Background:
There remains an urgent need for short-duration, potent, and safe anti-tuberculosis (TB) agents effective against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis. Quabodepistat (QBS; formerly OPC-167832) is a novel anti-TB agent that targets decaprenylphosphoryl-β-D-ribose 2′-oxidase (DprE1). In a prior study, QBS in combination with delamanid (DLM) and bedaquiline (BDQ) for 14 days was well tolerated and exhibited similar early bactericidal activity to the standard of care regimen, RHEZ (rifampicin, isoniazid, ethambutol, and pyrazinamide) in patients with drug-susceptible pulmonary TB (DS-TB).
Methods:
This interim analysis of the phase 2b/c, randomized trial (NCT05221502) evaluates the safety, efficacy, and pharmacokinetics of QBS in combination with DLM and BDQ for 4 months in participants with DS-TB compared to 6-month RHEZ treatment. Participants were randomized (1:2:2:1; stratified by chest x-ray bilateral cavitation and HIV status) to once-daily QBS 10 mg, 30 mg, or 90 mg in combination with DLM and BDQ, or RHEZ. The follow-up period (to 52 weeks post-randomization) is ongoing. The primary endpoint was proportion of participants achieving sputum culture conversion (SCC) by the end of the treatment period. Here, we report interim results after 117/122 (96%) randomized participants completed study treatment.
Results:
At enrollment, most participants were male (65%), of Black African race (68%) with a median age of 31 years (range 18–65), a median BMI of 19 kg/m2, with bilateral cavitation (19%), and HIV-negative (100%) status. In the modified intention-to-treat population (n=121), SCC at end of treatment was achieved by 96% (96/100) in the pooled QBS arms and 91% (19/21) in the RHEZ arm (Table 1). Similar SCC rates were observed in the per-protocol analysis (n=108). The percentages of participants experiencing at least one Division of AIDS ≥Grade 3 adverse event (AE) were 15%, 12%, 11%, and 5% in the QBS 10-mg, 30-mg, 90-mg, and RHEZ arms, respectively. There was one treatment discontinuation due to death (QBS 30-mg arm) from severe/worsening TB. No serious AEs were attributed to trial medications. No clinically significant QTc prolongation events, QTc prolongation ≥500 ms, or liver enzyme (ALT/AST) elevations ≥5 times the upper limit of normal were reported.
Conclusions:
In this interim analysis, high rates of SCC were achieved with the QBS-based three-drug treatment regimen. The regimen was generally well tolerated and warrants further investigation.
