IND Enabling Critical Path Project

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PROJECT 4 ABSTRACT The Film Antiretroviral Microbicide Evaluation (FAME) Program addresses the critical need to develop a highly effective, safe, and acceptable microbicide vaginal film with an extended window of protection from HIV infection that allows less frequent product dosing. The Program builds upon previous data showing vaginal films to be a safe and acceptable dosage form for delivery of antiviral drugs to the vagina. Specifically, a film formulation of the integrase inhibitor MK-2048 will be developed that achieves measurable drug levels consistent with HIV prevention in the cervical and vaginal tissues over one week following a single application. Such a product could be used consistently on a weekly basis to provide continuous protect or could be used to provide greater versatility for women planning for protection around a period of increased risk of infection. MK- 2048 is a potent 2nd generation integrase inhibitor for which an extensive amount of preclinical data including safety have already been established. The IND developed within Project 4 will cross reference drug substance data contained within previously approved INDs for the MK-2048 oral and intravaginal ring products. The overall goal of the IND Enabling Critical Path Project (Project 4) is to ensure that GMP MK-2048 is available for use in the planned studies within the program. Project 4 will coordinate and oversee manufacture of GMP compliant drug product. Formulations developed within Project 1 will be the basis for GMP manufacture. Project 4 will also manage preclinical safety studies including rabbit vaginal irritation and toxicity studies and lactobacillus compatiblity studies. These studies will be combined with existing data from previous IND submissions, in vitro and ex vivo safety and efficacy data from Project 2, and safety data from Core B to generate a safety package supportive of conducting the planned human clinical trials within Project 3. Project 4 will develop and integrate regulatory documents for submission of an IND application to support first-in-humans investigative clinical trials in the US (FAME-101, FAME-102, and FAME-103; Project 3). Finally, Project 4 will also generate the required Investigator Brochure. The activities within Project 4 are essential to generation of required data and appropriate regulatory documentation for initiation of human clinical trials of the novel non-coitally dependent (1 week) film dosage form that will be designed within this program.