Transcript Microbicides – A New Frontier in HIV Prevention

State of Global Rectal
Microbicide Research
Ian McGowan MD PhD FRCP
Magee-Womens Research Institute
University of Pittsburgh
Microbicides are products that
can be applied to the vaginal or
rectal mucosa with the intent of
preventing or significantly
reducing the risk of acquiring
STIs including HIV
Microbicide Mechanism of Action
McGowan I, Biologicals, 2006
Rationale for Rectal Microbicides
 Unprotected receptive anal intercourse
(RAI) is the highest risk sexual activity
for HIV transmission
 Men and women in the developed and
developing world practice RAI
 Murine and non human primate studies
have shown proof of concept that rectal
application of ARV microbicides can
prevent SIV/HIV infection
Lubricants As a Drug Delivery
System
MSM
Women
Developed
World
Percentage (%)
50
40
30
20
10
0
Seattle
Developing
World
St. Louis New Orleans
Clinical Development of
Rectal Microbicides
Phase 1 Studies
Early Nonoxynol-9 Studies
 Low-dose N-9 gel was not associated with
macroscopic rectal and penile epithelial
disruption or inflammation, but histologic
abnormalities were commonly observed
during N-9 gel as well as during placebo gel
use.
 Tabet S et al. Sex Trans Dis 1999
 2% N-9 showed rapid exfoliation of the rectal
epithelium.
 Phillips D et al. Contraception 2004
HPTN 056 Study Design
Week
-2
Screening
0
+2
Baseline
Week 2
Consent
Physical
Anoscopy
Rectal GC/CH
HIV Ab
CD4 / Viral load
McGowan et al. JAIDS 2007
+4
Week 4
Sigmoidoscopy
Intestinal biopsy at 10cm and 30cm
Cell isolation and flow cytometry
Tissue cytokines
Rectal immunoglobulins
Tissue / rectal secretion viral load
UC781 Trial Design
0.1%
Screening
Enrollment
Baseline
Endoscopy
Randomization
0.25%
Placebo
Single dose
2nd
Endoscopy
Anton P et al. PLoS ONE 2011
7 single
Doses
3rd
Endoscopy
Explant Data (TCID50 102)
6000
5000
4000
3000
2000
1000
0
V2
UC781 0.10%
UC781 0.25%
7000
7000
(ID=410)
6000
5000
4000
3000
2000
1000
0
V3
V2
6000
5000
4000
3000
2000
1000
0
V3
Visit
5000
4000
3000
2000
1000
0
V3
V2
7000
6000
5000
4000
3000
2000
1000
0
V2
V3
Visit
Cumulative P-24 at Day
14 (pg/ml)
7000
V2
6000
Visit
Cumulative P-24 at Day 14
(pg/ml)
Cumulative P-24 at Day 14
(pg/ml)
Visit
30cm
Cumulative P-24 at Day 14
(pg/ml)
7000
Cumulative P-24 at Day 14
(pg/ml)
10cm
Cumulative P-24 at Day 14
(pg/ml)
HEC Placebo
V3
Visit
V2: Baseline; V3: 30 minutes post single dose
7000
6000
5000
4000
3000
2000
1000
0
V2
V3
Vi si t
Oral or Topical ARV PrEP?
Blood
Mucosa
Oral
Topical
Concentration of ARV
RMP-02/MTN-006
Safety, PK / PD, acceptability
Baseline
Evaluation
Open label
Oral tenofovir
(N = 18)
Anton et al. CROI 2011
Single
rectal
tenofovir
(N = 18)
2:1
7 Day
Rectal
tenofovir
(N = 18)
2:1
Rectal Acceptability of Vaginal
Tenofovir
% of participants
80
Tenofovir
Placebo
60
40
20
0
Like
Discomfort
Likelihood of
Use
Pharmacokinetics in Tissue
105
104
Concentration (fmol/mg)
Concentration of TVF-DP
(fmol/mg)
TVF DP Tissue Homogenate
TFV DP Homogenate Comparison ~30min Post-Dose
103
102
101
100
Oral Dose
Route
Oral
N detectable
N Detectable
7/18
7/18
Single Rectal Dose
Rectal (S)
10/12
10/12
Multiple Rectal Dose
Rectal (7D)
12/12
12/12
PK/PD Relationship
Oral Dose
Single Rectal Dose
Multiple Rectal Dose
Cumulative p24 (pg/mL)
15000
r2 = 0.33
P = 0.0011
10000
5000
0
0
1
2
3
Log10 [Tissue TFV-DP ]fmol/mg
4
Mucosal Safety in RM Trials
 Epithelial sloughing
 Histopathology
 Mucosal mononuclear
cell phenotype
 Mucosal cytokine mRNA
 Luminex
 Microarray gene
expression
 Fecal calprotectin
 Rectal microflora
N-9
PRÉ
MTN-007
2% N-9
7-14 day
interval
7-14 day
interval
(N=15)
N=60
1%
Tenofovir
Baseline
Evaluation
Single
dose
7 day daily
doses
(N=15)
HEC
(N=15)
Screening
No
Treatment
(N=15)
Endoscopy
Safety/behavioral
assessment
DAIDS Integrated Preclinical
Clinical Program for HIV Topical
Microbicides
Microbicide Development
Program
 First IPCP focusing on rectal microbicide
development
 Provided proof of concept in the SIV NHP
model and development of explant platform
 Phase 1 clinical trials of the vaginal
formulation of tenofovir gel
 UC781 (RMP-01)
 Tenofovir (RMP-02/MTN-006)
 Behavioral correlates of RAI
Anton: IPCP U19 AI060614 / August 2004
CHARM Program
 Combination HIV Antiretroviral Rectal
Microbicide Program
 NIAID/DAIDS Integrated Preclinical Clinical
Program
 Consortium





University of Pittsburgh
UCLA
Johns Hopkins
UNC
CONRAD / Gilead
McGowan: IPCP U19 AI082637 / September 2009
CHARM Program Overview
 Development of rectal specific ARV
microbicides
 PK/PD evaluation in humanized mouse
model
 Phase 1 studies
 Tenofovir
 Maraviroc
 Tenofovir & Maraviroc
CHARM-01
 Pre-Phase 1 single dose comparison of
current formulations of tenofovir 1% gel:
 Vaginal formulation
 Reduced glycerin formulation
 Rectal specific formulation
 Endpoints
 General and mucosal safety
 PK/PD
 Current status
 Version 1.0
CHARM-02
 Pre-Phase 1 single dose comparison of
current formulations of tenofovir 1% gel
with and without simulated RAI
 Endpoints
 Pharmacokinetics
 Drug distribution using SPECT/CT imaging
 Current status
 Version 1.0
Project Gel
McGowan & Carballo-Dieguez: NICHD R01 / September 2009
Microbicide Safety and
Acceptability in Young Men
 NICHD R01
 Pittsburgh, Boston, Puerto Rico
 Phase 1 safety and acceptability of
tenofovir 1% gel
 Ethnically diverse MSM (18-30)
 Consensual RAI in last month
 Unprotected RAI in last year
Microbicide Safety and
Acceptability in Young Men
Stage 1A
Stage 1B
Stage 2
Screening
3 month Acceptability &
Adherence study with
placebo gel
Phase 1 Tenofovir
rectal
safety study
120 MSM
42 MSM
RAI in last 3 months
80% adherence in
Stage 1B
240 MSM
Consensual RAI
in last month
URAI in last year
STI negative
Phase 2 Studies
MTN-017
 Phase 2 rectal
safety study of
tenofovir gel
 N = 210
 International sites




United States (3)
Thailand (2)
South Africa (1)
Peru (1)
 Endpoints
 Safety
 Adherence
 Self report
 Objective
measures
 Acceptability
 PK/PD
MTN-017
12 weeks
TNF Gel
Daily
12 weeks
TNF Gel
ID
12 weeks
Oral
Truvada
BL
TNF Gel
ID
TNF Gel
Daily
Oral
Truvada
BL
Oral
Truvada
TNF Gel
ID
TNF Gel
Daily
BL
Mucosal PK/PD subset
Phase 2B/3 Studies
Combination Prevention
Conventional HIV Prevention Package + PrEP
SC
±
Oral
±
Rectal
± HIV Vaccine
±
Vaginal
iPrEx Study
 2,499 MSM and maleto-female
transgendered women
randomized to
Truvada or placebo
 44% reduction in HIV
acquisition
 Higher drug
concentrations
associated with
increased protection
Grant R et al. NEJM 2010
TMC-278 LA
 Rilpivirine NNRTI
 IM Nanosuspension
 Potential for 1-3 month
delivery
 Phase 1 PK/PD studies
ongoing
 Colorectal explants
 Cervicovaginal explants
 MWRI-01*
 University of Pittsburgh
 Liverpool University
*Funded by the Bill and Melinda Gates Foundation
MWRI-01
Screen
Baseline
Arm 1
1200mg
Arm 2
1200mg
+1
+2
+3
+4
900mg
Possible Arm 5
+5
900mg
1200mg + 900mg/ 3 monthly
Arm 3
600mg
Arm 4
600mg
600mg
Possible Arm 5/6
Initial Enrollment
600mg
300mg/ 1 monthly
600mg/2 monthly
Secondary Enrollment
Effectiveness Study Designs
 Option 1: Tenofovir gel versus placebo +
standard prevention package
 Option 2: Tenofovir gel versus placebo +
standard prevention package + permission to
use PrEP (HVTN 505)
 Option 3: Tenofovir gel versus placebo +
standard prevention package + Truvada
 Option 4: Tenofovir gel versus Truvada
versus TMC 278 LA + standard prevention
package
Sample Size Parameters
 Assumptions




Incidence rate ~ 5%
Effect size 60%
Lower bound 25%
Minimum FU 12
months
 Enrollment
300/month
 PrEP effect 46%
 Endpoints: 120
 Option1
 N = 2,400; FU 24
months
 Option 2
 N = 2,400; FU 30
months
 Option 3
 N = 2,400; FU 37
months
The VOICE Trial
 Both oral and topical tenofovir arms
stopped for futility
 Reasons for failure not yet known
 Non adherence
 Compartmental PK
 Biology
 Implications for rectal microbicide
development?
Rectal Microbicide Timeline*
2010 2011 2012 2013 2014 2015 2016 2017 2018
Phase 1
Phase 2
Phase 2B
Review
Available
Vaginal
microbicides
*An approximation based on tenofovir 1% gel
Summary
 Rectal microbicides are needed for men and
women in the developed and developing
world who are at risk of HIV associated with
unprotected RAI
 RM development has moved from Phase 1 to
Phase 2
 PK/PD models should increase likelihood of
success in Phase 2B/3
 Planning for an RM effectiveness study needs
to start now.
Acknowledgements