advances, the overall process of TB drug development is relatively slow in view of the therapeutic needs and speed of the drug resistance emergency. Thus, no new drugs have reached phase 3 trials or been approved for market regulation since the approval of pretomanid in 2019. Acceleration of clinical assessment of novel TB drugs is expected in the coming years as a result of new clinical trial platforms such as UNITE4TB and PAN-TB [87, 88]. Ongoing clinical trials The global pipeline of clinical research on TB treatment is evolving [89, 90]. The majority of trials aim to show non-inferiority of an experimental regimen with a shorter treatment duration compared to a control, which is usually standardised for DS-TB and individualised for RR-TB. For DS-TB, ongoing trials (table 7) focus on different approaches. A few trials implement high-dose rifampicin, with or without a fluoroquinolone (OptiRiMoxTB, and RIFASHORT and Hi-DoRi-3, respectively), building on growing evidence on rifampicin dose [91–95] optimisation. A high-dose rifampicin-based regimen, if non-inferior to the standard of care, could be more readily accessible than the current WHO-recommended 4-month rifapentine-based regimen [75], given rifapentine access and pricing issues [60, 96, 97]. Other TABLE 6 Novel anti-TB medicines in phase 1 and 2 clinical development Class Mechanism of action Trial phase Phase 1A Phase 1B Phase 2A Phase 2B/C Diarylquinolines Inhibits ATP synthase and bacterial respiration TBAJ-587 TBAJ-876 Sudapyridine (WX-081) Riminophenazine Inhibits ion transport and bacterial respiration Pyrifazimine (TBI-166) Oxozalidone Inhibits protein synthesis (23S ribosome) Delpazolid (LCB01-0371) Sutezolid (PNU-100480) Tedizolid TBI-223 Carbapenem Inhibits cell wall synthesis Sanfetrinem Amido-piperidine Inhibits cell wall synthesis via boosting ethionamide BVL-GSK098 DprE1 inhibitors Inhibits cell wall synthesis BTZ-043 Macozinone (PBTZ169) OPC-167832 TBA-7371 QcrB inhibitor Inhibits ATP synthesis Telacebec (Q203) MmpL3 inhibitor Inhibits cell wall synthesis SQ109 GyrB inhibitor Inhibits bacterial DNA synthesis SPR720 Cholesterol catabolism inhibitor GSK-286 LeuRS inhibitor Inhibits protein synthesis GSK-656 ATP: adenosine 5’-triphosphate. 130 https://doi.org/10.1183/2312508X.10024622 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY