Novel pharmacological approaches for the treatment of acne vulgaris

1. Introduction

2. Agents that primarily target

sebum production

3. Agents that primarily

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

Review

Novel pharmacologicalapproaches for the treatmentof acne vulgarisIsabel Cristina Valente Duarte de SousaPrivate 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-1ainhibitors have the potential to become legitimate alternative options to ret-

inoid 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 themost 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 sebumproduction; 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 GlobalAlliance are directed toward one or more of these pathogenic causes and includetopical and systemic antibiotics and retinoids, benzoyl peroxide (BPO), azelaicacid, salicylic acid and oral antiandrogens, depending on the severity of the dis-ease [1]. However, because of unwanted side effects (irritation, bacterial resistance,systemic side effects) and chronicity [1], new treatments that target the differentpathogenic mechanisms of acne with minimal side effects are desirable.

The main objective of this paper is to review the current research being developedfor 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 1All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/EID

from what is already established in current treatment guide-lines. Therefore, a comprehensive review of the pathogenesisof acne or its treatment is beyond the scope of this paper; nev-ertheless, relevant pathogenic pathways are evaluated and dis-cussed throughout the paper in relation to the mechanisms ofaction of these novel therapies.

2. Agents that primarily target sebumproduction (Table 1)

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

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

2.1 AntiandrogensAndrogens have been known to contribute to the onset andpersistence of acne [6,7] by increasing sebum productionthrough the activation of its androgen receptor (AR) locatedin the epithelial cells of sebaceous glands [7,8]. Interestingly,it has been noted that complete androgen-insensitive orcastrated males do not develop acne due to a reduction insebum production [9].

Although the exact mechanisms by which the interaction ofandrogen/AR regulates sebocyte activity in acne vulgaris arestill unclear, it is thought to be through an increase in lipidsynthesis, sebocyte proliferation and inflammation [7,10].Sebaceous glands are known to contain type I and type III5a-reductase [11,12], the enzymes that converts dehydroepian-drosterone and dehydroepiandrosterone sulfate into testoster-one and its most potent active form dihydrotestosterone(DHT) [8,13]; thus the skin has the capacity of synthesizingits own testosterone and DHT either by metabolizing weakercirculating androgens into more potent ones by using 5-areductase or by metabolizing cholesterol [8,13,14].

This capacity to locally produce DHT and testosteroneaggravates sebum production and consequently acnelesions [7]. Interestingly, it has been noted that skin fromacne patients have higher rates and amounts of testosteroneand 5a-reductase than skin from healthy individuals [8,15].Although the main mechanism of action of isotretinoin, anoral retinoid used in severe forms of acne, is the normalizationof follicular dyskeratosis [1], it has also been shown to decreaseAR levels in human skin, which might in part explain thereduction in sebum production observed in patients treatedwith isotretinoin [16].

ARs are also present in keratinocytes and their stimulationhas shown to induce local TNF-a expression [17], contributingto the local inflammation observed in acne patients.

Therefore, acne could be treated by either decreasing serumandrogen levels or by inhibiting the action of androgens in thesebaceous glands [7].

Antiandrogen therapy is not a novel concept in the treat-ment of acne; however, due to their oral administration andconsequent systemic side effects [18], antiandrogens are onlyrecommended in the treatment of moderate-to-severe acnein female patients who have not responded to conventionaltherapy alone [1]. Antiandrogens for topical use are currentlyundergoing clinical trials and seem to offer a safe approachfor controlling sebogenesis.

2.1.1 Cortexolone 17a-propionate (CB-03-01)Cortexolone 17a-propionate, also known as CB-03-01, is anew topical monoester of cortexolone [6,19], which exhibitspotent antiandrogen activities [6].

Animal studies have determined that CB-03-01 displaysstronger local antiandrogenic activity than other known

Article highlights.

. Four major factors have been implicated in theappearance of acne lesions: i) altered sebum production;ii) abnormal keratinization within the pilosebaceous unit;iii) Propionibacterium acnes proliferation; andiv) perifollicular inflammation.

. Past knowledge on the pathogenesis of sebumproduction was sparse and was thought to be mainly aconsequence of androgenic stimuli. However, recentfindings have determined that other hormones such asa-melanocyte-stimulating hormone and IGF-1 also playa role.

. Skin sebogenesis is further controlled by acetylcholine,acetyl coenzyme A carboxylase and the presence ofproinflammatory mediators, such as leukotriene B4, andtheir interaction with PPARs. These new findings haveopened an array of possibilities for newtreatment targets.

. Low levels of endogenous retinoic acid lead to abnormalkeratinization within the follicular epithelium andconsequently to comedo formation. Current treatmentstrategies to limit hyperkeratinization include exogenousadministration of retinoids, which can cause side effectssuch as irritation, erythema, desquamation and dryness,among others. New treatment strategies are focused onincreasing endogenous retinoic acid levels to limitside effects.

. Due to the growing concern over bacterial resistance,antibiotic use will decline over the next years and will besubstituted 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 migrationand inflammation, which in turn is associated withscarring and sequels. More recently, the presence ofIL-1a has also shown to be involved in comedoformation. Drugs that control IL-1a and IL-b secretionare currently being evaluated for the treatment of acne.

This box summarizes key points contained in the article.

I. C. Valente Duarte de Sousa

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

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Table

1.Agents

thatprimarily

targetsebum

production.

Examples

Mech

anism

of

action/advantages

Studies

available

Year

Purpose

ofstudy

Clinical

phase

Numberof

subjects

enrolled

Studydesign

Main

resu

lts

Antiandrogens

Theinteractionbetw

eenantiandrogensandtheandrogenreceptor(AR)decreaseslipid

synthesis,sebocyte

proliferationandinflammation

[7,10]

Cortexolone

17apropionate

Topicalapplication

decreaseslipid

synthesislocally

withoutany

androgenic

systemic

sideeffects[19]

[6]

2011

Toestablishthesafety

andefficacy

of

cortexolone17a

propionate

1%

cream

inacnevulgarisappliedto

theface

once

nightlyfor

8weeksin

comparisonto

placeboandto

tretinoin

0.05%

cream

Pilotstudy

77

Randomized,

double-blind,

comparative

study

versusplaceboand

tretinoin

Cortexolone17apropionate

1%

cream

wasstatistically

betterthanplaceboin

reducingtotallesioncount

(p=0.0017),inflammatory

lesioncount(p

=0.0134)

andAcneSeverity

Index

(p=0.0090),withoutany

majorsideeffects

[20]

2013

Toevaluate

theadrenal

suppressionpotentialand

pharm

acokineticproper-

tiesofcortexolone17a

propionate

1.0%

cream

appliedevery

12hfor

2weeksin

subjectswith

acne

Phase

II50

Interventional,

single-group

assignment,

open-labelstudy

Ongoingstudy,

nofinal

resultspublished

[21]

2014

Toevaluate

thesafety

andefficacy

of

cortexolone17a

propionate

cream

applied

totheface

twicedaily

for

12weeksin

the

treatm

entofacne

vulgaris

Phase

II360

Multicenter,

randomized,

double-blind,

vehicle-controlled

anddose-escalating

study

Ongoingstudy,

nofinal

resultspublished

ASC-J9cream

Selectively

promotes

thedegradationofthe

AR[22-24],andthus

exertsits

antiandrogeniceffects

byinhibitingthe

interactionof

circulatingandrogens

withtheirreceptor

andthusreducing

sebaceousglandsize

andsebum

production

[17,25]

[25]

2008

Toevaluate

thesafety

andefficacy

ofASC-J9

cream

atthreedifferent

concentrations(0.001%

,0.005%

,0.025%

)appliedtw

icedaily

for

12weeksforthe

treatm

entoffacialacne

vulgaris

Phase

IIa186

Multicenter,

randomized,

double-blind,

placebo-controlled

study

ASC-9

0.025%

,wassuperior

toplaceboin

changingthe

percentageofinflammatory

lesioncounts

(-44.8

±35.6

vs-37.4

±41.0),

respectively

Noseriousadverseeffects

were

reported

[26,27]

2012

Toevaluate

thesafety

andefficacy

oftw

odifferentconcentrations

ofASC-J9cream

(0.1

and

Phase

IIb181

Multicenter,

randomized,

double-blind,

Noofficialresultshave

been

published

Novel pharmacological approaches for the treatment of acne vulgaris

Expert Opin. Investig. Drugs (2014) 23(10) 3

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Table

1.Agents

thatprimarily

targetsebum

production(continued).

Examples

Mech

anism

of

action/advantages

Studies

available

Year

Purpose

ofstudy

Clinical

phase

Numberof

subjects

enrolled

Studydesign

Main

resu

lts

0.025%

)appliedtopically

twicedaily

for12weeks

forthetreatm

entofacne

vehicle-controlled

study

NVN1000

Topicalnitricoxide

decreasesskin

androgenlevelsand

reduces5-a

reductase

activity,

thusreducing

sebocyte

proliferation,

sebum

productionand

lipogenesis

[10]

2012

Todeterm

inetheeffect

ofadaily

topical

applicationofNVN1000

0.5,1.5

and3%

gelon

androgen-dependant

hamsters

flankglandsfor

28days

incomparisonto

vehicle

alone

Preclinical

study

(anim

al

model)

Notapplicable

Notapplicable

NVN1000dose-dependently

inhibitedthegrowth

of

androgen-dependentham-

sterflankglandswithout

evidence

ofsystemic

absorption

[36-39]

2013

Todeterm

inethesafety

andcutaneoustolerability

ofNVN1000gelapplied

totheface

twicedaily

for

2weeks

Phase

I30

Randomized,

double-blind,

multiple-dose,

parallel-group

study


been

published

[40-42]

2013

Tocompare

theefficacy,

tolerability

andsafety

of

NVN1000gel1and4%

withvehicle

geltw

ice

daily

inthetreatm

entof

acne

Phase

II/III

153

Multicenter,

randomized,

double-blinded,

vehicle-controlled,

parallel-group,

three-arm

study

NVN

issuperiorto

placeboin

reducinginflammatory

and

non-inflammatory

lesion

counts

(p£0.05).Italso

decreasedsebum

production

by80%

.

Examples

Mech

anism

of

action

Studies

available

Year

Purpose

ofthestudy

Clinical

phase

Numberof

subjects

enrolled

Studydesign

Main

resu

lts

Melanoco

rtin

receptorantagonists

Antagonists

ofthemelanocortin

receptor5(M

C5-R)inhibitsebocyte

differentiationandreduce

sebum

production

[4,5]

JNJ10229570

Decreasessebaceous

gland’s

size,

productionof

sebaceouslipidsand

theexpressionofthe

sebaceousdifferentia-

tionmarkerepithelial-

membrane

antigen

[48]

[53]

2011

Toevaluate

thesafety

andtolerability

ofasingle

topicalapplicationofJNJ

102295701.2

and3.6%

comparedto

placebo

Phase

I18

Randomized,

double-blind,

placebo-controlled

study


been

published

[54]

2012

Toevaluate

theefficacy

andsafety

ofaJNJ

10229570-AAA

topical

cream

appliedonce

daily

for12consecutives

weeks

Phase

II400

Multicenter,

double-blind,

vehicle-controlled

study


been

published



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Table

1.Agents

thatprimarily

targetsebum


Examples

Mech

anism

of

action

Studies

available

Year

Purpose

ofthestudy

Clinical

phase

Numberof

subjects

enrolled

Studydesign

Main

resu

lts

IGF-1inhibitors

IGF-1hasbeenshownto

stim

ulate

androgen-inducedlipogenesisandsebocyte

proliferation

[56,57,64]

Epigallocatechin-3-

gallate

(EGCG)

SuppressesIGF-1-in-

ducedlipogenesisand

cytokineexpressionin

sebocytes[65].Italso

inhibits5a-reductase-

1activity,

andthus

limits

dihydrotestosterone-

dependantsebum

production

[71]

[65]

2012

Toexaminedtheeffects

ofEGCG

on

IGF-1-inducedlipogenesis

andinflammationin

anim

almodelsin

vivo

and

inhumansebocytes

invitro

Preclinical

study

(anim

al

study,

invitro

model)

Notapplicable

Notapplicable

EGCG

significantlyreduces

size

ofsebaceousglands

(p<0.01),themeannumber

ofsebocytespergland

(p<0.05)andsize

of

comedos(p

<0.001)

EGCG

inhibitscell

proliferationandlipid

synthesisin

vitro(p

<0.001)

[74]

2006

Toexaminedtheeffects

ofEGCG

onlipogenesis

andinflammationin

humansebocytesin

vitro

Preclinical

study

(invitro

model)

Notapplicable

Notapplicable

EGCG

decreaseslipogenesis

inhumansebocytesby55%

,decreasesinflammationand

inducesapoptosisof

sebocytes

[75]

2006

Todeterm

inetheclinical

andhistologicaleffectsof

1and5%

EGCG

solution

appliedtopically

tothe

face

twiceadayfor

8weeksin

subjectswith

acne

Phase

I35

Randomized,

double-blind,

vehicle-controlled

study

Patients

treatedwithEGCG

solutionshoweda79--89%

reductionin

non-

inflammatory

and

inflammatory

lesioncounts

after8weeksoftreatm

ent

(p<0.05)withoutany

serioussideeffects

PPARsmodulators

PPARsare

transcriptionfactors

thatupregulate

lipid

synthesis.

LeukotrieneB4(LTB4)isaligandforPPAR,so

byinhibitingitsproduction,PPAR-m

ediatedsebogenesisiscontrolled

Zileuton

Zileutonisa

5-lipoxygenase

(5-LOX)

inhibitor.

Both

5-LOX,the

enzymeresponsible

forcatalyzingthe

conversionof

arachidonic

acidinto

LTB4,andPPARare

overexpressedin

skin

andsebaceousglands

ofacne

patients

[66,77]thus

providinglogical

[2]

2003

Todeterm

inetheeffects

ofzileutonin

human

sebocytesin

vitro

Experimental

study

Notapplicable

Notapplicable

Zileutonreducedneutraland

polarlipidsin

SZ95sebocytes

(p<0.001).Zileutonalso

reducesIL-6

release

from

SZ95sebocytes(-42±1%

;p<0.001)

[76]

2003

Todeterm

inetheeffects

ofzileutonin

patients

withinflammatory

acne

Pilotstudy

10

Single-blinded

Zileutonreducedthenumber

ofinflammatory

lesionsby

29%

(p<0.01),decreased

totalsebum

lipidsand

proinflammatory

freefatty

acidsby35%

(p<0.05)and

22%

,respectively

and

dim

inishedlipoperoxidesby



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Table

1.Agents

thatprimarily

targetsebum


Examples

Mech

anism

of

action

Studies

available

Year

Purpose

ofthestudy

Clinical

phase

Numberof

subjects

enrolled

Studydesign

Main

resu

lts

support

fortheuse

of

5-LOXinhibitors

toinhibitPPAR-m

ediated

lipogenesis

26%

.Thedegreeofclinical

improvementstrongly

correlatedwiththedescent

intotalsebum

lipids

(p=0.0009)andfreefatty

acids(p

=0.0003)

[2]

2003

Todeterm

inetheeffects

ofzileutonin

patients

withinflammatory

acne

Pilotstudy

10

Open-label,

cohort

study

Zileutondecreased

inflammatory

andnon-

inflammatory

lesionsby71%

(p=0.007)and36%

,respectively.Italsoreduced

theAcneSeverity

Indexby

59%

(p=0.01)and

suppressedtotalsebum

lipid

productionby65%

(p=0.038)after12weeks

oftreatm

ent

[82]

2005

Totest

thesafety

and

efficacy

ofzileutonin

the

treatm

entoffacialacne

Phase

II90

Randomized,

double-blind,

placebo-controlled,

parallel-group,

multicenterstudy

Zileutonwaseffectivein

reducingthenumberof

inflammatory

lesionby

41.6%

(p=0.025)

Acetylcholine(A

CH)inhibitors

Ach

increaseslipid

synthesisin

adose-dependentmanner

ANT-1207(Topical

form

ulationof

botulinum

toxin)

Botulinum

toxin

inhibitsthe

presynapticrelease

of

Ach,whichin

turn

reducessebum

production

[91]

2012

Todeterm

inethesafety,

tolerance

andefficacy

of

ANT-1207in

the

treatm

entofacne

Phase

II72

Randomized,

double-blind,

vehicle-controlled

study


been

published

Acetylco

enzy

meA

carboxylase

(ACC)inhibitors

ACCisinvolvedin

theregulatory

stepsofsebaceousfattyacidbiosynthesisresultingin

denovo

synthesisoflipids

DRM01B

InhibitorofACC

[95]

2014

Toassess

thesafety

and

tolerability

ofDRM01B

7.5%

topicalgelapplied

for1week

Phase

I6

Open-label

Expectedin

June2014

[96]

2014

Toassess

thesafety,

tolerability

and

prelim

inary

efficacy

of

12-w

eekapplicationof

DRM01B7.5%

topicalgel

Phase

II100

Randomized,

vehicle-controlled,

parallel-group

study

Expectedin

June2014



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antiandrogens such as progesterone, flutamide and finasteridewithout any systemic side effects. Although the mechanismthrough which topical CB-03-01 exhibits antiandrogeniceffects has still not been completely elucidated, an interactionwith the AR is proposed [19].

In 2011, Trifu et al. evaluated the safety and efficacy ofCB-03-01 1% cream in acne vulgaris in comparison toplacebo and to tretinoin 0.05% cream. A total of 77 malesubjects were randomized to receive CB-03-01 1% cream, tre-tinoin 0.05% cream or placebo once nightly for 8 weeks.CB-03-01 1% cream was statistically better than placebo inreducing total lesion count (p = 0.0017), inflammatory lesioncount (p = 0.0134) and Acne Severity Index (p = 0.0090),without any major side effects. Further, CB-03-01 1% creamshowed a faster onset of all the abovementioned improve-ments and was clinically more effective than tretinoin0.05% cream, although the results were not statistically signif-icant [6]. Another study designed to evaluate the adrenal sup-pression potential and pharmacokinetic properties of 1.0%CB-03-01 cream applied every 12 h for 2 weeks in subjectswith acne, was completed in November 2013. Approximately50 males and females aged ‡ 12 years were enrolled in thestudy. No official results have been published yet, as this studyis still ongoing [20].

The safety and efficacy of CB-03-01 cream in the treatmentof acne vulgaris is currently being investigated in the USA in aPhase II, multicenter, randomized, double-blind, vehicle-controlled and dose-escalating study. Approximately 360males and females, aged ‡ 12 years, were included in the studyand were instructed to apply either cortexolone cream atdifferent concentrations or vehicle cream to the face twicedaily for 12 weeks. The primary estimated completion datefor this trial is March 2014 [21].

2.1.2 ASC-J9 creamASC-J9� selectively promotes the degradation of the AR [22-

24] and thus exerts its antiandrogenic effects by inhibitingthe interaction of circulating androgens with their receptor.

A topical formulation of ASC-J9, ASC-J9 cream, has beenshown to reduce sebaceous gland size and sebum productionin animal studies [17] and in human subjects [25,26]. In 2008,a Phase IIa, multicenter, randomized, double-blind, placebo-controlled study to valuate the safety and efficacy of ASC-J9cream at 3 different concentrations (0.001%, 0.005%,0.025%) applied twice daily for 12 weeks for the treatmentof facial acne vulgaris was completed. A total of 186 subjectswere included in the study (76 female, 110 male, mean age17.9 ± 5.2). ASC-9 0.025%, but not ASC-J9 0.005 and0.001%, was superior to placebo in changing the percentageof inflammatory lesion counts from baseline to week12 (-44.8 ± 35.6 vs -37.4 ± 41.0, respectively). Percentageof participants who showed improvement in the Investigator’sGlobal Assessment (IGA) scale was also superior in the grouptreated with ASC-J9 cream in comparison to placebo (60.8 vs48.9%, respectively). No serious adverse effects were reported

in any of the ASC-J9 treatment groups; however, patientstreated with ASC-J9 cream had an overall higher number ofupper respiratory tract infections, nasopharyngitis andstreptococcal infections reported in comparison to the placebogroup [25].

Although, ASC-J9 clinically reduced inflammatory lesionscompared to placebo and seemed to have a therapeutic benefitcomparable to marketed acne drugs on inflammatory lesions,the study was not powered for statistical significance.AndroScience is, therefore, currently working on bolsteringefficacy through a new formulation [27].

The Phase IIb trial that followed was a multicenter,randomized, double-blind, vehicle-controlled study in whichthe safety and efficacy of two different concentrations ofASC-J9 cream (0.1 and 0.025%) applied topically twice dailyfor 12 weeks for the treatment of acne were evaluated. A totalof 181 male and female patients, aged ‡ 12 years old, wereenrolled [26] and were randomized to receive either 0.1%ASC-J9 cream, 0.025% ASC-J9 cream or placebo (~ 60 par-ticipants per group) [27]. The study was completed in 2012;however the official results of this study have not been dis-closed yet [26]. Nevertheless, ASC-J9 cream seemed to have apositive treatment response in patients with acne superior totreatment with vehicle alone. Patients treated with ASC-J9cream showed a reduction in total, inflammatory, and non-inflammatory lesion counts at weeks 2, 4, 8 and 12, as wellas an improvement in the IGA score, which is indicative ofASC-J9 superiority to placebo in the treatment of acne. Nosystemic or local side effects were reported during the study,thus making ASC-J9 a drug with an adequate safetyprofile [27].

2.1.3 NVN1000NVN1000, also called SB204, is a gel that releases nitric oxide(NO) when applied topically to the skin [10]. Animal studieshave previously established that steroidogenesis is inhibitedwhen concentrations of NO increase [28-30], due to inhibitionof the conversion of cholesterol into steroid hormones [29],such as testosterone DHT [10]. By inhibiting CYP450 andreducing 5-a reductase activity [10,31,32], both of which canbe found in sebocytes [13] and are required for independentskin steroidogenesis [8], NO is able to decrease skin androgenlevels, thus reducing sebocyte proliferation, sebum produc-tion [10] and lipogenesis [33].

Thus, NO exerts its antiandrogenic effects by inhibiting theandrogen-dependant sebum production pathway [10].

Considering that the skin from acne patients has higherrates and amounts of testosterone and 5a-reductase than theskin from healthy individuals [8,15], treatment with NO couldpotentially decrease androgen conversion and thus reducesebum production [10].

Further, as a reactive free radical, NO exhibits antibacterialeffects [34,35] by damaging the cell membrane and inhibitingcell function via oxidative and nitrosative stress [34], whichreduces P. acnes proliferation [10]. It is also proposed that by



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inhibiting sebum production, NO would altogether avoidabnormal P. acnes colonization [10].In animal studies, NVN1000 has proven to inhibit

sebaceous gland growth after 28 days of topical applicationwithout any systemic absorption, activity, side effects ortoxicity [10], thus suggesting that it could be a potential newtreatment for controlling sebum production. In humans, thetolerability, safety and efficacy of different concentrations(1%, 4%, 8%) of NVN1000 have also been evaluated infour Phase I clinical trials [36-39]. The last study, a randomized,double-blind, multiple-dose, parallel-group study to deter-mine the safety and cutaneous tolerability of NVN1000 gelapplied to the face twice daily for 2 weeks in 30 healthymale and female volunteers, was completed in June2013 [39]. The effects of NVN1000 gel on P. acnes countswere also evaluated in this trial [39]. The results showed thatSB204 gel reduced the colonization of P. acnes by 90%(p < 0.05) without any major side effects [40]. A Phase II/IIImulticenter, randomized, double-blinded, vehicle-controlled,parallel group, three-arm study, comparing the efficacy, toler-ability and safety of two concentrations of NVN1000 gel(1 and 4%) with vehicle gel applied twice daily in the treat-ment of acne was completed last November 2013. A total of153 patients, aged 12 -- 40 years, were enrolled in thestudy [41]. A total of 129 patients completed the 12-weekstudy period [42]. The results showed that both concentrationsof NVN1000 gel were superior to vehicle alone in reducingnon-inflammatory and inflammatory lesions count as earlyas week 4 (p £ 0.05). By week 12, the median reduction forinflammatory lesions was 62% in the intent to treat popula-tion. Moreover, no serious adverse effects were reported andtreatment with NVN1000 was as well tolerated as treatmentwith vehicle alone. It was also determined that NVN1000is able to reduce sebum production by 80% in 12 weeks [42].

2.2 Melanocortin receptor antagonistsAlthough 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-mela-nocyte-stimulating hormone (a-MSH) has been implicatedin increased sebogenesis in rodents [43] via the stimulation oftwo receptor subtypes, the melanocortin receptor 1(MC1-R) and the melanocortin receptor 5 (MC5-R), bothof which are expressed in human sebocytes [44-49] MC1-Ractivity has been found to be more pronounced in thesebocytes of skin of acne patients than in the skin of healthyindividuals, suggesting that it may be implicated with thepathogenesis of acne. MC1-R expression is upregulated byproinflammatory signals, which are also elevated in acne,which in turn also suggest that MC1-R may play a role in pro-tecting the sebocytes from cytotoxic stimuli released duringinflammation [50].MCR-5 has been associated with sebum production and

sebocyte differentiation [4].

Chen et al. determined that after disruption of the murineMC5-R gene, a reduction in hair lipid content wasobserved [51]. Further, MC5-R-deficient mice exhibit a reduc-tion in sebaceous lipids [4], which is consistent with previousfindings that a-MSH acts as a sebothropic hormone [43,52]

Studies in vitro have shown that antagonists of MC5-R inhibitsebocyte differentiation [4]. MC5-R antagonists are also capa-ble of reducing sebum production in human skin transplantedonto immunodeficient mice [4], which suggest a role forMC5-R antagonists as potential sebum-suppressive agents [4]

Eisinger et al. determined that JNJ 10229570, a MC1-Rand MC5-R antagonist, decreases sebaceous gland’s size, pro-duction of sebaceous lipids and the expression of the seba-ceous differentiation marker epithelial-membrane antigen incultured primary human sebocytes.

Further, a reduction in the hypercornification of the infun-dibulum is observed [48].

Two clinical trials have evaluated the role of JNJ 10229570cream in the treatment of acne: i) a randomized, double-blindstudy to evaluate the safety and tolerability of a single topicalapplication of JNJ 10229570-AAA cream at two differentconcentrations (1.2%, 3.6%) compared to placebo on 18Japanese subjects with acne aged 25 -- 35 years [53]; and ii) amulticenter, double-blind, vehicle-controlled, Phase II studyto evaluate the efficacy and safety of a JNJ 10229570-AAAtopical cream applied once daily for 12 consecutives weeksin 400 male and female acne patients, aged ‡ 12 years [54].Both studies have been completed but no official resultshave been published [53,54].

2.3 IGF-1 inhibitorsIGF-1 has been recently implicated in the pathogenesis ofacne. Interestingly, subjects with Laron syndrome, a congeni-tal IGF-1 deficiency, do not develop acne [55]. IGF-1 has beenshown to stimulate lipogenesis in human sebocytes [56,57] andinduce keratinocyte proliferation in vitro and in vivo [58-63]

Moreover, IGF-1 has been associated with increasedandrogen-induced lipogenesis and sebocyte proliferation [64],as well as with increased inflammatory cytokines productionsuch as IL-1, IL-6 and IL-8 [65], known to be elevated inacne [3,66].

High serum IGF-1 levels directly correlate with the severityof acne [67,68] and the amount of facial sebum [69]. Further,skin from acne lesions present higher levels of IGF-1 andIGF-1 receptor (IGF-1R) than skin from healthy individu-als [70]. Interestingly, IGF-1 and IGF-1R expression in kerati-nocytes can be stimulated by P. acnes [70].

Animal models have demonstrated that epigallocatechin-3-gallate (EGCG), a major polyphenolic constituent in greentea, significantly reduces size of sebaceous glands (p < 0.01),the mean number of sebocytes per gland (p < 0.05) and sizeof comedos (p < 0.001), similar to all-trans-retinoic acid(RA) [65]. Further, EGCG dose-dependently inhibits cellproliferation and lipid synthesis in SZ95 sebocytes in vitro(p < 0.001) via inhibiting IGF-1 [65].



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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. acnesand has proven to be clinically effective in the treatment ofacne without any major side effects [65,72-74]. Further, EGCGhas been shown to decrease lipogenesis in humanSEB-1 sebocytes in vitro by 55%, to decrease inflammationthrough the inhibition of NF-kB and AP-1 pathways and toinduce cytotoxicity of SEB-1 sebocytes via apoptosis [74].

A randomized, double-blind study to evaluate the effects of1 or 5% EGCG solution applied twice daily to the face for8 weeks in subjects with acne was completed in 2006 [75].The study included 35 subjects, aged 15 -- 40 years (mean age22.1), who showed significant improvement in acne lesions.Patients treated with EGCG solution showed a 79 -- 89%reduction in non-inflammatory and inflammatory lesioncounts after 8 weeks of treatment (p < 0.05). No serious sideeffects were reported. Mild side effects such as erythema werepresent in only four patients. Further, immunohistochemicalanalysis of acne-affected skin before and after treatmentshowed a reduction in the expression of IL-8, sterol regulatoryelement-binding proteins type 1, phospho-c-Jun and NF-kB,which suggests that EGCG decreases the inflammatoryresponse and increases apoptosis in acne lesions in vivo [74].

Zinc gluconate has also been shown to reduce the overex-pression of IGF-1 and IGF-1R caused by P. acnes [69].

2.4 PPARs modulatorsZileuton, an oral 5-lipoxygenase (5-LOX) inhibitor, has beenshown to reduce the number of inflammatory lesions in mod-erate acne by downregulating IL-6 and leukotrieneB4 (LTB4) and by temporarily inhibiting the synthesis ofsebaceous lipids [76]. Zileuton inhibits sebum production ina manner similar to that of isotretinoin in a mechanism [2]

thought to involve PPARs [76]. PPARs are ligand-activatedtranscription factors, highly expressed in human skin andother tissues [76], that have been shown to upregulate lipidsynthesis and regulate cell proliferation, differentiation andapoptosis [2,77-79]. The three described isoforms of PPARs,PPAR-a, PPAR-b/d and PPAR-g are encoded in differentgenes and thus exhibit different ligand specificities, targetgenes, tissue distribution and biological roles [2,77,78,80]; how-ever, all three have been implicated with increased lipogene-sis [2,77,80]. PPAR-a mainly contributes to sebocyte activitythrough 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 upregu-late keratinocyte differentiation, while limiting proliferation,reducing inflammation and accelerating skin barrierrepair [77].

LTB4, a ligand for PPAR-a and a major player in theinflammation cascade, induces lysosomal release and IL pro-duction by neutrophils, increases neutrophil adherence andmigration, promotes the generation of superoxide radicals,activates complement [2] and increases the synthesis of neutral

lipids [2,64]. Both 5-LOX, the enzyme responsible for catalyz-ing the first step in converting arachidonic acid intoLTB4 [2,64], and PPAR are overexpressed in skin and seba-ceous glands of acne patients [65,77], thus providing logicalsupport for the use of 5-LOX inhibitors to downregulateexpression of LTB4 in sebaceous gland [2], and thus inhibitPPAR-mediated lipogenesis.

In a pilot study that included four female and six male sub-jects, zileuton was found to decrease acne severity by reducingthe number of inflammatory lesions by 29% (p < 0.01),decreasing total sebum lipids and proinflammatory free fattyacids by 35% (p < 0.05) and 22%, respectively, and by dimin-ishing lipoperoxides by 26% [76]. It is important to mentionthat the degree of clinical improvement and the decrease ininflammatory lesion count strongly correlates with the descentin total sebum lipids (p = 0.0009) and free fatty acids(p = 0.0003) [2,76]. A Phase II, randomized, double-blind, pla-cebo-controlled, parallel-group, multicenter study to deter-mine the effects of zileuton on the count number ofinflammatory and non-inflammatory lesions and on sebumproduction in patients with moderate-to-severe facialacne [82], showed that zileuton was effective in reducing thenumber of inflammatory lesion by 41.6% (p = 0.025) [2].

In another study, zileuton proved to significantly decreaseinflammatory and non-inflammatory lesions by 71%(p = 0.007) and 36%, respectively, to reduce the Acne SeverityIndex by 59% (p = 0.01) and to suppress total sebum lipidproduction by 65% (p = 0.038) after 12 weeks of treatment.Zileuton also decreased free fatty acids and hydroperoxideslevels in sebum [2].

2.5 Acetylcholine inhibitorsEvidence for cholinergic signaling in sebaceous glands is stillsparse. Sebaceous glands express acetylcholine (Ach) recep-tors [83] in a highly regulated manner, suggesting a role ofAch in sebum production, probably through promoting sebo-cyte differentiation [84].

Recently it was established that Ach increases lipid synthesisin a dose-dependent manner, in both cultured sebocytes andin healthy volunteers, probably due to its interactionwith the Ach receptor a7 expressed in sebaceous glands [85].Botulinum toxin inhibits the presynaptic release ofAch [86,87] and has recently been found to noticeably decreasesebum production, oily skin and pore size [85,88,89].

Further, topical anticholinergic agents (poldine methyl-methosulfate) have also shown to reduce sebum production [90].Thus, Ach inhibitors could offer a potential benefit in the treat-ment of acne. The safety and efficacy of a topical formulationof botulinum toxin type A (ANT-1207) was evaluated in2012 in a Phase II, vehicle-controlled, double-blind, clinicalstudy; however, the results have not been published yet [91].

2.6 Acetyl coenzyme A carboxylase inhibitorsAnimal models have established that androgenic stimulationof sebaceous glands increases key enzymes involved in the



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regulatory steps of sebaceous fatty acid biosynthesis, such asacetyl coenzyme A carboxylase (ACC) [92,93].ACC catalyzes the conversion of acetyl-coenzyme A (CoA)

into malonyl-CoA, which in turn is determinant of whetherfatty acids are synthesized or oxidized [94].ACC has two isoforms (ACC1 and ACC2) and although

they both catalyze the conversion of acetyl-CoA intomalonyl-CoA, the product of this reaction exerts differentbiological activities [94].Both ACC1- and ACC2-mediated malonyl-CoA syntheses

can result in de novo synthesis of lipids, but only ACC2 iscapable of catalyzing malonyl-CoA involved in fatty acid oxi-dation. Further, inhibition of ACC has shown to significantlyincrease fatty acid oxidation and to reduce triglyceride synthe-sis [94]. Dermira, Inc. is currently recruiting male and femalesubjects, aged ‡ 18 years, to participate in a Phase I/II ran-domized, double-blind, parallel assignment clinical trail onthe safety, tolerability and preliminary efficacy of the topicalapplication of DRM01B (an inhibitor of the enzymeACC [95]) gel on healthy subjects and in subjects with acnevulgaris. Phase I of this clinical trial involves an open-labelstudy designed to assess the safety and tolerability ofDRM01B 7.5% topical gel on six healthy volunteers whowill be using the product for 1 week. If no major adverseeffects are reported and if local tolerability is acceptable, thestudy will move on to Phase II, a randomized, vehicle-controlled, parallel-group study that will assess the safety,tolerability and preliminary efficacy of 12-week applicationof DRM01B 7.5% topical gel in approximately 100 subjectswith acne vulgaris. The estimated primary completion dateof both studies is set for June 2014 [96].

3. Agents that primarily normalize abnormalkeratinization within the pilosebaceous unit(Table 2)

3.1 Retinoic acid metabolism-blocking agents

3.1.1 TalarozoleTalarozole, also called Rambazole or R115866, [97], is a selec-tive azole derivative [98] that potently inhibits the CYP26,known to be involved in the metabolism of RA [99]. RA isinvolved in the keratinization process within the follicular epi-thelium and thus is also involved in comedo formation [100].Rat studies have noted that high plasma levels of RA are asso-ciated with inhibition in keratinization [101]. The CYP450isozyme system is involved in the breakdown of RA throughoxidative metabolism [100]. Although several CYP isozymesare capable of initiating RA oxidation, CYP26 seems to bethe isozyme that is more specific for RA breakdown [100].The rational is that talarozole by inhibiting CYP26 increasesthe level of RA, allowing for normalization of desquamationof the follicular epithelium and thus reducing comedoformation [100].

CYP26 inhibitors are capable of enhancing RA levels thusdisplaying retinoidal actions, such as inhibition of keratiniza-tion and induction of epidermal hyperplasia, amongothers [100].

A gel formulations containing 0.35 and 0.7% talarozole hasbeen studied on human skin in a Phase I randomized trialperformed with 16 healthy individuals, and it was determinedthat topical talarozole presents retinoic acid effects with lessinflammation [102]. Topical talarozole has also been found toinduce these retinoid-like effects even after a single topicalapplication [98]. Taken together, these data suggest thatCYP26 inhibitors could potentially presents an advantageover topical retinoids. As with retinoids, some concerns havealso been raised with CYP inhibitors on the potential formutagenesis [103,104]. In 2011, Stiefel, a GSK Company, com-pleted a Phase II open--label, randomized, pilot trial to assessthe safety and efficacy of 1 mg oral R115866 taken once dailyfor 12 weeks in the treatment of moderate-to-severe facialacne in 16 male patients, aged 16 -- 50 years. No resultshave been published for this study [97].

3.2 Monoclonal antibodies anti IL-1aComedos or comedones, the primary lesion in acne, are a con-sequence of abnormal keratinization [105] and although theexact mechanisms underlying their formation remain unclear,IL-1a seems to play a role [106].

In vitro models of acne have determined that stimulation ofthe pilosebaceous infundibulum with IL-1a induced a hyper-keratinization response similar to that seen in comedos [107].Further, this effect was reversed with the administration ofIL-1 receptor antagonist (IL-1ra) [107]. Ingham et al. reportedhigh levels of IL-1a in comedos extracted from acnepatients [108].

The expression of IL-1a in acne seems to be controlled inpart by the activation of Toll-like receptors (TLRs), whichare major players of innate immunity [106]. TLRs recognizepathogen-associated molecular patterns (PAMPs), such aspeptidoglycans (PGN) and lipopolysaccharide, that arepresent in Gram-positive and Gram-negative bacteria,respectively, and initiate the release of antibacterial factors(b-defensins and reactive oxygen species [ROS]) andproinflammatory mediators such as IL-1a [106].

The expression of TLR-2, one of the main TLRs present inkeratinocytes and sebocytes [106], is increased in cultured epi-dermal keratinocytes exposed to P. acnes and in biopsies oflesional skin from acne patients [109]. Further studies in vitroshowed that human epidermal keratinocytes release 46%more IL-1a on TLR stimulation with PGN, the PAMPpresent in P. acnes, compared to stimulation with vehiclealone (p < 0.05) [106]. Further, sebaceous glands maintainedex vivo exposed to PGN for 7 days, showed increased hyper-keratosis similar to that observed after IL-1a treatment,whereas sebaceous glands exposed to vehicle alone didnot [106]. These data suggest that PAMPs not only exert aneffect on keratinocytes and induce the release of IL-1a, but



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Table

2.Agents

thatprimarily

norm

alize

abnorm

alkeratinizationwithin

thepilosebaceousunit.

Examples

Mech

anism

of

action/advantages

Studies

available

Year

Purpose

ofstudy

Clinical

phase

Numberof

subjects

enrolled

Studydesign

Main

resu

lts

Retinoic

acidmetabolism

-blockingagents

Highlevelsofall-trans-retinoic

acid(RA)are

associatedwithnorm

alizationofdesquamationofthefollicularepithelium

andthusreductionin

comedoform

ation

[100]

Talarozole

Azole

derivative

that

inhibitstheCYP26in

chargeofRA

breakdown,

thusincreasingRA

serum

levels

[102]

2009

Todeterm

inethe

effect

oftopical

talarozole

0.35and

0.7%

gelonretinoid

biomarkers

innorm

al

skin

Phase

I16

Open-label,

randomized

Talarozole

treatm

ent

increasedthemRNA

expressionofCRABP2,KRT4,

CYP26A1andCYP26B1,

consistentwithincreased

retinoicacidstim

ulation,

withoutinducingskin

inflammation

[97]

2011

Toassess

thesafety

andefficacy

of1mg

oraltalarozole

taken

once

daily

for

12weeksin

the

treatm

entof

moderate-to-severe

facialacne

Phase

II16

Open-label,

randomized

Noofficialresultspublished

yet

Monoclonalantibodiesanti-IL-1a

HighlevelsofIL-1ainduce

hyperkeratinizationofthepilosebaceousinfundibulum

andthusstim

ulate

comedoform

ation

[105-108]

RA-18C3

Monoclonalantibody

specificforIL-1a

[111]

2012

Todeterm

inethe

safety,pharm

acokinet-

icsandefficacy

of

threeinjectionsof

RA-18C3administered

subcutaneouslyon

subjectswithacne

Phase

II7

Open-label,

single-group

assignment

Inflammatory

lesioncount

showedanaverage

improvementof35±8%

(median34%

,range

25--48%

)onday42and

44±23%

(median42%

,range19--71%

)onday56



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they also mediate their effects on sebaceous glands viaTLRs [106].Thus, P. acnes seems to activate the release of IL-1a via

TLR-2 activation [110]. IL-1a, in turn, seems to play animportant role not only in the development of inflammatorylesions 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 specificfor IL-1a [111], to treat subjects with moderate-to-severeacne was concluded. Seven patients (five female, two male),aged 18 -- 30 years (median age 23), were treated with either100 or 200 mg of RA-18C3, depending on weight, via subcu-taneous injection on days 0, 21 and 42 for a total of threeinjections [111,112]. After three injections, the total facialinflammatory lesion count showed an average improvementof 35 ± 8% (median 34%, range 25 -- 48%) on day 42 and44 ± 23% (median 42%, range 19 -- 71%) on day 56 [111].

4. Agents that primarily work by modulatingP. acnes (Table 3)

4.1 Antimicrobial peptidesAntimicrobial peptides (AMPs), discovered in the 1980s, areconsidered to be a primitive mechanism of immunity andhave 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 immu-nity [113]. AMPs can be produced by virtually all human cellsin the presence of microbes [114]. Two of the most importantAMPs are the defensins and the cathelicidins that are mainlyproduced by epithelial cells and neutrophils [114].MBI 226, currently known as omiganan pentahydrochlor-

ide [115], is a topical cationic peptide [116] derived from thebovine AMP indolicidin [114] that is shown to have rapid(2 -- 6 h) in vitro microbicidal activity against a variety ofGram-positive and Gram-negative bacteria [113-115,117] by dis-rupting their cytoplasmic membranes and causing depolariza-tion followed by cell death [117,118]. Hemolysis, a side effect ofindolicidin, is not as common with omiganan pentahydro-chloride [119], which is an important characteristic. ThreePhase I studies have determined that omiganan pentahydro-chloride solution is well tolerated and not systemicallyabsorbed after topical administration [114,119].In 2001, a Phase IIa, randomized, placebo-controlled,

double-blind study to evaluate the safety and efficacy ofMBI 226 2.5 and 5.0% solutions in the treatment of acne vul-garis was completed. The solution was applied topically on75 male and female subjects, aged ‡ 13 years, with acne vul-garis [120]. After 6 weeks of treatment, patients treated withomiganan presented with a reduced count of comedos (25%reduction in the omiganan group compared to 10% reductionin the placebo group) and of papules and pustules (39%reduction in the omiganan group compared to 21% reductionin the placebo group). Also, according to the Physician’sGlobal Severity Assessment scores, 41% of patients treated

with omiganan presented good-to-excellent improvement inacne lesions compared to 32% of patients in the placebogroup. Treatment with the 2.5% omiganan solution provedto be equal or superior to the 5% solution [114].

In 2003, a Phase II, randomized, vehicle-controlled, dou-ble-blind, multicenter clinical trial was completed to evaluatethe safety and efficacy of MBI 226 1.25 and 2.5% acne solu-tions applied topically for 12 weeks on subjects with acne vul-garis. A total of 241 patients, aged 12 -- 45 years, wereenrolled. Six weeks into the treatment, patients treated withthe 2.5% omiganan pentahydrochloride solution showed sta-tistically significant improvement of non-inflammatory andinflammatory lesion count [121]. Omiganan pentahydrochlor-ide was able to reduce inflammatory lesions by 40% [119].

4.2 AntioxidantsVitamin C, a potent antioxidant and ROS scavenger [122], hasshown to exert antimicrobial effects on P. acnes, to prevent upto 40% of ultraviolet A-induced sebum oxidation and toimprove acne lesions in up to 76.9% of patients [123].Woolery-Lloyd et al. recently conducted a randomized, dou-ble-blind, placebo-controlled trial to determine the efficacyof a twice-daily sodium L-ascorbyl-2-phosphate 5% lotion, astable vitamin C derivative and potent antioxidant [124], for12 weeks, in the treatment of acne vulgaris in subjects aged18 -- 35 years [125]. It was determined that sodiumL-ascorbyl-2-phosphate 5% lotion was superior to vehiclealone in reducing lesion counts, while having similar tolerabil-ity and adverse reactions frequency [124].

5. Agents that primarily work by modulatingthe inflammatory response (Table 4)

5.1 Phosphodiesterase inhibitorsPDEs are known to degrade intracytoplasmic levels of cAMP.Low levels of cAMP lead to preferential expression of proin-flammatory cytokines such as TNF-a, IL-1, IL-8, IL-12 andIL- 23 [126,127]. Therefore, agents that inhibit PDEs, andthus elevate cAMP, may play a role in chronic inflammatorydiseases that have elevation of IL-1 and TNF-a, such asacne, rosacea and atopic dermatitis. Because PDE4 is themain cAMP-degrading isoenzyme [126], inhibiting PDE4elevates cAMP levels and thus decreases the activity of proin-flammatory cytokines [126].

Therefore, drugs such as apremilast, a small-moleculePDE4 inhibitor [128], could potentially play a role in acnetreatment in the future. Apremilast has so far been proveneffective in psoriasis and arthritic psoriasis [129]; however, itmay have a role in other inflammatory diseases, such asacne, especially in women of child-bearing age in whomretinoids are best avoided [126]. An open-label, pilot study todetermine the efficacy of 20 mg of apremilast taken orallytwice a day for 12 weeks in the treatment of rosacea hasalready been completed, but results have not yet beenpublished [130].



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Table

3.Agents

thatprimarily

work

bymodulatingP.acn

es.

Examples

Mech

anism

of

action/advantages

Studies

available

Year

Purpose

ofstudy

Clinical

phase

Number

ofsu

bjects

enrolled

Studydesign

Main

resu

lts

Antimicrobialpeptides

Antimicrobialpeptides(AMPs)

are

primitivemechanism

ofim

munityproducedbyepithelialcells

andneutrophils

thatact

asim

munomodulators

toenhance

immunityandthat

whichhave

activityagainst

bacteria,amongst

others

[113,114]

MBI226

MBI226isapeptide

derivedfrom

theAMP

indolicidin

thathasrapid

microbicidalactivity

against

Gram-positive

and

Gram-negative

bacte-

ria[113-117]

[114,119]

2000

Todeterm

inesafety

of

topically

appliedMBI

226in

healthyvolunteers

andpatients

withacne

Phase

I71

Open-label

Omigananpentahydrochlor-

idesolutioniswelltolerated

andnotsystemically

absorbedaftertopical

administration

[114]

2001

Toevaluate

thesafety

andefficacy

ofMBI226

2.5

and5.0%

solutions

appliedtopically

for

6weeksin

thetreatm

ent

ofacnevulgaris

Phase

IIa75

Randomized,

placebo-controlled

double-blindstudy

Reducedcountofcomedos

(25%

)andofpapulesand

pustules(39%

)in

omiganan

groupin

comparisonto

controlgroup

[119,121]

2003

Toevaluate

thesafety

andefficacy

ofMBI226

1.25and2.5%

acne

solutionsappliedtopically

for12weeksin

subjects

withacnevulgaris

Phase

II241

Randomized,

vehicle-controlled,

double-blind,

multicenter

clinicaltrial

Significantim

provement

(40%

reduction)of

non-inflammatory

and

inflammatory

lesioncount

Antioxidants

Antioxidants

have

shownto

exert

antimicrobialeffectsonP.acnes

Vitamin

CVitamin

Cpresents

action

against

P.acnesand

preventultravioletA

(UVA)-inducedsebum

oxidation

[123]

[123]

2005

Todeterm

inethe

invitroeffect

of

vitamin

ConP.acnes

Experimental

study(invitro)

Notapplicable

Notapplicable

1%

vitamin

Csolutionhasa

strongantimicrobialeffect

withalogreductionof

5after8honP.acnes

[123]

2005

Todeterm

inetheeffects

ofvitamin

Csolutionon

UV-inducedsebum

oxidation

Pilotstudy

20

Open-label

Vitamin

Cprevents

the

UVA-inducedsebum

oxidationupto

40%

[123]

2005

Todeterm

inetheeffect

ofa5%

vitamin

Csolutionappliedtopically

for12weeksonsubjects

withacne

Pilotstudy

60

Open-label,

placebo-controlled

76.9%

ofpatients

enrolled

showedim

provementin

acnelesionswithoutany

majorsideeffects

[124,125]

2010

Todeterm

inetheefficacy

ofatw

ice-daily

sodium

L-ascorbyl-2-phosphate

5%

lotionfor12weeks

inthetreatm

entofacne

Phase

II50

Randomized,

double-blind,

placebo-controlled

trial

Vitamin

Cissuperiorto

vehicle

alonein

reducing

lesioncounts,while

having

similartolerability

and

adversereactionsfrequency

P.acnes:

Propionibacterium

acnes.



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Table

4.Agents

thatprimarily

work

bymodulatingtheinflammatory

resp

onse.

Examples

Mech

anism

of

action/advantages

Studies

available

Year

Purpose

ofstudy

Clinical

phase

Number

ofsu

bjects

enrolled

Studydesign

Main

resu

lts

PDEinhibitors

PDEinhibitors

limittheproductionofIL-1

andTNF-apresentin

inflammatory

acnelesions

Apremilast

PDE4inhibitors

limitthe

degradationofcA

MP.High

levelsofcA

MPare

associated

withadecrease

inlevelsof

proinflammatory

cytokines

[131]

2010

Todeterm

inethesafety

andefficacy

of20mg

apremilast

takentw

icea

dayfor12weeksin

the

treatm

entofmoderate-

to-severe

acne

Phase

II3

Openlabel,

single-group

assignmentstudy

Studyterm

inatedforlack

offunding

Inhibitors

ofIL-1b-m

ediatedinflammatory

resp

onse

P.acnescausesdirect

IL-1bsecretionandthusstim

ulatesinflammation.IL-1bisfoundto

beoverexpressedin

acnecorrelatingwithdisease

activityandseverity

incorrelationwith

disease

developmentandseverity

[132,134,137]

XOMA

052

Gevokizumab(XOMA

052)isa

humanizedmonoclonal

IgG2antibodywithhighaffinity

andspecificity

toIL-1b.

InhibitingIL-1bincreases

IL-6

release,reducesTNF-a

levelsanddecreasesneutrophil

migration,thusreducingacute

inflammationin

vivo

[132,139]

[140]

2013

Todeterm

inewhether

gevokizumabiseffective

inthetreatm

entof

moderate-to-severe

acne

vulgaris

Phase

II127

Randomized,

double-blind,

placebo-controlled

study

Thisstudyiscurrently

activeandnoprelim

inary

resultshave

been

publishedyet.Resultsare

expectedin

2014

Vitamin

D(VD)analogs

VD

analoguesmodulate

TNFa

andIL-8

andIL-6

expression,allofwhichare

alteredin

acnelesionsdueto

thepresence

ofP.acnes[141,142]

VD

VDanditsanalogshave

been

shownto

decrease

inflammatory

cytokineexpressionandto

induce

theexpressionofAMPs,

such

asb-defensinand

cathelicidin.

Further,somecomedolytic

effectshave

beenattributedto

someanalogs

[141]

2013

Todeterm

inechangesin

inflammatory

biomarkers

from

culturedsebocytes

aftertreatm

entwithVD

Experimental

study

(invitro

study)

Notapplicable

Notapplicable

ELISAshowedadecrease

intheexpressionofIL-6,

IL-8

andMMP-9,anda

decreasesin

the

expressionofMMP-1

and

MMP-3,aftertreatm

ent

withVD

(10-6M)

Calcipotriol

[144]

2009

Totest

theeffect

of

calcipotriolonthe

expressionofAMPsin

humancultured

keratinocytes

Experimental

study

(invitro

study)

Notapplicable

Notapplicable

Calcipotriolinducesithe

expressionofAMPs,

such

asbeta-defensinand

cathelicidin

LL-37,in

culturedkeratinocyte

Maxacalcitol

[146]

2006

Totest

thecomedolytic

potentialofaonce-daily

applicationoftopicalVD

analogfor4weeksin

the

rhinomouse

Experimental

study(ani-

malmodel)

Notapplicable

Notapplicable

Maxacalcitolhas

comedolyticactionsimilar

totretinoin

Calcipotriene

[148]

2014

Tostudytheeffectsof

twicedaily

applicationof

topicalVDcream

for

12weeksin

subjectswith

acne

Phase

II/III

54

Randomized,

double-blind,

single-group

assignmentstudy

Resultsare

expectedin

December2014

P.acnes:

Propionibacterium

acnes.



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In 2010, the University of North Carolina, Chapel Hill, incollaboration with Celgen Corp. started recruiting male andfemale patients, aged 18 -- 45 years, to participate in a studydesigned to determine the safety and efficacy of 20 mg apre-milast taken twice a day for 12 weeks in the treatment ofmoderate--to-severe acne. However, the study was terminatedbefore its completion due to lack of funding [131].

5.2 Inhibitors of IL-1b-mediated inflammatory

responseIL-1b is a potent mediator of inflammatory responses,expressed by monocytes, macrophages, dendritic cells, B-lym-phocytes, natural killer cells and epithelial cells [132,133], that isfound to be overexpressed in several inflammatory and auto-immune diseases [134], in correlation with disease developmentand severity [132]. The secretion of active IL-1b requires cleav-age and activation by caspase-1 [132,133]. Caspase-1 has beenrecently shown to be elevated in neutrophils in the presenceof P. acnes, suggesting that P. acnes is capable of activatinginflammation [135,136] by indirectly increasing IL-1b [135]. Fur-ther, P. acnes causes direct IL-b secretion in monocyticcells [137], which suggests that the perifollicular interaction ofP. acnes with macrophages could induce secretion ofIL-1b [137], and thus stimulate inflammation.

Gevokizumab, also known as XOMA 052, is a humanizedmonoclonal IgG2 antibody that shows high affinity and spec-ificity to IL-1b [132,138] Inhibition of IL-1b has shown toincrease IL-6 release [132,139], reduce TNF-a levels anddecrease neutrophil migration [139], thus reducing acuteinflammation in vivo [132].

The potential use of gevokizumab to treat moderate-to-severe acne vulgaris is currently being studied in a Phase II,randomized, double-blind, placebo-controlled trial in whichapproximately 171 male and female subjects, aged ‡ 17 years,are subcutaneously administered either high-dose gevokizu-mab, low-dose gevokizumab or vehicle solution only ondays 0, 28 and 56. Data based on the mean absolute changefrom baseline in inflammatory facial lesion and the propor-tion of subjects with successful treatment outcomes will becollected at day 84. This study is currently active and nopreliminary results have been published yet [140].

5.3 Vitamin D analogsAbnormal colonization by P. acnes stimulates keratinocytesand sebocytes through TLR to produce proinflammatorycytokines and chemokines such as IL-1a, IL-1ra, IL-1b,IL-8, IL-12, TNF-a and MMP-9 [141,142]. Treatment ofcultured sebocytes with vitamin D (VD) decreases expressionof IL-6, IL-8 and MMP-9 [141,143]. Further, VD and its analogcalcipotriol, have shown to regulate innate immunity byinducing the expression of AMPs, such as b-defensin andcathelicidin LL-37, in cultured keratinocytes [144,145].

It has also been noted that binding of VD to its receptorstimulates the proliferation, while inhibiting the

differentiation of sebocytes, thus decreasing lipid synthe-sis [141]. Some VD analogs have also shown to have comedo-lytic effects in animal models [146,147].

A Phase II/III, randomized, double--blind, single-groupclinical trial to determine the efficacy of 1g calcipotrienecream applied twice daily in the treatment of acne in maleand female patients aged ‡ 18 years is currently being con-ducted. This study is estimated to be completed in December2014 [148].

6. Conclusion

An ideal therapy in acne would target sebum production,comedo formation and P. acnes colonization and wouldmodulate the inflammatory response associated with acnelesions. However, to date, no single treatment designed foracne targets all four pathogenic factors involved in the appear-ance of acne lesions; therefore, combination treatment iscommon [1,149]. As a chronic illness, acne characteristicallypresents with recurrences, relapses and psychological andsocial distress [1] that affect the patient’s quality of life [150],so new treatment strategies, which potentially are more effec-tive and present with less side effects than current treatmentoptions, are desirable. Topical retinoids, the current mainstayof therapy for mild and moderate acne [1], act by reducingdyskeratosis at the pilosebaceous unit [151] and thus theyinhibit the formation of microcomedones and comedos [152]

Further, they also have mild anti-inflammatory effects [1,151]

However, they commonly cause skin irritation [149], whichlimits their use in some patients. Topical retinoic acidmetabolism-blocking agents (RAMBAs), such as talarozole,which also normalize keratinization with the follicular units,present a new alternative to retinoid therapy with minimumlocal side effects [98,101]. The possible role of oral talarozolein the treatment of acne remains to be disclosed [97]; however,by increasing endogenous levels of RA [100] they could offer analternative to oral isotretinoin. Oral isotretinoin, the mosteffective acne treatment developed to date [1] not only actsby reducing dyskeratosis in the pilosebaceous unit [151], butit also induces apoptosis of sebaceous glands, thus reducingsebum production [153]. Until recently, only isotretinoin andantiandrogen therapy had shown to modulate sebum produc-tion [74,154]. Nevertheless, new pathogenic findings relating toskin lipogenesis have opened a new array of possibilities inlocal lipid synthesis control. Future strategies mainly include:the downregulation of IGF-I signaling to reduce 5-areductase 1-mediated sebum production and the inhibitionof PPAR-mediated lipogenesis by downregulating the produc-tion of LTB4 [2]. Oral antiandrogen therapy for sebumcontrol will be most likely be substituted by topical antiandro-gens, such as cortexolone, topical NO and ASC-J9 cream, asthey reduce sebum production with an apparent absence ofsystemic absorption and side effects [6,19,25], which makesthem suitable to treat both male and female patients.



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Topical and oral antibiotics are currently recommended forthe treatment of mild, moderate and severe acne [1] becausethey target P. acnes colonization and the inflammation cas-cade [155]; however, due to the growing concerns on bacterialresistance [1], new non-antibiotic molecules that target thesepathogenic factors are highly desirable.Due to its highly efficient bactericidal properties and lack

of bacterial resistance, BPO is currently recommended forthe treatment of acne instead of prolonged antibiotic use [1];however, skin irritation is also an issue presented by manypatients [149].AMPs, such as omiganan pentahydrochloride, offer an

alterative to antibiotics and BPO, as they exert antimicrobialactions [113,114,117,118] without any apparent side effects [114,119].Further, omiganan pentahydrochloride reduces comedocount [114], and thus it attacks two of the pathogenic mecha-nisms involved in acne development. Topical vitamin C alsoexerts antimicrobial effects on P. acnes [122] and thus couldbe used in conjunction with current accepted treatments tolimit antibiotic use. P. acnes is able to induce the expressionof IL-1b [137], which in turn is associated with inflammatoryacne lesions [133]; thus, molecules that target IL-1b, such asGevokizumab, may play a role in nodular or conglobata casesof acne where inflammation is severe. The possible role ofPDE4 inhibitors as modulator of proinflammatory cytokineexpression in the management of acne remains to be deter-mined, for they are associated with severe gastrointestinalside effects, with nausea being the most common [126]. Topi-cal PDE4 inhibitors are already being developed [156] andcould potentially be an option to limit inflammation in severeforms of acne with fewer side effects than their oral counter-parts. VD analogs not only modulate the inflammatoryresponse but also reduce sebogenesis [141] and comedo forma-tion [146,147]; however, their future role in the management ofacne remains to be seen [148].

7. Expert opinion

Acne is a seemingly simple but actually complex disease. Itspathogenesis is very convoluted and most mechanismsinvolved in its clinical course and severity remain unknown.Although we know that sebum production, dyskeratosis,P. acnes colonization and inflammation play a role, we stilldo not understand how these mechanisms interact with eachother to determine patient outcome and response to treat-ment. There is also still a lot of information lacking regardingthe potential for chronicity and/or relapses. This is in partbecause there was a previous lack of scientific interest inacne as a disease, and in part because it is impossible to re-create the acne model in a Petri dish or in an animal, somost studies focus only on one of the four pathogenic factorsat a time, which limits the applicability of the data tohuman patients.

Before retinoids became available for the treatment of acnein 1972 [157], acne’s therapeutic regimen had been unchangedfor 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 combina-tion products, primarily of retinoids with antibiotics, that arenot significantly different from the current monotherapiesavailable.

With the recent characterization of acne as a chronic dis-ease, new interest in deciphering the molecular mechanismsresponsible for acne lesions have peaked, which in turn hasresulted in a spurt in research on the mechanisms involvedin the appearance of acne lesions. One of the biggest void inthe market is the current deficit of products that target sebo-genesis, so it is no surprise that current researchers havefocused their efforts in determining the mechanisms throughwhich sebum is produced. Topical sebum modulators, suchtopical antiandrogens and PPAR modulators, will surelyfind a place in the treatment guidelines for patients withacne in the future. In fact, it could be hypothesized that byeffectively controlling sebum production, P. acnes populationwould be normalized, which in turn would limit inflamma-tion, eliminating the need for antibiotic use in acne.

Current available treatments to control dyskeratosis, suchas exogenous retinoids, are irritating, which limits their usein many patients, so research should focus on the develop-ment of molecular-based drugs that increase retinoic acidlevels through selective inhibition of endogenous retinoidbreakdown. Topical RAMBAs, for example, seem promisingas retinoid substitutes.

Although MCR antagonists, Ach inhibitors, ACC andmonoclonal antibodies seem fascinating and promising asnovel therapeutic strategies in the management of acne, theyare still a long way from being available to clinician.

The market is in urgent need of a blockbuster drug thatideally would target all of the pathogenic mechanismsinvolved in acne lesions without skin irritation and withoutsystemic side effects. However, until this drug is developed,combination therapy will still be the foundation of acnetreatment, so these new management modalities will mostlikely be incorporated into current treatment guidelines asto cover the most pathogenic factors possible for optimumdisease control.

Declaration of interest

IC Valente Duarte de Sousa has acted as a medical consultantfor the More Pharma Corporation in the past. The author hasno other relevant affiliations or financial involvement withany organization or entity with a financial interest in orfinancial conflict with the subject matter or materialsdiscussed in the manuscript apart from those disclosed.



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Med Surg 2008;27:177-82

AffiliationIsabel Cristina Valente Duarte de Sousa1,2 MD1Private Dermatology Practice, Manzanas 44,

Piso 5, Col. Tlacoquemecatl, Del. Benito Juarez,

03200 DF Mexico, Mexico City, Mexico

Tel: +5215510056226;

E-mail: [email protected] ABC Campus Santa Fe, Private

Dermatology Practice, Av. Carlos Graef

Fernandez 154, Col. Tlaxcala Santa Fe,

Delegacion Cuajimalpa, Mexico City, 05300,

Mexico



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Novel pharmacological approaches for the treatment of acne vulgaris

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