GROUNDBREAKING Phase 2 clinical trial data show that sorfequiline, combined with pretomanid and linezolid (SPaL), may enhance efficacy and safety in drug-sensitive tuberculosis (TB).
Sorfequiline Outperforms Current Standard
The NC-009 trial, a multicentre Phase 2 study conducted across 22 sites in South Africa, the Philippines, Georgia, Tanzania, and Uganda, evaluated sorfequiline alongside pretomanid and linezolid. The 100 mg SPaL regimen demonstrated superior anti-TB activity compared with standard HRZE therapy (isoniazid, rifampin, pyrazinamide, ethambutol) and showed a comparable safety profile. Notably, sorfequiline exhibited higher bactericidal potency than bedaquiline, offering potential advantages in treating drug-sensitive TB and addressing emerging bedaquiline-resistant strains.
Implications for Shortened Treatment
Diarylquinolines, including sorfequiline and bedaquiline, inhibit the mycobacterial ATP synthase enzyme critical for energy production. Preclinical studies of sorfequiline indicated approximately tenfold greater activity than bedaquiline and a favourable safety profile, including low risk of QT prolongation. Clinical Phase 1 data in 165 healthy volunteers confirmed tolerability, with mostly mild adverse events. The NC-009 trial suggests that incorporating sorfequiline into SPaL could reduce treatment duration, aligning with the goal of developing ultra-short, all-oral regimens for both drug-sensitive and drug-resistant TB.
Next Steps in Clinical Development
The TB Alliance plans to advance sorfequiline into Phase 3 trials in 2026, leveraging prior experience with BPaL regimens. Potential formulation strategies include oral therapy and long-acting injectable delivery, aiming to shorten treatment to as little as 1 month. Researchers emphasise that optimised dosing and combination strategies will be critical to achieving maximal efficacy while maintaining safety, particularly in high-burden settings.
Conclusion
Sorfequiline represents a promising addition to TB pharmacotherapy, with the potential to improve efficacy, shorten treatment, and address resistance. Phase 3 trials will clarify its role in next-generation TB regimens.
Reference
TB Alliance. Phase 2 Clinical trial results Show Potential to Shorten TB Treatment Time. 2025. Available at: https://www.tballiance.org/phase-2-clinical-trial-results-show-potential-to-shorten-tb-treatment-time/. Last accessed: 24 November 2025.
