PREVENT (Pre-exposure prevention of viral entry) is an Integrated Preclinical/Clinical Program, with the overall goal to provide a comprehensive set of data to facilitate an informed decision on whether the antiviral lectin Griffithsin (GRFT) shoul progress in the topical microbicides pipeline. GRFT has broad-spectrum activity against human immunodeficiency viruses (HIV) types 1 and 2, herpes simplex virus type 2 (HSV-2) and hepatitis C virus (HCV). Our product target is a rectal microbicide gel, containing GRFT as the primary Active Pharmaceutical Ingredient (API). People who practice unprotected receptive anal intercourse (URAI) represent the population most vulnerable to HIV-1 transmission due to the high preponderance of HIV target cells in the rectal mucosa, and mucosal trauma commonly associated with RAI. As a small protein, unlikely to be widely used in antiretroviral therapy, the GRFT PREVENT program stands apart from pre-exposure prophylaxis (PREP) strategies that involve small molecule antiretrovirals (ARV), which bear the potential risk of selecting for viral resistance. Broad spectrum antiviral prophylaxis that is offered by lubricant gels containing GRFT offer a much needed option for HIV infected people who require effective PREP against superinfection with HIV as well as HSV-2, HCV and other enveloped viruses that are transmitted by URAI. Three Projects and four Cores will all contribute to the Specific Aims of the Overall Program.
Aim 1 : Provide a comprehensive set of safety and efficacy data to facilitate a Go/No-Go decision on progression of GRFT rectal microbicides into later stage clinical studies.
Aim 2 : Manage and integrate the PREVENT U19 Program with the goals and expectations of the NIH sponsor and future sponsors and investors in GRFT microbicide gel products.
PREVENT is an integrated preclinical/clinical project that aims to determine whether a gel based drug delivery system for a potent, broad spectrum antiviral protein, Griffithsin, is safe in preclinical models and a pre-phase I clinical trial. Preclinical studies are also designed to predict whether the microbicide we develop might be effective against HIV-1 transmission. A safe and effective rectal microbicide gel would have significant impact on preventing expansion of the domestic and global HIV-1 epidemic. Project 1: PREVENT Program Critical Path Project Project Leader (PL): Tuse, Daniel DESCRIPTION (as provided by applicant): The overall goal of the Critical Path Project (CPP;Project 1) is to coordinate cGMP-compliant Drug Substance and Drug Product manufacture and release, manage preclinical safety and efficacy studies, and develop and integrate regulatory documents for submission of an Investigational New Drug (IND) application to US Food and Drug Administration (FDA), in support of an investigative clinical trial. Project 1 will establish the manufacturing methodology for the new product and help define an accelerated development path towards demonstration of clinical efficacy and product licensure. The novel active pharmaceutical ingredient (API) of our microbicide is Griffithsin (GRFT), a marine algal natural protein for which we have developed and scaled an efficient recombinant manufacturing process. GRFT is the most potent HIV-1 entry inhibitor known and also has high activity against other viruses that may be co-transmitted with HIV, such as HSV-2. Through our collaborators in the PREVENT Program, we have produced more than 200 g of GRFT for research use, and developed effective and stable microbicide gel dosage forms. These prototype gels have been evaluated for initial safety in an ex vivo human explant system, physicochemical stability and API release characteristics with very encouraging results. In Aim 1 of this Project, we will apply methods we have successfully used to date to further optimize the API manufacturing process for maximum yield and recovery. The manufacturing process will be brought to compliance with FDA cGMP guidelines, together with supporting documentation. Compliant API will be used to cGMP manufacture the rectal gel final dosage form optimized in Core B. In Aim 2, the safety and tolerability of the rectal gel product will be determined in regulation-compliant toxicology in 3 animal species, with endpoints to include topical and systemic safety, tolerability, irritation, sensitivity and immunotoxicity. Preliminary Chemistry, Manufacturing and Controls (CMC) and safety information along with a draft clinical Protocol will be discussed with FDA in a pre-IND meeting. Agency feedback will assist us in finalizing an IND application, activation of which by FDA will allow us to initiate a first-in-humans clinical trial f the GRFT microbicide in Project 3.