BioVersys is developing Alpibectir (BVL-GSK098) in combination with ethionamide (Eto)/prothionamide (Pto) as an oral treatment of pulmonary tuberculosis (TB). BVL-GSK098 entered Phase 1 development with first-subject-first-visit on November 27, 2020. BVL-GSK098 originates from BioVersys’ Transcriptional Regulator Inhibitory Compound (TRIC) platform in collaboration with GSK, the Pasteur Institute Lille and University of Lille. BVL-GSK098 has completed GLP toxicology studies and is being prepared to enter First in Human (FiH) clinical trials in 2H 2020. The development of BVL-GSK098 has also been supported since May 2019 by the Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU) through a grant of 6.92 million EUR (TRIC-TB project).
Eto and Pto are valuable drugs in the treatment of TB. However, due to their suboptimal bioactivation within M. tuberculosis, high doses are required to achieve clinical efficacy and are typically associated with increasing adverse events, most commonly gastrointestinal intolerance, and hepatotoxicity. The bioactivation and subsequent dose limitations of Eto/Pto prevent delivery of their maximum bactericidal effect against M. tuberculosis. Despite this, Eto/Pto are an essential part of a second-line anti-TB regimen for the treatment of multi-drug resistant (MDR)-TB.
BVL-GSK098 acts via a new mechanism on bacterial transcriptional regulators, stimulating novel bioactivation pathways for Eto resulting in an increase of Eto efficacy, while simultaneously overcoming resistance to Eto. BVL-GSK098 renders Eto rapidly bactericidal and reduces the emergence of Eto-resistance development in vitro and in vivo.
Based on animal efficacy data, it is expected that BVL-GSK098 could lower the efficacious human oral dose of Eto by at least 3-fold, with the potential to significantly minimize dose-dependent side effects and improve patient compliance allowing to finally tap into the full potential of this 50 year old drug.
The combination of BVL-GSK098 and low dose Eto/Pto would allow for a safer and better tolerated dose of Eto/Pto, of this fast-acting anti-tuberculosis drug, without differentiating potency on drug resistant or sensitive strains. This could result in Eto/Pto becoming a valuable treatment for MDR, extensively drug-resistant (XDR) and isoniazid mono-resistant TB treatment. Furthermore, it opens the opportunity for use of Eto/Pto to be considered as a first line therapy against M. tuberculosis replacing Isoniazid.
Bacterial transcriptional regulators are new targets in drug R&D for bacterial infections that have not been exploited commercially to date. BVL-GSK098 will be the first example to be assessed in clinical trials.
Publications (related to the TRIC technology)
- A compound called SMARt-420 renders ethionamide-resistant strains of Mycobacterium tuberculosis fully susceptible. New England J. of Medicine (2017): http://www.nejm.org/doi/full/10.1056/NEJMcibr1703502
- Blondiaux et al. Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420. Science (2017), Vol. 355, Issue 6330, pp. 1206-1211. https://pubmed.ncbi.nlm.nih.gov/28302858
- Willand et al. Synthetic EthR inhibitors boost antituberculous activity of ethionamide. Nature Medicine (2009), Vol. 15(5) pp. 537-44. https://pubmed.ncbi.nlm.nih.gov/19412174/
- Weber et al. A synthetic mammalian gene circuit reveals antituberculosis compounds. PNAS (2008), Vol. 105(29), pp 9994-9998 https://pubmed.ncbi.nlm.nih.gov/18621677/