Dose flexible ultra-long-acting prodrug formulations for pediatric populations

Abstract While antiretroviral therapy (ART) has significantly reduced AIDS-related mortality, significant treatment gaps remain among children living with HIV-1 infection. The potential impact of emerging potent pediatric formulations on viral suppression rates has been limited by factors common to daily oral ART. Additionally, the pharmacokinetic (PK) profiles of orally administered drugs in children is dynamic making drug delivery by this route unpredictable. Therefore, long-acting (LA) non-oral drug delivery approaches that could potentially overcome these challenges are of significance. We have created a 6-month aqueous injectable formulation of a bictegravir (BIC) prodrug with a shorter PK tail. The nanoformulated esterified medicine referred to as NDBIC sustains plasma BIC concentrations of > 4X the 95% inhibitory concentration after a single injection. Based on these encouraging results, we seek funds to launch an innovative approach that will produce a complete every 6-months integrase strand transfer inhibitor (INSTI) based regimen for treatment of HIV-1 infected pediatric patients. Our innovative approach is focused on transforming well established daily oral pediatric therapies; BIC with dolutegravir as the alternative INSTI, emtricitabine (FTC) and tenofovir (TFV) prodrugs, into ultra- long-acting (ULA) dose flexible prodrug formulations. Pediatric friendly formulation excipients, prodrug linkages and aqueous buffers will be used to further de-risk the process. We will leverage on the expertise of our multidisciplinary team with a strong history of collaboration, pharmaceutical industry support, animal models of pediatric drug development and PK/PD modeling to identify a safe and efficacious complete prescription ULA- ART formulation. Our approach is supported by extensive and rigorous preliminary data. Drug choices, prodrug, and formulation development, in vitro and in vivo screening and mechanisms, toxicology, PK, and pharmacodynamic (PD) profiles in relevant animal models of pediatric drug development (Sprague Dawley rats, humanized mice and non-human primates) will follow thoughtfully well-designed milestone-driven Go-No Go criteria that seek to address the unmet needs of the pediatric patient, simplify manufacturing, scale up and storage, evaluate potential adverse reactions of non-oral ART, and clinical pharmacology. We posit that sustaining therapeutic drug levels in viral target cells (monocyte-macrophages and CD4+ T cells) and tissues will improve treatment outcomes. A twice/year complete pediatric ART regimen will be identified for future clinical development following the guidance and recommendations by the US FDA.