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Rectal Microbicide Introduction Ian McGowan MD PhD FRCP 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

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 Model Development Macaca nemestrina

Clinical Development of Rectal Microbicides Phase 1

RMP-01 Study (UC781) Screening EnrollmentRandomization 0.1% 0.25% Placebo Baseline Endoscopy Single dose 2 nd Endoscopy 7 single Doses 3 rd Endoscopy Anton PA et al. PLoS ONE 2011

RMP-02/MTN-006 Baseline Evaluation Open label Oral tenofovir (N = 18) Single rectal tenofovir (N = 18) 2:1 7 Day Rectal tenofovir (N = 18) 2:1 Safety, PK / PD, acceptability Anton PA et al. AIDS & Human Retroviruses 2012

Phase 1 GI Adverse Events GI Adverse Events in the Tenofovir Arm MTN-007 (N = 16) RMP-02/MTN-006 (N = 12) N% Abdominal pain316%650% Rectal urgency00%542% Bloating00%542% Nausea00%433% Diarrhea16%758% Flatulence638%325% Proctalgia16%00% Other425%542% Total956%12100%

Product Acceptability

Pharmacokinetics in Tissue Concentration of TVF-DP (fmol/mg) RouteOralRectal (S)Rectal (7D) N Detectable7/1810/1212/12

PK/PD Relationship

MTN-007 N=60 HEC (N=15) 1% Tenofovir (N=15) 2% N-9 (N=15) Single dose 7 day daily doses 7-14 day interval Endoscopy Safety/behavioral assessment Screening No Treatment (N=15) Baseline Evaluation 7-14 day interval McGowan I et al. PLoS ONE 2013

Phase 1 GI Adverse Events GI Adverse Events in the Tenofovir Arm MTN-007 (N = 16) RMP-02/MTN-006 (N = 12) N% Abdominal pain316%650% Rectal urgency00%542% Bloating00%542% Nausea00%433% Diarrhea16%758% Flatulence638%325% Proctalgia16%00% Other425%542% Total956%12100%

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 AI / 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 AI / 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

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.

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