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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