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International Partnership for Microbicides
ARV-Based Microbicides - Cause for Optimism
Dr. Zeda Rosenberg, CEO
Mexico City, 4 August 2008
Early Generation Efficacy Trials
 9.5 trials completed or stopped
• N9, Savvy – surfactants
• CS, Carraguard, PRO 2000 (2%) –
polyanions
 2 trials ongoing
• BufferGel, PRO 2000 (0.5%) –
polyanions
The Next Generation
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Highly potent and HIV-specific (ARV-based)
Established safety & efficacy in AIDS treatment
Multiple mechanisms of action against HIV
Developed as single drugs and in combination
Can be formulated for sustained protection
 Once a day / once a month
Gel applicator
Ring
Tablet, capsule, film
Why Vaginal Dosing?
 Protection specifically for women
 High drug levels where virus enters the body
 Low systemic exposure
• Reduced chance of systemic side effects
• Precedent in contraception
• Theoretically, less chance of selection for
resistance
 No one prevention option will satisfy all
• Microbicides, PrEP, vaccines, etc.
Topical Tenofovir
 NRTI
 Most advanced ARV
microbicide in the pipeline
 Preclinical development
began in late 1990s
 Proof-of-concept efficacy trials ongoing/planned
 Gilead license to CONRAD and IPM
 Viread® marketed as AIDS therapeutic
Topical Tenofovir Trials
Study
Phase
Sponsor/Developer
Countries
Results/Status
HPTN 050
1
NIAID / HPTN
USA
COMPLETED in 2004
• Well tolerated, HIV-/+ women
CONRAD
A04-099
1
CONRAD, IPM
USA
COMPLETED in 2006
• Male tolerance study
HPTN 059
2
NIH / MTN
USA, India
COMPLETED in 2007
• Good safety and
acceptability profile
CONRAD
A04-095
1
CONRAD, IPM
USA,
Dominican R.
DATA ANALYSIS
• PK results expected 2008
CAPRISA
004
2B
USAID, SA DST /
CONRAD, CAPRISA
SA
ONGOING since May 2007
• Results expected 2010
MTN 002
1
NIH / MTN
USA
ONGOING since June 2008
• PK study, pregnant women
MTN 001
2
NIH / MTN
USA, Uganda,
SA
ONGOING since July 2008
• Topical and oral tenofovir
MTN 003
(VOICE)
2B
NIH / MTN
Malawi,
Uganda, SA,
Zambia,
Zimbabwe
PLANNED for Q1 2009
• Topical tenofovir, oral
tenofovir, oral Truvada
Dapivirine (TMC120)
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Highly potent NNRTI
Developed by Tibotec,
licensed to IPM
Originally tested as oral
therapeutic (11 studies)
H3 C
CH3
CN
N
N
CH3
H
N
N
H
Multiple vaginal dosage forms in development
(gels, rings, films, tablets, other)
Phase 1/2 studies completed and ongoing;
Phase 3 planned 2010
Dapivirine Ring & Gel - Completed Trials
Study
Design
Countries
Study Results
IPM 001,
IPM 008
7 days
25 or 200 mg
N=25
Belgium
• Good safety profile and well tolerated
• High drug levels (> 1000 x EC50) well
distributed in vaginal tissues & fluids
• Low levels in plasma (<50 pg/mL)
IPM 018
28 days
25 mg
N=24
Belgium
• Reservoir & matrix rings have good
safety profile and are well tolerated
• High drug levels (> 4 logs x EC50),
significantly more drug with matrix
• Low levels in plasma (<2 ng/mL)
Study
Design
Countries
Study Results
IPM 003,
IPM 005B
42 days
2.5 ml
N=148
Rwanda
South Africa
Tanzania
• Good safety profile and well tolerated
• No drug-related SAEs
IPM 004
10 days
2.5 ml
N=18
South Africa
• Good safety profile and well tolerated
• No drug-related SAEs
• PK data supports once-daily use
UC-781
 Highly potent NNRTI
 Cellegy license to CONRAD
 4 Phase 1 studies completed
or in data analysis (Thailand,
US) – vaginal and rectal
H
N
O
CH3 S
O
Cl
 2 Phase 1 studies ongoing
– vaginal and male tolerance
 2 studies planned:
• Single agent PK and expanded safety – planned early 2009
• Combination UC-781/tenofovir safety – planned early 2010
Source: CONRAD
UC-781 Trials - Completed/Ongoing Trials
Study
Phase
Sponsor/Developer
Countries
Results/Status
CONRAD
A02-033
1
CONRAD
USA
COMPLETED
• Tolerance, abstinent women
CDC-4744
1
CDC, MoH Thailand
/ CONRAD
Thailand
DATA ANALYSIS
• Safety/acceptability women,
acceptability male partners
U19 AI051661
1
NIH, CONRAD /
Univ of Pittsburg
USA
DATA ANALYSIS
• Safety/persistence,
abstinent women
U19 AI060614
1
NIH, CONRAD,
UCLA
USA
DATA ANALYSIS
• Rectal safety/acceptability,
men and women
CONRAD
A06-104
1
CONRAD, CFHC
USA
ONGOING
• Male tolerance
HC 101
1
CDC, CONRAD /
Emory Univ
USA
ONGOING
• Safety/acceptability,
HIV-/+ women
PC-815
 MIV-150 (NNRTI) + Carraguard
 Medivir license to Population Council
 In vitro activity
• EC50 of PC-815 is ~10X stronger than Carraguard
• PC-815 is active against wide variety of HIV isolates
• Seminal fluid does not impede activity
 HIV prevention studies ongoing in primate model
 Phase 1 clinical trials being planned
Source: Population Council
Topical Maraviroc
 CCR5 blocker
• Pre-formulation ongoing
 Pfizer license to IPM
 Combination dapivirine/maraviroc
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Silicone & EVA ring feasibility initiated
Gel initiated
Film to be initiated
Virology ongoing
 Preclinical assessment
• 28-day vaginal rabbit dosing study ongoing
 PK and safety studies planned 2009-10
 Selzentry™ marketed as AIDS therapeutic
Pipeline
 BMS 793
 Pyrimidinediones
 S-DABO
 M167
 RANTES analogs
 L’644 peptide
 NCp7’s
 GM Biotics
 Cyanovirin-N
 Others?
 Integrase inhibitors
 Small molecule fusion inhibitors
 Important to add back-up drugs, especially drugs in late stage
development or marketed therapeutics
Lessons Learned from Prior Trials
Lessons learned
What can be done going forward
Prioritization
• Advance best-in-class product only into Phase 3
Safety
• Continue early looks for harm
Adherence
• Longer acting formulations
• Product acceptability studies
• Explore novel adherence strategies/technologies
Incidence
• Epi studies conducted in advance
Futility
• Early stop if unlikely to show efficacy
Pregnancy
• Contraceptives and counseling
provided on site where feasible
Regulatory
• Obtain feedback/input in advance of trial
Locations
• Address co-enrollment concerns
Why Optimism?
 New generation of microbicides
with highly potent ARVs
 Multiple mechanisms of action against HIV
 Single drugs or combinations
 Longer duration of protection
 Multiple formulations to give women
more options
 Increased focus on adherence
 Novel trial designs
 Increased support from donors, pharma,
scientific, advocacy and local communities
Women Urgently Need Microbicides
“A microbicide could mean the difference
between life and death for millions of women.
Let us do everything in our power to accelerate
its development.” Mrs. Graça Machel, March 2008