TABLE 1.
New drugs in clinical development for the treatment of active TB, including ongoing clinical trials and the preclinical evidence base that supports each triala
| Drug (abbreviation) | Class | Mechanism(s) of action | Target | Trial objective (clinicaltrials.gov identifier) | Preclinical evidence base (references) |
|---|---|---|---|---|---|
| Existing TB drugs in dose optimization studies | |||||
| Isoniazid (INH) | Nicotinamide analog | Inhibition of mycolic acid synthesis | 2-trans-Enoyl-acyl carrier protein reductase (InhA) | Dose-ranging EBA vs. INH-resistant mutants (NCT01936831) | 19, 150, 151 |
| EBA of high-dose INH vs. INH-resistant mutants (NCT02236078) | |||||
| Rifampin (RIF) | Rifamycin | Inhibition of RNA synthesis | DNA-dependent RNA polymerase (RpoB) | Dose-ranging activity of RIF in the intensive phase (NCT00760149, NCT01408914, NCT02153528) | 110, 152, 153 |
| Dose-ranging activity of RIF in a 4-month regimen (NCT02581527) | |||||
| Rifapentine (RPT) | Rifamycin | Inhibition of RNA synthesis | DNA-dependent RNA polymerase (RpoB) | Efficacy of 4-month regimens based on high-dose RPT (NCT02410772) | 153–155 |
| Repurposing of anti-infectives for TB treatment | |||||
| Moxifloxacin (MXF) | Fluoroquinolone | Inhibition of DNA synthesis | DNA gyrase (GyrA) | Efficacy of 4-month regimens based on high-dose RPT with or without MXF (NCT02410772) | 155, 156 |
| Efficacy of MXF in place of EMB in retreatment of TB (NCT02114684) | 73, 74, 157, 158 | ||||
| Efficacy of regimens containing BDQ, PA-824, and PZA ± MXF (NCT02193776) | 77, 78 | ||||
| Efficacy of 4- and 6-month regimens containing PA-824, MXF, and PZA (NCT02342886) | 75, 77, 109 | ||||
| EBA of MXF vs. ofloxacin-resistant mutants (NCT02236078) | 159–161 | ||||
| Efficacy of MDR-TB regimens containing BDQ, PA-824, LZD ± MXF, or CFZ (NCT02589782) | E. Nuermberger, unpublished; 70*, 76 | ||||
| Levofloxacin (LVFX) | Fluoroquinolone | Inhibition of DNA synthesis | DNA gyrase (GyrA) | Dose-ranging activity of LVFX in MDR-TB (NCT01918397) | 161–163 |
| Efficacy of MDR-TB regimen containing DLM, LZD, LVFX, and PZA (NCT02619994) | 76 | ||||
| Efficacy of a 4.5-month regimen containing 1st-line drugs + LVFX (NCT02901288) | 157 | ||||
| Clofazimine (CFZ) | Riminophenazine | Redox cycling, production of reactive oxygen species | N/A | Efficacy of a short-course CFZ-containing regimen for MDR-TB (NCT02409290) | 164 |
| Efficacy of MDR-TB regimens containing BDQ, PA-824, LZD ± MXF, or CFZ (NCT02589782) | Nuermberger, unpublished; 70, 76 | ||||
| Linezolid (LZD) | Oxazolidinone | Inhibition of protein synthesis | Ribosomal initiation complex | Dose-ranging EBA of LZD (NCT02279875) | 29, 33, 40, 165 |
| Efficacy of a short-course regimen of BDQ, PA-824, and LZD for MDR/XDR-TB (NCT02333799) | 76 | ||||
| Efficacy of MDR-TB regimen containing DLM, LZD, LVFX, and PZA (NCT02619994) | 76* | ||||
| Efficacy of MDR-TB regimens containing BDQ, PA-824, LZD ± MXF, or CFZ (NCT02589782) | Nuermberger, unpublished; 70*, 76 | ||||
| New chemical entities in clinical development for TB | |||||
| Bedaquiline (BDQ) | Diarylquinoline | Inhibition of ATP synthesis | F1F0 proton ATP synthase (AtpE) | Efficacy of a short-course regimen of BDQ, PA-824, and LZD for MDR/XDR-TB (NCT02333799) | 76 |
| Efficacy of regimens containing BDQ, PA-824, and PZA ± MXF (NCT02193776) | 77, 78 | ||||
| Efficacy of MDR-TB regimens containing BDQ, PA-824, LZD ± MXF, or CFZ (NCT02589782) | |||||
| Efficacy of a short-course CFZ-containing regimen for MDR-TB (NCT02409290) | Nuermberger, unpublished; 70*, 76 | ||||
| Delamanid (DLM) | Nitroimidazo-oxazole | Inhibition of mycolic acid synthesis, production of reactive nitrogen species | Unknown | Efficacy of MDR-TB regimen containing DLM, LZD, LVFX, and PZA (NCT02619994) | 76* |
| Pretomanid (PA-824) | Nitroimidazo-oxazine | Inhibition of mycolic acid synthesis, production of reactive nitrogen species | Unknown | Efficacy of a short-course regimen of BDQ, PA-824, and LZD for MDR/XDR-TB (NCT02333799) | 76 |
| Efficacy of regimens containing BDQ, PA-824, and PZA ± MXF (NCT02193776) | 77, 78 | ||||
| Efficacy of MDR-TB regimens containing BDQ, PA-824, LZD ± MXF, or CFZ (NCT02589782) | Nuermberger, unpublished; 70*, 76 | ||||
| SQ109 | Diethylamine | Dissipation of proton motive force, inhibition of menaquinone synthesis | Mycobacterial membrane protein-large 3 (MmpL3), MenA, MenG | Completed phase 1 | |
| No active trials** | |||||
| Sutezolid (SZD) | Oxazolidinone | Inhibition of protein synthesis | Ribosomal initiation complex | Completed phase 1 | |
| No active trials** | |||||
| PBTZ169 | Benzothiazinone | Inhibition of arabinogalactan synthesis | Decaprenylphosphoryl-b-d-ribose | Phase 1 | |
| 2′-epimerase (DprE1) | |||||
| OPC-167832 | 3,4-Carbostyril derivative | Inhibition of arabinogalactan synthesis | Decaprenylphosphoryl-b-d-ribose | Phase 1 | |
| 2′-epimerase (DprE1) | |||||
| Q203 | Imidazopyridine amide | Inhibition of electron transport chain | Cytochrome bc1 complex (QcrB) | Phase 1 | |
a
*, regimen(s) tested in pre-clinical study and clinical trial may differ by at least one drug in the same class. **, no active trials registered on clinicaltrials.gov (last confirmed on May 18, 2017). EBA, early bactericidal activity; PZA, pyrazinamide.