Summary of the main new antituberculosis drugs with the most relevant studies and related findings
| Drug | Class | Study ID number | Clinical trial phase | Registration number | Main findings | [Ref.] |
| Bedaquiline | Diarylquinoline | TMC207-TIDP13-C208 | II | NCT00449644 | The addition of delamanid (TMC207) to OBR reduced the time to C conversion, as compared with OBR (HR 11.8, 95% CI 2.3–61.3; p=0.003) and increased the proportion of C converters (48% versus 9%). The mean log10 CFU count in SS declined more rapidly in the TMC207 group than in OBR group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without C conversion. Most AEs were mild to moderate. | [41] |
| Delamanid (OPC 67683) | Nitroimidazole | 242-07-204 | II | NCT00685360 | Among patients who received OBR plus 100 mg of delamanid twice daily, 45.4% had C conversion at 2 months, as compared with 29.6% of patients receiving OBR (p=0.008). As compared with OBR, the group receiving OBR plus delamanid 200 mg twice daily had a higher proportion of SS and C conversion (41.9%, p=0.04). Most AEs were mild to moderate and evenly distributed across groups. Although no clinical events due to QT prolongation on ECG were observed, QT prolongation was reported significantly more frequently in the delamanid groups. | [42] |
| 242-09-213 | III | NCT01424670 | Patients who participated in the above trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Favourable outcomes were observed in 143 (74.5%) out of 192 patients receiving delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among XDR-TB patients. | [43] | ||
| Pretomanid (PA-824) | Nitroimidazole | NC-001-(J-M-Pa-Z) | II | NCT01215851 | The 14-day EBA of PaMZ (n=13; mean±sd 0.233±0.128) was significantly higher than that of bedaquiline (n=14; 0.061±0.068), bedaquiline–pyrazinamide (n=15; 0.131±0.102), bedaquiline–Pa (n=14; 0.114±0.050) but not PaZ (n=14; 0.154±0.040) and comparable with that of standard treatment (n=10; 0.140±0.094). Treatments were well tolerated and appeared safe. One patient on PaMZ was withdrawn because of corrected QT interval changes exceeding pre-specified criteria. | [44] |
| NC-002-(M-Pa-Z) | II | NCT01498419 | The study evaluated a novel regimen for efficacy and safety in DS-TB and MDR-TB during the first 8 weeks of treatment. Smear positive DS, treatment-naïve PTB patients randomised were enrolled to receive 8 weeks of M, Pa (100 mg) and Z (MPa100Z, regimen 1) or M, Pa (200 mg) and Z (MPa200Z, regimen 2) or the current standard regimen for DS-PTB (HRZE) as positive control. A group of MDR-TB participants received M 400 mg, Pa 200 mg and Z 1500 mg (DRMPa200Z). The regimen 1 BA days 0–56 (n=54; 0.155, 95% BCI 0.133–0.178) in DS-TB patients was significantly greater than for standard regimen (n=54; 0.112, 95% BCI 0.093–0.131). Regimen 2 had similar BA to the standard regimen. The day 7–14 BA correlated well with days 7–56. AEs were equally distributed among group and control subjects. The most common AE was hyperuricaemia in 59 (28.5%) patients spread similarly across treatment groups. Other common AEs were nausea in 37 (17.9%) and vomiting in 25 (12.1%) patients. No patient had corrected QT interval exceeding 500 ms. No phenotypic resistance developed. The MPaZ combination, previously found to have promising activity over 14 days in DS-TB, was safe, well tolerated and demonstrated superior BA in DS-TB during 8 weeks treatment. Results were consistent between DS-TB and MDR-TB. | [45] | ||
| NC-003-(C-J-Pa-Z) | II | NCT01691534 | Experimental and clinical evidence suggests that the new drugs Bdq and Pa, combined with an existing drug, Z, and a repurposed drug, Cfz, may assist treatment shortening of both DS-TB and DR-TB. The study evaluated the 14-day EBA of Cfz and Z in monotherapy and in combinations with Pa and Bdq. Groups of 15 treatment-naïve, SS-positive PTB patients were randomised to receive combinations of Bdq with ZCfz, PaZ, PaZCfz and PaCfz, or Cfz or Z alone, or standard combination treatment for 14 days. The primary end-point was the mean daily fall in log10 CFU·mL−1 SS estimated by joint nonlinear mixed effects Bayesian regression modelling. Results: estimated activities were 0.167 (95% CI 0.075–0.257) for BdqPaZ, 0.151 (95% CI 0.071–0.232) for standard treatment, 0.124 (95% CI 0.035–0.214) for BdqZCfz, 0.115 (95% CI 0.039–0.189) for BdqPaZCfz and 0.076 (95% CI 0.005–0.145) for BdqPaCfz. Z alone had modest activity (0.036, 95% CI −0.026–0.099). Cfz had no activity alone (−0.017, 95% CI −0.085–0.053) or in combinations. Treatments were well tolerated and safe. BdqPaZ, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new TB treatment regimen. Cfz had no measurable activity in the first 14 days of treatment. | [46] | ||
| Sutezolid (PNU-100480) | Oxazolidinone | B1171003 | II | NCT01225640 | All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% CI for bactericidal activity in sputum over the 14-day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious AEs, premature discontinuations or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven (14%) sutezolid-treated patients had transient, asymptomatic ALT elevations to 173±34 U·L−1 on day 14 that subsequently normalised promptly; none met Hy's criteria for serious liver injury. The mycobactericidal activity of sutezolid 600 mg twice daily or 1200 mg once daily was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. | [47] |
| SQ109 | Ethylenediamine | LMU-IMPH-SQ109-01 | II | NCT01218217 | Study to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days. SQ109 was safe and generally well tolerated. Mild-to-moderate dose-dependent gastrointestinal complaints were the most frequent AE. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC0–24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with R resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of R. The daily fall in log10 CFU·mL−1 of sputum (95% CI) was 0.093 (0.126-0.059) with R, 0.133 (0.166–0.100) with R plus 150 mg of SQ109 and 0.089 (0.121–0.057) with R plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity. SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with R, 300 mg of SQ109 yielded a higher exposure than the 150-mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment. | [48] |
| Benzothiazinones (BTZ043) | 2-[(2S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl]-8-nitro-6-trifluoromethyl-4H-1,3-benzothiazin-4-one/Rv3790 | Pre-clinical development phases | Studied the interaction profiles of BTZ043 with several anti-TB drugs or drug candidates against M. tuberculosis strain H37Rv, namely, R, H, E, delamanid, Pa, M, meropenem with or without clavulanate and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. BTZ043 acts synergistically with delamanid, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng·mL−1) used in combination with BTZ043 (quarter MIC 0.375 ng·mL−1) had a stronger bactericidal effect on M. tuberculosis than delamanid alone at a concentration of 80 ng·mL−1. This synergy was not observed when the combination was tested on a BTZ-resistant M. tuberculosis mutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. Hypothesis that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of delamanid to its target. Synergy between two new antimycobacterial compounds (delamanid and BTZ043) with novel targets offers an attractive foundation for a new anti-TB regimen | [49] |
OBR: optimised background regimen; C: culture; HR: hazard ratio; CFU: colony-forming unit; SS: sputum smear; AE: adverse event; XDR: extensively drug-resistant; TB: tuberculosis; EBA: early bactericidal activity; Pa: pretomanid; M: moxifloxacin; Z: pyrazinamide; DS: drug-susceptible; MDR: multidrug-resistant; PTB: pulmonary tuberculosis; H: isoniazid; R: rifampicin; E: ethambutol; BA: bactericidal activity; BCI: Bayesian credibility interval; Bdq: bedaquiline; Cfz: clofazimine; DR-TB: drug-resistant; WBA: whole-blood bactericidal activity; ALT: alanine transaminase; MIC: minimum inhibitory concentrations; AUC0–24: area under the curve in the first 24 h.