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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
McGowan I, Biologicals, 2006
Microbicide Mechanism of Action
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
MSM
DevelopedWorld
Women
0
10
20
30
40
50
Seattle St. Louis New Orleans
Per
cen
tag
e (%
)
DevelopingWorld
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
Screening
Week - 2 0 + 2 + 4
Baseline Week 2 Week 4
ConsentPhysicalAnoscopyRectal GC/CHHIV AbCD4 / Viral load
SigmoidoscopyIntestinal biopsy at 10cm and 30cmCell isolation and flow cytometryTissue cytokinesRectal immunoglobulinsTissue / rectal secretion viral load
McGowan et al. JAIDS 2007
UC781 Trial Design
Screening Enrollment Randomization
0.1%
0.25%
Placebo
Baseline Endoscopy
Single dose2nd
Endoscopy7 singleDoses
3rd
Endoscopy
Anton P et al. PLoS ONE 2011
Explant Data (TCID50 102)
0
1000
2000
3000
4000
5000
6000
7000
V2 V3
Visit
Cu
mu
lati
ve P
-24
at D
ay 1
4 (p
g/m
l)
0
1000
2000
3000
4000
5000
6000
7000
V2 V3Visit
Cu
mu
lati
ve P
-24
at D
ay 1
4 (p
g/m
l)
(ID=41 0)
0
1000
2000
3000
4000
5000
6000
7000
V2 V3Visit
Cu
mu
lati
ve P
-24
at D
ay 1
4 (p
g/m
l)
0
1000
2000
3000
4000
5000
6000
7000
V2 V3Visit
Cu
mu
lati
ve P
-24
at D
ay 1
4 (p
g/m
l)
0
1000
2000
3000
4000
5000
6000
7000
V2 V3Visit
Cu
mu
lati
ve P
-24
at D
ay 1
4 (p
g/m
l)
0
1000
2000
3000
4000
5000
6000
7000
V2 V3Visit
Cum
ulat
ive
P-24
at D
ay
14 (p
g/m
l)
HEC Placebo UC781 0.10% UC781 0.25%
10cm
30cm
V2: Baseline; V3: 30 minutes post single dose
Oral or Topical ARV PrEP?
Oral
Topical
Concentration of ARV
Blood Mucosa
RMP-02/MTN-006
BaselineEvaluation
Open labelOral tenofovir
(N = 18)
Single rectal
tenofovir(N = 18)
2:1
7 DayRectal
tenofovir(N = 18)
2:1
Safety, PK / PD, acceptability
Anton et al. CROI 2011
Rectal Acceptability of Vaginal Tenofovir
0
20
40
60
80
PlaceboTenofovir
Like Discomfort Likelihood ofUse
% o
f p
arti
cip
ants
Pharmacokinetics in TissueC
on
cen
tra
tion
of T
VF
-DP
(fm
ol/m
g)
Route Oral Rectal (S) Rectal (7D)
N Detectable 7/18 10/12 12/12
PK/PD Relationship
0 1 2 3 40
5000
10000
15000
r2 = 0.33P = 0.0011
Oral Dose Single Rectal Dose Multiple Rectal Dose
Log10[Tissue TFV-DP ]fmol/mg
Cum
ulati
ve p
24 (p
g/m
L)
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
N=60
HEC(N=15)
1% Tenofovir
(N=15)
2% N-9(N=15)
Single dose
7 day daily doses
7-14 dayinterval
EndoscopySafety/behavioral
assessment
ScreeningNo
Treatment(N=15)
BaselineEvaluation
7-14 dayinterval
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
Screening
240 MSM
Consensual RAI in last month
URAI in last year
Stage 1B
3 month Acceptability & Adherence study with
placebo gel
120 MSM
RAI in last 3 months
STI negative
Stage 2
Phase 1 Tenofovirrectal
safety study
42 MSM
80% adherence in Stage 1B
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-01712 weeks 12 weeks 12 weeks
BLTNF Gel
Daily
TNF Gel
ID
Oral
Truvada
BLTNF Gel
ID
TNF Gel
Daily
Oral
Truvada
BLOral
Truvada
TNF Gel
ID
TNF Gel
Daily
Mucosal PK/PD subset
Combination Prevention
SC ± Oral ± Rectal ± Vaginal
Conventional HIV Prevention Package + PrEP
± HIV Vaccine
iPrEx Study 2,499 MSM and male-
to-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
Arm 1
Arm 2
Arm 3
Arm 4
1200mg
1200mg
600mg 600mg600mg
600mg
900mg 900mg
1200mg + 900mg/ 3 monthlyPossible Arm 5
Possible Arm 5/6 300mg/ 1 monthly600mg/2 monthly
Initial Enrollment Secondary Enrollment
Screen Baseline +1 +2 +3 +4 +5
MWRI-01
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.