This project brings a new anti-TB molecule, BVL-GSK098, to the current drug armamentarium. BVL-GSK098 greatly augments the activity of, and overcomes resistance to, the well-established second line drug ethionamide (Eto) at a lower and well-tolerated dose.
The overall aim of the project is to find a combination of BVL-GSK098 and low-lose Eto that is well tolerated, highly active and free of bacterial resistance so that the combination can be proposed to replace INH or to add a novel bactericidal drug to future TB regimens.
Objectives
- To determine the EBA of boosted Eto (bEto) by combining BVL-GSK098 and various doses of Eto
- To compare the EBA of bEto to standard and lower dose Eto and standard dose INH
- To evaluate the safety and tolerability of bEto
- To determine the pharmacokinetic (PK) profile of bEto at steady-state
Study design
This will be a phase IIa multiple ascending dose, randomized, controlled trial to determine the EBA, safety tolerability, and pharmacokinetic profile of multiple doses of bEto, standard and low dose Eto and standard dose INH in adults with drug-susceptible pulmonary tuberculosis. The EBA will be determined by the change in colony forming unit (CFU) counts and time to culture positivity (TTP) over 7 days of treatment. Participants will be hospitalized for tolerability and safety assessments. bEto pharmacokinetics will be determined at steady state.
Purpose
To compare the early bactericidal activity (EBA) of boosted ethionamide (bEto), using lower doses of ethionamide (Eto), to standard and lower doses of Eto alone. We will also evaluate the comparative anti-TB activity of bEto to that of standard dose isoniazid (INH) and thus explore the potential for bEto as replacement of INH in the current first-line regimen and also as a novel bactericidal agent to be included in new future TB regimens.
Relevance of the project to the call topic
While progress has been made in the development of new anti-TB drugs recently, TB continues to be the leading cause of death from a single infectious agent world-wide, responsible for approximately 1.6 million deaths in 2021 alone (WHO global tuberculosis report 2022). In the same year, an estimated 10 million people developed TB globally, with almost 500 000 of those having drug-resistant TB. Multi-drug or rifampicin resistant TB (MDR/RR-TB: resistance to at least INH and rifampicin or rifampicin only), is a public health crisis and a growing threat to TB elimination, affecting 3.5% of new and 18% of previously treated cases of TB globally. INH mono-resistance has been estimated to be as high as 11.6% globally1. M.tb also remains on the World Health Organization (WHO) list of antibiotic-resistant priority pathogens and is a key focus area of the EDCTP2 programme. Patients with drug-resistant TB have a significantly lower rate of treatment success, roughly 50% globally1, with a large proportion of cases ending in treatment failure, death or loss to follow-up. The development of new effective drugs to fight drug-resistant TB remains a priority if we are to achieve the goal of global TB elimination in the foreseeable future.
This project aims to progress a new antituberculosis (anti-TB) compound, BVL-GSK098, into phase II clinical development. BVL-GSK098 is a small-molecule transcriptional modulator able to boost the activity of, and overcome resistance to Eto, a WHO recommended second-line agent for the treatment of drug-resistant pulmonary TB and TB meningitis.
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