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Project 4 Summary & Aims

Project 4 Summary

Exploratory human trials of rectal microbicides.

In this Project, we hypothesize that (1) detailed assessment of mucosal architecture and immunological function will demonstrate microbicide-associated toxicity that would not be recognized using visual and symptomatic criteria and (2) that rectal administration of reverse transcriptase (RT) microbicides will be associated with quantitative reduction in rectal secretion and mucosal viral load but does not lead to the development of HIV resistance mutations in the mucosal or systemic compartments.

A series of experiments are proposed that will characterize the mucosal consequences of rectal administration of an RT microbicide, determine whether such administration alters the distribution and bioavailability of these compounds, and what the virological sequelae are of using an RT compound. UC-781 (Biosyn, Inc., Huntingdon Valley, PA) has been chosen as the candidate RT microbicide for these experiments. Anne-Marie Corner, President and CEO of Biosyn, Inc. will be Project Leader, as required by the PA. After conducting the pre-clinical animal studies needed to file an Investigational New Drug (IND) application to allow human rectal studies, three sequential pilot studies of UC-781 will be undertaken. The first will determine the distribution and bioavailability of UC-781 in the distal rectum following simulated coitus; the second study will be in HIV-1 seronegative subjects and will be used to optimize the doses and safety assessment of RT rectal microbicides. The third study will be in HIV-1 seropositive individuals, characterizing the virological sequelae of rectal administration of UC-781.

We envisage that the data generated by these studies will allow a streamlining of the safety and virological assays needed to evaluate candidate microbicides. They will provide a logical continuation from the pre-clinical / discovery activities of Project 1, and will be responsive to data on formulation acceptability emerging from Project 3.

Specific Aim #1. To determine the optimal mucosal safety assessment of rectal microbicides using UC-781 as a candidate microbicide.

Specific Aim #2. To characterize the virological sequelae of rectal administration of UC-781 in subjects with HIV.

Project 4 Aims: Milestones

Project Specific Aim Milestone Date Completion Anticipated Before Year 2.5 Review (10/06)
Project 4      
  Aim 1: Preclinical studies    
  28 day rat study 01/05 Yes
  28 day dog study 01/05 Yes
  Complete IND 02/05 Yes
  Aim 1: Microbicide distribution study    
  Subject enrollment starts 03/05 Yes
  Last subject out 11/05 Yes
  Preliminary study report completed 03/06 Yes
  Aim 1: UC-781 HIV seronegative study    
  Subject enrollment starts 11/05 Yes
  Last subject out 01/07  
  Preliminary study report completed 04/07  
  Aim 2 :  UC-781 HIV seropositive study    
  Subject enrollment starts 12/07  
  Last subject out 02/09  
  Preliminary study report completed 06/09