Welcome South Africa 4 Rectal Microbicides A Stakeholder Consultation on Rectal Microbicide Research...
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Welcome
South Africa 4 Rectal MicrobicidesA Stakeholder Consultation on Rectal Microbicide Research and Advocacy
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Rectal Microbicide Introduction
Ian McGowan MD PhD FRCPUniversity 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
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
Microbicides
Microbicide Mechanism of Action
Preclinical Evaluation of Candidate Microbicides
Colorectal Intestinal Explants
Endoscopic biopsies + Absorbable gelatin sponge
Abner SR et al. JID 2005, Watts P et al. AIDS 2006
Rectal ModelDevelopment Macaca nemestrina
Clinical Development of Rectal Microbicides
Phase 1
RMP-01 Study (UC781)
Screening Enrollment Randomization
0.1%
0.25%
Placebo
Baseline Endoscopy
Single dose2nd
Endoscopy7 singleDoses
3rd
Endoscopy
Anton PA et al. PLoS ONE 2011
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 PA et al. AIDS & Human Retroviruses 2012
Phase 1 GI Adverse Events
GI Adverse Eventsin the Tenofovir Arm
MTN-007(N = 16)
RMP-02/MTN-006(N = 12)
N %
Abdominal pain 3 16% 6 50%
Rectal urgency 0 0% 5 42%
Bloating 0 0% 5 42%
Nausea 0 0% 4 33%
Diarrhea 1 6% 7 58%
Flatulence 6 38% 3 25%
Proctalgia 1 6% 0 0%
Other 4 25% 5 42%
Total 9 56% 12 100%
Product Acceptability
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)
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
McGowan I et al. PLoS ONE 2013
Phase 1 GI Adverse Events
GI Adverse Eventsin the Tenofovir Arm
MTN-007(N = 16)
RMP-02/MTN-006(N = 12)
N %
Abdominal pain 3 16% 6 50%
Rectal urgency 0 0% 5 42%
Bloating 0 0% 5 42%
Nausea 0 0% 4 33%
Diarrhea 1 6% 7 58%
Flatulence 6 38% 3 25%
Proctalgia 1 6% 0 0%
Other 4 25% 5 42%
Total 9 56% 12 100%
DAIDS Integrated Preclinical Clinical Program for HIV Topical Microbicides
• Microbicide Development Program
• CHARM Program
• DREAM Program
• PREVENT Program
MDP 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 PA: 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 I: IPCP U19 AI082637 / September 2009
CHARM-01 Pre-Phase 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 Completed
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 Completed
Imaging Product Distribution
Goldsmith J et al. Ann Stat App 2011
CHARM-03 Pre-Phase 1 single dose comparison of
oral and topical maraviroc Rectal Vaginal
Endpoints General and mucosal safety PK/PD
Current status Enrolling
Clinical Development of Rectal Microbicides
Phase 2
MTN-017
Summary Rectal microbicides have moved from theory
to clinical evaluation Complex Phase 1 PK/PD microbicide studies
may help optimize the product pipeline Phase 2 evaluation of tenofovir 1% gel will be
completed in July 2015 The time has arrived to consider whether
tenofovir should be moved to a Phase 3 study
Acknowledgements
Acknowledgements
The Microbicide Trials Network is funded by the National Institute of Allergy and Infectious Diseases (UM1AI068633, UM1AI068615,
UM1AI106707), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health
and Human Development and the National Institute of Mental Health, all components of the
U.S. National Institutes of Health.
Thank You