Prodrug Formulations Create Sustained-Release Antiretrovirals - Abstract Long acting (LA) therapeutics offer real potential for improved regimen adherence and disease outcomes for chronic infectious diseases. For human immunodeficiency virus (HIV) infections only cabenuva has emerged as a sole complete LA regimen to affect long-term viral suppression. However, the requirements for every two- months dosing, injection site reactions, health care practitioner administration, high dosing volumes, and prolonged “tail phase” pharmacokinetic (PK) profiles are challenges for broad use. Ultra-LA (ULA) therapies are therefore obvious next step needs. Such ULA antiretroviral therapies (ART) would increase dose intervals to simplify treatment, limit emergence of viral mutations through improved adherence to therapy, and synchronize regular six-month lab tests clinic visits with dosing. In our prior funding cycle we developed then licensed one of the “first” ULA antiretrovirals. It is a monomeric stearate ester of cabotegravir (CAB, named XVIR-110), a potent HIV integrase strand transfer inhibitor. We are pleased to affirm its clinical candidate selection status for HIV-1 prevention. XVIR-110 has a projected dosing interval of beyond every six months. The formulation has successfully completed IND-enabling GLP toxicity studies for a planned Phase I clinical trial and found to be safe. With this success as a foundation we now present our next research goal. It is to develop a next generation ULA ART that favorably addresses the needs for combinatorial ULA regimens, shorten the PK tail in existing LA formulations and XVIR-110, and further decrease injection volumes. In support of each goal is extensive preliminary data offered through the selection of homodimeric bictegravir (BIC) ester prodrugs demonstrating superiority over dolutegravir (DTG) and CAB. We posit that process chemistry design and development for the lead BIC dimer prodrug and prodrug design for rilpivirine (RPV) and tenofovir (TFV) will produce a complete six month dual therapy (BIC/RPV and BIC/TFV) for treatment of HIV-1 infection. Drug choices, prodrug and formulation development, in vitro and in vivo screening and mechanisms, toxicology, PK, and pharmacodynamic profiles will follow comprehensive Go-No Go criteria that advanced XVIR-110. To accomplish our research goals, a partnership was made between a medicinal and polymer chemist (B Edagwa) and a virologist, cell biologist, and immunologist (H Gendelman). Our complementary team has a strong history of collaboration and will continue to leverage on technical and scientific support from Exavir Therapeutics Inc. and Gilead Sciences. We posit that harnessing of natural viral target cells (monocyte-macrophages and CD4+ T cells) as drug carriers and depots will improve treatment outcomes. We will use a milestone-driven approach to identify and advance the most promising six month complete two drug regimen towards clinical translation.
