very low tissue toxicity or irritation.54
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3. Antimicrobial peptides (AMP)
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MBI 226 or omiganan pentahydrochloride, is a topical cationic peptide derived from bovine
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AMP indolicidin. MBI 226 have rapid in vitro microbicidal activity against a variety of bacteria
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by disrupting their cytoplasmic membranes and causing depolarization followed by cell death.32
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The safety and efficacy of MBI 226 2.5% and 5.0% solutions in the treatment of acne vulgaris is

being evaluated(NCT00211523).55
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Tyrothricin, produced by Bacillus brevis, is polypeptide antibiotic substance consists of the two

cyclic decapeptides, gramicidin S (22%) and tyrocidine A (78%). Both peptides have broad

bactericidal activity against Gram-positive bacteria due to intercalation of the peptides into

bacterial membranes. The efficacy and tolerability of topical tyrothricin 0.1% in acne is being

evaluated.56
 4. Bacteriophages

Ten phage capable of lysing P. acnes were isolated from human skin microflora and formulated

into cetomacrogol cream aqueous at a concentration of 2.5x108 PFU per gram and is being

evaluated as a future anti acne product.57

5. Antioxidants

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Vitamin C have shown action against P. acnes and prevent ultraviolet A (UVA)-induced sebum

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oxidation.32 The efficacy and safety of twice-daily sodium L-ascorbyl-2-phosphate 5% lotion,

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for 12 weeks, in the treatment of acne vulgaris has been evaluated.58

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6. Vaccines against P. acnes
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It has not been clearly shown that vaccines against P. acnes antigenic structures are effective in

humans with acne. In sebocytes treated with the antiserum from mice immunized with the heat
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inactivated P. acnes vaccine, the percent cytotoxicity and level of IL-8 were significantly
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reduced. However, it did not affect the survival/growth rate of P. acnes.59

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P. acnes surface enzyme sialidase plays a significant role in the adhesion of P. acnes to host cells

(required for P. acnes colonization of sebaceous glands). Anti-serum from mice vaccinated with
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recombinant P. acnes sialidase was shown to decrease P. acnes-induced human sebocyte

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cytotoxicity, IL-8 production and macrophage-inflammatory protein-2. As with the inactivated P.

acnes vaccine, the sialidase-component vaccine did not affect the survival/growth rate of P.

acnes.59
Agents decreasing inflammation around PSU (Table 4)

1. Nitric oxide–releasing nanoparticle (NO-np)

P. acnes causing induction of IL-1 cytokines through the NLRP3 inflammasome has been

recently highlighted as a dominant etiological factor for acne vulgaris. Nitric oxide (NO), a

potent biological messenger has broad-spectrum antimicrobial and immunomodulatory

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properties. Qin M et al utilized an established nanotechnology capable of generating/releasing

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nitric oxide over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of

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NO-np. NO-np also significantly suppressed IL-1β, TNF-α, IL-8 and IL-6 from human

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monocytes and IL-8 and IL-6 from human keratinocytes respectively.60

2. an
Phosphodiesterase inhibitors (PDEs inhibitors): Apremilast

PDE inhibitors degrade intracytoplasmic levels of cAMP. Low levels of cAMP lead to
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preferential expression of proinflammatory cytokines TNF-α, IL-1, IL-8, IL-12 and IL- 23.
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Apremilast, an oral PDE4 inhibitor, elevates cAMP levels and inhibit TNF-α and IL-8 and thus,
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could potentially play a role in acne treatment.32 A clinical trial to determine the safety and
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efficacy of 20 mg apremilast in the treatment of moderate--to-severe acne was undertaken but

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was later terminated due to lack of funding.61

3. Inhibitor of α isoform of p38 mitogen-activated protein kinase (p38 MAPK or p38): SCIO-
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469

P. acnes induced proinflammatory cytokine release, is mediated by P. acnes-induced activation

of p38 mitogen-activated protein kinase (p38 MAPK or p38) in human keratinocytes. SCIO-469

is a relatively selective inhibitor of α isoform of p38 MAPK. Topical treatment of SCIO-469

 inhibited the P. acnes-induced phospho-p38 and cytokine secretion in human epidermal

equivalents.62

4. Gevokizumab/(XOMA 052)

IL-1b is a potent mediator of inflammatory responses. P. acnes is capable of activating

inflammation by indirectly increasing IL-1b via activation by caspase-1 in neutrophils. Also,

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perifollicular interaction of P. acnes with macrophages induce secretion of IL-1b.32

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Gevokizumab, is a humanized monoclonal IgG2 antibody that shows high affinity and specificity

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to IL-1b. Inhibition of IL-1b increase IL-6 release, reduce TNF-a levels and decrease neutrophil

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migration, thus reducing acute inflammation in vivo.63 The potential use of gevokizumab to treat

moderate-to severe acne vulgaris was studied in a clinical trial in 2011.64

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5. Human anti-IL-17A monoclonal antibody, CJM112
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Kelhala HL et al demonstrated the presence of interleukin (IL) 17A positive T cells and the

activation of Th17-related cytokines in acne lesions.65 A clinical trial (NCT02998671), to assess

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preliminary efficacy and safety of human anti-IL-17A monoclonal antibody, CJM112, in patients
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with moderate to severe inflammatory acne is ongoing.66

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6. Vitamin D (VD) analogues

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Sebocytes have been identified as bioactive vitamin D-responsive target cells. Cultured sebocytes

after treatment with vitamin D showed significant decrease in the expression of IL-6, IL-8, and

matrix metalloproteinases 9.67 A clinical trial (NCT01694433), to determine the efficacy of 1g

calcipotriene cream in the treatment of acne is currently being conducted.68

Conclusion

Newer evidence that sebocyte activity being controlled via a range of cellular pathways apart

from androgen alone, dietary influence on acne, emphasizes the complex pathogenesis of acne.

The role of P.acnes biofilm in the formation of acne and treatment resistance cannot be ignored.

With emerging P. acnes resistance towards antibiotics, the traditional practice of mainly targeting

the role of P.acnes in the development of acne, may no longer suffice. There is urgent need for

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more translational research and clinical studies for development of treatment modalities targeting

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the ever emerging concepts in pathophysiology of acne.

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Funding details: Nil

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Disclosure statement: The author report no conflict of interest
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Ac
Table 1 - Future of acne therapy - Agents that decrease sebum production.
Name of drug Study Purpose of study Study design Result
started
Via action on androgen-dependant sebum production pathway
CB-03-01/ 2016 To determine the Multicentre, open Ongoing study
Cortexolone long-term safety of label, long-term
17α propionate CB-03-01 cream, extension study
1%, applied twice (NCT02682264)
daily for an
additional nine
months in study
participants with

t
ip
acne vulgaris that
participated in the
Phase 3 pivotal

cr
studies for a total
treatment of up to

us
12 months.
ASC-J9 2007 To evaluate the Phase 2, multi- ASC-J9 cream (0.001%
safety and efficacy center, randomized, vs 0.005vs 0.025%) in
of two different
an
concentrations of
double-blind,
vehicle-controlled
changing the
percentage of
ASC-J9 cream (0.1 dose-ranging inflammatory lesion
and 0.025%) clinical study counts
M
applied topically (NCT00525499) -34.7 vs -30.7 vs -
twice daily for 12 44.8 SD
weeks Improvement in
d

Investigator Global
e

Assessment by at
Least One Grade
pt

(0.001% vs 0.005vs
0.025% ASC-J9)
20 vs 23 vs 28
ce

participants
NVN1000 2013 To compare the Phase 2/3,multi Both 1% and 4%
efficacy, tolerability center, randomized, NVN1000 gel
Ac

and safety of double-blinded, significantly

NVN1000 gel 1% vehicle-controlled, decreased
and 4% with parallel-group, noninflammatory
vehicle gel twice three-arm study lesions; 4% NVN1000
daily (NCT01844752) gel also significantly
decreased the
inflammatory lesions
Epigallocatechin-3- 2012 To determine the Phase 1, No official results
gallate (EGCG) clinical and randomized, have been posted in
histological effects double-blind, ClinicalTrials.gov
of 1% and 5% EGCG vehicle-controlled
 solution applied study
topically to the (NCT01687556)
face twice a day for
8 weeks
Via action on α-Melanocyte- Stimulating Hormone (α-MSH)
JNJ 10229570 2011 A study of JNJ Phase 2, multi No official results
10229570-AAA to center, have been posted in
evaluate safety and double-blind, ClinicalTrials.gov
tolerability in vehicle-controlled
Japanese study
participants with (NCT01492647)
acne vulgaris

t
ip
Peroxisome proliferator activated receptor (PPAR) modulators.

cr
Zileuton 2004 To test the safety Phase 2, No official results
5-lipoxygenase (5- and efficacy of oral randomized, have been posted in

us
LOX) inhibitor zileuton in the double-blind, ClinicalTrials.gov
treatment of facial placebo -controlled,
acne parallel-group,
an multicenter study
(NCT00098358)
N-Acetyl-GED- 0507– 2016 To evaluate the Phase 2, double- No official results
M
34-LEVO efficacy and safety blind, randomised, have been posted in
of N-Acetyl-GED- placebo-controlled ClinicalTrials.gov
0507-34-LEVO gel, clinical study
1 and 2%, applied (2016-000540-33)
d

once daily for 12

e

weeks in patients
with mild acne.
pt

Acebilustat 2015 To study the Phase II, multi- No official results

(CTX-4430) efficacy and safety centre, double- have been posted in
ce

leukotriene A4 study of oral CTX- blind, randomized, ClinicalTrials.gov

hydrolase inhibitor 4430, 100 mg, parallel group
once-daily for 12 (NCT02385760)
weeks for the
Ac

treatment of
moderate to severe
facial acne vulgaris.
Acetylcholine (ACH) inhibitors.
ANT-1207 (Topical 2012 To determine the Phase 2, No official results
formulation of safety, tolerance randomized, have been posted in
botulinum toxin) and efficacy of double-blind, ClinicalTrials.gov
ANT-1207 vehicle-controlled
study
(NCT01293552)
Acetyl coenzyme A carboxylase (ACC) inhibitors.
DRM01B/ 2017 To assess the long- Phase 3, Ongoing
Olumacostat term safety of randomized,
Glasaretil Olumacostat double-blind,
Glasaretil gel, 5.0% vehicle controlled,
in patients with efficacy and safety
acne vulgaris study
(NCT03127956)

IGF-1R/phosphatidylinositide 3 kinase/Akt/sterol response element–binding protein-1 (SREBP-1)

signaling pathway modulator
Lupeol 2015 To explore Experimental (in Lupeol attenuated the

t
ip
alternative acne vitro nad in vivo manifestation of
medications, skin study) infiltrated
specimens inflammatory cells

cr
including typical around comedones or
acne lesions were sebaceous glands.

us
acquired from Also, it significantly
patients before and decreased expressions
after applying 2% of IGF-1R, SREBP-1,

for 4 weeks.
an
lupeol twice daily NF-kB p65, and IL-8 in
the human acne lesion
M
5α-reductase inhibitors
Finasteride 2015 To evaluate the Phase 2, double- No official results
efficacy and safety blind, randomized, have been posted in
d

of once weekly, placebo-controlled, ClinicalTrials.gov

e

high-dose oral dose-ranging study

finasteride (23.5 (NCT02502669)
pt

and 33.5 mg)

compared to
placebo for the
ce

treatment of
severe
nodulocystic acne
Ac

in male subjects
Table 2 Future of acne therapy- Agents that primarily normalize abnormal keratinization within the
PSU
Name of Study year Purpose of study Study design Result
drug
Talarozole 2005 To assess the safety Exploratory A mean reduction in
(Rambazole and efficacy of 1 mg trial inflammatory lesion count of
/ R115866) oral talarozole taken 77.4% (P <0.001), in
once daily for 12 weeks noninflammatory lesion count
in the treatment of of58.3% (P <0.001) and in total
moderate -to-severe lesion count of 76.0% (P <0.001)
facial acne was observed as compared with
baseline.

t
ip
Monoclonal 2011 To assess the safety, Phase 2, open No official results have been
antibody pharmacokinetics, and Label study posted in ClinicalTrials.gov

cr
against efficacy of a true (NCT01474798)
interleukin human anti-

us
1α (IL-1α) inflammatory
RA-18C3 therapeutic antibody
(RA-18C3) in subjects
with moderate to
severe acne vulgaris
an
M
e d
pt
ce
Ac
Table 3 - Future of acne therapy- Agents acting on P.acnes
Name of drug Study Purpose of study Study design Result
year
Newer antibiotics
Pentobra 2015 To engineer a P. acnes Experimental Bactericidal activity against a
antibiotic by (in vitro wide range of P. acnes clinical
combining the potent study) isolates. Effectively killed P.
ribosomal activity of acnes from human donors in
aminoglycosides with micro comedone sebum-rich
the bacteria-selective environment. Safe ,
membrane- nonirritating on various skin
permeabilizing cells.

t
ip
abilities of AMPs
Sarecycline 2014 To evaluate the Phase 3 Results submitted
efficacy and safety of Randomized, No official results have been

cr
an approximate multicenter, posted in ClinicalTrials.gov
1.5mg/kg/day dose of double-blind,

us
oral sarecycline placebo-
compared to placebo controlled
in the treatment of Study
moderate to severe
facial acne vulgaris
an
(NCT02320149)

Zolav© 2015 To investigate the Experimental A concentration of 50µg/ml

M
effectiveness of (in vitro and in (q8h) elicited a two log
Zolav©, a novel vivo difference in colony forming
antibiotic as a study) unit / gram between treatment
treatment for acne and control group
d

vulgaris.
e

NAI 2014 Evaluation of the Randomized, No official results have been

efficacy and safety of double-blind, posted in ClinicalTrials.gov
pt

a new gel, NAI-Acne placebo-

gel 3% applied twice- controlled
ce

a-day for 12 weeks to Study

patients with facial (2014-001491-
acne vulgaris in 62)
comparison with
Ac

placebo.
Agents against P. acnes biofilm
Rifampicin 2011 To investigate the Experimental Rifampicin demonstrated
activity of rifampicin study highest in vitro activity against
alone and in (in vitro and in P. acnes biofilm as a single
combination with vivo study) agent. Rifampicin and
other antimicrobials daptomycin combination was
against P. acnes most active regimen against
biofilm in vitro and in experimental P.acnes biofilm
a foreign-body guinea
pig infection model.
NAG 2015 To study the effect of A multi-site, Decrease of inflammatory
topical NAG gel vs double-blind, lesions by 44% and non-
vehicle for 12 week in vehicle- inflammatory lesions by 32%
subjects with mild to controlled after 12 weeks
moderate facial acne. study
(NCT02404285)
Antimicrobial peptides
MBI 226 2005 To evaluate the safety Phase 2 No official results have been
and efficacy of MBI Randomized, posted in ClinicalTrials.gov
226 2.5% and 5.0% vehicle-
solutions applied controlled,
topically double-blind,

t
ip
for 12 weeks multicenter
clinical trial
(NCT00211523)

cr
Tyrothricin 2013 To investigate the A randomized, The mean differences in
efficacy and active inflammatory lesion counts

us
tolerability of topical comparator- from baseline were –12.3 in
tyrothricin ontrolled, clindamycin + BPO , –10.2 in
0.1% in the treatment exploratory, BPO 5%, and –7.7 in
of mild to severe acne
vulgaris compared
an
observer-blind
clinical study
tyrothricin.

clindamycin to 2013-001716-
clindamycin and 30
M
BPO 5%.
Bacteriophages
P.acnes To isolate and Experimental Cetomacrogol cream was
d

bacteriophage characterise phage (in vitro and in capable of killing P. acnes, even
e

as which could lyse vivo after the formulation was

Cetomacrogol P.acnes and to study) stored for upto 90 days
pt

cream formulate the phage

into a delivery form
for potential
ce

application in topical
treatment
Antioxidants
Ac

Vitamin C 2008 To determine the Phase 2, No official results have been

efficacy randomized, posted in ClinicalTrials.gov
of a twice-daily double-blind,
sodium placebo-
L-ascorbyl-2- controlled
phosphate (APS) 5% trial
lotion for 12 weeks (NCT00714454)
Vaccines against P. acnes
Whole- 2008 To evaluate whether Experimental Antibodies elicited by
inactivated P. vaccination against P. (in vivo inactivated P. acnes based
acnes vaccine acnes suppressed P. study) vaccine attenuated IL-8
 acnes-induced skin production in human
inflammation. sebocytes. However, it did not
affect the survival/growth rate
of P. acnes.

P. acnes 2007 To develop a vaccine Experimental Antibodies against sialidase

sialidase- using P. acnes surface (in vivo provoked in
based vaccine enzyme sialidase that study) vaccinated mice effectively
suppress P. acnes- suppressed the P. acnes-
induced inflammation induced inflammation and
and pathogenesis neutralized the cytotoxicity of
P. acnes to human sebocytes

t
ip
cr
us
an
M
e d
pt
ce
Ac
Table 4 – Future of acne therapy - Anti-inflammatory agents
Name of drug Study Purpose of study Study design Result
year
NO-np / 2014 To utilized an Experimental P. acnes was found to be highly
Nitric oxide– established in vitro and in sensitive to all concentrations
releasing nanotechnology vivo of NO-np. NO-np significantly
nanoparticle capable of study suppressed IL-1ß, TNF-a, IL-8
generating/releasing and IL-6
nitric oxide over time from human monocytes and IL-
(NO-np). 8 and IL-6 from human
keratinocytes respectively.

t
ip
PDE inhibitor: 2010 To determine the Phase 2, open Study terminated for lack of
Apremilast safety and efficacy of label, funding
20 mg apremilast single-group

cr
taken twice a assignment
day for 12 weeks in study

us
the treatment of (NCT01074502)
moderate to- severe
acne
an
SCIO-469: 2014 To investigate Experimental Propionibacterium acnes
Inhibitor of whether P. acnes- study induced activation of p38.
M
the α isoform induced (in vitro study) Inflammatory cytokine
of p38 proinflammatory /chemokine secretion in
mitogen- cytokine release is keratinocytes is dose-
d

activated mediated by P. acnes- dependently inhibited by SCIO-

e

protein induced activation of 469

kinase (p38 p38 mitogen-activated
pt

MAPK) protein kinase (p38

MAPK) in human
keratinocytes.
ce

XOMA 052 2011 To evaluate the Phase 2, No official results have been
/ efficacy and safety of randomized, posted in ClinicalTrials.gov
Gevokizumab: gevokizumab in double-blind
Ac

Humanized moderate to severe placebo-

monoclonal acne controlled
IgG2 antibody study
with high (NCT01498874)
affinity
and
specificity to
IL-1β
CJM112: 2016 To assess preliminary A randomized, Ongoing
Human anti- efficacy and safety of double blind,
IL-17A CJM112 in patients placebo-
monoclonal with moderate to controlled,
antibody, severe inflammatory multi-center,
acne and to determine parallel group
if CJM112 has an study
adequate clinical (NCT02998671)
profile for further
clinical development
Vitamin D 2012 To determine the Phase 2/3, No official results have been
analogue clinical efficacy of a randomized, posted in ClinicalTrials.gov
topical vitamin D double--blind,
analogue single-group
(Calcipotriene)on acne clinical trial

t
(NCT01694433)

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