An Early Bactericidal Activity, Safety and Tolerability of GSK3036656 in Subjects With Drug-sensitive Pulmonary Tuberculosis

Summary

Tuberculosis remains a concerning health problem, with Mycobacterium Tuberculosis (MTB) now causing more deaths than acquired immune deficiency syndrome (AIDS). GSK3036656 is a compound with a novel mechanism of action under development for the treatment of tuberculosis. It suppresses protein synthesis in MTB by selectively inhibiting the enzyme Leucyl t-ribose nucleic acid (RNA) synthetase. Thus, this study will investigate the early bactericidal activity, safety and tolerability of GSK3036656 in up to four sequential cohorts of subjects with rifampicin-susceptible tuberculosis. The primary objective of this dose-escalation study is to establish the anti-tuberculosis effect of GSK3036656 on serial colony forming units (CFU) counts of MTB in sputum over 14 days of therapy. Subjects in each cohort will be randomized in 3:1 ratio to one of two treatments: either GSK3036656 or standard-of-care (RIFAFOUR® e-275) regimen. The approximate duration of the study for an individual subject will be 5 weeks, including 1 week of screening, 2 weeks of treatment period and another 2 weeks of final follow-up visit. RIFAFOUR e-275 is a registered trademark of Sanofi-Aventis.

Timeline

Start

2019-03-22

Primary completion

2021-12-03

Completion

2021-12-14

Publications

• Diacon AH, Barry CE 3rd, Carlton A, Chen RY, Davies M, de Jager V, Fletcher K, Koh GCKW, Kontsevaya I, Heyckendorf J, Lange C, Reimann M, Penman SL, Scott R, Maher-Edwards G, Tiberi S, Vlasakakis G, Upton CM, Aguirre DB. A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial. Nat Med. 2024 Mar;30(3):896-904. doi: 10.1038/s41591-024-02829-7. Epub 2024 Feb 16.
• Volynets GP, Usenko MO, Gudzera OI, Starosyla SA, Balanda AO, Syniugin AR, Gorbatiuk OB, Prykhod'ko AO, Bdzhola VG, Yarmoluk SM, Tukalo MA. Identification of dual-targeted Mycobacterium tuberculosis aminoacyl-tRNA synthetase inhibitors using machine learning. Future Med Chem. 2022 Sep;14(17):1223-1237. doi: 10.4155/fmc-2022-0085. Epub 2022 Jul 25.

Drugs

Indications