Intravaginal ring delivery of tenofovir and emtricitabine

DESCRIPTION (provided by applicant): The long term goal of this project is to prevent HIV transmission. Using the drug delivery platform we developed for the ganciclovir intraocular implant, the Vitrasert(R), we propose to develop an intra-vaginal ring microbicide formulation releasing the antiretroviral agents tenofovir and emcitritabine. This drug combination has been chosen for potency, synergistic action, and the prevention of resistance. The rationale for the choice of the drugs is very strong as theseare currently the only drugs to have demonstrated efficacy in clinical studies of HIV transmission. Funded in part by R21, R33, and SBIR grants from the NIAID, we have successfully adapted the Vitrasert(R) platform and safely delivered multiple antiretrovirals in multiple animal models. The specific aims of this proposal are to manufacture drug-eluting IVRs suitable for human, sheep and macaque studies, to confirm release of the drugs by in vitro dissolution testing, to perform pharmacokinetic testing in the sheep model, and to demonstrate safety in the sheep. This will be followed by confirmation of safety and pharmacokinetics in the macaque, and demonstration of prevention of transmission in the standard SHIV model. The milestones for the successful completion of this work are the demonstration of safety and pharmacokinetics in two species and of efficacy in the macaque challenge model. The development of an effective microbicide IVR could save millions of lives per year and is therefore highly significant. As the developers of the only FDA approved antiviral delivery device we believe we are uniquely qualified to develop such a product. We believe our IVRs demonstrate dramatic improvement over the current state of the art. We can deliver drugs of high andlow aqueous solubility simultaneously, with control of release rate over a wide range. We have already demonstrated the ability of our ring platform to safely deliver the antiretroviral tenofovir in macaques and sheep. The team of investigators is expert in chemistry, pharmacokinetics, drug development, PK/PD, animal models and infectious disease. We have experience in all aspects of the drug development process, from concept to approval and marketing. The co-PI led the team that developed the only sustained release antiviral drug delivery device in clinical use. Gilead has signed a MTA to provide the drug product for this project. The successful completion of this work will be followed by studies and programs to enable an FDA Investigational New Drug Application. Phase I and Phase II clinical studies will subsequently form the basis for a decision to proceed to large scale pivotal trials to prove safety and efficacy. PUBLIC HEALTH RELEVANCE: The development of an effective microbicide intravaginalring could save millions of lives every year. Only two drugs, tenofovir and emcitritabine, have proven clinical efficacy in trials of transmission: the milestones for the successful completion of this work are the demonstration of safety, pharmacokinetics,and efficacy of an intravaginal ring eluting these drugs. The successful completion of this work will be followed by studies and programs to enable an FDA Investigational New Drug Application. As the developers of the only FDA approved antiviral deliverydevice we believe we are uniquely qualified to develop such a product.