Transcript Microbicide Overview HIV Prevention Conference

State of the Field:
Microbicide Science and
Trials
M2008 Preconference Workshop
Delhi, India
Sharon Hillier, PhD
University of Pittsburgh
Microbicide Trials Network
February 24, 2008
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
Topical Microbicides
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Ideal if option available for use with sex or
daily (independent of sex)
Local drug levels can be high and systemic
exposure low
 Maximum drug:virus level
 Lower chance for adverse events related
to systemic drug
No one prevention option will satisfy all;
multiple approaches needed to address
acceptability preferences
Types of Microbicide
Delivery Platforms
Vaginal applicator for gel
Vaginal ring
Vaginal film
 Ideally
long acting, safe, effective, low
cost and user-friendly
 Potential
for combinations of drugs to
increase effectiveness
How Does the Virus Get In?
How Could Microbicides
Prevent Infection?
McGowan I, Biologicals, 2006
Who is Developing
Microbicides?
Microbicide Manufacturers

Gilead Sciences Inc.
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StarPharma Holdings Ltd
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Indevus Pharmaceuticals
Inc.
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Reprotect LLC
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Tibotec Pharmaceuticals
Ltd
The Microbicide Trials
Network
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NIH funded network
PI: Dr. Sharon Hillier
Founded in 2006
Based in Pittsburgh
Domestic (n=5) and
international (n=10) sites
funded directly by NIH
Conducting Phase 1, 2
and 2B microbicide
studies
http://www.mtnstopshiv.org/
MTN does not do any product
development or formulation
MTN Clinical Trials
Year
Study
Phase
N
HPTN-035
2/2B
3220
HPTN-059
2
200
MTN-001
2
144
MTN-002
1
40
MTN-003
2B
4200
MTN-004
1
60
MTN-015
HIV+
Registry
225
MTN-016
Pregnancy
registry
Ongoing Studies
06
07
08
09
10
11
Planned Studies
12
13
CONRAD
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Established in 1986
Executive Director:
Henry Gabelnick
Strategic focus:
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Contraception
Prevention of sexual
transmission of
HIV/AIDS and other
infections.
http://www.conrad.org/
Product Portfolio
•
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•
Cellulose sulfate
Tenofovir
UC-781
International Partnership for
Microbicides (IPM)
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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
http://www.ipm-microbicides.org
Product Portfolio
•
•
TMC-120
Tenofovir
IPM does product formulation
and scale-up research
United Kingdom
Microbicides Development
Program (MDP)
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Funded through grants from
the UK Medical Research
Council (MRC) and the UK
government Department for
International Development
(DFID)
Conducting the microbicide
trial
of PRO-2000
Lead investigators- Charles
Lacey, Sheena McCormack
http://www.mdp.mrc.ac.uk/
MRC MDP Trial Sites
•
•
•
•
South Africa
Tanzania
Zambia
Uganda
Population Council

Conducts research worldwide to
improve policies, programs, and
products in three areas
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HIV and AIDS
Poverty, gender, and youth
Reproductive health.
Just released data from Phase 3
study of Carraguard®
Ongoing research program with
combination microbicide – PC
815
Director-Naomi Rutenberg
Carraguard® Gel
http://www.popcouncil.org/
Microbicide Trial Design
Safer sex counseling
Diagnosis & treatment of STIs
Condom provision
Randomization
Active Drug 1
Active Drug 2
Primary Endpoint
HIV seroconversions
Placebo
DSMB Review Process
Safety
• Adverse events
• Laboratory tests
• HIV infection
Trial conduct
• Accrual
• Retention
• Adherence
DSMB Decision
Continue
Continue with study
Modification:
• Drop a study arm
Pause/stop study
• Futility
• Success
• Safety concerns
Reasons for Premature
Study Discontinuation
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Overwhelming evidence of efficacy
Safety concerns
Futility
 Inability to achieve primary study endpoint
New treatments or prevention strategies emerge
that change clinical equipoise
Economic considerations
Social or political issues
Why Were Some Studies
Stopped by the DSMB?
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C31G (Savvy™)
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Stopped due to futility
Insufficient HIV seroconversions (endpoints) to
determine whether product effective
Cellulose sulfate (CS) studies
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CONRAD study stopped because of safety concerns
• Unequal distribution of HIV endpoints
• CS group had more endpoints than anticipated
• CS might increase risk of HIV transmission

FHI study showed no increased risk of HIV acquisition
but also no evidence of efficacy (benefit)
http://www.global-campaign.org/CS-background.htm#interim
Population Council Study
of Carraguard
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USAID & Gates Foundation
Carraguard vs placebo
S Africa (Durban; Cape Town and
Medunsa) 6203 women enrolled
First phase 3 trial of microbicides to be
completed
Safe but not effective
Can now be used as a delivery vehicle
for next generation product
Effectiveness Studies of Savvy
(C31G), Cellulose Sulfate, and
Carraguard
PRODUCT
STUDY OUTCOME
Savvy (C31G)
Trial stopped due to futility,
trend toward harm in
frequent users
Cellulose Sulfate
CONRAD
FHI
Carraguard
Stopped, evidence of
harm
No evidence of harm
Trial completed, no benefit
Drug Discovery, Development
and Review Process
250 compounds
10,000
compounds
6.5 years
Stage 3
Clinical trials
Phase I
Phase II
5 compounds
7 years
Phase III
Marketing application submitted
Stage 2
Pre-clinical
First clinical trial application submitted
Stage 1
Drug discovery
Stage 4
Regulatory
review
1
approved
drug
1.5 years
Adapted from: Pharmaceutical Research and Manufacturers of America, 2006
HPTN 035: BufferGel and
PRO2000 (0.5%)
Objective:To estimate the safety and
effectiveness of BufferGel and 0.5%
PRO2000/5 (P) when applied
intravaginally by women at risk for
sexually-transmitted HIV infection
 7 sites (1 US, 6 Africa)
 Full accrual of 3100 women July 2007
 Follow-up to be completed
July/August 2008
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MDP-301 Study of PRO2000
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PRO 2000 0.5% and 2%
Sponsored by the Microbicide Development
Programme (MDP) of the UK
Intended sample size: 9,590
First enrollment: 25 Oct. 2005
16 years or older, except in S Africa and
Zambia: 18years
Last SDMC meeting: Feb 2008 resulting in
closure of 2% PRO 2000
Estimated complete enrollment: July 08, results
late 09 or early 2010
HPTN-035 / MDP-301
HPTN-035
MDP-301
PRO-2000
(0.5%)
PRO-2000
(0.5%)
BufferGel
PRO-2000
(2%)
Condom
Placebo
Placebo
The Ideal HIV Prevention
Drug

PrEP = Pre-Exposure Prophylaxis

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oral, vaginal, rectal
Specific antiretroviral microbicide
One dose daily – or less
 Potent, good tissue penetration at site of
infection
 Well tolerated, safe (including pregnancy)
 Minimal drug interactions
 Minimal resistance, preserve options
 Affordable: drug cost and monitoring

Topical Microbicides
Containing Antiretroviral
Drugs = Topical PrEP
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Products that can be applied topically for
prevention of HIV .
Ideal if option available for use with sex or daily
(independent of sex)
Local drug levels can be high and systemic
exposure low
 Maximum drug:virus level
 Lower chance for adverse events related to
systemic drug
 May be safer for pregnant or breastfeeding
women
ARV-Based Microbicides
Tenofovir
UC-781
MIV
TMC120
(Dapivirine)
1% Tenofovir Vaginal Gel
Active ingredient is tenofovir, an
antiretroviral
 Has specific action against HIV and proven
safety and activity as a therapeutic agent
 Provided in pre-filled applicators
 Low levels of drug in the blood
 Low frequency of side effects

Tenofovir Gel Studies
2006
2007
2008
HPTN 050 Phase I Safety
HPTN 059 Phase II Expanded Safety
Male Tolerance
Tissue PK
MTN-002 Pregnancy
MTN-001 Oral vs. Topical PK
MTN-003 VOICE STUDY
CAPRISA 004 Study
CAPRISA 004 Study of
Tenofovir
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Funded by USAID
Tenofovir 1% gel vs placebo
Proof-of-concept trial (Phase 2b)
Sample size: 980 women in Durban
18 years and older
Family planning attendees, STI clinic clients
and sex workers (3/2/1)
Required to use contraception
Screening started on 18 May 2007
Gel use within 12 hours before and 12
hours after sex, max. 2 applications within
24 hours
Coital Dosing in CAPRISA
004
Participants advised to use gel which is in single-use,
pre-filled applicators, as follows:
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Coitally dependent use - 2 doses of gel per sex act
Participants asked to apply the first dose of the
assigned gel within 12 hours prior to coitus and to
apply a second dose as soon as possible, within 12
hours, after coitus.
Not more than two doses of gel in a 24-hour period.
The VOICE Study:
Vaginal and Oral Interventions to Control the Epidemic

Phase IIb trial with five study groups testing two
different HIV prevention approaches in women:
- A once-a-day antiretroviral tablet (PrEP)
- A once-a-day application of a vaginal gel
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4,200 women to be enrolled at 10 centers in Africa
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Target start date Fall 2008
The VOICE Study
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Safety and effectiveness study of tenofovir gel, tenofovir tablet
and Truvada tablet for prevention of HIV infection in 4,200
women
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Randomized trial with 5 study groups. Two sequential
randomizations. Women will use product for average of 21
months
TOTAL SAMPLE
(4200)
Oral Pill
(2520)
Truvada
(840)
Tenofovir
(840)
Vaginal Gel
(1680)
Oral Placebo
(840)
Tenofovir Gel
(840)
Placebo Gel
(840)
VOICE and CAPRISA-004
Status
VOICE*
CAPRISA-04
Planned start
Q3 2008
Ongoing
4200
980
Tenofovir gel
Viread®
Truvada®
Placebo gel/tablet
Tenofovir gel
Placebo gel
No
Yes
Enrollment
Arms
Coital dosing
*Protocol in development
Why VOICE?
Tenofovir
Tenofovir Gel
Truvada
Which is safer?
Which is effective?
Which will women use?
Why a head to head trial or
oral vs vaginal regimens?
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Each approach carries specific theoretical
and operational advantages
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vaginal use may confer less systemic toxicity
oral use is less closely linked to sexual
practices, and can be administered by the
woman without knowledge of her partner
Theoretical reasons to favor either
approach for efficacy and/or selection of
resistance
Only a head-to-head trial of these two
approaches will answer this question
TMC120 (Dapivirine)
 NNRTI developed by Tibotec/J&J, licensed to IPM
(2004)
 Developed originally as therapeutic, 11 clinical
studies conducted via oral administration
 Highly potent ARV
 Low cytotoxicity, non-mutagenic, non-teratogenic
 Easily manufactured, cheap
 Stable drug substance H C
CH
CN
N
 IP clarity
N
N
N
CH
H
H
 Multiple dosage forms
3
3
3
Dapivirine gel/ring: Clinical studies
Study
Study Name
Location
IPM003
Gel 002 Safety
SA, Tanzania,
Rwanda
112
completed
IPM004
Gel 002 PK
South Africa
18
completed
Gel 002 Expanded Safety
Belgium
36
completed
IPM001
PC Ring Feasibility
Belgium
12
completed
IPM008
WC Ring Feasibility
Belgium
13
completed
IPM011
WC Placebo Ring Safety
/Acceptability
South Africa,
Kenya, Tanzania
200
ongoing
IPM012
Gel pK and Safety
Belgium
36
11-07 start
IPM018
Matrix and Reservoir Ring
pK
Belgium
24
completed
IPM005B
Volunteers
Status
Planned trial: International
Partnership for Microbicides
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TMC 120 – no final decision on
formulation yet: gel or ring or both
Directly monitored treatment
No sample size calculations yet
Planned start at the end of 2008
UC-781
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Carboxanilide type of NNRTI
Potent anti-HIV-1 activity (nM range)
 Tight binding to HIV-1 RT
 Active against cell-free and cellassociated virus
Little to no cytotoxicity (>M)
Active against RT inhibitor resistant
strains
 Reduced likelihood for resistance
selection
Exhibits so-called “Memory Effect”
UC781 Gel: Clinical Studies
2006
2007
2008
Phase I Safety n=48
Phase 1 Safety 14 day-US & Thailand
Male Tolerance
Vaginal pK and Safety
N=60
Rectal Safety n=36
MIV-150: A Combination

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PC-815, Carraguard plus MIV-150 (NNRTI)
Phase 1 crossover study (Dominican
Republic, PC-815 and Carraguard
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20 women, 1 week single dose/day followed
by 1 week twice dosing/day
Safety and pK
Planned start 2008
Phase I male tolerance
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Safety and pharmacokinetic for systemic
absorption of MIV-150
10 circumcised and 10 uncircumcised males
IRB approved;
Planned start following Phase I in women
Rectal Microbicides
Receptive Anal Intercourse
Common
Country
Ever Experienced RAI Source
(%)
Brazil
31.0
Guimares MD et al.
1995
Peru
12.0
Caceres C et al.
1997
South Africa
42.8
Karim SS and
Ramjee G 1998
Kenya
40.8
Schwandt M et al.
2006
Rectal Safety Phase 1
Studies
Product
Status
Timeline
Sponsor
UC-781
Ongoing
Q2 2008
NIAID/DAIDS
Tenofovir gel
Planned
Q3 2008
NIAID/DAIDS
PRO-2000
Gel
Planned ?
Q1 2008
MDP MRC-UK
UC-781
(Rectal
formulation)
Possible
Q4 2010
TBD
State of the Field and Science
First generation products have been
evaluated in efficacy studies with no level of
effectiveness detected to date
 Potent antiretroviral microbicides (topical
PrEP) now in efficacy studies
 Oral versus topical microbicide use is a key
scientific question
 Rectal safety studies have started
 Community engagement in research agenda
is more critical than ever

Ten years ago, 1 percent of women in South Africa had contracted HIV; today
the number is 25 percent. These women are living a nightmare, but we in rich
countries are the ones who have to wake up. We need to develop prevention
tools that can give women a chance to defend themselves. We need to deliver
them as soon as they’re available, and we need to deploy now the prevention
tools we already have.
Melinda French Gates, Newsweek, May 15, 2006