Q-GRFT Enema Development Supporting a Multi-Administration Clinical Study

Project Summary Unprotected receptive anal intercourse (RAI) is the sexual behavior with the highest per-act risk of HIV acquisition, conferring 10 to 20 times more risk than unprotected vaginal intercourse. We are developing an antiviral rectal rinse (enema) using a novel HIV entry inhibitor, the lectin Griffithsin (GRFT), because there is a lack of on-demand antiviral HIV prevention products that can be applied during a user-selected window prior to RAI. Our product aims to satisfy this unmet need. Despite the proven benefits of anti-retroviral (ARV) treatments and their long-term control of HIV infection, there is growing concern about the numerous adverse effects and resistance to current ARV drugs. In sharp contrast, GRFTandapos;s antiviral activity and potential toxicity have been studied extensively and results have shown GRFT to be a highly potent HIV entry inhibitor while being remarkably safe. GRFT has nanomolar affinity for glycans on the HIV envelope glycoprotein, gp120, and neutralizes HIV-1 at picomolar concentrations. Additionally, GRFT suppresses cell-to-cell HIV-1 transmission, exhibits synergy with multiple ARV drugs, has broad neutralizing activity against sexually co-transmitted viruses including HSV-2 and HCV and is minimally cytotoxic. GRFT’s capacity to protect against multiple sexually transmitted viruses simultaneously positions the lectin as a promising candidate for preexposure prophylaxis (PrEP). Investigators at the University of Louisville, who are now members of GROW Biomedicine, LLC, developed a more stable variant of GRFT (Q-GRFT) and recently guided the compound to a first-in-human Phase I clinical study as an enema-based topical prophylactic within the NIAID-supported PREVENT U19 Program Project. The Q-GRFT enema was developed because the formulation is compatible with the active pharmaceutical ingredient (API) and because a pre-intercourse rinse is behaviorally congruent with practices of people engaging in RAI, hence encouraging compliance. Further, the enema formulation has a drug-release profile that offers users a flexible option for application in relation to sexual activity (e.g. 0-2 h post-administration). In preparation for the ongoing clinical trial, an IND was submitted and FDA accepted the protocol for a directly observed single-administration clinical trial. However, FDA also requested additional characterization of the product as a prerequisite to any future clinical development where multiple administrations of the product are planned. Therefore, the goal of this project is to address FDA’s concerns and provide the necessary data to support a future multi-administration clinical study with the Q-GRFT enema product. Multi-exposure clinical evaluation is essential because the commercial enema rinse is intended for use prior to every sexual encounter. The FDA-required tasks will be satisfied within the four Specific Aims described in this Phase I STTR project and help support further clinical development of GROW Biomedicineandapos;s first-in-class, Q-GRFT non-ARV PrEP biotherapeutic.Narrative Investigators at University of Louisville who are now part of GROW Biomedicine LLC (small business partner) and University of Pittsburgh (academic partner) developed a prototype rectal rinse (enema) containing the potent anti-HIV lectin Q-GRFT, which is currently under evaluation in a single-administration Phase I clinical study as a candidate rectal microbicide (NIAID-funded PREVENT Study). FDA requested additional characterization of the product as a prerequisite to any future clinical development where multiple administrations of the product are planned. The goal of this project is to address FDA’s concerns and provide the necessary data to support a future multi-administration clinical study with GROW Biomedicineandapos;s first-in-class, Q-GRFT non-ARV PrEP biotherapeutic.