quabodepistat (OPC-167832) / Otsuka - LARVOL DELTA

In Vitro and Intracellular Inhibitory Activities of OPC-167832 against Mycobacterium abscessus and Mycobacterium chelonae (ASM Microbe 2025) - "OPC-167832 has potent inhibitory activities against M. abscessus and M. chelonae in vitro as well as in macrophages. Altogether, OPC-167832 exhibits a safe clinical profile and could be considered a promising drug candidate for M. abscessus and M. chelonae infection treatment."

Preclinical • Infectious Disease • Respiratory Diseases • Tuberculosis

Verapamil and its metabolite norverapamil inhibit the Mycobacterium tuberculosis MmpS5L5 efflux pump to increase bedaquiline activity. (PubMed, Proc Natl Acad Sci U S A) - "Here, we show that the MmpS5L5 efflux pump reduces susceptibility to bedaquiline as well as its new, more potent derivative TBAJ-876 and other antimicrobial substrates, including clofazimine and the DprE1 inhibitors PBTZ-169 and OPC-167832...Finally, norverapamil, the major verapamil metabolite, which has greatly reduced calcium channel activity, has equal potency in reducing resistance to MmpS5L5 substrates. Our findings highlight verapamil's potential for enhancing bedaquiline TB treatment, for preventing acquired resistance to bedaquiline and other MmpS5L5 substrates, while also providing the impetus to identify additional MmpS5L5 inhibitors."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=93 | Terminated | Sponsor: Bill & Melinda Gates Medical Research Institute | N=514 ➔ 93 | Active, not recruiting ➔ Terminated; Data generated in the Gates MRI-TBD06-201 trial do not support the investigational regimens being able to achieve the trial objective of identifying a new regimen to treat tuberculosis in 3 months or less.

Enrollment change • Trial termination • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis. (PubMed, Pharmaceuticals (Basel)) - "Isoniazid, thioamides, and delamanid primarily disrupt mycolic acid synthesis, with recent evidence indicating that delamanid also inhibits decaprenylphosphoryl-β-D-ribose-2-epimerase, thereby impairing arabinogalactan biosynthesis. Furthermore, ethambutol interferes with arabinogalactan synthesis by targeting arabinosyl transferase enzymes, particularly embB- and embC-encoded variants. Beyond these, six promising molecules currently in Phase II clinical trials are designed to target arabinan synthesis pathways, sutezolid, TBA 7371, OPC-167832, SQ109, and both benzothiazinone derivatives BTZ043 and PBTZ169, highlighting advancements in the development of cell wall-targeting therapies."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

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. (PubMed, Lancet Infect Dis) - P1/2 | "In this 14-day trial, quabodepistat plus delamanid plus bedaquiline, a novel three-drug combination, appeared to be safe, well tolerated, and provided robust early bactericidal activity in adults with drug-susceptible pulmonary tuberculosis. Further evaluation is warranted."

Combination therapy • Journal • PK/PD data • Dermatology • Infectious Disease • Pain • Pruritus • Pulmonary Disease • Respiratory Diseases • Tuberculosis • STAT3

Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=514 | Active, not recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute | Trial completion date: Oct 2024 ➔ Jan 2025 | Trial primary completion date: Oct 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=514 | Active, not recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute | Recruiting ➔ Active, not recruiting | Trial completion date: Oct 2027 ➔ Oct 2024 | Trial primary completion date: Oct 2027 ➔ Oct 2024

Enrollment closed • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB (clinicaltrials.gov) - P2 | N=122 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Completed

Combination therapy • Trial completion • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4

Targeting decaprenylphosphoryl-β-D-ribose 2'-epimerase for Innovative Drug Development Against Mycobacterium Tuberculosis Drug-Resistant Strains. (PubMed, Bioinform Biol Insights) - "Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=514 | Recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute | Trial completion date: Mar 2027 ➔ Oct 2027 | Trial primary completion date: Mar 2027 ➔ Oct 2027

Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A 4-Month Regimen of Quabodepistat, Delamanid, and Bedaquiline for Pulmonary TB: Interim Results (CROI 2024) - P2 | "Quabodepistat (QBS; formerly OPC-167832) is a novel anti-TB agent that targets decaprenylphosphoryl-β-D-ribose 2′-oxidase (DprE1). 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."

Human Immunodeficiency Virus • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A minimal PBPK model to accelerate preclinical development of drugs against tuberculosis. (PubMed, Front Pharmacol) - " The model has been successfully tested and validated against 11 anti-TB compounds-rifampicin, rifapentine, pyrazinamide, ethambutol, isoniazid, moxifloxacin, delamanid, pretomanid, bedaquiline, OPC-167832, GSK2556286 - showing robust predictability power in recapitulating PK dynamics in mice. Discrepancies in plasma and lung levels for the latest BPaMZ and HPMZ regimens have been analyzed in terms of their impact on preclinical experiment design and on PK/PD indices. The framework we developed requires limited drug- and species-specific information to reconstruct accurate PK dynamics, delivering a unified viewpoint on anti-TB drug distribution at the site-of-action and a flexible fit-for-purpose tool to accelerate model-informed drug design pipelines and facilitate translation into the clinic."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB (clinicaltrials.gov) - P2 | N=122 | Active, not recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Recruiting ➔ Active, not recruiting | Phase classification: P2b ➔ P2

Combination therapy • Enrollment closed • Phase classification • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4

Quabodepistat (OPC-167832), a Novel Antituberculosis Drug Candidate: Enhancing Oral Bioavailability via Cocrystallization and Mechanistic Analysis of Bioavailability in Two Cocrystals. (PubMed, Mol Pharm) - "This result was consistent with the results of bioavailability studies in beagle dogs. We conclude that a larger quantity of orally administered quabodepistat-2HBA remained in its cocrystal form while being transferred to the small intestine compared with quabodepistat-2,5DHBA."

Journal • Infectious Disease • Respiratory Diseases • Tuberculosis

Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=514 | Recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute | Phase classification: P2b ➔ P2

Phase classification • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Crystal structure of a 1:1 co-crystal of quabodepistat (OPC-167832) with 2,5-di-hydroxy-benzoic acid using microcrystal electron diffraction. (PubMed, Acta Crystallogr E Crystallogr Commun) - "The amide group of quabodepistat participates in a cyclic hydrogen bond with the carb-oxy-lic group of the 2,5DHBA. Additional hydrogen bonds involving the quabodepistat amide and hydroxyl groups result in a three-dimensional network."

Journal

Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis (clinicaltrials.gov) - P2b | N=514 | Recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Efficacy and Safety Evaluation of Two to Four Months of Treatment With the Combination Regimens of DBOS and PBOS in Adults With Pulmonary Tuberculosis (clinicaltrials.gov) - P2b | N=514 | Not yet recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute

New P2b trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Phase I Single Ascending Dose and Food Effect Study in Healthy Adults and Phase I/IIa Multiple Ascending Dose Study in Patients with Pulmonary Tuberculosis to Assess Pharmacokinetics, Bactericidal Activity, Tolerability, and Safety of OPC-167832. (PubMed, Antimicrob Agents Chemother) - "Once-daily OPC-167832 showed 14-day bactericidal activity from 3 mg (log CFU mean ± standard deviation change from baseline; -1.69 ± 1.15) to 90 mg (-2.08 ± 0.75), while the EBA of Rifafour e-275 was -2.79 ± 0.96. OPC-167832 demonstrated favorable pharmacokinetic and safety profiles, as well as potent EBA in participants with drug-susceptible pulmonary TB."

Journal • P1/2 data • PK/PD data • Dermatology • Infectious Disease • Pain • Pruritus • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A phase 2a, randomised, active-control, open-label trial evaluating the safety/efficacy of OPC-167832 combined with delamanid and/or bedaquiline for drug-susceptible pulmonary tuberculosis for fourteen days (ECCMID 2023) - No abstract available

Clinical • P2a data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis. (PubMed, Drugs) - "An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided...Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating..."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Mycobacterium tuberculosis DprE1 Inhibitor OPC-167832 Is Active against Mycobacterium abscessus In Vitro. (PubMed, Antimicrob Agents Chemother) - "Due to its moderate potency compared to that against Mycobacterium tuberculosis, the compound lacked efficacy in a mouse model and is thus not a repurposing candidate. These results identify OPC-167832-DprE1 as a lead-target couple for a M. abscessus-specific optimization program."

Journal • Preclinical • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB (clinicaltrials.gov) - P2b | N=120 | Recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD4

A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis (clinicaltrials.gov) - P1/2 | N=122 | Completed | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis (clinicaltrials.gov) - P1/2 | N=122 | Active, not recruiting | Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. | Recruiting ➔ Active, not recruiting | Trial completion date: Nov 2021 ➔ Apr 2022 | Trial primary completion date: Nov 2021 ➔ Feb 2022

Enrollment closed • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis