Dr. Shuihua Lu: Trends in PAN-TB Treatment and Mid-term Report Review on QDB Study丨CROI Commentary

Editor’s Note: In recent years, the concept of PAN-TB treatment, representing a comprehensive approach to tuberculosis (TB) therapy, has seen numerous developmental breakthroughs. This universal treatment method is applicable to all types of TB patients and is not limited by the resistance of traditional anti-tuberculosis drugs (i.e., there’s no need to test for drug resistance), offering advantages such as simplified treatment and shortened course duration. At the recently concluded 31st Conference on Retroviruses and Opportunistic Infections (CROI 2024), a Phase 2b/c study (Abstract No: 163) presented in the form of a late-breaking abstract was selected for oral presentation. This study explored the efficacy and safety of a 4-month regimen of Quabodepistat, Delamanid, and Bedaquiline in treating pulmonary TB. Infectious Disease Frontier has invited Dr. Shuihua Lu’s team from The Third People’s Hospital of Shenzhen to form a TB research progress interpretation team to introduce and review this study as follows:

Study Brief:

Abstract No: 163

A 4-Month Regimen of Quabodepistat, Delamanid, and Bedaquiline for Pulmonary TB: Interim Results

Background:

There is an urgent need for short-term, potent, and safe anti-tuberculosis (TB) drugs effective against both drug-sensitive and drug-resistant Mycobacterium tuberculosis strains. Quabodepistat (QBS, originally OPC-167832) is a novel anti-TB drug targeting the decaprenylphosphoryl-β-D-ribose 2′-oxidase (DPRE1). In a previous study, a 14-day combination of QBS with Delamanid (DLM) and Bedaquiline (BDQ) showed good tolerance in patients with drug-sensitive pulmonary TB (DS-TB) and exhibited early bactericidal activity similar to the standard treatment regimen RHEZ (Rifampicin, Isoniazid, Ethambutol, and Pyrazinamide).

Methods:

This mid-term analysis of a Phase 2b/c randomized trial (NCT05221502) assessed the safety, efficacy, and pharmacokinetics of a 4-month treatment with QBS combined with DLM and BDQ in DS-TB patients compared to a 6-month RHEZ regimen. Participants were randomly assigned (in a 1:2:2:1 ratio, stratified by bilateral cavitary lesions on chest X-ray and HIV status) to receive daily doses of QBS at 10 mg, 30 mg, or 90 mg combined with DLM and BDQ, or RHEZ. The follow-up period (up to 52 weeks post-randomization) is ongoing. The primary endpoint was the proportion of participants achieving sputum culture conversion (SCC) at the end of treatment. Here, mid-term results after completion of the study treatment are reported for 117/122 (96%) randomized participants.

Results:

At enrollment, the majority of participants were male (65%), African Black (68%), with a median age of 31 years (range 18-65), and a median BMI of 19 kg/m2. Nineteen percent had bilateral cavitary lesions, and all (100%) were HIV negative. In the modified intent-to-treat population (n=121), the combined QBS group (QBS 10 mg, 30 mg, or 90 mg combined with DLM and BDQ) and the RHEZ group had SCC rates of 96% (96/100) and 91% (19/21) respectively at the end of treatment (see table below). Similar rates of SCC were observed in the per-protocol analysis (n=108).

In the groups receiving 10 mg, 30 mg, and 90 mg doses of Quabodepistat (QBS), and the RHEZ regimen, the percentages of participants experiencing at least one Grade ≥3 AIDS adverse event (AE) were 15%, 12%, 11%, and 5%, respectively. One patient in the 30-mg QBS group discontinued treatment due to severe/worsening tuberculosis and subsequently died. No severe adverse events were attributed to the trial drugs. There were no reports of clinically significant prolongations of QTc, QTc prolongations ≥500 ms, or increases in liver enzymes (ALT/AST) to ≥5 times the upper limit of normal.

Conclusion:

In this mid-term analysis, the QBS-based three-drug treatment regimen achieved high rates of sputum culture conversion (SCC). Overall, the regimen was well-tolerated, warranting further investigation.

Study Commentary:

In recent years, PAN-TB (Pan-Tuberculosis Treatment) represents a comprehensive approach to tuberculosis treatment, aiming to develop a universal therapy applicable to all types of TB patients, regardless of their resistance to traditional anti-tuberculosis drugs (i.e., without the need to test for resistance). This research direction focuses on simplifying treatment processes, shortening the duration of treatment, and minimizing the risk of resistance development.

Key aspects of PAN-TB research include: (1) Drug combinations: Developing new drug combinations that can effectively treat all forms of tuberculosis, including multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). (2) Treatment duration: Shortening treatment cycles to reduce patient burden and improve treatment adherence. (3) Safety and tolerability: Ensuring the safety and tolerability of new treatment regimens for widespread use globally. (4) Global applicability: Creating treatment regimens effective across different patient populations, taking into account genetic variations and resistance patterns that may exist in different regions. The pursuit of PAN-TB treatment research is a forward-looking and challenging effort, requiring interdisciplinary and international cooperation. This type of research is not only crucial for improving the effectiveness of tuberculosis treatment but also has significant implications for global public health.

As mentioned, one of the keys to PAN-TB is the development of effective new drugs and drug combinations. Quabodepistat (Q), formerly known as OPC-167832 or simply OPC, is an anti-tuberculosis drug under investigation that targets the decaprenylphosphoryl-β-D-ribose 2′-oxidase (DprE1) of Mycobacterium tuberculosis. Relevant clinical trials include:

(1) XBOS Study: The Project to Accelerate New Treatments for Tuberculosis (PAN-TB collaboration) conducted pharmacokinetic and relapse mouse model (RMM) studies from 2020-2023, with data now available through the Critical Path Institute’s data sharing platform. These preclinical studies assessed the novel four-drug combination pharmacokinetics and joint efficacy of seven priority anti-tuberculosis drugs and candidates: Bedaquiline (B), Pretomanid (Pa), Sutezolid (Sut), GSK286 (286), GSK830 (830), Delamanid (Del), and Quabodepistat (Q, or QBS).

The PAN-TB collaboration announced on August 9, 2023, the commencement of a Phase 2b/c clinical trial (NCT05971602). The study drugs included five antibiotics: Bedaquiline, Delamanid, Pretomanid, Quabodepistat, and Sutezolid. The experimental arms included two regimens: DBQS (Delamanid, Bedaquiline, Quabodepistat, and Sutezolid) and PBQS (Pretomanid, Bedaquiline, Quabodepistat, and Sutezolid), collectively known as the XBOS regimen. The first phase of the study will enroll 129 patients with drug-sensitive TB, with the experimental arm treatment duration being 17 weeks (4 months), and the control arm receiving the standard 6-month HRZE treatment. Based on the results of the first phase, second and third phases of the study will be conducted.

(2) QDB Study: In earlier studies, a 14-day combination of QBS with Delamanid and Bedaquiline showed early bactericidal activity similar to the standard anti-tuberculosis drug combination HREZ and exhibited good tolerability in patients with drug-sensitive pulmonary TB.

In a subsequent multicenter, Phase 2b/c, open-label, randomized, dose-finding trial (NCT05221502), the safety, efficacy, and pharmacokinetics of a 4-month treatment of drug-sensitive pulmonary TB patients with Quabodepistat (in different dose groups) combined with Delamanid and Bedaquiline were evaluated and compared with the standard treatment regimen. The study focused on safety,