This project brings a new molecule, alpibectir (formerly BVL-GSK098), to the current drug armamentarium. Alpibectir greatly augments the activity of, and overcomes resistance to, the well-established second line drug ethionamide (Eto) at a lower and better-tolerated dose. Eto has been recently rejected in regimen planning due to poor gastrointestinal tolerability at recommended doses while newer drugs become available. Eto has never been studied as monotherapy in an early bactericidal activity (EBA) study and thus far, there is insufficient evidence to indicate the lowest effective dosage levels.
The overall aim of the project is to find a combination of alpibectir (BVL-GSK098) and low-dose Eto (bEto) that is well tolerated thus promoting the acceptance of this efficacious drug, while ensuring the combination is highly active and free of bacterial resistance. This combination may then be proposed to either replace INH or be added as a boosted bactericidal drug to future regimens.
Project objectives:
- To determine the EBA of boosted Eto (bEto) by combining alpibectir 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
The consortium is pleased to report that recruitment for a Phase IIa randomized, controlled trial to determine the EBA, safety, tolerability, and pharmacokinetic profile of multiple doses of bEto in patients with pulmonary TB (NCT05473195) has been completed. The last participant visit took place in April 2024. This study was conducted at the renowned EBA unit at the TASK Clinical Research Centre in Cape Town, South Africa. EBA is a well-established measure of drug activity and will be assessed by changes in colony-forming unit (CFU) counts and time to culture positivity (TTP) over a 7-day treatment period. We look forward to the expected results in 2025.
We anticipate three main potential impacts of a highly active, well-tolerated combination:
- Second-Line TB Regimens: replacing Eto with bEto as alpibectir significantly improves Eto bioactivation and can overcome pre-existing Eto resistance.
- First-line TB Regimens: replacing INH with bEto negates the vast majority of INH resistance, overcoming the rising rates of often undetected INH resistance.
- Long-term potential impact: use in novel TB regimens. Novel TB drugs (bedaquiline, pretomanid, delamanid) don’t achieve the high EBA that INH does. With growing INH and fluoroquinolone resistance, bEto may serve as a highly bactericidal component to protect novel companion drugs from acquired resistance.
For more information, please see the twitter account https://twitter.com/bEtoTB1?s=20 and the latest results presented at the Conference on Retroviruses and Opportunistic Infections https://www.croiconference.org/abstract/early-bactericidal-activity-of-the-alpibectir-ethionamide-alpe-combination-against-tuberculosis/. Additional information on the phase 1 work can be found at https://amr-accelerator.eu/project/tric-tb/.
