TB resistance remains a great challenge for current public health, and effective treatment strategies are urgently needed. Here, we report the early bactericidal effects of our novel agent JDB0131. In this phase 2a trial, 3 different doses of JDB0131 were tested for their activities and safety profiles. Compared with those of delamanid, all levels of JDB0131 presented good EBA and tolerability. Some patients achieved drastic radiographic responses. The current results warrant further phase III studies to confirm the findings in clinical practice.

Nitroimidazoles are promising antimycobacterial agents known to inhibit both aerobic and anaerobic mycobacterial activity. Under aerobic conditions, nitroimidazoles—including pretomanid—act by inhibiting mycolic acid biosynthesis, a critical process for maintaining mycobacterial cell envelope integrity, ultimately compromising structural stability and resulting in bacterial lysis.²¹ Under hypoxic or anaerobic conditions, these prodrugs undergo enzymatic reduction via mycobacterial nitroreductases (such as Ddn), generating reactive nitrogen intermediates, notably nitric oxide.²² This leads to respiratory inhibition and lethal oxidative stress in nonreplicating bacilli through disruption of central carbon metabolic pathways, including the pentose phosphate pathway.^23,24 Delamanid and pretomanid are 2 nitroimidazoles approved by regulatory agencies for MDR-TB treatment.^4,5 Pretomanid and delamanid both possess antituberculosis activity. However, both agents result in unsatisfactory absorption and QTc prolongation.^11,12,13,14 In addition, the potential for additive QTc prolongation requires careful consideration, particularly when nitroimidazoles are used in combination with other QTc-prolonging agents, such as QT, fluoroquinolones, or clofazimine.^{15,25,26,27,28,29} JDB0131 is a newly developed nitroimidazole derivative with both strong activity and improved safety. JDB0131 represents a structurally optimized third-generation nitroimidazole agent that integrates the advantages of its predecessors while addressing their limitations. Notably, pretomanid or delamanid are recommended for several anti-RR/MDR-TB regimens,³⁰ but in some developing countries, such as China, neither is available. Patients suffering from MDR-TB must receive combination chemotherapy, which is both lengthy and toxic, with a curation rate of only 66%.^31,32 The emergence of JDB0131 provides a new therapeutic option for these patients, and short-course treatment regimens have become more accessible in these countries.

In our previous search for a safer nitroimidazole, we discovered JDB0131.¹⁶ It exhibited excellent antimycobacterial activity against M. tuberculosis H37Rv in vitro and in vivo, improved PK and absorption, and reduced the QT prolongation potential of delamanid. In this multicenter phase 2a trial in China, we reported the promising anti-TB activity of JDB0131, together with favorable safety profiles. In particular, it caused fewer QT-prolongation events in patients. The results were in good concordance with our preclinical data. These data support the promising future of JDB0131 as a novel anti-TB agent.

In this dose escalation trial, 3 different doses of JDB0131 were tested. Each dose was effective. Compared with each other, JDB0131 at a dose of 200 mg bid was the most effective and had acceptable toxicity. In addition, the bid dosing regimen of JDB0131 may offer an advantage in maintaining drug concentrations above the minimum inhibitory concentration (MIC) for a longer duration, thereby supporting sustained antimicrobial activity. This regimen also appears feasible for long-term clinical use. We recommend a dose of 200 mg bid for future phase III trials. However, it remains uncertain whether the prolonged half-life of JDB0131 may allow for extended dosing intervals—such as achieving a frequency of three times per week, comparable to the maintenance phase of bedaquiline regimens—which warrants further investigation.³³

Multiple aspects can be used to evaluate antituberculosis efficacy, among which radiographic responses—particularly changes in pulmonary cavities—are considered the most indicative. The formation of the tuberculosis cavity is related to bacterial burden, virulence, and body immunity. Once formed, the tuberculosis cavity always indicates severe illness because it destroys vessel supplies to the lung, leading to a decreased drug concentration that is insufficient to inhibit bacterial growth. To overcome these changes, a combination of at least 4 effective anti-TB drugs lasting for 2 months is recommended. Five to twenty-two percent of patients have significantly smaller cavities or adsorbed lesions. A longer duration was required for complete disappearance of the cavity. However, some patients have persistent cavities. In this study, 6 patients either had lesions that had adsorbed significantly or whose cavities had decreased after JDB0131 treatment. However, only 1 patient presented with slightly decreased lesions in the delamanid cohort. These data provide supportive evidence that JDB0131 serves as a novel agent with promising rapid bactericidal activity.

Dose-dependent QT interval prolongation is a serious AE for delamanid. This was in part due to the delamanid metabolite DM6705.^13,14,34 It is a strong hERG inhibitor and has an extremely long half-life in humans. JDB0131 generates the similar-type metabolite DM131 in animals.¹⁶ However, JDB0131 did not inhibit any ion channels, and DM131 had moderate inhibitory activity against hERG. In our previous study, no QT interval prolongation signal was observed in GLP toxicology studies in dogs.¹⁶ In vitro studies have assessed the inhibitory effects of JDB0131 and its major metabolite on the hERG potassium channel in comparison with those of delamanid and its metabolite. These results support the conclusion that JDB0131 is less likely to cause QT interval prolongation. The results of the present study provide direct clinical evidence supporting the lower cardiac toxicity of JDB0131 than delamanid.

The lower cardiac toxicity was a good explanation. Compared with delamanid, with a T1/2 of 30–38 h, JDB0131 has a much shorter T1/2. In this study, the T1/2 of JDB0131 was 11.92–18.05 h (in different cohorts). In addition, the metabolite of JDB0131 has a short T1/2. In delamanid, the T1/2 was 121–322 h.³⁵ It was reasonable that the short in vivo duration of retention of JDB0131 led to fewer cardiac events.

Furthermore, the potential implications of JDB0131 in tuberculosis patients with comorbid diabetes warrant attention, as diabetes mellitus is known to exacerbate TB severity and impair treatment response.³⁶ Future studies should explore the pharmacokinetics and efficacy of JDB0131 in this high-risk subpopulation to assess its utility in optimizing TB-diabetes co-management.

EBA refers to an agent’s ability to kill mycobacteria originating within pulmonary cavities during the first weeks of treatment.¹⁰ Usually, EBA is determined by quantifying the number of viable colony formation units (CFUs) of M. tuberculosis in an overnight sputum collection. Initially, this was conducted over the first 2 days of treatment, and further experience has shown that significant advantages may accrue from extending the study period from 2 to 14 days after treatment. The TTP reflects the metabolic activity of inoculated viable M. tuberculosis in the sputum. The TTP might represent an alternative method for estimating the activity of viable M. tuberculosis in sputum. The present study reported planned parallel measurements of CFU and TTP. CFU counting relies on the visual enumeration of colonies on solid media and has been the standard in EBA studies for many years. TTP is a less laborious, potentially more robust measurement using calibrated standardized equipment and fewer steps in preparing sputum for analysis. Despite the debate over which one deserves greater significance, in the current study, JDB0131 presented impressive activities in both measurements. However, owing to the influence of the limited sample size and random variation, the baseline bacterial load (CFU in sputum) differed slightly among the groups. Nevertheless, on the basis of the observed changes in EBA within each cohort, we believe that JDB0131 has promising activity, which supports further clinical development. This baseline imbalance is unlikely to have a substantial effect on the overall conclusion. Furthermore, we are planning to conduct a trial to test JDB0131 in resistant TB.

This study has several limitations. First, it comprises 5 cohorts, each containing only a limited number of patients. Second, this study enrolled only Chinese patients. These results cannot be easily extrapolated to all ethnic groups. Third, this study included 3 types of treatment regimens, namely, JDB0131, delamanid and FDC, which made comparisons of different treatments difficult. Furthermore, the twice-daily dosing regimen of JDB0131 may pose challenges to medication adherence. While this concern is important and should not be dismissed, it may be mitigated by the fact that tuberculosis patients are generally familiar with long-term pharmacotherapy. Therefore, the actual impact of the twice-daily regimen on adherence warrants formal investigation in subsequent clinical trials.

In conclusion, in this phase 2a study, we confirmed the potent anti-TB activities of our novel agent JDB0131. It has superior EBA, as shown by both TTP and CFU changes. Additionally, in the radiographic examinations, JDB0131 led to obvious alleviation of TB-related lesions. In addition, it was related to almost no toxicity related to QT interval prolongation. We recommend a dose of 200 mg bid as the suitable dose for future phase III trials. This trial identified a promising new drug for overcoming the increasing TB burden worldwide.