Quabodepistat combo shows promise for safer, faster tuberculosis treatment

By Dr. Priyom Bose, Ph.D.Reviewed by Benedette Cuffari, M.Sc.Dec 1 2024

Cutting-edge tuberculosis therapy: Researchers test quabodepistat combinations, aiming for shorter, safer treatments to combat drug resistance and improve patient outcomes.

Study: Safety, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both in adults with pulmonary tuberculosis: a randomised, active-controlled, open-label trial. Image Credit: Komsan Loonprom / Shutterstock.com

A recent Lancet Infectious Diseases study investigates the safety and bactericidal efficacy of quabodepistat in combination with delamanid and bedaquiline for treating pulmonary tuberculosis.

Tuberculosis: prevalence and treatment

Approximately 1.3 million fatalities occurred due to tuberculosis in 2022.

Currently, standard treatment of pulmonary tuberculosis involves inhibiting bacilli replication, eliminating dormant bacilli, and preventing drug resistance. Furthermore, patients with drug-susceptible pulmonary disease are treated with a six-month course of rifampicin, isoniazid, ethambutol, and pyrazinamide.

Long-duration regimens have been the main strategy to combat drug-resistant tuberculosis for several decades; however, many patients often experience difficulty tolerating and completing the course. Furthermore, 3.3% of new tuberculosis patients and 17% of previously treated patients previously exhibit resistance to isoniazid and rifampicin.

Thus, there is an urgent need for safer drugs that can be used together to shorten the therapy duration and reduce potential side effects. To treat multidrug-resistant tuberculosis, diarylquinoline, bedaquiline, nitroimidazoles, delamanid, and pretomanid have been recommended for combination therapy.

What is quabodepistat?

Previous in vitro and in vivo studies have highlighted the high bactericidal activity of quabodepistat with low minimum inhibitory concentrations in the laboratory and clinically isolated tuberculosis strains. Quabodepistat is a 3,4-dihydrocarbostyril derivative that can inhibit ecaprenylphosphorylβ-D-ribose 2´-oxidase, a vital enzyme for Mycobacterium tuberculosis cell-wall biosynthesis.

Healthy adults exhibited tolerance to quabodepistat at doses between 10 mg and 480 mg. The first stage of an early bactericidal activity (EBA) study identified that a daily dose of 30 mg could be an optimal dose for further assessment in the second stage of the EBA study.

The current study reports the second stage of the EBA study, which is an open-label, randomized, active-controlled, and parallel-group study conducted in two research sites in South Africa.

About the study

Study participants were randomly divided into four quabodepistat treatment groups: quabodepistat (30 mg) + delamanid (300 mg), quabodepistat (30 mg) + bedaquiline (400 mg), and quabodepistat (30 mg) + delamanid (300 mg) + bedaquiline (400 mg) for two weeks, as well as the control standard combination therapy of rifampicin, isoniazid, ethambutol, and pyrazinamide for twenty days.

Each participant received one oral dose daily. The safety and tolerability of each treatment during and after the 14-day period was assessed.

A pilot study was also conducted to evaluate the pharmacokinetics and bactericidal activity of quabodepistat when combined with delamanid and bedaquiline on days one and 14 of the trial.

The efficacy of the quabodepistat treatment for tuberculosis was determined based on the reduction of sputum colony-forming units (CFUs) on agar media from baseline to day 14. Sputum lipoarabinomannan concentrations were determined through a lipoarabinomannan enzyme-linked immunosorbent assay (ELISA) and mycobacterial growth indicator tube (MGIT) time-to-detection method.

Lipoarabinomannan was selected as a biomarker because it is an important cell wall component of M. tuberculosis. Therefore, a decrease in sputum lipoarabinomannan concentrations reflected a decline in viral load.

Study findings

Among the 98 participants initially screened for participating in the second stage of the EBA study, 44 received at least one of the medications for two weeks for safety analysis. Most study participants were male, whereas 63% of the cohort constituted Black or African participants.

Approximately 73% of the patients experienced at least one treatment-emergent adverse event. Furthermore, most study participants developed side effects of mild or moderate severity, such as headache, abdominal pain, pruritus, and nausea. About 5% of participants belonging to the quabodepistat + bedaquiline group developed serious adverse events; however, these effects were not attributed to the studied drug.

Hyperkalemia of moderate severity occurred in the bedaquiline cohort, which was due to a pre-existing medical condition at baseline. Overall, 7% of all study participants developed adverse events of greater severity. No change in physical examinations, vital signs, laboratory parameters, or electrocardiograms (ECGs) was observed that indicated any clinical significance.

Maximum quabodepistat concentrations were observed three hours after administration of quabodepistat in all combinations. The mean elimination half-life was shorter in quabodepistat combined with bedaquiline than without bedaquiline.

Although CFU counts of sputum samples were similar in all participants across study groups at baseline, changes were observed after the study period. The maximum change in CFU count from baseline was observed in the quabodepistat + delamanid + bedaquiline treatment and for the control.

Conclusions

The current study indicated a robust bacteriological effect and safety of quabodepistat when administered in combination with delamanid and bedaquiline to treat tuberculosis in adults. Nevertheless, these findings must be validated by large-scale and long-term trials in the future.