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AnTBiotic – progressing TB drug candidates to clinical proof of concept

Periodic Reporting for period 3 - anTBiotic (AnTBiotic – progressing TB drug candidates to clinical proof of concept)

Reporting period: 2020-01-01 to 2021-06-30

The anTBiotic consortium aims to fuel the long-term Tuberculosis (TB) clinical pipeline while also immediately offering new options to clinicians when confronted with multidrug-resistant (MDR)-TB.

TB is the leading cause of death from infectious diseases. The number of TB patients has never been higher and the growing proportion of drug-resistant TB, as well as the COVID-19 pandemic effects, is threatening control strategies.
Given the increasing incidence of drug-resistant TB cases worldwide, effective drugs are urgently needed for incorporation into new regimens that can improve outcomes and potentially shorten treatment.

More specifically, the project objectives are to:

1. Establish the proof of concept of anti-TB efficacy in humans of a pioneering, first-in class, low-dose oxaborole clinical drug candidate in an Early Bactericidal Activity (EBA) Phase IIa study. GSK´656 is an exciting new molecule, with a novel mechanism of action that has no pre-existent resistance in the field and the potential to be developed into an oral drug as part of future drug combination regimens.

2. Identify a combination of β-lactam antibiotics suitable for the treatment of MDR-TB orally or as a once daily intravenous or intramuscular application. This second EBA study aims to
- Repurpose an optimized combination of meropenem or ertapenem and amoxicillin-clavulanate for drug-resistant TB chemotherapy. The repurposing strategy of β-lactam combinations is based on a positive proof of concept generated within FP7 and EDCTP-funded projects for the combination of meropenem with amoxicillin-clavulanate.
- Re-establish the efficacy of rifampicin for the treatment of drug-resistant -TB. Despite its well-established status as the cornerstone of TB chemotherapy, resistance to rifampicin is becoming progressively more common. The β-lactam class has been shown to act with synergy when combined with rifampicin in vitro and we hypothesize that this effect will translate into the clinic.

3. Explore personalized treatment duration by comparing therapy outcomes of MDR-TB patients (receiving β-lactam-containing treatment) with biomarker defined therapy durations vs. standard of care. This approach has the potential to significantly shorten drug-exposure whilst also reducing adverse events and costs. The identification of patients being at risk for therapy failure may improve patient outcomes.

4. Identify optimal pathways through early phase TB drug development using biomarkers and in-silico dose modelling approaches:
- Explore the predictive potential of Positron Emission Tomography (PET) integrated with computed tomography (CT) as a non-invasive approach to evaluate drug action to complement the more traditional CFU (colony forming units) and TTP (time to culture positivity) EBA sputum markers. Should a correlation between early PET/CT signals and the sterilizing potential of individual drugs or drug regimens be confirmed, this would impact future clinical trial design, shortening clinical development timelines and lowering the associated uncertainties.
- Validate new EBA biomarkers as surrogates for treatment outcome. The identification of biomarkers that reflect the early therapy-induced immunological and bacteriological changes could lead to improved treatment monitoring, better prediction of treatment response and a better classification of patients demanding longer treatments.
- Develop and validate in silico predictions that could be used to shorten the drug development cycle. Mathematical models can inform optimal dosing strategies from data collected in preclinical development and address bottlenecks between early clinical development and phase III, where TB relapse is assessed. A new in silico approach connecting processes within single bacteria with the dynamics of entire bacterial populations within patients, enables the extrapolation of basic molecular mechanisms of drug action into response signals to treatment.
By the end of the third reporting period, enrollment has been completed in all seven arms of the 2-weeks EBA study with β-lactam antibiotics, aiming to identify a combination suitable for the treatment of MDR TB that could be administered once day either orally, intravenously or intramuscularly (WP2). The study data is being analyzed and two related reports are expected shortly.

The EBA study that aims to establish proof of concept of anti-TB efficacy in humans of a low-dose oxaborole drug (WP1) completed recruitment of the third cohort in June 2021 and will proceed to the fourth one. The study results are expected around the project end date.

PET/CT scan images from participants in these two trials, as well as blood and urine samples, have been collected and are being 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 was in accord with the terms of the informed consents under an approved protocol.

Following the same objective, and based on former research, a non-inferiority trial has started enrollment that will compare therapy outcomes of patients with biomarker-guided therapy durations (transcriptomic signature-based model) vs. standard of care, aiming to validate a set of biomarkers for individualized treatment shortening (WP3). The study set up and pace has been (and is still being) severely affected by the COVID-19 pandemic.

Finally, the modeling work (WP5) aims to find optimal dosing and identify promising combination regimens to be further developed. In this period, this WP has completed the validation, of a mathematical model to predict optimal dosing, that incorporate chemical reaction kinetics of the antibiotic with its target with bacterial population biology. It has also developed a mathematical model for two drug interactions and tested it using in vitro experimental data, and is now ready to be applied on the new datasets. Besides this, collaboration agreements with other projects in the field performing similar studies are expected to increase the impact of the planned scientific publications.
EXPECTED RESULTS

- A novel chemical entity that could be ready for progression to Phase IIb clinical trials, towards becoming a new TB drug within a suitable combination.
- Optimised drug regimen options for the treatment of resistant TB with agents that are presently out of patent protection and available in the market.
- A defined set of biomarkers to guide individualized treatment duration able to improve patient outcomes by enabling personalized treatment-shortening.


EXPECTED IMPACTS

This project will contribute to address major challenges and needs identified in the TB field, namely:
- Address the large mortality and morbidity associated with drug resistant TB by providing novel and repurposed drugs for new combination therapies
- Contribute to the TB treatment shortening agenda, one of the main goals pursued by major TB stakeholders
- Shorten TB drug development cycles by identifying biomarkers with the potential to predict phase 3 endpoints at earlier phases.
- Contribute to the Sustainable Development Goals of the United Nations on TB.
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