Microbicide Research: A Promising HIV/AIDS

Prevention Strategy for Women

Roberta Black, Ph.D.Division of AIDS, National Institute of Allergy

and Infectious DiseasesNational Institutes of Health

December 3, 2008

DHHS/NIH/NIAID

Microbicide Products Purposes and Indications

Singular indication product, e.g., HIV microbicide

Combination sexual and reproductive health product, e.g., HIV microbicide + contraceptive

Combination disease prevention product, e.g., HIV + HSV microbicide

DHHS/NIH/NIAID

NIAID Topical Microbicide ProgramNIAID Topical Microbicide Program

o YearsWeeks

Progression to AIDS

To identify and support/facilitate development of safe, effective and acceptable topical microbicides to prevent HIV/AIDS and other STIs

Overarching Goal

Intervention Points for Microbicides in HIV Infection and Disease

HIV Negative Individuals HIV Positive Individuals

DHHS/NIH/NIAID

SuccessfulMicrobicide

Or Microbicide

Strategy

Lead IdentificationLead IdentificationAndAnd

OptimizationOptimization

Pipeline DevelopmentPipeline DevelopmentMultiple activities driven by Multiple activities driven by Milestones Milestones that that may occur sequentially or simultaneouslymay occur sequentially or simultaneously

Product Product EliminatedEliminated

Product RecycledProduct RecycledInto DiscoveryInto Discovery

Product recycled Product recycled In In

Pipeline Pipeline

LEADLEAD

Discovery Preclinical

Virology

Preclinical Studies

(Critical Path) Clinical Studies

I II IIIPilot

Studies Deployment

The Microbicide Development Pipeline

DHHS/NIH/NIAID

10,000cndts 250

51

Basic biomedical research

Foster basic science and preclinical pipeline studies

Nonclinical product development

Identify and advance the most promising approaches to clinical testing

Clinical evaluation

Evaluate safety, efficacy and acceptability in populations most in need

NIAID Topical Microbicide Program

DHHS/NIH/NIAID

Successfulcompound

Or Strategy

Lead IdentificationLead IdentificationAndAnd

OptimizationOptimization

DiscoveryPreclinical Virology

Preclinical Studies

(Critical Path)Clinical Studies

I II IIIPilot

Studies Deployment

Successfulcompound

Or Strategy

Lead IdentificationLead IdentificationAndAnd

OptimizationOptimization

DiscoveryPreclinical Virology

Preclinical Studies

(Critical Path)Clinical Studies

I II IIIPilot

Studies Deployment

Three Areas of Emphasis

Understand the basic biologic processes of the female reproductive tract and its interaction with seminal plasma

Define mechanisms of infection Identify targets for microbicide discovery

Discover new microbicide candidates HIV targets

STI targets

Cellular/tissue targets

Understand the interaction of microbicides with the tissues

Basic Biomedical ResearchBasic Biomedical Research

DHHS/NIH/NIAID

gp120V3

gp41

V1/2

Virus

Coreceptor CD4

Cell

UC781(Vaginal and Rectal)

Identify and help advance the most promising approaches to clinical testing Feasibility –compatible with use as a microbicide? Proof-of-concept –prevent HIV transmission in vitro and/or in

vivo?

Develop and use relevant and predictive in vitro and in vivo safety, efficacy and adherence models to select the best candidates

Establish partnerships/collaborations among private sector, industry and NGOs with NIH and its grantees

Encourage and promote the integration of new expertise and technologies into the microbicide pipeline

Non-Clinical Product Non-Clinical Product DevelopmentDevelopment

EndometrialToxicity

Behavioral

DHHS/NIH/NIAID

Microbicide Evolution

Nonoxynol-9

Nonspecific inhibitors

HIV specific inhibitors

1st Generation

2nd Generation

3rd Generation

4th Generation Combination Inhibitors

NRTNNRTCCR5

DHHS/NIH/NIAID

Primary Objectives: To evaluate the safety of BufferGel and 0.5% PRO 2000/5 Gel (P) when

applied intravaginally by women at risk for sexually-transmitted HIV infection.

To estimate the effectiveness of these gels in preventing HIV infection.

Design: A phase II/IIb, four-arm, multisite, randomized, controlled, trial comparing BufferGel and 0.5% PRO 2000/5 Gel (P) with a placebo gel and with no treatment (condom only arm).

Population: Sexually active HIV-uninfected women

Sample Size: 3100 participants

Countries: Malawi, South Africa, USA, Zambia, Zimbabwe

HPTN 035: Phase II/IIb Trial of Vaginal Microbicides for the Prevention of HIV Infection in Women

SUMMARY

DHHS/NIH/NIAID

Trial initiated in February 2005Enrollment and follow up completeData analysis ongoingResults expected February 2009

HPTN 035: Phase II/IIb Trial of Vaginal Microbicides for the Prevention of HIV Infection in Women

STATUS

DHHS/NIH/NIAID

Vaginal and Oral Interventions Vaginal and Oral Interventions

to Control the Epidemicto Control the Epidemic

MTN-003:The VOICE StudyMTN-003:The VOICE Study

Phase 2B, Safety and Phase 2B, Safety and Effectiveness Study Effectiveness Study

1% Tenofovir (PMPA) Gel1% Tenofovir (PMPA) Gel

Tenofovir DF (TDF) TabletTenofovir DF (TDF) Tablet

TDF/FTC (emtricitabine) TabletTDF/FTC (emtricitabine) Tablet

MTN-003: The VOICE Study

TOTAL SAMPLE

(4200)

ORAL(2520)

TOPICAL(1680)

FTC/TDF(840)

TDF(840)

ORAL PLACEBO

(840)

PMPA GEL(840)

PLACEBO GEL(840)

Why a Head-to-Head Trial?

• Theoretical reasons to favor either approach for safety, acceptability, efficacy and/or selection of resistance– vaginal use may confer less systemic toxicity and less

resistance– vaginal use may be more culturally acceptable– oral use is less closely linked to sexual practices, and can

be administered by the woman without knowledge of her partner

– NO HUMAN DATA

• Only head-to-head trial will answer questions

PMPA Gel: Following a Classic Drug Development

Paradigm2006 2007 2008

HPTN 050 Phase I Safety

HPTN 059 Phase II Expanded Safety

Male Tolerance

Tissue PK

MTN-001 Oral vs. Topical PK

MTN-002 Pregnancy

MTN-003 VOICE STUDY

Discovery and development of new basic and preclinical science and concepts required to support/enhance microbicide clinical trialsSafety

Microbicides for prevention of other STIs Associated with enhancement of HIV transmission

Microbicides for use during pregnancyIncreased susceptibility of pregnant women

Tools for measuring adherence and acceptability

Additional Priority Areas

0 0.5

0

0.2

0.4

0.6

Optical Coherence Tomography (OCT)

DHHS/NIH/NIAID

Discovery and development of new basic and preclinical science and concepts required to support/enhance microbicide clinical trialsSafety

Microbicides for prevention of other STIs Associated with enhancement of HIV transmission

Microbicides for use during pregnancyIncreased susceptibility of pregnant women

Tools for measuring adherence and acceptability

Additional Priority Areas

DHHS/NIH/NIAID

1. Grants

Unsolicited Grants

Specific Initiatives

2. Contracts

Microbicide-specific product advancement

Gap-filling resources for nonclinical development

3. Partnerships

How does NIAID make this How does NIAID make this all happen?all happen?

DHHS/NIH/NIAID

Controlling the HIV Pandemic

PreventionPrevention

Anti-Retroviral Therapy

MicrobicidesHIV

Other STIsCombinations

Perinatal Perinatal Mother-to-child Mother-to-child

Transmission (MTCT)Transmission (MTCT)

VaccinesHIV

Other STIs

Antiretroviral TherapyPre-exposure Prophylaxis (PrEP)

Intervention StrategiesRisk reductionVoluntary counseling (VCT)

STI ReductionSTI ReductionHSV-2

Ultimate Goal: Multi-Component Prevention Strategy

DHHS/NIH/NIAID