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State of Global Rectal Microbicide Research

State of Global Rectal Microbicide Research. Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh.

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State of Global Rectal Microbicide Research

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  1. State of Global Rectal Microbicide Research Ian McGowan MD PhD FRCP Magee-Womens Research Institute University of Pittsburgh

  2. 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

  3. Microbicide Mechanism of Action McGowan I, Biologicals, 2006

  4. 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

  5. Lubricants As a Drug Delivery System

  6. MSM Women Developed World Developing World

  7. Clinical Development of Rectal Microbicides

  8. Phase 1 Studies

  9. 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

  10. HPTN 056 Study Design Week - 2 0 + 2 + 4 Screening Baseline Week 2 Week 4 Sigmoidoscopy Intestinal biopsy at 10cm and 30cm Cell isolation and flow cytometry Tissue cytokines Rectal immunoglobulins Tissue / rectal secretion viral load Consent Physical Anoscopy Rectal GC/CH HIV Ab CD4 / Viral load McGowan et al. JAIDS 2007

  11. 0.1% Baseline Endoscopy 0.25% Enrollment Randomization Screening Placebo 7 single Doses 2nd Endoscopy 3rd Endoscopy Single dose UC781 Trial Design Anton P et al. PLoS ONE 2011

  12. HEC Placebo UC781 0.10% UC781 0.25% 10cm 30cm Explant Data (TCID50 102) V2: Baseline; V3: 30 minutes post single dose

  13. Oral or Topical ARV PrEP? Blood Mucosa Oral Topical Concentration of ARV

  14. RMP-02/MTN-006 Safety, PK / PD, acceptability Single rectal tenofovir (N = 18) 2:1 7 Day Rectal tenofovir (N = 18) 2:1 Open label Oral tenofovir (N = 18) Baseline Evaluation Anton et al. CROI 2011

  15. Rectal Acceptability of Vaginal Tenofovir

  16. Pharmacokinetics in Tissue Concentration of TVF-DP (fmol/mg)

  17. PK/PD Relationship

  18. 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

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

  20. DAIDS Integrated Preclinical Clinical Program for HIV Topical Microbicides

  21. 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

  22. 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

  23. CHARM Program Overview • Development of rectal specific ARV microbicides • PK/PD evaluation in humanized mouse model • Phase 1 studies • Tenofovir • Maraviroc • Tenofovir & Maraviroc

  24. 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

  25. 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

  26. Project Gel McGowan & Carballo-Dieguez: NICHD R01 / September 2009

  27. 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

  28. Microbicide Safety and Acceptability in Young Men 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 Stage 1A Screening 240 MSM Consensual RAI in last month URAI in last year

  29. Phase 2 Studies

  30. 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

  31. MTN-017 Mucosal PK/PD subset

  32. Phase 2B/3 Studies

  33. SC ± Oral ±Rectal ± Vaginal Combination Prevention Conventional HIV Prevention Package + PrEP ± HIV Vaccine

  34. 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

  35. 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

  36. MWRI-01 Arm 1 1200mg Arm 2 1200mg 900mg 900mg Possible Arm 5 1200mg + 900mg/ 3 monthly Arm 3 600mg 600mg Arm 4 600mg 600mg 300mg/ 1 monthly 600mg/2 monthly Possible Arm 5/6 Initial Enrollment Secondary Enrollment

  37. 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

  38. 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 Sample Size Parameters

  39. 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?

  40. Rectal Microbicide Timeline* *An approximation based on tenofovir 1% gel

  41. 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.

  42. Acknowledgements

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