Tuberculosis (TB) is the world’s leading infectious disease. It killed 1.7 million people in 2016 and 10.4 million people developed active TB in the same year. In 2016, 480’000 of TB cases were multidrug-resistant (MDR-TB) and 9% percent of those cases are extensively drug-resistant (XDR), with mortality rates as high as 70%. Ethionamide (ETH) is a vital part of the WHO essential medicines list of 2nd-line TB therapy for MDR-TB, however, ETH suffers from significant levels of resistance and side effects at current dosing levels. BVL-GSK038 and BVL-GSK098 are proprietary to BioVersys/GlaxoSmithKline and have been developed through an extensive Lead Optimization program with collaborators from Lille University. Low doses of both compounds fully restore and “boost” the activity of ETH to rapidly kill Mycobacterium tuberculosis (Mtb) including MDR strains at significantly lower doses of ETH than previously reported, thus making MDR-TB sensitive to ETH once again. Through a comprehensive IND enabling package including in vitro and in vivo assessment of ETH with BVL-GSK038 and BVL-GSK098, including PK/PD, resistance development, safety, mechanism of action and synergistic studies with different drug compound combinations and then first in human clinical studies the consortium aims to: i) Define the future placement of a boosted ETH (ETH + BVL-GSK038 or BVL-GSK098) in a universal TB treatment regimen, including overcoming MDR-TB with improved safety, time to cure and relapse rates; Ultimately, we expect to identify a new and clinically proven TB regimen that leads to better patient outcomes independently of the starting resistance status of the TB infection. The TB and wider scientific communities will benefit from an improved understanding of ETH and the exploration of a novel class of therapeutic compounds acting on transcriptional modulators (BVL-GSK038 and BVL-GSK098).

The European Regimen Accelerator for Tuberculosis (ERA4TB) has the explicit goal of developing a new combination therapy to treat all forms of TB starting from ~20 leads and drug candidates provided by EFPIA. Since details of these are as yet unavailable, we will implement an agile drug development algorithm that entails profiling and portfolio construction. Profiling involves characterisation and ranking molecules in preclinical studies comprising in vitro drug combination assays, hollow fiber and single cell analysis, innovative murine and non-human primate models, PK/PD studies, combined with biomarker discovery and non-invasive NIR or PET/CT imaging to monitor disease progression and response to treatment. Modelling, simulation and artificial intelligence tools will help progress compounds from early preclinical to clinical development and to predict drug exposure, human doses and the best combinations. After extensive preclinical profiling, selected compounds will enter portfolio development for first time in human tests and phase I clinical trials in order to ensure that they are safe, well-tolerated and bioavailable with negligible drug-drug interactions. If needed, formulation studies will be conducted to improve pharmacological properties. ERA4TB has assembled the best expertise and resources available in Europe, to build a highly effective and sustainable drug development consortium with a flexible and dynamic management system to execute the profiling and portfolio strategy, aided by clearly defined go/no-go decision points. The expected outcome of ERA4TB is a series of highly active, bactericidal, orally available drugs to constitute two or more new combination regimens with treatment-shortening potential ready for Phase II clinical evaluation. These regimens will be compatible with drugs used to treat common comorbidities, such as HIV-AIDS and diabetes, and should impact UN Sustainable Development Goal 3, namely, ending TB by 2030.

In 2022, the World Health Organization (WHO) recommended bedaquiline (BDQ)-based, all-oral regimens including pretomanid (Pa), linezolid (L), and moxifloxacin (M) (BPaLM), lasting 6-9 months However, BDQ-resistance is rising dramatically and threatening these advancements. Mozambique has reported BDQ resistance in 28% of MDR-TB isolates in 2024, up from 3% in 2016 and at 10% in South Africa (Ndjeka N, personal communication). Spread of BDQ-R TB must be slowed by antibiotic stewardship through more rapid, accurate, and near-patient diagnostics, and optimized management; until new treatment options with drugs that have no pre-existing resistance or are able to overcome small shifts in MIC will be available. The proposed EX-DR TB project includes diagnostic capacity strengthening, adapting treatment recommendations, and a trial of two new regimens composed of new drugs. The EDCTP EX-DR TB project will: 1. Develop treatment recommendations by a Delphi process with stakeholders - to make use of targeted next generation sequencing (tNGS) that is being rolled out by most national TB programmes - this will yield short-term benefit for patients and NTPs; and will slow the spread of BDQ-resistant bacteria; 2. Rigorously evaluate two treatment regimens composed of new drugs, in a phase 3 clinical trial conducted to the highest regulatory standard – this will be the main focus of EX-DR TB. The trial objective will be to move a regimen towards regulatory approval by FDA and/or EMA, and WHO if supported by results. Thus, EX-DR will create the tools for containing the nascent epidemic of BDQ-R TB and make them available to healthcare providers and TB Programmes. EX-DR TB will be embedded in a larger coalition of funders and partners focused on implementing and evaluating diagnostics and performing the trial beyond of the EDCTP funded area.

Tuberculosis (TB) today rivals HIV/AIDS as 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 is threatening control strategies both in the developing and developed world, Eastern Europe being a particularly worrying point in case. The anTBiotic consortium aims to fuel the long-term TB clinical pipeline while immediately offering new options to clinicians when confronted with multidrug-resistant (MDR)-TB. More specifically, the proposed studies aim to: a) Establish the proof of concept of anti-TB efficacy in humans of a pioneering, first-in-class, low-dose GSK oxaborole clinical drug candidate; b) Identify a combination of β-lactam antibiotics suitable for the treatment of MDR TB orally or as a once daily intravenous or intramuscular application and c) Incorporate the best β-lactam combination into an explorative salvage regimen for untreatable patients with extensively drug-resistant TB The anti-TB activity in humans will be established in a two-week EBA clinical studies that combine established (CFU, TTP) and new clinical markers (biomarkers, PET/CT). These datasets will help ascertain anti-TB efficacy in humans and generate confidence on their validity in longer-term drug combination trials. A variety of modelling approaches to predict optimal dosing will be used. Finally, we intend to use at least one of these novel anti-TB entities as part of a pioneering, non-controlled clinical trial in highly drug resistant subjects in Europe and South Africa. This final clinical intervention will hopefully be of immediate benefit to drug-resistant patients in the EU and elsewhere in addition to generating a strong precedent for further adoption worldwide.

According to the WHO there are 8 million persons chronically infected by Chagas disease (CD) resulting in 12.000 reported deaths annually. CD is one of the most significant health problems of Latin America. However, nowadays it has been reported worldwide. Benznidazole (BZ) has been recently approved in US (30/08/2017) as the first option treatment for CD but can only administered for 14 days or less, while it is known that at least 2-3 months of treatment are required for full efficacy. This approval for short-term CD therapy is due to the severe side effects associated with extended use, which severely impacts the applicability of BZ as a universal CD treatment. Importantly, Trypanosoma cruzi (Tc) parasite reservoirs have been localized into the Lymphatic System (LS). Poor compound distribution into the LS could be the reason why extended BZ treatment is required and why reactivation of the parasites in the chronic stage is commonly found. Chagas infected people treated with BZ develop rashes, fever, nausea, headache, allergic dermatitis, digestive intolerance (anorexia), peripheral neuropathy and insomnia. These severe side effects limit its use and foster non-compliance. BZ formulations that reduce compound exposure in system circulation while facilitating distribution into the LS could reduce the efficacious dose (at present 5-7mg/kg/day), reduce side effects, and possibly contribute treatment shortening. This project will develop BZ formulations based on solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) to achieve these three goals.