Pre-clinical development of PPCM Vaginal Microbicide

DESCRIPTION (provided by applicant): The Problem: The limited availability of convenient and acceptable birth control methods has produced a global epidemic - uncontrolled population growth. This is inextricably linked to another public health problem, an epidemic of HIV (human immunodeficiency virus) and other sexually transmitted infections (STI). For women, a safe and effective vaginal contraceptive/microbicide would allow women to protect themselves, and help suppress these epidemics. Vaginal microbicide development has suffered numerous setbacks. No microbicide has been shown to be effective in recent clinical trials, and some may even increase the risk of acquiring HIV. Contraceptive development has also been limited - and the only non prescription widely available vaginal contraceptive - Nonoxynol -9 has serious safety concerns. Clearly, microbicide development needs to incorporate better preclinical methods for evaluating safety, develop combinations of active microbicidal ingredients to improve efficacy, and place more focus on their contraceptive effectiveness. NIH NICHD, NIAID) supports contraceptive research (NICHD), and development of methods to prevent STIs. Previous NIH funded accomplishments: PPCM is a second generation vaginal contraceptive/microbicide with the potential for HIV, HSV, HPV, and gonorrhea protection. PPCM inhibits HSV-2 infection of epithelial cells in culture and protects mice from genital herpes infection. PPCM, unlike other polyanions, is active in semen. PPCM is also contraceptive in vitro and in the rabbit. PPCM inhibits infections by laboratory and clinical R5 and X4 clade B and clade C HIV strains in cell culture and blocks transfer of HIV to target T-cells via migratory cells. When combined with tenofovir, PPCM shows synergistic anti-HIV activity in vitro. PPCM has been formulated into an aesthetically pleasing gel using GRAS ingredients at two concentrations. The gel maintains preclinical microbicidal and contraceptive activity, is lubricious and appears safe. SBIR Phase I grant goal and proposed project plan: The goals of our Phase I SBIR are to: a) finalize analytical methods for PPCM API and formulated gel in order to complete CGMP scale up and production;b) ensure PPCM can be scaled up from 20 gm quantities to production scale quantities of 1 kg;c) determine if PPCM is systemically absorbed via vaginal application in a rabbit model and;d) complete development of our preclinical, Phase 0 and Phase I clinical trial safety protocols. Accomplishing these goals will allow us to be prepared to conduct all work required to submit an IND application. Our long term goals are to: 1) launch PPCM as a contraceptive vaginal gel;2) to evaluate PPCM for prevention of non-HIV STIs (specifically HSV and gonorrhea) and;3) develop a contraceptive combination microbicidal product including an RTI with PPCM, to enhance HIV prevention and 3) to explore alternative delivery forms such as a vaginal tablet or vaginal ring. PUBLIC HEALTH RELEVANCE: Safe and effective contraception for women and the prevention of sexually transmitted diseases are closely linked. The goal of this Phase I SBIR is to further develop PPCM as a vaginal contraceptive microbicide. PPCM, a novel drug polymer, has received extensive preclinical evaluation in several major laboratories and is considered a very promising candidate for both contraception and sexually transmitted disease (STI) protection (1-5). As a microbicide, it has significant advantages in safety and effectiveness compared to other microbicides in development, and in combination with a reverse transcriptase inhibitor (RTI) promises to offer significant STI protection. As a contraceptive, PPCM has a dual mechanism for sperm inactivation. Unlike currently available spermicides, PPCM is not a surfactant and is not cytotoxic. This grant will provide funding necessary to complete a portion of the studies required by the FDA needed for submission of an IND application, and subsequent human clinical testing.