Transcript Slide 1

Microbicides
A Scientific Update
Ian McGowan MD PhD FRCP
Center for Prevention Research
David Geffen School of Medicine at UCLA
Overview








Mucosal transmission of HIV infection
The microbicide pipeline
RT-Inhibitor microbicides
Combination microbicides
Formulation science
Rectal microbicides
Microbicides and PREP
Microbicide development and the
community
Mucosal Transmission of
HIV Infection
Mucosal
Targets for HIV
Infection
Mucosal Transmission
of HIV
Infection
R.J. Shattock and J.P. Moore. Nat. Rev. Microbiol. 1, 25-34 (2003)
Shattock and Moore, Nat Rev Microbiol, 2003
Not Just the Mucosa….
HIV
Afferent
lymphatics
Increased
virus
replication
and spread
Draining
lymphoid tissue
The Microbicide Pipeline
Microbicide Mechanisms of
Action
 Killing or inactivating pathogens
 Creating physical barriers
 Strengthening body’s natural
defenses
 Preventing viral entry into cells
 Inhibiting viral replication
Viral Targets for Microbicides
Shattock and Moore, Nat Rev Microbiol, 2003
Preclinical Microbicide Candidates
Uncertain
 Ciclopiroxolamine
 Praneem polyherbal
Membrane
Disruption
 Alkyl sulfates
 Savvy (C31G)
 Beta cyclodextrin
Defense
Enhancers
 MucoCept HIV
 Lime Juice
 Acidform™ gel
Replication
Inhibitors
 Tenofovir
 TMC-120
 UC-781
 MIV-150
 MC1220
 C-731, 988
Entry / Fusion
Inhibitors
 Cellulose sulfate
 Cellulose acetate
 Carraguard
 VivaGel
 Dextrin-2 sulfate
 Cyanovirin-N
 C85FL
 K5-N, OS(H)
 SAMMA
 Invisible condom
 Novaflux
 Porphyrins
 PSC Rantes
 BMS-806
 BMS-378806
 CMPD167
 C52L
 Tobacco-derived
antibodies / fusion
proteins
 Anti-ICAM-1 Ab
mAb B12, 2G12
 mAb 2F5, 4E10
 CD4 IgG2
 T20
 T-1249
 SCH-C, D
 UK-427,857
 TAK 779
 AMD3100
 SFD-1
 Bicyclams
 Aptamers
Microbicides in Clinical Trials
Phase Membrane
Disruption
1
1/2
Invisible
CondomTM
2
(Praneem)
2/2B
C31G
3
Defense
Enhancers
Entry Fusion
Inhibitors
Replication
Inhibitors
AcidformTM
Lime Juice
Lactobacillus
VivaGelTM
Cellulose acetate
PC-815
UC-781
TMC-120
Tenofovir
BufferGelTM
PRO-2000
(0.5% & 2%)
Carraguard®
Cellulose Sulfate
RT-Inhibitor Microbicides
RT-Inhibitor Microbicides
Microbicide
Phase
Sponsor
Tenofovir
2
Gilead
Sciences
UC-781
1
Biosyn, Inc.
TMC-120
1
IPM/Tibotec
MIV-150
(PC-815)
(1)
Population
Council
The Issues
 Resistance
– Seroconversion on study
– Exposure in chronically infected subjects
– Community implications
 Pharmacokinetics
– Plasma
– Tissue
 RT Combinations
– Possible synergy
HPTN-050
Group
Category
A1
A2
A3
Sexually abstinent
HIV-negative
A4
Tenofovir
Dose
N
0.3%
QD
12
1.0%
QD
12
0.3%
BID
12
1.0%
BID
12
B
Sexually abstinent
HIV-negative
1.0%
BID
12
C
Sexually abstinent
HIV-positive
1.0%
BID
12
D
Sexually active
HIV-positive
1.0%
BID
12
Mayer et al. AIDS 2006
HPTN-050 PK
Mayer et al. AIDS 2006
Resistance Issues
 What is the relationship between systemic
absorption and the development of
resistance?
 Will the risk be altered by the presence or
absence or oral combination therapy?
 Could resistance occur during
seroconversion?
 How should we assess resistance?
 What are the therapeutic implications?
The Geneva “Consensus”
September 2004
 RT-Microbicide studies should move
ahead in HIV-1 seronegative
populations.
 Studies in HIV-1 seropositive subjects
are also important but should be
considered with caution.
Combination Microbicides
Combination Microbicides
 Rhesus macaque
challenge model
 BMS-378806
– Binds to gp120
 CMPD167
– Binds to CCR5
 C52L
– Inhibits gp41 mediated
fusion
Veazey et al. Nature 2005
Group
Infection
CMPD167 [5.0 mM] + BMS-378806 [5.5 mM] +
C52L [1.5 mM]
+++
BMS-378806 [2.0 mM] + C52L [1.5 mM]
CMPD167 [5.0 mM] + BMS-378806 [2.0 mM]
CMPD167 [1.0 mM] + C52L [1.5 mM]
No Infection
++++++
+++
+++
+
+++++
CMPD167 [5.0 mM] + C52L [1.5 mM]
++
CMPD167 [5.0 mM] + Mannan [50 mg ml-1]
++
C52L [1.5 mM]
CMPD167
++
++
[5.0 mM]
++
++++++
$$$$$$$$
++
BMS-378806 [5.5 mM] Challenge delay [2-6 h]
BMS-378806 [5.5 mM]
+++
+++
++++++
CMPD167 [5.0 mM] Challenge delay [2-12 h]
++++++
CMPD167 [5.0 mM]
++++++
++
CMPD167 [1.0 mM]
Mannan [50 mg ml-1]
Controls
+
++
++
++++++
+++
Veazey et al. Nature 2005
Formulation Science
Formulation Innovation
 First generation of formulations were not
optimized for vaginal or rectal use
 2nd generation products being developed
on the basis of:
– Stability
– Rheological properties
– Absorption
– Local environment (rectum vs. vagina)
– Acceptability
 Broader range of delivery systems
– Gels, foams, films, suppositories, and rings
Imaging Where the Product
Goes
Charles Lacey MD, & Craig Hendrix MD
TMC120 Vaginal Rings
Malcolm et al., Journal of Antimicrobial Chemotherapy, 2005
Rectal Microbicides
Why Develop Rectal Microbicides?
 Anal intercourse (AI) is the primary risk factor for
HIV transmission among MSM.
 The prevalence of AI among the heterosexual
population is underappreciated and represents a
significant risk for HIV transmission.
 Much AI is unprotected.
 The rectal mucosa is highly vulnerable to HIV
infection.
 Based on the N-9 experience, vaginal products may
not be suitable for rectal administration.
Prevalence of AI
International Studies
50
45
40
35
30
25
20
15
10
5
0
Men
Women
Peru (1)
Peru (2)
China
South
Africa
Prevalence of Anal Receptive Sex
Population
N
Prevalence
of AI
MSM in
EXPLORE study
4295
48 – 54%
High risk women
1268
32%
Gross M et al.
2000
College students
210
20%
Civic D 2000
12,571
35-40%
Mosher WD et al.
2005
3545
6-8%
Erickson PI et al.
1995
US Survey
15 – 44 years
NSFG
Californian
residents
Reference
Koblin et al. 2003
US HIV Infection by Transmission
Category* (2004)
Transmission
Category
N
(%)
MSM contact
18,203
47
IDU
5,962
15
MSM + IDU
1,372
4
High Risk Heterosexual contact
12,683
33
335
1
Other / not identified
Total
38,553
* CDC data from 35 areas with HIV surveillance
UK HIV Infection by
Transmission Category
Heterosexual subcategories
undetermined
Number of diagnoses
5000
infected in Africa
4500
infected abroad (not Africa)
4000
infected by high risk partner*
3500
infected in the UK
Sex between men
3000
2500
2000
1500
1000
500
0
1995
1996
1997
1998
1999
2000
Year of diagnosis
2001
2002
2003
2004
Rectosigmoid Anatomy
Modeling Rectal Microbicide Efficacy
2
2
1.5
1.5
R
R
1
1
0.5
0.5
No microbicide use
0
0
0.2
0.4
0.6
10% microbicide use
0
0.8
0
1
0.2
0.6
0.8
1
0.8
1
Efficacy
Efficacy
2
2
1.5
1.5
R
0.4
R
1
1
0.5
0.5
30% microbicide use
0
0
0.2
0.4
0.6
50% microbicide use
0
0.8
1
0
0.2
0.4
0.6
Adapted from Breban et al. (In Press)
Rectal Safety Assessment
Vaginal Microbicide
(Cellulose sulfate)
Animal
Toxicology
•
Rectal Microbicide
(Product X)
•
Combination Microbicide
(Tenofovir)
Phase 1
Rectal Safety
Preclinical Evaluation
• Cell lines
• Explant studies
• Animal models
• Animal toxicology
Human studies
• Phase 1
• Phase 2
• Phase 2B/3
Rectal Safety of Vaginal Microbicides
Candidate
Murine
Primate
Explant
Human
N-9
+++
+++
+++
+++
Buffergel
Neg
Neg
?
?
?
Neg
?
?
Neg
Neg
?
?
Cellulose sulfate
?
Neg
?
?
PRO 2000
?
?
Neg
?
SPL7013
?
Neg
?
?
Octylglycerol
?
Neg
?
?
PMPA
?
Neg
Neg
?
TMC120
?
?
Neg
?
Neg
Neg
Neg
?
C31G
Carraguard
UC781
Where to Protect and
What to Measure?
Hendrix et al., 2004
HPTN-056 Study Groups
 Group 1
– HIV-1 negative / anal receptive (N = 4)
 Group 2
– HIV-1 negative / not anal receptive (N = 4)
 Group 3
– HIV-1 positive / anal receptive + plasma viral load
> 10,000 (N = 4)
 Group 4
– HIV-1 positive / anal receptive + plasma viral load
< 50 (N = 4)
HPTN 056 Study Design
Week
-2
Screening
Consent
Physical
Anoscopy
Rectal GC/CH
HIV Ab
CD4 / Viral load
0
+2
Baseline
Week 2
+4
Week 4
Sigmoidoscopy
Intestinal biopsy at 10cm and 30cm
Cell isolation and flow cytometry
Tissue cytokines
Rectal immunoglobulins
Tissue / rectal secretion viral load
Microbicides and PREP
PREP – The Key Issues




Availability of efficacy data for PREP
Long term safety in seronegative subjects
Tissue PK profile at site of infection
Potential for differential resistance
patterns
 Animal studies of PREP inconclusive
– TDF – negative
– TDF / FTC - positive
 Consumer preference
 Cost
Microbicide Development and
the Community
Regulatory Challenges
Kaplan et al. Science. 2004
Community Resistance
Mills et al., BMC Int Health Hum Rights 2005
Grant et al. Science. 2005
Phase 3 Study of Savvy in Ghana
"The reason we decided to stop the trial was
that the group of women who volunteered to
participate had such a low incidence of HIV that
there was no way for this study to show
whether use of Savvy, compared with a placebo
gel, would prevent HIV or not,"
Leigh Peterson FHI
A New Network?
MTN Clinical Trials Portfolio
Thank You!
Los Angeles Skyline