Efficacy of quabodepistat alone and in combination with delamanid and bedaquiline against Mycobacterium tuberculosis in an NHP model evaluated by [18F] FDG PET/CT and bacterial burden.

Multidrug-resistant tuberculosis (MDR-TB) is challenging. Bedaquiline (B), delamanid (D), and pretomanid (P) are used in combination regimens with other anti-TB drugs for MDR-TB; however, agents with novel mechanisms of action are needed. DprE1 inhibitor quabodepistat (Q) was developed for combination use. In this study, Q alone or in combination with human-equivalent doses of D and/or B was evaluated in a marmoset TB model using in vivo imaging, with terminal bacterial counts from all lung lesions. Marmosets were infected with H37Rv Mycobacterium tuberculosis and allowed to develop the disease for 7 weeks. They were then administered a pre-treatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan and randomized into seven treatment groups (n = 5/group). At 2 weeks, the quabodepistat-treated groups showed a significant reduction in lesion volume compared to those without the agent in a post hoc analysis. After 2 months, the animals were euthanized, and the bacterial burden and histology were assessed. Marmosets treated with all agents showed reduced lung disease on PET/CT (>70%) compared to their pre-treatment disease volume. B reduced extrapulmonary bacteria more significantly than Q or D. Cavities and necrotic lesions from DBQ-treated animals had lower bacterial burdens than lesions treated with any of the single-agent or two-agent combinations. In a preliminary comparison, DBQ showed no statistically detectable difference from the standard-of-care regimen isoniazid-rifampicin-pyrazinamide-ethambutol (HRZE). Additionally, the activities of D and P monotherapies were similar in this model. The evaluation of these agents in the marmoset TB model supports further investigation of Q as a component of shorter TB regimens.