BTZ-043 / Radboud University, German Center for Infection Research, Hans Knöll Institute - LARVOL DELTA

Low-level BTZ-043 resistance in Mycobacterium tuberculosis and cross-resistance to bedaquiline and clofazimine. (PubMed, IJTLD Open) - "Rv0678 mutations confer low-level cross-resistance to BTZ-043, BDQ, and CFZ, with variable effects on susceptibility. These findings highlight the complexity of resistance mechanisms and the need for ongoing surveillance and early resistance assessments in drug development."

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

PanACEA - STEP2C -01 (clinicaltrials.gov) - P2 | N=390 | Recruiting | Sponsor: Michael Hoelscher | N=270 ➔ 390 | Trial completion date: Feb 2025 ➔ Dec 2027 | Trial primary completion date: Feb 2025 ➔ Oct 2027

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

Early Bactericidal Activity, Safety & Tolerability of Oral GSK3036656 in a Dual Combination With Novel and Established Antitubercular Agents, or Standard of Care in Adults With Rifampicin Susceptible Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=127 | Completed | Sponsor: GlaxoSmithKline | Recruiting ➔ Completed | Trial completion date: Nov 2024 ➔ May 2025 | Trial primary completion date: Nov 2024 ➔ May 2025 | Recruiting ➔ Completed

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

First-in-human study of the benzothiazinone and DprE1 inhibitor BTZ-043, a novel drug candidate for the treatment of Tuberculosis. (PubMed, JAC Antimicrob Resist) - "No relevant differences in systemic exposures between males and females were observed. BTZ-043 was safe, well tolerated and underwent rapid absorption, metabolism and elimination, supporting further clinical development."

Journal • P1 data • Cardiovascular • Hypertension • Infectious Disease • Pain • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Population pharmacokinetics and exposure-response relationship of the antituberculosis drug BTZ-043. (PubMed, J Antimicrob Chemother) - "We characterized the population PK/PD of BTZ-043 in trial participants with pulmonary TB. An exposure-response relationship was only apparent for the first 2 days on treatment, indicating the need for further dose-finding studies."

Clinical • Journal • PK/PD data • Infectious Disease • Respiratory Diseases • Tuberculosis

Ganfeborole in combination with novel antitubercular agent BTZ-043 administered for 14-days to participants with rifampicin-susceptible pulmonary tuberculosis: interim analysis results (ESCMID Global 2025) - No abstract available

Combination therapy • Infectious Disease • Respiratory Diseases • Tuberculosis

Translational modeling of BTZ-043 in predicting phase IIA efficacy and evaluating drug-drug interactions with BPaL in murine models. (PubMed, J Infect Dis) - "The translational modeling platform adequately predicted the efficacy of BTZ-043 monotherapy. In the absence of drug-drug interactions, co-administration of BTZ-043 with bedaquiline, pretomanid, and linezolid in combotherapy is predicted to improve treatment efficacy."

Journal • P2a data • Preclinical • 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

The clinical-stage drug BTZ-043 accumulates in murine tuberculosis lesions and efficiently acts against Mycobacterium tuberculosis. (PubMed, Nat Commun) - "This is the first study that visualizes an efficient penetration and accumulation of a clinical-stage TB drug in human-like centrally necrotizing granulomas and that also determines its lesional activity. Our results most likely predict a substantial bactericidal effect of BTZ-043 at these hard-to-reach sites in TB patients."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • IL13

Safety, bactericidal activity, and pharmacokinetics of the antituberculosis drug candidate BTZ-043 in South Africa (PanACEA-BTZ-043-02): an open-label, dose-expansion, randomised, controlled, phase 1b/2a trial. (PubMed, Lancet Microbe) - P1/2 | "Based on a small sample size, BTZ-043 is a promising antituberculosis drug candidate with favourable safety and good bactericidal activity. Larger follow-up studies are needed to detect any less frequent safety signals, further explore drug-drug interactions, identify the best dose, and evaluate efficacy in combination with other drugs."

Journal • P1/2 data • PK/PD data • Cardiovascular • Hematological Disorders • Hepatology • Human Immunodeficiency Virus • Hypertension • Infectious Disease • Pain • Pulmonary Disease • Pulmonary Embolism • Respiratory Diseases • Tuberculosis • CYP1A2 • CYP2C9 • CYP3A4

A Comparative Pharmacokinetics Study of Orally and Intranasally Administered 8-Nitro-1,3-benzothiazin-4-one (BTZ043) Amorphous Drug Nanoparticles. (PubMed, ACS Pharmacol Transl Sci) - "BTZ043 was cleared faster from the lung and plasma following intranasal administration with a shorter time above the minimum inhibitory concentration (MIC) compared to oral ADN. Since time > MIC is reported to drive activity, oral ADN may represent a promising delivery strategy for BTZ043."

Journal • PK/PD data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Real-time evaluation of macozinone activity against Mycobacterium tuberculosis through bacterial nanomotion analysis. (PubMed, Antimicrob Agents Chemother) - "We evaluated the in vitro activity of two benzothiazinone drug candidates (MCZ, PBTZ169; BTZ043) and their main metabolites against MTB using advanced nanomotion technology. PBTZ169 and H2-PBTZ169 achieved 100% separation between the susceptible H37Rv and a resistant dprE1 mutant strain NTB1. These findings support nanomotion technology's potential for faster antibiotic susceptibility testing of novel MTB drug candidates targeting the DprE1 enzyme that could reduce empirical treatment duration and antibiotic resistance selection pressure due to inaccurate treatments."

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

Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility. (PubMed, Eur J Med Chem) - "Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH2 group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H37Rv and MDR-MTB strains (MIC:  2000 μg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery."

Journal

Pharmacophore mapping, 3D QSAR, molecular docking, and ADME prediction studies of novel Benzothiazinone derivatives. (PubMed, In Silico Pharmacol) - "Clinical trial drugs such as BTZ043, BTZ038, PBTZ169, and TMC-207 have shown promising results as DprE1 inhibitors. Docking validation via RMSD values supported the reliability of the docking results. This comprehensive approach aids in the design of novel benzothiazinone derivatives with potential anti-tubercular properties, contributing to the development of novel anti-tubercular agents which can be pivotal in the eradication of tuberculosis."

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

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

In vitro exposure to BTZ-043 selects for efflux pump mutants, leading to the development of resistance in Mycobacterium tuberculosis against BTZ-043, bedaquiline, and clofazimine (ECCMID 2024) - No abstract available

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

In vitro susceptibility testing of BTZ-043 against Mycobacterium tuberculosis complex isolates to establish the epidemiological cut-off values and MIC distribution (ECCMID 2024) - No abstract available

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

Early Bactericidal Activity, Safety & Tolerability of Oral GSK3036656 in a Dual Combination With Novel and Established Antitubercular Agents, or Standard of Care in Adults With Rifampicin Susceptible Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=128 | Recruiting | Sponsor: GlaxoSmithKline | N=70 ➔ 128

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

PARADIGM4TB: Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB (clinicaltrials.gov) - P2 | N=2500 | Recruiting | Sponsor: University College, London | Not yet recruiting ➔ Recruiting

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

DECISION: BTZ-043 Dose Evaluation in Combination and Selection (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Michael Hoelscher

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

PARADIGM4TB: Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB (clinicaltrials.gov) - P2 | N=2500 | Not yet recruiting | Sponsor: University College, London | Phase classification: P2b ➔ P2

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

DECISION: BTZ-043 Dose Evaluation in Combination and Selection (clinicaltrials.gov) - P2 | N=90 | Recruiting | Sponsor: Michael Hoelscher | Not yet recruiting ➔ Recruiting | Phase classification: P2b ➔ P2

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

Early Bactericidal Activity, Safety & Tolerability of Oral GSK3036656 in a Dual Combination With Novel and Established Antitubercular Agents, or Standard of Care in Adults With Rifampicin Susceptible Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=70 | Recruiting | Sponsor: GlaxoSmithKline | Phase classification: P2a ➔ P2 | Trial completion date: Sep 2023 ➔ Nov 2024 | Trial primary completion date: Sep 2023 ➔ Nov 2024

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

Design and synthesis of benzofuran- and naphthalene-fused thiazinones as antimycobacterial agents. (PubMed, Arch Pharm (Weinheim)) - "In vitro testing showed micromolar activity for both compounds, and molecular docking simulations provided insights into their reduced inhibitory capacity toward the enzymatic target (DprE1). Calculated electrochemical potentials revealed a lower susceptibility to reduction as opposed to BTZ drug candidates, in line with the mechanistic requirement for covalent binding."

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

PARADIGM4TB: Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB (clinicaltrials.gov) - P2b | N=2500 | Not yet recruiting | Sponsor: University College, London

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