Harnessing potent next-generation diarylquinolines for long-acting injectable formulations to prevent and treat tuberculosis

PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is the most common cause of premature death among people living with HIV (PLWH), and effective TB prevention and treatment strategies are critical for preventing TB-related deaths in PLWH. Treat- ment of active TB requires the daily intake of multiple drugs for at least 6 months. Although a promising regimen for TB preventive therapy (TPT) requires only one month of daily drugs (isoniazid and rifapentine or “1HP”), current World Health Organization (WHO) approved regimens require 4-9 months of daily treatment, and for PLWH in high TB burden settings, continuous TPT (≥36 months) is recommended. There is clear evidence that shorter regimens are as associated with higher completion rates and, for both TPT and active TB, failure to complete therapy decreases treatment efficacy. The use of long-acting injectable (LAI) drug formulations may simplify regimens for TB prevention and treatment and increase completion rates by reducing the burdens, both for individual patients and for public health systems, associated with months to years of daily pill intake. Recently, an LAI formulation of the diarylquinoline (DARQ) bedaquiline demonstrated superior bactericidal activity to a WHO-approved regimen (rifampin monotherapy) in a validated mouse model of TPT. The next generation DARQs TBAJ-876 and TBAJ-587, now in phase 1 trials as oral drugs, are more potent against Mycobacterium tuberculosis in mouse models of active TB treatment and have physiochemical properties highly amenable to LAI formulation. The objective of this milestone-driven R61/R33 project is to develop LAI formulations of a next-generation DARQ for TPT and DARQ co-formulated with a companion agent (pretomanid, delamanid, and/or rifabutin), for use during the continuation phase of active TB treatment. In the R61 phase, research will focus on development and selection of optimized LAI formulations of a next-generation DARQ and/or a combination of a DARQ plus companion agent, physiologically-based pharmacokinetic modeling and non-clinical pharmacokinetic/pharmacodynamic studies to predict efficacious doses and testing proof-of- concept in a validated mouse model of TPT and a well-characterized mouse model of active TB treatment. In the R33 phase, research will focus on investigational new drug (IND)-enabling non-clinical characterization of 1-2 LAI formulations developed and selected in the R61 phase, including injection site safety and tolerability, and relevant chemistry, manufacturing, and control issues, including heat stability. In addition, advanced non- clinical efficacy testing will be conducted in mouse models of TPT and active TB treatment to confirm the long- term, sterilizing activity of LAI regimens. The ultimate goal of this project is to develop and non-clinically validate a “one-shot” DARQ-based LAI treatment for TPT as well as an optimized LAI-based treatment strategy for use in the continuation phase of active TB treatment.