Highlights
The PanACEA-DECODE-01 trial marks a significant milestone in the quest for safer tuberculosis (TB) treatments. The key highlights include:
- Delpazolid at a dose of 1200 mg once daily was identified as the optimal dosage, providing maximal microbiological activity.
- The addition of delpazolid to a backbone of bedaquiline, delamanid, and moxifloxacin (BDM) resulted in a 38% faster decline in mycobacterial load compared to the BDM regimen alone.
- Crucially, the study reported a lack of typical oxazolidinone-class toxicities, such as peripheral or optical neuropathy, which frequently limit the use of linezolid.
- Pharmacokinetic-pharmacodynamic (PK-PD) modelling suggests that a total daily exposure (AUC0-24) of 50 mg/L per h is the target for clinical efficacy.
The Oxazolidinone Dilemma in Tuberculosis Care
For decades, the treatment of drug-resistant tuberculosis has been hampered by the limited number of effective antimicrobial classes. The introduction of oxazolidinones, specifically linezolid, revolutionized the management of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Linezolid is highly effective, yet it is a double-edged sword. Its long-term administration is frequently complicated by severe adverse events, including myelosuppression (anemia, leukopenia, thrombocytopenia) and irreversible peripheral or optical neuropathy. These toxicities often necessitate dose reductions or premature discontinuation, compromising the efficacy of the entire treatment regimen.
Consequently, the development of a safer oxazolidinone has been a top priority in global health. Delpazolid (formerly LCB01-0371) is a novel oxazolidinone designed to maintain the potent protein-synthesis-inhibiting properties of its class while minimizing the off-target effects on mitochondrial protein synthesis that are believed to drive linezolid’s toxicity. The PanACEA-DECODE-01 trial was designed to evaluate whether delpazolid could fulfill this clinical promise.
Study Design and Methodology
The PanACEA-DECODE-01 trial was a prospective, randomised, open-label, phase 2b, multicentre, dose-finding study. Conducted across five sites in Tanzania and South Africa, the trial recruited 76 adults aged 18-65 years with newly diagnosed, smear-positive pulmonary tuberculosis. Participants were required to have a body weight between 40 and 90 kg.
The trial utilized a complex five-arm design to identify the optimal dose. Participants were randomly assigned (1:1:1:1:1) to receive either no delpazolid (D0) or one of four delpazolid dosing regimens: 400 mg once daily (D400), 800 mg once daily (D800), 1200 mg once daily (D1200), or 800 mg twice daily (D800BD). All arms received a standardized backbone therapy of bedaquiline (400 mg daily for 14 days, then 200 mg thrice weekly), delamanid (100 mg twice daily), and moxifloxacin (400 mg once daily). This backbone represents a highly potent, modern regimen, making the detection of additional efficacy from delpazolid a rigorous challenge.
Randomization was stratified by bacterial load (GeneXpert cycle threshold), clinical site, and HIV status to ensure balanced groups. The primary efficacy objective was the development of an exposure-response model based on the change in mycobacterial load, measured by the time to positivity (TTP) in the liquid culture mycobacterial growth indicator tube (MGIT) system. This approach allowed for a more granular assessment of bacterial killing than traditional binary culture conversion status.
Key Findings: Efficacy and Optimal Dosing
The primary analysis focused on the modified intention-to-treat population. The PK-PD modelling provided a clear signal of delpazolid’s contribution to the regimen. The model estimated that maximal microbiological activity occurred at a total daily exposure (AUC0-24) of approximately 50 mg/L per h. This level of exposure was most closely achieved by the 1200 mg once-daily dose.
When comparing the delpazolid-enhanced regimens to the control (D0), the 1200 mg dose was associated with a 38% faster decline in bacterial load (95% CI 4-83; p=0·025). This statistically significant acceleration in bacterial clearance suggests that delpazolid adds meaningful anti-mycobacterial activity even when combined with other highly potent drugs like bedaquiline and delamanid.
In terms of secondary outcomes, the time to sustained culture conversion (TSCC) was evaluated. While the study was not primarily powered to show significant differences in TSCC between individual arms, the combined analysis of all delpazolid-containing groups showed a hazard ratio of 1·53 (95% CI 0·84-2·76) for culture conversion compared to the control group. This trend further supports the efficacy of delpazolid, though the relatively small sample size in this phase 2b trial limited the statistical power for this specific endpoint.
Safety and Tolerability: A Critical Breakthrough
The most encouraging results from the DECODE-01 trial pertain to the safety profile of delpazolid. A primary concern with any oxazolidinone is the risk of cumulative toxicity over 16 weeks of treatment. Remarkably, no cases of peripheral or optical neuropathy were observed across any of the delpazolid arms. Furthermore, there were no reported adverse events consistent with a tyramine pressor response, a known risk with some oxazolidinones.
Only two drug-related serious adverse events (SAEs) occurred, both in the highest-exposure group (D800BD). One participant experienced gastritis and another developed anemia. The anemia was observed in a patient with a very high individual AUC0-24, reinforcing the importance of dose optimization to avoid excessive exposure. Apart from one brief, moderate episode of neutropenia in the D800 group (which was not characteristic of cumulative oxazolidinone toxicity), the hematological profile of delpazolid remained stable. These findings suggest that at the recommended 1200 mg once-daily dose, delpazolid avoids the severe toxicity profile that has long plagued linezolid-based treatments.
Expert Commentary: Clinical Implications and Future Directions
The results of the PanACEA-DECODE-01 trial have profound implications for the design of future TB treatment regimens. Current WHO-recommended regimens for drug-resistant TB, such as BPaLM (bedaquiline, pretomanid, linezolid, and moxifloxacin), rely heavily on linezolid. However, the toxicity of linezolid often forces clinicians to reduce the dose from 600 mg to 300 mg or stop the drug entirely after the first few months. A safer oxazolidinone like delpazolid could potentially be administered at full therapeutic doses for the entire duration of treatment, potentially increasing cure rates and preventing the emergence of further resistance.
The use of TTP and PK-PD modelling in this trial provides a robust framework for dose selection in phase 3 trials. By identifying 1200 mg QD as the dose that reaches the Emax (maximal effect) on the exposure-response curve while maintaining a favorable safety margin, the researchers have provided a clear pathway for the next stage of clinical development. However, it is important to note that this was a phase 2b study with a relatively small cohort. Larger, phase 3 trials will be required to confirm these findings and to evaluate the long-term outcomes, including relapse rates.
Conclusion
Delpazolid represents a promising advancement in the pharmacotherapy of pulmonary tuberculosis. By demonstrating significant additive efficacy to a potent backbone regimen and maintaining a superior safety profile compared to historical data for linezolid, delpazolid addresses a major unmet medical need. The PanACEA-DECODE-01 trial successfully identified 1200 mg once daily as the optimal dose for further investigation. If these results are replicated in larger populations, delpazolid may become a cornerstone of safer, more effective short-course treatments for both drug-sensitive and drug-resistant tuberculosis.
Funding and Trial Registration
This study was funded by LigaChem Biosciences, the EDCTP2 programme supported by the European Union, the German Ministry for Education and Research, the German Center for Infection Research, the Swiss State Secretariat for Education, Research and Innovation, and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek. The trial is registered with ClinicalTrials.gov, number NCT04550832.
References
Minja LT, van der Feltz I, Manyama C, et al. Delpazolid in combination with bedaquiline, delamanid, and moxifloxacin for pulmonary tuberculosis (PanACEA-DECODE-01): a prospective, randomised, open-label, phase 2b, dose-finding trial. Lancet Infect Dis. 2025 Nov;25(11):1219-1229. doi: 10.1016/S1473-3099(25)00289-0.
