Project: Novel Clinical Candidates to Kill TB

Acronym	CLICK-TB (Reference Number: RIA2017T-2030)
Duration	01/10/2019 - 30/09/2024
Project Topic	Tuberculosis is the world´s most deadly infectious disease, and with drug-resistance becoming increasingly prevalent, new drug combinations with novel modes of action that avoid existing resistance are desperately needed. This proposal aims to identify a universal regimen based on at least one novel clinical candidate from three new chemical entities and two other entities with limited regulatory approval: • Sanfetrinem cilexetil; a safe, oral carbapenem with TB ß-lactamase stability previously progressed by GSK through successful Phase II trials as a broad-spectrum antibiotic, offering the opportunity to move directly into Phase IIa EBA studies as a repurposing asset for TB. • GSK3036656; a first-in-class selective inhibitor of mycobacterial LeuRS that has recently completed Phase I studies with proven efficacy in both murine and marmoset models of TB infection. The H2020-sponsored EBA study is scheduled to start in 2018. • DprE1 inhibitors; two novel non-covalent inhibitors preclinical candidates identified by TB Alliance and Otsuka are currently being progressed to the clinic. Either could constitute a good partner drug for the proposed combination studies. Phase IIa EBA results will be obtained for sanfetrinem within this grant. We will then perform two-week EBA studies with up to 10 two-drug combinations from the three innovative drug classes and two new drugs that have received approval from EMEA and/or FDA: one nitroimidazole (either delamanid (Deltyba) or pretomanid) and bedaquiline (Sirturo). All proposed arms would incorporate novel TB radiological and immunological biomarkers (currently known as NextGen EBA as developed by PIs within this consortium) to complement traditional sputum microbiological readouts. A statistical model will be developed to compare the microbiological readouts of the 10 duos and extract the contribution of each single drug in its respective combinations. The model will be refined by quantitative changes on PET/CT markers and differential profiles on other biomarkers. The model will then predict the most powerful 3- or 4-drug combinations from which those with potential safety concerns will be removed. The remaining best 3- or 4-drug regimens will progress into 4-week studies with the same EBA readouts plus sputum culture conversion (traditional Phase IIb endpoint). We hypothesize that by performing sequential Ph-IIa EBA trials on single agents, then with all possible duos, and finally by extended EBA studies on the most promising combinations we will deliver at least one new 3- or 4-drug combination regimen ready to enter into definitive Ph-IIb/III studies that could be the focus of future EDCTP strategic grants.
Network	EDCTP2
Call	Treatment innovations for poverty-related diseases

Project partner

Number	Name	Role	Country
1	GlaxoSmithKline Investigación y Desarrollo	Coordinator	Spain
2	Forschungszentrum Borstel Leibniz-Zentrum für Medizin ud Biowissenschaften	Partner	Germany
4	TASK Foundation NPC	Partner	South Africa
6	University of Cape Town	Partner	South Africa