ART containing vaginalART containing vaginal

microbicides in the clinical pipeline: microbicides in the clinical pipeline:

A status of the studiesA status of the studies

Salim S. Abdool KarimSalim S. Abdool Karim

Director: CAPRISADirector: CAPRISAPro Vice-Chancellor (Research): University of KwaZulu-NatalPro Vice-Chancellor (Research): University of KwaZulu-Natal

Professor in Clinical Epidemiology, Columbia UniversityProfessor in Clinical Epidemiology, Columbia University

Executive Committee Member, Microbicide Trials NetworkExecutive Committee Member, Microbicide Trials Network

OutlineOutline

Is there still a need for microbicides?Is there still a need for microbicides?

Past & current microbicide clinical trialsPast & current microbicide clinical trials

ARV microbicides in clinical and pre-ARV microbicides in clinical and pre-clinical developmentclinical development

Challenges in ARV microbicidesChallenges in ARV microbicides

ConclusionConclusion

Vaginal gel applicator Vaginal ring Vaginal film

A microbicide is a product that can be applied to the vaginal or rectal mucosa with the

intention of preventing the transmission of sexually transmitted infections including HIV

Microbicides containing antiretroviral drugs =Microbicides containing antiretroviral drugs =

Topical PrEP (Pre-exposure prophylaxis)Topical PrEP (Pre-exposure prophylaxis)

Is there stillIs there still

a need fora need for

microbicides?microbicides?

Source: Abdool Karim Q, Abdool Karim SS, Singh B, Short R, Ngxongo S. AIDS 1992; 6: 1535-9

Age and gender distribution ofAge and gender distribution ofHIV infection in South AfricaHIV infection in South Africa

00

<9<9 10-1410-14

Pre

vale

nce

(%

)P

reva

len

ce (

%)

15-1915-19 20-2420-24 25-2925-29 30-3930-39 40-4940-49

22

44

66

88

1010

FemaleFemaleMaleMale

>49>49

Source: Data from South African Department of Health Antenatal Surveys. www.doh.gov.za/

0

5

10

15

20

25

30

35

1989 1991 1993 1995 1997 1999 2001 2003 2005 2007

HIV

Pre

vale

nce

(%

)H

IV P

reva

len

ce (

%)

The HIV epidemic in South AfricaThe HIV epidemic in South Africa

HIV prevalence in pregnant women attending public antenatal clinics HIV prevalence in pregnant women attending public antenatal clinics in South Africa 1989-2006in South Africa 1989-2006

Past & Current Microbicide Clinical TrialsPast & Current Microbicide Clinical Trials

Stopped for futility Safe but not effective Increased HIV infection

Zena Stein Zena Stein publishes publishes seminal article seminal article “HIV “HIV prevention: the prevention: the need for need for methods women methods women can use”can use”

KenyaN-9 sponge

trial

FHIN-9 film trial

UNAIDSCOL-1492

trial

CONRADCS trial

FHI SAVVY trial

PopCouncilCarraguard trial

HPTN PRO2000 &

BufferGel trial

1st class:Surfactants

eg. N9, SAVVY

2nd class:Polymers

eg. PRO2000,Carraguard,

Cellulose Sulfate (CS)

3rd class:ARVs

eg. Tenofovir gel,Dapivirine gel/ring

4th class:Co-receptor

Blockers

eg. CD4 blocker,CCR5 Blockers

CAPRISATenofovir gel trial

MTNTenofovir

gel & tablet trial

MDP 0.5%PRO2000

trial

‘‘90 ‘92 ’98 ’00 ‘03 ‘04 ‘04 ’05 ’05 ’07 ’09 90 ‘92 ’98 ’00 ‘03 ‘04 ‘04 ’05 ’05 ’07 ’09 ‘10 ‘10

IPMDapivirinegel & ring

trial

FHI CSTrial

2% PRO2000

ARV microbicidesARV microbicides

Tenofovir gelTenofovir gel

nRTI from Gilead Sciences, licensed to CONRAD & IPMnRTI from Gilead Sciences, licensed to CONRAD & IPM

Effective & licensed therapeutic agentEffective & licensed therapeutic agent

Very good safety profile with long half lifeVery good safety profile with long half life

Shows protection in several animal challenge studiesShows protection in several animal challenge studies

Multiple genetic changes needed for resistanceMultiple genetic changes needed for resistance

Tenofovir Concentrations single dose oral and topical administration

Time Post-Dose (hr)

0 4 8 12 16 20 24

Co

nce

ntr

atio

n (

ng

/mL

)

100

101

102

103

104

105

106

107

Gel --Cervicovaginal Fluid

Gel-- Vaginal Tissue

Tablet-- Cervicovaginal Fluid

Tablet --Blood Plasma

Gel --Blood Plasma

CONRAD PK Study ResultsCONRAD PK Study Results

Information courtesy of Jill Schwartz, CONRAD

Tablet data: Dumond et. al AIDS 2007

Tenofovir Clinical Development PathwayTenofovir Clinical Development Pathway

1995 // 2006 2007 2008 2009 20101995 // 2006 2007 2008 2009 2010

HPTN Phase I safety & PK

HPTN Phase IIa safety &PK

CONRAD tenofovir gel male tolerance

MTN Phase I gel and tablet PK

MTN Phase I safety in pregnancy

MTN VOICE Phase IIb trial

CAPRISA Phase IIb Test of Concept trial

1st Macaque challenge study

20th Macaquechallenge study

CONRAD gel PK

CAPRISA 004 Tenofovir gel trial: StatusCAPRISA 004 Tenofovir gel trial: Status

Phase IIb randomized, double-blind, ToC trialPhase IIb randomized, double-blind, ToC trial

845 of 1250 participants enrolled845 of 1250 participants enrolled

Overall 12 month retention rate: 91%Overall 12 month retention rate: 91%

Gel adherence: 88% & Condom use: 74%Gel adherence: 88% & Condom use: 74%

Pregnancy rate: 2.8 per 100 person-yearsPregnancy rate: 2.8 per 100 person-years

Challenge: co-enrolled participants – 183 terminatedChallenge: co-enrolled participants – 183 terminated

Quarter of total HIV endpoints reached (on target)Quarter of total HIV endpoints reached (on target)

Estimated completion: 1Estimated completion: 1stst quarter 2010 quarter 2010

VVaginal and aginal and OOral ral IInterventions to nterventions to CControl the ontrol the EEpidemicpidemic

Five-arm, multi-site, randomized trialFive-arm, multi-site, randomized trial

Status: Protocol approved – accrual to start in mid-2009Status: Protocol approved – accrual to start in mid-2009

TOTAL TOTAL SAMPLESAMPLE

(4200)(4200)

ORAL(2520)

TOPICAL(1680)

Truvada (840)

Viread(840)

Placebo tablet(840)

Tenofovir Gel(840)

Placebo Gel(840)

MTN-VOICE : Phase IIb Tenofovir gel MTN-VOICE : Phase IIb Tenofovir gel Viread tablet & Truvada tablet trialViread tablet & Truvada tablet trial

Information courtesy of Jeanne Marrazzo, MTN

Dapivirine (TMC120)Dapivirine (TMC120)

NNRTI developed by Tibotec, licensed to IPMNNRTI developed by Tibotec, licensed to IPM

Developed originally as therapeutic - highly Developed originally as therapeutic - highly potent ARVpotent ARV

Low toxicityLow toxicity

Easily manufactured, stable & cheapEasily manufactured, stable & cheap

Also as combination: Dapivirine + MaravirocAlso as combination: Dapivirine + Maraviroc

N

C

H3

N

C

H3

C3

H C

H

N N

H

N

Information courtesy of IPM

Dapivirine Clinical Development PathwayDapivirine Clinical Development Pathway

2007 2008 2009 2010 20112007 2008 2009 2010 2011

IPM Dapivirine gel male tolerance

IPM Dapivirine ring PK

IPM Dapivirine ring safety & PK

IPM Dapivirine gel PK

IPM Dapivirine gel safety (mulitple studies)

IPM Dapivirine gel & ring efficacy trial

Information courtesy of IPM

IPM: Phase III trial designIPM: Phase III trial design

Adaptive trial design with multiple armsAdaptive trial design with multiple arms• Only the best in class moves forwardOnly the best in class moves forward

Strong focus on safety (early looks for harm)Strong focus on safety (early looks for harm)

Early stop for futilityEarly stop for futility

Powered for licensurePowered for licensure

Improved adherenceImproved adherence• Daily participant contactDaily participant contact• Smart applicatorSmart applicator• Longer-acting formulationsLonger-acting formulations

Anticipated start date: mid 2010Anticipated start date: mid 2010Information courtesy of IPM

UC-781UC-781

Licensed to CONRADLicensed to CONRAD

NNRTI with potent anti-HIV activityNNRTI with potent anti-HIV activity

Low toxicityLow toxicity

Also as combination: UC-781 + TenofovirAlso as combination: UC-781 + Tenofovir

UC-781 Clinical Development PathwayUC-781 Clinical Development Pathway

20062006 20072007 20082008

Phase I Safety

Phase 1 Safety (14 day)

Male Tolerance

Vaginal pK and safety

Rectal Safety

Information courtesy of Sharon Hillier, MTN

MIV-150MIV-150

NNRTI licensed to the Population CouncilNNRTI licensed to the Population Council

Combination (PC-815): MIV-150 + CarraguardCombination (PC-815): MIV-150 + Carraguard

Trials starting in 2008/9:Trials starting in 2008/9:• Phase 1 safety and PKPhase 1 safety and PK• Male toleranceMale tolerance

Information courtesy of Louise Pedneault, PopCouncil

MaravirocMaravirocMaravirocMaraviroc

Licensed to IPMLicensed to IPM

Being developed as a gel and ring as combination Being developed as a gel and ring as combination product: Dapivirine + Maravirocproduct: Dapivirine + Maraviroc

Currently in pre-clinical assessment:Currently in pre-clinical assessment:

• Animal vaginal dosing studies ongoing Animal vaginal dosing studies ongoing

Information courtesy of IPM

CompoundCompound LicenseLicense YearYear Type/StageType/Stage Development StatusDevelopment Status

M167, M872, M882

Merck 2005 CCR5 blockers

Pre-clinical (on hold)

BMS793 BMS

2005 gp120 binder

Early pre-clinical

L’644 peptide

Merck 2008 gp41 binder Early pre-clinical

IPM pipeline: other compoundsIPM pipeline: other compoundsIPM pipeline: other compoundsIPM pipeline: other compounds

Information courtesy of IPM

Challenges in ARV microbicide trialsChallenges in ARV microbicide trials

Criteria for selection of candidates:Criteria for selection of candidates:• No validated animal model - so multiple criteria usedNo validated animal model - so multiple criteria used• Promising new approach: ex-vivo challenge modelPromising new approach: ex-vivo challenge model

No surrogate markers of safety & protectionNo surrogate markers of safety & protection• HIV endpoint: only gold standard for safety & efficacyHIV endpoint: only gold standard for safety & efficacy

Real world adherence to daily or coital use esp. over Real world adherence to daily or coital use esp. over years years (eg. daily acyclovir use at 12 months = 34.5%)(eg. daily acyclovir use at 12 months = 34.5%)##

Potential for drug resistance - Potential for drug resistance - will this affect their will this affect their subsequent care and choice of ARV treatment?subsequent care and choice of ARV treatment?

Trial design challenges (IOM report):Trial design challenges (IOM report):

# Source: Watson-Jones, Weiss, Rusizoka, et al: NEJM 2008; 358: 1560-71

ConclusionConclusion

3 RTI ARVs (Tenofovir, Dapivirine & UC-781) are well 3 RTI ARVs (Tenofovir, Dapivirine & UC-781) are well along in the clinical development pathwayalong in the clinical development pathway

First ARV microbicide effectiveness trial underwayFirst ARV microbicide effectiveness trial underway

Two large effectiveness trials (VOICE & IPM-009) to Two large effectiveness trials (VOICE & IPM-009) to start within next 2 yearsstart within next 2 years

New ring formulation – important advanceNew ring formulation – important advance

Two other ARVs (MIV-150: NNRTI) and (Maraviroc: Two other ARVs (MIV-150: NNRTI) and (Maraviroc: CCR5 inhibitor) are in advanced pre-clinical testingCCR5 inhibitor) are in advanced pre-clinical testing

Combination microbicides are being developedCombination microbicides are being developed

AcknowledgementAcknowledgement

My appreciation to the following people who My appreciation to the following people who provided information for this presentation:provided information for this presentation:

Sharon Hillier, Jeanne Marrazzo, Lisa NoguchiSharon Hillier, Jeanne Marrazzo, Lisa Noguchi Pam Norick, Zeda RosenbergPam Norick, Zeda Rosenberg Henry Gabelnick, Jill Schwartz, Chris MauckHenry Gabelnick, Jill Schwartz, Chris Mauck Louise PedneaultLouise Pedneault Quarraisha Abdool KarimQuarraisha Abdool Karim Leya HassanallyLeya Hassanally