A new study published in The Lancet Infectious Diseases evaluates the safety and early bactericidal activity of quabodepistat in combination with delamanid and bedaquiline for the treatment of pulmonary tuberculosis. The research aims to address the critical need for shorter, safer, and more effective treatments for tuberculosis, especially in the face of increasing drug resistance.
In 2022, tuberculosis resulted in approximately 1.3 million deaths worldwide. The current standard treatment involves a six-month regimen of rifampicin, isoniazid, ethambutol, and pyrazinamide for drug-susceptible strains. However, long treatment durations and the rise of drug-resistant strains necessitate the development of new therapeutic strategies.
Quabodepistat: A Novel Approach
Quabodepistat is a 3,4-dihydrocarbostyril derivative that inhibits ecaprenylphosphoryl-β-D-ribose 2'-oxidase, an enzyme crucial for Mycobacterium tuberculosis cell wall biosynthesis. Previous studies have shown its high bactericidal activity against both laboratory and clinically isolated tuberculosis strains. This study represents the second stage of an early bactericidal activity (EBA) assessment.
The open-label, randomized, active-controlled, parallel-group study was conducted at two research sites in South Africa. Participants were divided into four groups: quabodepistat (30 mg) + delamanid (300 mg), quabodepistat (30 mg) + bedaquiline (400 mg), quabodepistat (30 mg) + delamanid (300 mg) + bedaquiline (400 mg), and a control group receiving standard treatment (rifampicin, isoniazid, ethambutol, and pyrazinamide). All medications were administered orally once daily for two weeks, except for the control group, which was treated for 20 days. The primary outcome was the change in sputum colony-forming units (CFUs) from baseline to day 14.
Key Findings
Of the 98 participants screened, 44 received at least one dose of the study medications. The majority of participants were male (73%) and of Black or African ethnicity (63%). Treatment-emergent adverse events were reported in approximately 73% of patients, with most being mild to moderate in severity, including headache, abdominal pain, pruritus, and nausea. Serious adverse events occurred in 5% of the quabodepistat + bedaquiline group, but were not attributed to the study drugs. One patient in the bedaquiline cohort experienced moderate hyperkalemia due to a pre-existing condition.
Pharmacokinetic analysis showed that maximum quabodepistat concentrations were observed three hours post-administration. The mean elimination half-life of quabodepistat was shorter when combined with bedaquiline. Although baseline sputum CFU counts were similar across all groups, the greatest change in CFU count from baseline was observed in the quabodepistat + delamanid + bedaquiline group and the control group.
Clinical Implications
The study suggests that quabodepistat, when combined with delamanid and bedaquiline, demonstrates a robust bacteriological effect and acceptable safety profile in treating tuberculosis in adults. These findings support further investigation of quabodepistat-based regimens in larger, longer-term clinical trials to validate these results and explore their potential to shorten tuberculosis treatment duration and improve patient outcomes.
