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MTN-007

MTN-007. A Phase 1 Randomized, Double-Blind , Placebo-Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel.

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MTN-007

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  1. MTN-007 A Phase 1 Randomized, Double-Blind, Placebo-Controlled Rectal Safety and Acceptability Study of Tenofovir 1% Gel Ian McGowan, Craig Hoesley, Ross Cranston, Philip Andrew, Laura Janocko, James Dai, Alex Carballo-Dieguez, Ratiya Kunjara Na Ayudhya, Jeanna Piper, Florian Hladik, Ken Mayer, and the MTN-007 Protocol Team. 19th Conference on Retroviruses and Opportunistic Infections Seattle 6th March, 2012

  2. Background • Receptive anal intercourse is a high risk but common sexual behavior among men and women in the developed and developing world. • Non human primate studies have demonstrated that an antiretroviral rectal microbicide (RM) can reduce the acquisition of SIV#. • RMP-02/MTN-006 demonstrated a favorable PK/PD profile for rectal tenofovir (TFV) 1% gel but suboptimal safety profile* • Gastrointestinal symptoms #Cranage M et al. PLoS Med, 2008; *Anton PA et al. CROI 2011

  3. Rationale for MTN-007 • To characterize the safety and acceptability of a reduced glycerin (RG) formulation of TFV 1% gel • Original TFV 1% gel: 3111 mOsmol/kg • RG TFV 1% gel: 836 mOsmol/kg • Iso-osmolar: 290 mOsmol/kg • To evaluate the utility of a broad range of biomarkers of mucosal safety

  4. Study Population • Healthy, receptive anal intercourse abstinent, HIV-1 uninfected men and women • Key exclusion criteria • Rectal or reproductive tract STI • Hepatitis B surface antigen positive • Bleeding tendency • Pregnancy or breastfeeding

  5. Study Design 7-14 day interval 7-14 day interval 2% N-9 (N=17) N=65 Baseline Evaluation Single dose 7 day daily doses 1% TFV (N=16) HEC (N=16) Endoscopy Safety/behavioral assessment Screening No Treatment (N=16)

  6. Study Endpoints • Primary • Grade 2 or higher adverse events • Secondary • The proportion of participants who at their final clinic visit report via the acceptability questionnaire that they would be very likely to use the candidate microbicide during receptive anal intercourse • Changes in mucosal parameters

  7. Mucosal Safety Endpoints • Histopathology • Epithelial sloughing • Fecal calprotectin • Rectal microflora • Mucosal mononuclear cell phenotype by flow cytometry • Cytokines and chemokines • qRT-PCR • Luminex • Gene expression by microarray

  8. Baseline Demographics by Arm

  9. Incident Adverse Events by Arm

  10. Incident GI Adverse Events

  11. Gastrointestinal Adverse Events

  12. Acceptability

  13. Mucosal Safety Assays • No significant changes were seen in histology, fecal calprotectin, and epithelial sloughing after single dose (SD) or 7 daily doses (7D) • Suggestive evidence of change(▲ and ▼) were seen with flow cytometry, qRT-PCR, and Luminex assays at SD and 7D • The majority of changes were seen when comparing N-9 to the other arms of the study

  14. Mucosal qRT-PCR BL SD 7D BL SD 7D 9 cm 15 cm

  15. Mucosal Safety Parameters (1)

  16. Mucosal Safety Parameters (2)

  17. Microarray Data • Gene array studies were performed on a subset of 8 participants per study arm (9 cm and 15 cm samples) • Labeled cRNA were hybridized to Illumina Human-HT12 v4 gene expression BeadChips. • The Benjamini Hochberg method was used to control for multiple testing (false discovery rate). • Fold change was calculated as the fold difference between treatment over baseline.

  18. 9 cm Gene Expression at Day 7 No Treatment HEC gel N-9 gel Tenofovir gel

  19. Summary of Microarray Data N9 TNF HEC No Rx Gene expression 9 cm rectum following 7 days of product application

  20. Summary • The reduced glycerin formulation of TFV 1% gel was safe and acceptable and should move forward to Phase 2 development • The majority of mucosal safety signals were associated with the use of N-9 • TFV 1% gel associated changes in gene expression require further evaluation

  21. Key Issues Moving Forward • Determine whether gene array signals are important • Validation initial observations • MTN-007 & Project Gel • Linked to hyperosmolar formulations: • CHARM-01 • Linked to tenofovir: • MTN-017 • Implications for vaginal microbicides

  22. Acknowledgements • The MTN-007 study participants • CONRAD • MTN is funded by NIAID (5UM1AI068633), NICHD and NIMH, all of the United States National Institutes of Health

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