Clinical safety and pharmacokinetic studies of intravaginal rings releasing multiple antiretrovirals

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 DESCRIPTION (provided by applicant): The goal of this project is to prevent HIV transmission. Using the drug delivery platform that we developed for the ganciclovir intraocular implant, Vitrasert(r), we propose to develop an intra-vaginal ring (IVR) releasing the antiretrovirl agents tenofovir, emtricitabine and maraviroc. This drug combination has been chosen for potency, synergistic action, and the prevention of resistance. The rationale for the choice of tenofovir and emtricitabine is very strong: these are the drugs in Truvada(r) and have demonstrated efficacy in clinical studies of HIV transmission. Maraviroc has demonstrated protection against SHIV transmission in macaques. 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 goal of Phase I of this SBIR project was to perform the necessary pre-clinical work for allowance of an FDA Investigational New Drug Exemption (IND) to test this formulation in a clinical study. This milestone has been achieved: IND 123099 has been allowed by the FDA. The goal of this Phase II SBIR proposal is to carry out this first in human study. Rings releasing single drugs and combinations will be worn by normal volunteers for 7 days. Safety will be determined by colposcopy and a novel ultrasound procedure which we pioneered, as well as cytokine measurements and assessments of the microbiome. Pharmacokinetics will be determined by measurement over time in local tissues and fluids, as well as in plasma. On completion of the 7 day study there will be a washout period and the data will be presented to the FDA. If there are no safety concerns after wearing the ring for 7 days, the study will be repeated over a 28 day period. Subsequent SBIR Phase III studies are planned in African populations. The development of an effective microbicide IVR could save millions of lives per year and is therefore highly significant. We believe we are uniquely qualified to develop such a product and that our rings demonstrate dramatic improvement over the current state of the art. The team of investigators is expert in chemistry, pharmacokinetics, engineering, gynecological clinical trials and drug development, and we have experience in all aspects of the drug development process, from concept to approval and marketing. The milestone of this proposal will be the successful completion of this clinical trial demonstrating safety and local delivery of the drug sufficient to merit further clincal trials in pursuit of FDA approval and clinical implementation. The successful completion of this work will be followed by studies and programs to manufacture these rings on a large scale and perform the clinical trials necessary for ultimate approval. As the developers of the only FDA approved sustained release antiviral delivery device we believe we are uniquely qualified to carry out such an ambitious program.