Triplet Regimen Shortens Effective TB Treatment

— Three-drug combo over 4 months was comparable to standard treatment over 6 months

Last Updated March 14, 2024

DENVER -- Combining the investigational drug quabodepistat with established anti-tuberculosis (TB) drugs delamanid and bedaquiline resulted in comparable efficacy over 4 months as a standard four-drug regimen over 6 months, according to an interim analysis of a phase IIb/c randomized trial.

In a modified intention-to-treat analysis of patients with pulmonary TB, 96% of those receiving the three-drug combination achieved sputum culture conversion compared with 90.5% of those on a standard regimen of rifampicin, isoniazid, ethambutol, and pyrazinamide (RHEZ), reported Simbarashe Takuva, MBChB, MSc, of Otsuka Novel Products GmbH in Munich, at the Conference on Retroviruses and Opportunistic Infections.

When it comes to TB treatment, "there's an urgent need for shorter-duration, more potent, and safer anti-TB agents that are not only effective against drug-susceptible TB but also drug-resistant TB," Takuva told attendees.

Quabodepistat is a novel decaprenyl-phosphoryl-β-D-ribose-2'-epimerase (DprE1) inhibitor that "has a new mode of action and new target," Takuva explained, acting by inhibiting the DprE1 enzyme, an essential enzyme in the mycobacteria cell wall synthesis.

Patrick Phillips, PhD, of the University of California San Francisco School of Medicine, told app that "it is encouraging to see the three-drug combination of quabodepistat, bedaquiline, and delamanid leading to modestly faster sputum culture conversion than first-line therapy. These are promising results that suggest quabodepistat has a role as part of a four-drug regimen of short duration."

Forthcoming post-treatment relapse data from the trial will provide more information about the treatment-shortening potential of quabodepistat, he added. "If there are ultimately no more than a couple of relapses, this would be promising data to take this three-drug regimen forward to a larger confirmatory phase III trial for a new regimen for drug-sensitive TB," Phillips said.

He also noted the higher number of severe and serious adverse events in the quabodepistat group. "Although numbers were small, it would be of interest to see what types of adverse events occurred to understand whether this imbalance was likely related to drugs or just a chance imbalance."

The study enrolled 122 patients in South Africa, stratified by bilateral cavitation on screening chest x-ray. Most participants were Black (68%) males (64.8%) with a mean age of 33.7, and 19% had bilateral cavitation status, but "unfortunately we were unable to recruit persons with HIV," Takuva said.

After a screening period of 14 days, participants were randomized 1:2:2:1 to four treatment arms: a once-daily dose of 10 mg quabodepistat with 300 mg delamanid and 400 mg followed by 200 mg of bedaquiline; 30-mg quabodepistat with the same dosages of delamanid and bedaquiline; 90-mg quabodepistat with the same dosages of delamanid and bedaquiline; and a control RHEZ group. The quabodepistat groups were treated for 17 weeks, while the RHEZ group was treated once daily with RHEZ for 8 weeks, followed by 18 weeks of rifampin and isoniazid.

The primary endpoint was safety and sputum culture conversion by the end of the treatment period. Takuva presented the interim results in which 117 out of 122 participants had completed treatment. Two patients in the 30 mg quabodepistat group and one in the 90 mg group discontinued the study, and two patients in the RHEZ group had not completed treatment by the time of analysis.

In the modified intention-to-treat analysis, 100% of the 10 mg quabodepistat participants, 92.9% of the 30 mg quabodepistat participants, and 97.4% of the 90 mg quabodepistat participants achieved sputum culture conversion, compared with 90.5% of the RHEZ participants.

Among those with bilateral cavitation, 100% of the combined quabodepistat participants and 75% of the RHEZ participants achieved sputum culture conversion. In the patients without bilateral cavitation, 95.4% of the combined quabodepistat participants and 94.1% of the RHEZ participants achieved sputum culture conversion.

There were no clear differences in time to sputum culture conversion between the quabodepistat and RHEZ groups, and no clear dose-response relationship occurred for quabodepistat, Takuva said.

Serious adverse events occurred in 4% of the participants receiving quabodepistat and none of those receiving RHEZ. One participant in the RHEZ group and 10% of those in the quabodepistat groups experienced severe adverse events. Any adverse events determined to be related to the study drug occurred in 18% of quabodepistat participants and 28.6% of RHEZ participants.

The mean aspartate transaminase (AST)/alanine transaminase (ALT) ratio did not increase in the quabodepistat group, and no clinically significant heart-rate corrected QT interval prolongation events occurred. There were also no observed dose-related effects on liver enzymes or on heart-rate corrected QT interval overall. There were no treatment discontinuations related to the study drug.

The one death in the study was a 25-year-old man in a quabodepistat group who had presented as ill at the start of the study and progressively worsened. He was stopped from taking the study drug at week 8 and admitted to a hospital and provided standard of care.

Correction: This story has been updated to reflect that Phillips said quabodepistat could have a role as part of a four-drug regimen.

  • Tara Haelle is an independent health/science journalist based near Dallas, Texas. She has more than 15 years of experience covering a range of medical topics and conferences.


The research was funded by Otsuka Pharmaceuticals and the Bill & Melinda Gates Foundation.

Takuva is an employee at Otsuka Novel Products GmbH.

Phillips reported consulting for Gates Medical Research Institute, and his institution has received grants for his research from LegoChem Biosciences.

Primary Source

Conference on Retroviruses and Opportunistic Infections

Takuva S, et al "A 4-month regimen of quabodepistat, delamanid, and bedaquiline for pulmonary TB: interim results" CROI 2024.