1 / 22

Rectal Safety Study of Tenofovir 1% Gel

MTN-007 Phase 1 study evaluates safety and acceptability of Tenofovir 1% gel for receptive anal intercourse. The study includes a comparison of a reduced glycerin formulation with the original formulation using various mucosal safety parameters and gene expression analysis. Study participants are HIV-1 uninfected men and women abstinent from anal intercourse. This study is pivotal in advancing towards Phase 2 development of the gel.

sryan
Download Presentation

Rectal Safety Study of Tenofovir 1% Gel

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related