Preven&ng(HIV(in(Women:(Current'Status'of'Microbicide'Efficacy'Trials'

Zeda%Rosenberg,%Sc.D.%European)AIDS)Treatment)Group)(EATG))

December)12,))2014)

•  Female(o  HIV/AIDS)leading)cause)of)death)globally)

among)women)15H44)

o  Nearly)60%)of)adults)living)with)HIV)in)

subHSaharan)Africa)are)women)

•  Young(o  Young)women)are)at'least'as)twice)as)

likely)to)be)infected)than)young)men))

•  Married(or(living(with(a(partner(o  Stable)relaOonships)not)a)haven)

•  (A(mother(o  12H18%)of)pregnancyHrelated)deaths)due)

to)HIV/AIDS)

The)Face)of)HIV/AIDS)in)Africa)

2)

What)Are)Microbicides?)

Vaginal(gel(applicator( Long?ac&ng(vaginal(ring(

Vaginal(film(tablet,(soD(gel,(capsule(

•  Products)being)developed)to)help)prevent)HIV)during)sex))

•  Most)contain)ARVs,)already)used)successfully)to)treat)HIV)•  Microbicides)for)women)could)offer)convenience,)more)opOons)

o  Use)around)the)Ome)of)sex;)monthly)or)longer)

o  OpOon)to)combine)ARVs,)contracepOves)and)other)drugs)

)

•  Ideally)safe,)effecOve,)low)cost,)userHfriendly)

)

)

3)

Evidence)of)ARVs)for)HIV)PrevenOon)

•  PrevenOon)of)motherHtoHchild)transmission)(PMTCT))

•  Early)ARV)treatment)as)prevenOon)(TasP))

•  Oral)Truvada)approved)by)FDA)(PrEP)))•  Tenofovir)gel)proofHofHconcept)(microbicide))

•  Work)is)under)way)to)idenOfy)the)most)promising)ARV)

drugs,)combinaOons)and)delivery)mechanisms)that)

would)be)acceptable)for)use)in)mulOple)populaOons))

There(will(be(no(silver(bullet(for(HIV(preven&on(–((((((((women(need(mul&ple(choices((

4)

ARV)Microbicides)in)Development)

Free(virus(

AHachment(

Fusion(

Reverse(Transcrip&on(

Protein(synthesis(and(assembly(

Budding(

Matura&on(

Integra&on(

(Maraviroc((

BMS(793(L167,(L872,(L882(((()

Tenofovir((TFV)(Emtricitabine((FTC)(Dapivirine(

MIV?150(MIV?170(

Pyrimidinediones(

L’644(pep&de(

Darunavir(

Integrase(inhibitors(

5)

Microbicides)in)Efficacy)Trials)

Tenofovir(gel)• FACTS)001)• Results)Q1)2015)

Dapivirine(ring((• The)Ring)Study)and)ASPIRE)• Results)by)2016)

Source:'FACTS'001'

Source:'IPM'

6)

7)

Tenofovir(Gel(

Source:'Mapping'Pathways'

Tenofovir)Gel)

•  Tenofovir:(NucleoOde)reverse)transcriptase)inhibitor)(NRTI))o  Stops)HIV)from)copying)its)geneOc)material)inside)human)cells)

o  Marketed)as)oral)therapeuOc)Viread®))

o  Gilead)license)to)CONRAD)&)IPM)(2006))for)HIV)prevenOon))

•  Tenofovir(gel:(most)clinically)advanced)ARVHbased)microbicide)

o  Proof?of?concept:)CAPRISA)004)trial)showed)39%)))))))))))))))))))))))))))))))))))))))))))))))))))))efficacy)against)HIV)

!  VOICE)trial)stopped)for)fuOlity)(onceHdaily)dosing)))o  Efficacy)against)HSVH2:)CAPRISA)004)(51%))))))))))))))))))))))))))))))))))))))))))))))))))))

and)VOICE)(46%))trials)

o  FACTS)001)confirmatory)study))

8)

•  FACTS:(FollowHon)African)ConsorOum)for)

Tenofovir)Studies)

•  FACTS(001(•  Phase)III)tenofovir)gel)safety)and)effecOveness)trial)

•  To)confirm)whether)before)and)afer)sex)dosing)(BAT24))

regimen)is)effecOve)for)HIV)and)HSVH2)prevenOon)

•  To)provide)addiOonal)safety)and)efficacy)data)for)product)

registraOon)

9)

FACTS)001:)atHaHglance)

FACTS)001:)atHaHglance)

•  Randomized,)doubleHblind)

•  Endpoint)driven))•  PopulaOon:)2,900)women)18H30)years)at)nine)

sites)in)South)Africa)

o )Includes)subset)of)300)women)over)age)30)

•  Screening)began)Oct.)2011)•  Results%expected%early%2015%

10)

Tenofovir)Gel:)Next)Steps)

!  FollowHup)studies)•  CAPRISA)008:)Ongoing,)HIVHnegaOve)parOcipants)

•  CAPRISA)009:)Ongoing,)HIVHposiOve)parOcipants)

•  Studies)in)adolescents,)postHmenopausal)women,)

drugHdrug)interacOons)

!  Approvals)and)access)•  Possible)regulatory)approvals)in)2016/17)

11)

Dapivirine(Ring(

Source:'IPM'

12)

Dapivirine)Ring)

Dapivirine:)NonHnucleoside)reverse)transcriptase)inhibitor)(NNRTI))

o  Acts)inside)cells)in)the)vagina)to)block)the)ability)of)HIV)to)mulOply))

o  Originally)tested)by)Janssen)as)therapeuOc)in)11)studies)o  Licensed)to)IPM)in)2004,)expansion)to)exclusive)worldwide)rights)

in)2014))

)

Dapivirine)vaginal)ring)

o  OffHwhite)flexible)ring)o  SelfHinserted)every)4)weeks)o  Slowly)releases)drug)into)vaginal)Ossue)o  Good)safety)profile)in)17)Phase)I/II)studies)(dapivirine)ring)or)gel))o  Dapivirine)Ring)Licensure)Program)launched)in)2012)

13)13)

Dapivirine)Ring)Licensure)Program)

Long?term(safety(and(efficacy(study)•  1959)parOcipants,)ongoing)(2012H2016))in)Africa)

IPM(027(The'Ring'Study'

Safety(and(efficacy)study)•  2629)parOcipants,)ongoing)(2012H2015))in)Africa)

MTN?020(ASPIRE'

•  DrugHdrug)interacOon)(completed))

•  Male)condom)funcOonality)(data)analysis))

•  Female)condom)funcOonality)(data)analysis))

•  Extended)use)PK)(data)analysis))•  Safety)in)women)>45)(ongoing))

•  Safety)in)adolescents)(ongoing))

AddiOonal)safety)

studies)

14)

The(Ring(Study((IPM(027)( ASPIRE((MTN?020)(Objec&ves( LongHterm)safety)and)efficacy) Safety)and)effecOveness)

Study(design( DoubleHblind,)randomized)(2:1),)

placeboHcontrolled)

DoubleHblind,)randomized)(1:1),)

placeboHcontrolled)

Endpoints( 96)endpoints,)2)year)on)IP) Endpoint)driven:)120)endpoints)

Power( 81%)power)to)detect)50%)treatment)

effect)

90%)power)to)detect)60%)

treatment)effect)

Enrollment( 1959)women,)ages)18H45))))))))))

(completed)enrollment))

2629)women,)ages)18H45)

(completed)enrollment))

Sites(in(Africa( 7)IPM)research)center)partners)))))

(South)Africa)and)Uganda))

15)MTN)research)centers))

in)4)countries)(NIH)CTUs))

Par&cipant(follow?up(

2)years)+)6)weeks)following)ring)

disconOnuaOon)

Approx)1H2)years)+)4)weeks)

following)ring)disconOnuaOon)

Ini&a&on( Q1H2012) Q2H2012)

Dapivirine)Ring)Phase)III)Studies)

15)

16)

Dapivirine)Ring)Licensure)Program)

2014) 2015) 2016) 2017) 2018) 2019)

Dapivirine)ring)regulatory)

consultaOons)

The)Ring)Study)

ASPIRE)

SupporOng)safety)

&)PK)studies)

Open)label)studies)

))EMA)

WHO)

PQ'

))FDA)

MCC)

Submission' Approval'

African)NRAs)

Ar&cle(58((

Summary)

•  Proof?of?concept(established(for(ARV(preven&on(products(in(adults(o  ARVs)can)reduce)risk)of)infecOon)in)certain)populaOons)

)

•  Adherence(maHers;(consistent(use(leads(to(greater(protec&on(o  LongerHacOng)products)such)as)monthly)vaginal)rings)or)injectable)PrEP)

could)increase)adherence,)effecOveness)

•  Resistance(not(a(concern(in(trials(to(date;(research(con&nues(o  Evaluated)in)all)efficacy)trials)and)followHup)studies)

)

•  Mul&ple(preven&on(tools(needed(o  No)one)prevenOon)opOon)will)saOsfy)all)

17)

DEVELOPING MICROBICIDES: PRE-CLINICAL AND CLINICAL STUDIES

Charles Kelly

1.  Discovery of new microbicide candidates

2.  Developing drug combinations

3.  Testing in non-human primate models: •  drug distribution after application •  efficacy in preventing infection

4. Phase I Trial (safety)

ARV$Microbicides$in$Development$Free$virus$

A*achment$

Fusion$

Reverse$Transcrip5on$

Protein$synthesis$and$assembly$

Budding$

Matura5on$

Integra5on$

$Maraviroc$$

BMS$793$L167,$L872,$L882$$$$$

Tenofovir$(TFV)$Emtricitabine$(FTC)$Dapivirine$

MIVP150$MIVP170$

Pyrimidinediones$

L’644$pep5de$

Darunavir$

Integrase$inhibitors$

3$

UAMC 4 UAMC 4

UAMC / Ref

Wild type EC50 (nM)

NNRTI- resistant viruses EC50 (nM) Cytotoxicity CC50 (nM)

TZM-bl Ba-L V106A (NVP)

VI829 Y181C (NVP)

VI829 L100l+ K103N (EFV)

Ba-L * (TMC120)

VI829 ** (TMC120)

Ba-L VI829

01398 (E) 1.3 1.3 1.9 2.6 6.8 23 89 24540

01411 (Z) 1.1 1.1 5.2 12.0 123 236 1393 30830

TMC 278 0.7 1.0 0.9 2.5 3.6 27 130 7740

TMC 120 2.0 2.0 2.5 10.8 673.5 > 1000 > 1000 2877

New Microbicides: Cyanovinyltriazines

PCT/EP2013/055525 filed on 18th March 2013

* = K101E + K103N + V108VI + V179M + Y181C + E138Q ** = L100l + E138K + T369l

Venkatraj Muthusamy,Koen Augustyns, Pieter Van der Veken, Jurgen Joosens, Paul Lewi, Jan Heeres

UAMC 01398 formulated as vaginal gel Testing in macaque challenge

Dapivirine (NNRTI) co-formulated with Darunavir (protease inhibitor) in carbopol gel (0.05% dapivirine,0.2% darunavir; Particle Sciences) Why combine drugs? 1.  Increase breadth of activity – e.g. virus resistant to darunavir

but susceptible to dapivirine

2.  Additive activity

3.  Increase barrier to development of resistance

Darunavir – highly effective in therapy

- high barrier to resistance

Antiviral activity of single and combined Dapivirine and Darunavir

PM71$cells$ Colorectal$;ssue$

Double$combina;on:$Dapivirine$(TMC120):Darunavir$(DRV)$

**$Non7formulated$compounds$

-40

-20

0

20

40

60

80

100

0.000001 0.0001 0.01 1

Inhibition (%)

[Drug] (&M)

TMC120DRVTMC120-DRVTMC120-DRV

-40

-20

0

20

40

60

80

100

120

0.001 0.01 0.1 1 10

Inhibition (%)

[Drug] (&M)

TMC120

DRV

TMC120-DRV

TMC120-DRV

Julia$Makinde:$Imperial$College$

DECEMBER 15, 2014 DECEMBER 15, 2014

Gel application

1h 2h 0 4h 24h

Blood/Vaginal Fluid collection

Blood and vaginal fluid samples collected prior to gel application and at different time points post gel administration for evaluation of dapivirine and darunavir concentrations

≠ Six female cynomolgus macaques/Test item

≠ No Depo-Provera® treatment

≠ Administration: Vaginal route - 2ml Vaginal fluid samples collected on Weck-Cel

spears

8h 48h 72h

DARUNAVIR AND DAPIVIRINE GEL PK STUDIES IN MACAQUES

In vivo study protocol

PK RESULTS

Dapivirine/darunavir gel

≠ Mean amount of dapivirine administered: 0,936 mg +/- 0,009 mg

Conc. in vaginal fluid (ng/g)_Dotted line: LOQ Conc. in serum (pg/ml)_Dotted line: LOQ

Alain Pruvost_CEA

DAP/DRV gel delivers dapivirine and darunavir to

the vaginal region at concentrations over 4 logs

and 3 logs greater than the reported EC50 for wild-

type HIV-1, respectively (EC50 of dapivirine: 0.3 ng/

ml - EC50 of darunavir: 1.6 ng/ml (Koh and al.,

2003))

Dapivirine/darunavir gel

≠ Mean amount of darunavir administered: 3,745 mg +/- 0,038 mg

Darunavir gel

≠ Mean amount of darunavir administered: 3,862 mg +/-0,042 mg

S tudy&Acronym:&DAPIDAR& A&randomised,&double&blind&phase&I&study&to&assess&the&safety,&pharmacokinetics&and&pharmacodynamics&of&single&and&14&days&dosing&with&two&vaginal&microbicide&

formulations &containing&either&Darunavir,&or&Dapivirine&and&Darunavir&

•  determine generic procedures for co-formulation of incompatible drugs (Tenofovir and Darunavir)

•  determine mechanisms of drug distribution in

vagina and rectum •  develop formulations for optimal drug delivery

Rectal Microbicides Non-Human Primate Challenge Studies: 1.  Cyanovirin–N : 1% and 2% gel - 100% protection

(Tsai et al. 2001 AIDS Res Hum Retroviruses) 2. Tenofovir: 1% gel - 6/9 protected (+2 modified)

(Cranage et al. 2008 PLoS Med)

3. MIV-150: 100% protection (gel applied up to 4h before (Singer et al. 2011 J Virol) challenge)

4. Tenofovir/Maraviroc: Protection: 1% TFV, 83% ; 1% MVC, 82% 1%TFV + 1% MVC, 82% (Heneine et al 2014 HIVR4P Conference, CapeTown)

Rectal Microbicides Clinical Trials: 1.  RMP-02/MTN-006: Phase I Tenofovir gel vs Oral

- inhibition of HIV in ex vivo tissue - need to reduce osmolality

2. MTN-007: Phase I Tenofovir gel, reduced glycerin (osmolality) - gel safe and acceptable

3. MTN-017: Phase II rectal safety and adherence Tenofovir gel – in progress

+ other Phase I safety + acceptability (CHARM-01, -02)

Rectal Microbicides or Oral Pre-Exposure Prophylaxis?

July 2012: Truvada approved by FDA July 2012 for

Oral PrEP (iPrEx and Partners PrEP trials)

Oct 2014: all participants in PROUD trial offered

immediate Truvada Oct 2014: all participants in IPERGAY trial offered... “D-Day for the Pill for HIV” Gus Cairns

(?80% protection)

All CHAARM and MOTIF participants (chaarm.eu; www.motifproject.eu) CHAARM and MOTIF projects received funding from the European Union’s Seventh Programme for research, technological development and demonstration.

Acknowledgements

A"PREVENTIVE"HIV"VACCINE"WHEN?"

José%Esparza%MD,%PhD%Adjunct%Professor%of%Medicine,%University%of%Maryland%School%of%Medicine(BalAmore)%Formerly:%WHO%(Geneva),%UNAIDS%(Geneva)%and%Bill%&%Melinda%Gates%FoundaAon%(SeaMle)%

European%AIDS%Treatment%Group%(EATG)%Webinar,%December%12,%2014%

0%

500,000%

1,000,000%

1,500,000%

2,000,000%

2010% 2015% 2020% 2025% 2030% 2035% 2040% 2045% 2050% 2055% 2060% 2065% 2070%

Current%Trend%Current%Trend%+%Vaccine*%

IFE%IFE%+%Vaccine*%

A"Vaccine"is"essen*al"to"end"AIDS"

Modeling project – UNAIDS, Futures Institute, IAVI, AVAC [funded by USAID]2%

*%%IllustraAve%vaccine%with%an%assumed%efficacy%of%70%,%not%representaAve%of%any%specific%candidate.%Coverage%in%generalized%epidemics:%rouAne%10%years%old%70%,%catchbup%11b14%%years%old%60%,%15b17%years%old%55%,%18b49%years%old%50%;%in%high%risk%populaAons%in%concentrated%epidemics:%50%%

New

%InfecAon

s%with

%HIV%%%

PotenAal%impact%of%an%AIDS%vaccine%as%part%of%the%UNAIDS%Enhanced%Investment%Framework%(IFE)%%

Courtesy%of%Margie%McGlynn,%iAVI%Presented%at%R4P,%Cape%Town,%October%2014%%

2027%

"""A"brief"history"of"HIV"vaccines

• AIDS"described"in"1981"• HIV"discovered"as"the"cause"of"AIDS"in"1983=1984"• First"FDA"approved"phase"I"trial"of"an"HIV"vaccine"in"1988"• Since"then,"more"than"200"(mostly)"phase"I"trials"of"HIV"vaccines"• First"efficacy"trial"of"an"HIV"vaccine"started"in"1998"• First"“successful”"efficacy"trial,"RV144,"in"2009"• Plans"to"confirm"and"expand"results"from"RV144""

"""Why"it"has"been"so"difficult"to"develop"an"HIV"vaccine? •  "Gene*c"and"immunological"variability"of"the"virus."

•  ="Geographic"variability"(clades"or"subtypes)"•  ="Immune=escape"in"infected"individuals"

•  "Lack"of"an"appropriate"(predic*ve)"animal"model."•  "Natural"immunity"is"not"protec*ve."

•  ="“We"need"to"beVer"than"nature”"•  ="Perhaps"vaccines"need"to"induce"“non=natural”"immunity"

•  "Need"to"prevent"mucosal"transmission."•  "HIV"infects"and"destroy"cells"of"the"immune"system"and"integrates"in"the"host"""cell"stablishing"a"chronic"infec*on."•  ="Very"short"window"of"opportunity."

•  "Broadly"neutralizing"an*bodies"are"difficult"to"induce""""•  "Short"durability"of"vaccine=induced"immune"responses"•  "Vaccine"induce"immune=ac*va*on"can"facilitate"HIV"acquisi*on""

Efficacy"trials"have"been"criBcal"in"changing"paradigms"and"advancing"HIV"vaccine"development

No%

The"RV144"trial

Courtesy"of"Punee"Pi\su*thum"

Sanofi’s"ALVAC" GSID"(VaxGen)"gp120"B/E"

The"RV144"Thai"trial:"primary"results

P5:"Timeline"of"the"development"program"in"the"Republic"of"South"Africa"

Summary • An%HIV%vaccine%is%needed%to%bring%the%epidemic%under%control%•  The%RV44%trial%tells%us%that%an%HIV%vaccine%is%possible%• Work%proceeds%to%confirm%and%expand%results%from%RV144%(P5)%

WE%NEED%T0%%• Proceed%to%advanced%clinical%evaluaAon%of%other%promising%vaccines%• Bring%more%scienAfic%innovaAon%to%the%field%(new%paradigms)%• Bring"a"renewed"sense"of"urgency"to"the"search"for"an"HIV"vaccine."