The goal of this project is to continue development of a novel, dual indication vaginal contraceptive anti-herpes microbicide product containing PPCM. We will conduct all tasks required to generate the Pharmacology/Toxicology and Chemistry Manufacturing and Controls (CMC) information required for IND submission, and outline the early clinical study designs with FDA. Development will be Go/No Go Decision and milestone driven to efficiently (resource, cost and time) evaluate the drug product in biologically relevant models for activity and safety, meet FDA and ICH requirements and manufacture drug and product suitable for early clinical trial material. We will address compliance issues experienced in recent HIV microbicide trials by developing three prototypes and evaluating their consumer acceptability, safety and efficacy;then selecting the superior product form for final preclinical studies. Within ten months of grant approval, prototype formulations of three different vaginal formulations (aqueous gel, ovule and thin film) will be quickly prepared using modified recipes from industry, analytically tested and evaluated in four non GLP models: 10-day Rabbit Vaginal Irritation (RVI), cutting edge in vitro models for safety, HSV-prevention in the mouse model and contraception in the rabbit (funded by NICHD) providing us with data to select one product form for further development. Utilizing the 1kg of PPCM manufactured by Regis Chemical in the Phase I SBIR, one dosage form will be selected, incorporating consumer feedback using vehicle control products, to be taken forward by a commercial contract manufacturer through thorough development of the product formula, process and package. The CMO will produce product for use in IND enabling GLP toxicology and product stability studies. Reasonably priced quotes were obtained from the most reputable CMOs in the field. From the initiation of Phase II SBIR grant approval, a pre-IND meeting briefing document will be compiled and issued. The document will be accompanied with IND development questions addressed to FDA for response. These will include questions to finalize the Pharmacology/Toxicology study protocols and Phase I-II clinical study designs. In parallel to that, preparations will be made for manufacturing and quality control testing of a 1kg GMP batch of drug substance (PPCM) for clinical use. The first item will be to implement the Quality Agreement (commitments by both parties to satisfy quality and regulatory requirements);manufacturing controls;and qualified/validated analytical test methods required to release and monitor the stability of the GMP lot of drug substance suitable for early clinical trials.
The goal of this Phase II SBIR is to further develop Polyphenylenecarboxymethylene (PPCM) as a dual indication vaginal contraceptive microbicide. PPCM, a novel drug polymer, has received extensive preclinical evaluation by several major laboratories and is considered a very promising candidate for both contraception and sexually transmitted infections (STI) protection. Statistics from CDC inform us that there are 19 million new STI in the USA each year and 16.2% of adults have genital herpes (HSV). Moreover, 49% of all pregnancies are unplanned. As a microbicide, PPCM has significant advantages in safety and effectiveness compared to polyanion microbicides 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. During this grant we will also address the problem of consumer acceptance of vaginal products by seeking early consumer input on product aesthetics. This grant will provide funding necessary to select an aesthetically acceptable, safe and effective product form and complete all preclinical studies required by the FDA for submission of an Investigational New Drug (IND) application subsequent to human clinical testing.