Development of Q203 (Telacebec) for the Treatment of Tuberculosis and Related Mycobacterial Infections

National Center For Advancing Translational Sciences

Investigators

Abstract

Extensive preclinical and clinical studies were performed previously by the collaborators to characterize the potential efficacy and safety of telacebec. Phase 1 safety studies and a Phase 2 clinical proof-of-concept study in TB patients demonstrated dose-related bactericidal activity of telacebec given as monotherapy. The Phase 2 study results recapitulated the preclinical data, demonstrating the mycobacterial cellular respiration pathway as an attractive therapeutic target for treatment with telacebec. However, the previously available manufacturing route for telacebec has a very poor overall yield of only 3%. The NCATS team is evaluating improvements to the current synthetic process, and is also working to develop an alternate route to produce telacebec in fewer steps, using commercially-available, lower-cost materials. The optimization of the current manufacturing route identified several key steps for improvement, resulting in successful removal of impurities and an increase in the yield. A scale-up production run is ongoing using the original process with these improved steps to determine the final yield. In parallel, the NCATS team is exploring the possibility of developing an entirely alternative route. To that end, three different synthesis paths have been proposed, with one promising path chosen for further optimization based on preliminary data. This candidate alternate route is being used to synthesize a pilot batch of telacebec at laboratory benchtop scale to confirm the general efficiency of the process. Once the pilot batch is completed, additional studies will be conducted at larger scale to determine the final yield and feasibility of deploying the new process.