Efficacy of Investigational Drug OPC-167832 against Mycobacterium tuberculosis Evaluated by [18F]FDG PET/CT and Bacterial Burden in an NHP Model
Via L.E.1, M. Zimmerman 2, D. Weiner1, M. Sutphin1, M. Piel2, E. Dayeo1, H.I.M. Boshoff1, V. Dartois2, C.E. Barry 3rd,1
1Tuberculosis Research Section, and 2Tuberculosis Imaging Program, National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health, Bethesda MD; 3Center for Discovery and Innovation, Hackensack Meridian Health, Nutley NJ.
New cases of multidrug resistant tuberculosis (MDR-TB) are increasing worldwide. New chemotherapeutics are needed to augment treatment for MDR-TB, with the ultimate goal of a new drug regimen useful for both drug susceptible and resistant disease. Bedaquiline (BDQ), Delamanid (DLM) and Pretomanid (PA) are new drugs used specifically for salvage treatment of MDR-TB, but are being increasingly investigated for use in a pan-TB regimen. The investigational agent OPC-167832 (OPC) is also being considered for such a universal-use regimen. The common marmoset, a small, non-human primate (NHP) model, is useful in assessing Mycobacterium tuberculosis (MTB) drug efficacy. These four new agents were evaluated in the marmoset using in-vivo imaging and terminal bacterial assays. Marmosets were infected with MTB for approximately 7 weeks, given a pre-treatment 18F-fluorodeoxyglucose (FDG) PET/CT scan, and sorted into treatment groups. The NHP were administered oral daily doses of BDQ, DLM, PA, or OPC or combinations of BDQ/OPC or DLM/OPC. After 2 weeks, BDQ administration was reduced to thrice weekly. Serial PET/CT scans were performed during the 2 months of treatment and computationally evaluated to assess TB-associated abnormalities. After treatment, the animals were euthanized, and the bacterial burden and histology were assessed. Marmosets treated with all agents survived and showed reduced lung disease by PET/CT, compared to untreated controls. Animals treated with BDQ, DLM, and OPC experienced the most consistent response showing reductions in both abnormal lung volume (average of 70%) and FDG uptake (85%). Lesion bacterial burdens were reduced in marmosets administered BDQ and OPC (~ 3 LOG). In addition, the combination of OPC and BDQ showed a higher fraction of sterile lung samples and lower total bacterial loads than either drug alone. This combination also appeared to reduce the incidence of cavities. Quantitative reductions in abnormal lung volumes and FDG uptake were highly associated with lower bacterial burdens. Studies of drug penetration into caseum partially predicted the activity of these agents. These results support further investigation of the drugs as components in shorter MDR-TB regimens.