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

Lubricants As a Drug Delivery System

MSM Developed World Women Developing World

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 Screening Week BaselineWeek 2Week 4 Consent Physical Anoscopy Rectal GC/CH HIV Ab CD4 / Viral load Sigmoidoscopy Intestinal biopsy at 10cm and 30cm Cell isolation and flow cytometry Tissue cytokines Rectal immunoglobulins Tissue / rectal secretion viral load McGowan et al. JAIDS 2007

UC781 Trial Design Screening EnrollmentRandomization 0.1% 0.25% Placebo Baseline Endoscopy Single dose 2 nd Endoscopy 7 single Doses 3 rd Endoscopy Anton P et al. PLoS ONE 2011

Explant Data (TCID ) HEC PlaceboUC %UC % 10cm 30cm V2: Baseline; V3: 30 minutes post single dose

Oral or Topical ARV PrEP? Oral Topical Concentration of ARV BloodMucosa

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 et al. CROI 2011

Rectal Acceptability of Vaginal Tenofovir

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

PK/PD Relationship

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 day interval Endoscopy Safety/behavioral assessment Screening No Treatment (N=15) Baseline Evaluation 7-14 day interval

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 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: IPCP U19 AI / 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 Tenofovir rectal safety study 42 MSM 80% adherence in Stage 1B

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 weeks BL TNF Gel Daily TNF Gel ID Oral Truvada BL TNF Gel ID TNF Gel Daily Oral Truvada BL Oral Truvada TNF Gel ID TNF Gel Daily Mucosal PK/PD subset

Phase 2B/3 Studies

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 mg 600mg 900mg 1200mg + 900mg/ 3 monthly Possible Arm 5 Possible Arm 5/6 300mg/ 1 monthly 600mg/2 monthly Initial EnrollmentSecondary Enrollment ScreenBaseline 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* 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