Both 2-week EBA clinical studies planned have been completed at project end:
- The EBA study with β-lactam antibiotics meropenem and ertapenem in combination with amoxicillin/clavulanate, aimed to identify a once daily regimen for drug resistant TB that could be administered intravenously or intramuscularly (WP2), completed enrolment in 2020. During the last period the team focused on compilation and analysis of results, clinical study report writing and preparation for publication (expected late 2022).
- The EBA study of a low-dose oxaborole drug (WP1) aimed to establish proof of concept of anti-TB activity in humans completed enrolment of the last 2 cohorts during the last period. The clinical study report was finalised in June 2022. Topline study results was presented at the Keystone Symposia on Molecular and Cell Biology in August 2022 and the study manuscript is in preparation for submission later this year.
PET/CT scan images from participants in these trials, as well as blood and urine samples, have been collected and analyzed with the objective of validating biomarkers that accurately reflect the early therapy-induced immunological, radiological and bacteriological changes (WP4). The human biological samples were sourced ethically and their research use is in accordance with the terms of the informed consents under the approved protocols.
PET/CT scan images have been analyzed both manually and computationally and “cubes” (unit of measurement) categorised into 3 types describing presence of TB-related lesions at baseline, day 14 or both. Statistical analysis showed that the computational model detected a dose effect on reduction in lesion volume and FDG uptake (WP1 study).
For immunological biomarkers, main results are 1) a novel urine trDNA assay developed and validated on a WP2 study cohort, 2) the identification of clusters of immune response within the first 14 days of therapy in EBA trials via RNA transcriptomic analysis, 3) the development of an RNA based model predicting TTP results during the EBA trial, 4) the correlation of this model with PET/CT readouts, and 5) the identification of a set of potential biomarkers (cytokines, chemokines, and growth factors) for monitoring treatment response in 14-day EBA studies. Research will continue after project end to enable uptake for use in clinical studies.
Finally, in WP5, a meropenem model was developed to investigate the relationship between EBA and PK measures as well as the target occupancy of different dosing regimens, as part of the modelling work aimed to find optimal treatment strategies for carbapenem antibiotics. A two-drug mathematical model was developed based on binding kinetics to simulate the drug interaction and investigate the possibility of synergy or antagonism between the drugs.
