Why Do We Need Microbicides?

All You Need to Know

About Microbicides

Ian McGowan MD PhD FRCP

Co-PI Microbicides Trial Network (MTN)
Center for Prevention Research
David Geffen School of Medicine at UCLA

Global Prevalence of HIV/AIDS

Overview Biomedical Prevention

• What is a microbicide?
• Abstinence
• How do microbicides work? • Condoms
• Who is developing microbicides? • Behavioral modification
• What products are being developed? • Diagnosis and treatment of STIs
• How close to a product are we? • HSV suppression
• What are rectal microbicides? • PREP/PEP
• Why has the development of some • Circumcision
products been stopped prematurely? • Vaccines
• What news is on the horizon? • Microbicides

1

What is a Microbicide?
What Might Microbicides Look
Like?
How Does the Virus Get In?
McGowan I, Biologicals, 2006
A microbicide is a product that can
be applied to the vaginal or rectal
mucosa with the intention of
preventing or significantly reducing
the transmission of sexually
transmitted infections including HIV
infection
How do Microbicides Work?
How Do Microbicides Prevent
Infection?
McGowan I, Biologicals, 2006
2
 Where Do Products Go?

Who is Developing
Microbicides?

Charles Lacey MD, & Craig Hendrix MD

Microbicide Manufacturers The Microbicide Trials Network

• NIH funded network
• Gilead Sciences Inc. • PI: Dr. Sharon Hillier
• Founded in 2006
• StarPharma Holdings Ltd • Based in Pittsburgh
• Domestic and
• Indevus Pharmaceuticals Inc. International sites
• Conducting Phase 1, 2
• Reprotect LLC and 2B microbicide
studies

• Tibotec Pharmaceuticals Ltd http://www.mtnstopshiv.org/

MTN Clinical Trials CONRAD

Year

Study Phase N 06 07 08 09 10 11 12 13
• Established in 1986
HPTN-035 2/2B 3220
• Executive Director:
HPTN-059 2 200 • Henry Gabelnick
MTN-001 2 60 • Strategic focus: Product Portfolio
MTN-002 1 40 – Contraception
– Prevention of sexual • Cellulose sulfate
MTN-003 2B 4000
transmission of • Tenofovir
MTN-007 2 200 HIV/AIDS and other • UC-781
infections.
MTN-015 Registry 225

Ongoing Studies Planned Studies http://www.conrad.org/

3
 International Partnership for
Microbicides (IPM)
• IPM is a non-profit
product development
partnership (PDP)
established in 2002 to
prevent HIV transmission
by accelerating the
development and
availability of a safe and
effective microbicide for
use by women in
developing countries
• CEO: Zeda Rosenberg
United Kingdom Microbicide
Development Program (MDP)
• Funded through grants
from the UK Medical
Research Council
(MRC) and the UK
government Department
for International MRC MDP Trial Sites
Product Portfolio Development (DFID)
• Conducting the largest • South Africa
• TMC-120 ongoing microbicide trial • Tanzania
• Tenofovir (N = 9673) of PRO-2000 • Zambia
• Uganda

http://www.ipm-microbicides.org http://www.mdp.mrc.ac.uk/

Population Council
• The Population Council
conducts research worldwide
to improve policies, programs,
and products in three areas What Products are Being
– HIV and AIDS
– Poverty, gender, and youth Developed?
– Reproductive health.
• 2007 budget $71.5 million
• Just completed Phase 3 study
of Carraguard®
• Ongoing research program
with combination microbicide – Carraguard® Gel
PC 815

http://www.popcouncil.org/

Microbicide Development The Microbicide Pipeline

Uncertain Defense Entry / Fusion
Preclinical Clinical Enhancers Inhibitors
• Ciclopiroxolamine • MucoCept HIV • Cellulose acetate • C52L
• Praneem polyherbal • Acidform™ gel • Carraguard • Tobacco-derived
antibodies / fusion
Phase 1 • BufferGel™ • VivaGel
proteins
• Cyanovirin-N
Safety (N = 40) • T20
• C85FL
Membrane Replication • K5-N, OS(H) • T-1249
• SAMMA • SCH-C, D
Phase 2 Disruption Inhibitors
• UK-427,857
• Alkyl sulfates • Tenofovir • Invisible condom
Safety (N = 200) • Novaflux • TAK 779
• Beta cyclodextrin • TMC-120
• Porphyrins • AMD3100
• UC-781
• PSC Rantes • SFD-1
Phase 2B/3 • MIV-150
• Bicyclams
• MC1220 • BMS-806
Efficacy (N = 4000) • BMS-378806 • Aptamers
• C-731, 988
• CMPD167
Licensure

4
 Microbicides in Clinical Trials
Phase Membrane Defense Entry Fusion Replication
Disruption Enhancers Inhibitors Inhibitors
1 AcidformTM VivaGelTM PC-815
Lactobacillus Cellulose acetate UC-781 How Close to a Product are
1/2 Invisible
phthalate TMC-120
We?
CondomTM
2 Praneem Tenofovir
2/2B BufferGelTM PRO-2000
(0.5% & 2%)
3 Carraguard®

Status of Microbicide Efficacy

Trials in 2007
Product Sponsor N End of Clinical Follow-Up
Why has the Development of
2006 2007 2008 2009

Carraguard™ Population
Council 6299
Some Products been Stopped
Savvy™ FHI / USAID
4284 Prematurely?
Cellulose FHI / USAID
sulfate 2160

PRO2000 (2%) MTN /

DAIDS 3220
BufferGel™
Cellulose CONRAD/
sulfate 2574
USAID
PRO2000 MDP MRC
(0.5% and 2%) (UK) 9673

Reasons for Premature Study Why Were Recent Microbicide

Discontinuation Studies Stopped?
• Overwhelming evidence of efficacy • C31G (Savvy™)
• Safety concerns – Stopped due to futility
• Change in natural history of disease – Insufficient HIV seroconversions (endpoints) to
determine whether product effective
– CMV retinitis
• Futility • Cellulose sulfate (CS) studies
– CONRAD study stopped because of safety concerns
– Inability to achieve primary study endpoint
• Unequal distribution of HIV endpoints
• New treatments emerge that change clinical • CS group had more endpoints than anticipated
equipoise • CS might increase risk of HIV transmission
• Economic considerations – FHI study showed no increased risk of HIV acquisition
but also no evidence of efficacy (benefit)
• Social or political issues
http://www.global-campaign.org/CS-background.htm#interim

5
How Does This Impact Ongoing
Microbicide Studies?
• No major changes anticipated
What News is on The
• All microbicide efficacy studies are
designed to monitor safety in real time Horizon?
• Independent review committees (DMCs or
DSMBs) conduct periodic reviews of the
emerging clinical trial data
• More integration between MTN and MDP
(UK) trials

Hot Topics in Microbicides Topical Antiretrovirals

• Cellulose sulfate trials

• Results of the MIRA diaphragm study
• Results of the Carraguard study
MIV-150
• Developments of reverse transcriptase Tenofovir

inhibitor microbicides Tenofovir

• The CAPRISA and VOICE Studies
• Rectal microbicides
UC-781 TMC120

Human Explant Infection Tenofovir Prevents Explant

Studies Infection
Accumulated HIV-1 p24 pg/mL

15000
Media
Placebo
10000 PMPA

Endoscopic biopsies + Absorbable gelatin sponge 5000

0
0 5 10 15
Day Following HIV-1 Bal Viral Challenge

6
 Concerns with Antiretroviral
Microbicides
• PrEP will select drug-resistant virus
– In the inoculum (unlikely)
– After wildtype infection is established, yielding
mixed population of resistant/wildtype virus CAPRISA 004
Phase IIb trial to assess the safety & effectiveness
• Resistant virus will persist, on or off PrEP, of the vaginal microbicide 1% Tenofovir gel to
and be transmitted, promoting spread of prevent HIV infection in women in South Africa
resistance
• Loss of treatment options
• Again, essentially no human data (N=1)
1

CAPRISA 004 Study Schema

ƒ Purpose of study: To assess the safety &
effectiveness of the vaginal microbicide 1%
tenofovir gel for the prevention of HIV infection in
women in South Africa VOICE
ƒ Design: Phase IIb, two-arm, double-blind,
randomized, controlled trial
ƒ Study size & population: ± 980 sexually active,
HIV-uninfected women aged 18 to 40 yrs
ƒ Study sites: Vulindlela & eThekwini
ƒ Study Population: Family planning clients, STI
clinic clients, women with multiple partners Vaginal and Oral Interventions
to Control the Epidemic
2
27 June 2007

Tenofovir Gel: Following a Classic

Drug Development Paradigm
The VOICE Study
2006 2007 2008 Primary Objectives:
• Estimate the effectiveness of daily tenofovir 1% gel, oral
HPTN 050 Phase I Safety
TDF, and oral FTC/TDF in preventing HIV in women
HPTN 059 Phase II Expanded Safety • Evaluate the extended safety of daily tenofovir 1% gel,
oral TDF, and oral FTC/TDF in preventing HIV in women
Male Tolerance
Secondary Objectives:
Tissue PK
• Evaluate adherence and acceptability to the daily
MTN-002 Pregnancy vaginal and oral regiments
• Assess the selection of HIV-1 drug resistance in women
MTN-001 Oral vs. Topical PK
acquiring HIV-1 in the study
MTN-003 VOICE STUDY

7
 MTN-003:The VOICE Study VOICE Study Sites
Site City Country Key Experience
TOTAL Lilongwe Central Hospital Lilongwe Malawi HPTN 035
SAMPLE
(4200) Queen Elizabeth Hospital Blantyre Malawi HPTN 035

Botha’s Hill Durban South Africa MIRA Diaphragm

Umkomaas Durban South Africa MIRA Diaphragm

University of Cape Town Cape Town South Africa Phase 3 Carraguard

ORAL TOPICAL
(2520) (1680) RHRU Orange Farm Johannesburg South Africa MDP301; CONRAD Ph. 2 Acidform;
IPM 011 & 015; DAIDS CTU
R. H. Khan Hospital Durban South Africa HPTN 035

CAPRISA Durban South Africa PEPFAR, CHAVI

ORAL Makerere University Kampala Uganda HIVNET 006 and HIVNET 012;
FTC/TDF TDF PMPA GEL PLACEBO GEL
PLACEBO Cellulose sulfate
(840) (840) (840) (840)
(840) Kamwala Health Centre Lusaka Zambia HPTN 035 and HPTN 039

University of Zimbabwe Harare Zimbabwe HPTN 035 and HPTN 039

VOICE Study Timeline

Develop NIAID DAIDS IRB/EC Start Complete Complete
SWG protocol PSRC approval approval accrual accrual follow-up

June 2007 Q3 2007 Q4 2007 Q1 2008 Q2 2008 Q3 2008 Q1 2010 Q1 2011

Revise Rectal Microbicides
Submit protocol as
Select protocol to needed for Obtain
Present protocol Prevention Medical IRB/EC Recruit,
study co-chairs Science Officer and approval screen and
concept to and write Review Regulatory at study enroll study Follow-up
SWG protocol Committee approval sites participants period

Community input will be solicited throughout this timeline, following

projected steps for community involvement.

The Rectal Mucosa is Very Why Do We Need Rectal

Vulnerable to HIV Transmission Microbicides?
Population N Prevalence of AI Reference

High risk women 1268 32% Gross M et al.

2000
College students 210 20% Civic D 2000

US Survey 12,571 35-40% Mosher WD et al.

15 – 44 years 2005
NSFG
Californian 3545 6-8% Erickson PI et al.
residents 1995

8
 And Elsewhere Rectal Safety Phase 1 Studies
Country Ever Experienced Source
RAI (%) Product Status Timeline Sponsor

UC-781 Ongoing NIAID/DAIDS

Brazil 31.0 Guimares MD et al.
1995
Dendrimer Planned Q3 2007 NIAID/DMID
Peru 12.0 Caceres C et al.
1997 Gel

Karim SS and PRO-2000 Planned Q1 2008 MDP MRC-UK

South 42.8
Ramjee G 1998 Gel
Africa
UC-781 Possible Q4 2010 TBD
Kenya 40.8 Schwandt M et al.
(Rectal
2006
formulation)

Community Issues

Mills et al., BMC Int Health Hum Rights 2005 Grant et al. Science. 2005

Microbicide Development in 2007

• First generation products such as cellulose
sulfate have been evaluated in efficacy
studies with limited success
Summary • Potent antiretroviral microbicides are
moving into efficacy studies
• Oral versus topical microbicide use is a
key scientific question
• Rectal safety studies have started
• Community engagement in research
agenda is critical

9
 Integration of Prevention Trial
Information on Microbicides
Results
HSV-2
Microbicides Treatment – • Alliance for Microbicide Development
Carraguard Susceptibility
– http://www.microbicide.com/
Vaccines –
Adenovirus • Global Campaign for Microbicides
Female Community Microbicide Oral PrEP -1
Barrier - VCT and HIV Oral PrEP – Coitally MSM Adenovirus – http://www.global-campaign.org/
Diaphragm Support IDU Related PMPA Heterosexual -2
Male • Microbicide Trial Network
Circumcision HSV-2
- Treatment – Microbicides Index
– http://www.mtnstopshiv.org/
Infectiousnes Infectiousnes •BG/PRO2000 Vaccines – Microbicide Partner
s s •PRO2000 Prime/Boost VOICE Study Treatment • Rectal Microbicide Working Group
– http://www.irmwg.org/
2007 2008 2009 2010 2011 2012

Microbicides 2008

http://www.microbicides2008.com/

10