bedaquiline analogue (TBAJ-587) / Global Alliance for TB Drug Development - LARVOL DELTA

SYNERGY: Study of Combinations of Novel Promising Drugs for Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=135 | Not yet recruiting | Sponsor: TASK Applied Science

New P2 trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Advances in tuberculosis treatment: novel regimens, new drug pipelines, host-directed therapies, and updated management guidelines. (PubMed, Lancet Microbe) - "In 2024, an estimated 10·7 million people developed tuberculosis of whom approximately 390 000 developed multidrug-resistant (MDR) or rifampicin-resistant (RR) tuberculosis...Novel and repurposed compounds, including DprE1 inhibitors, next-generation oxazolidinones (including TBAJ-587 and TBAJ-876), cytochrome bc1 inhibitors, and long-acting formulations, are in late-stage evaluation. Host-directed therapies are also advancing as adjunctive strategies to reduce inflammation-mediated tissue damage and long-term morbidity, although they remain investigational. This Series paper synthesises advances in adult and paediatric tuberculosis therapeutics from Nov 15, 2020, to Jan 15, 2026, and highlights priorities to translate therapeutic innovation into equitable population-level effects."

Journal • Review • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Pediatrics • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Pharmacokinetics and safety of TBAJ-587, a novel antimycobacterial diarylquinoline, in healthy participants. (PubMed, Antimicrob Agents Chemother) - P1 | "TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535."

First-in-human • Journal • PK/PD data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

In vitro pharmacokinetics and pharmacodynamics of the diarylquinoline TBAJ-587 and its metabolites against Mycobacterium tuberculosis. (PubMed, Front Microbiol) - "The first-in-class diarylquinoline (DARQ) bedaquiline (BDQ) is in the medicines list for drug-resistant tuberculosis. PKPD analyses determined that Mtb was killed with lower exposures of TBAJ-587 and M3 than expected in ST and FA broth, suggesting previously underestimated potency in these media. Unlike commonly performed in in vitro PKPD studies that solely rely on nominal drug concentrations, our work precisely relates compound activity to actual effective concentrations that are measured over time directly in Mtb cultures, providing improved longitudinal data to feed in silico models for translational research."

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

Cu-Catalyzed dynamic kinetic asymmetric allylation enabled enantioselective assembly of sterically congested triaryl tertiary alcohols. (PubMed, Nat Commun) - "When combined with subsequent transformations, this method establishes a highly flexible platform for the synthesis of antitubercular agent (S,S)-TBAJ-587 and bedaquiline stereoisomers. Mechanistic investigations, including control experiments, density functional theory calculations, and interaction region indicator analyses, indicate that the steric characteristics of the ligand and weak intermolecular interactions synergistically lower the reaction energy barrier and enhance both reaction activity and stereocontrol."

Journal

Development of high-concentration long-acting injectable formulations of TBAJ-587 and TBAJ-876 as an extended treatment strategy against tuberculosis. (PubMed, J Control Release) - "Analysis of both compounds by X-ray powder diffraction (XRPD) revealed no major changes in the crystal structure following milling or after 24 weeks of storage at 40 °C. The in vivo pharmacokinetic study in rats showed that the suspensions containing either TBAJ-587 fumarate or TBAJ-876 tartrate offered a promising LAI option for the prolonged treatment of TB, as all formulations achieved prolonged drug plasma exposure for at least three months following administration."

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

Population pharmacokinetics of TBAJ-587 and its main metabolites-Evaluation of different loading dose strategies and early dose selection. (PubMed, Br J Clin Pharmacol) - P1 | "The final model simultaneously described the PK of TBAJ-587, M2 and M3 well. Simulations of final model identified that all simulated doses and regimens resulted in exposures that were below the safety references. A loading dose for 2 weeks resulted in initially higher concentrations, but a limited difference in exposure at 4 weeks and onwards, compared with no loading dose. A 100 mg once daily dose and higher reached the efficacy targets and can be studied further in combinations in phase 2a studies. Name of trial: Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults."

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

The kinetics of bedaquiline diffusion in tuberculous cavities open a window for emergence of resistance. (PubMed, J Infect Dis) - "The slow kinetics of diffusion of bedaquiline into and out of caseum creates spatio-temporal windows of subtherapeutic concentrations. Site-of-disease simulations of TBAJ587 and TBAJ876 predict reduced opportunities for resistance development."

Journal • Infectious Disease • Pulmonary 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

Therapeutic Strategies for Tuberculosis: Progress and Lessons Learned. (PubMed, Biomed Environ Sci) - "Promising agents such as second-generation bedaquiline analogs (TBAJ-587, TBAJ-876), sudapyridine (WX-081), delamanid, pretomanid, and TBI-166 (pyrifazimine) have shown efficacy against resistant Mtb strains...Agents such as vitamin D, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), statins, metformin, and biological agents like interleukins and granulocyte-macrophage colony-stimulating factor are under exploration...Despite these advancements, significant challenges remain in achieving the World Health Organization's "End TB Strategy" goals, particularly as the COVID-19 pandemic has diverted resources and attention. Ongoing research and global collaboration are crucial to develop novel therapeutic strategies, optimize treatment regimens, and ultimately reduce the global burden of TB."

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

TBAJ-587, a novel diarylquinoline, is active against Mycobacterium abscessus. (PubMed, Antimicrob Agents Chemother) - "TBAJ-587 is a novel diarylquinoline, which shows higher anti-tuberculosis activity, lower lipophilicity, and weaker inhibition of hERG channels than bedaquiline (BDQ). TBAJ-587 expressed bactericidal activity and was compatible with eight anti-NTM drugs commonly used in clinical practice; no antagonism was discovered. As such, TBAJ-587 represents a potential candidate for the treatment of NTM infections."

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

Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587. (PubMed, Nature) - "Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs."

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

Telacebec's Contribution to Combination Drug Regimens Is Strain-Dependent in a Mouse Model of Tuberculosis (ATS 2024) - "In H37Rv-infected mice, addition of pyrazinamide or clofazimine significantly increased the bactericidal activity of the next-generation diarylquinoline TBAJ-587, while telacebec did not; nor did telacebec increase the activity of either diarylquinoline TBAJ-587 or TBAJ-876 combined with clofazimine. However, in HN878-infected mice, addition of telacebec significantly increased the activity of bedaquiline+clofazimine ± pretomanid. Likewise, adding telacebec to the pretomanid+linezolid combination was antagonistic in H37Rv-infected mice but additive in HN878-infected mice; and addition of telacebec significantly increased the activity of rifapentine+moxifloxacin+pyrazinamide in HN878-infected, but not H37Rv-infected, mice...These experiments clearly highlight differences in the vulnerability of two commonly used M. tuberculosis strains to telacebec, which impact on its contribution to combination therapy. Recent work suggests that the H37Rv laboratory strain more..."

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

A novel diarylquinoline, TBAJ-587, is active against Mycobacterium abscessus in vitro (ECCMID 2024) - No abstract available

Preclinical

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis. (PubMed, Antimicrob Agents Chemother) - "In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587."

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

Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults (clinicaltrials.gov) - P1 | N=106 | Completed | Sponsor: Global Alliance for TB Drug Development | Active, not recruiting ➔ Completed

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

Synergistic Li/Li Bimetallic System for the Asymmetric Synthesis of Antituberculosis Drug TBAJ-587. (PubMed, J Org Chem) - "TBAJ-587, an analogue of the antituberculosis drug bedaquiline (BDQ), bearing a diarylquinoline skeleton retains the high bacterial potency, is less toxic, and has a better pharmacokinetic profile than the parent molecule, which has entered phase I clinical trials. Furthermore, the reaction could be conducted on a 5 g scale, and the product was obtained with 99.9:0.1 er after a simple recrystallization. The realization of this protocol will greatly aid the demand for clinical drug production."

Journal • Infectious Disease • Respiratory Diseases • Tuberculosis

A Novel Tool to Identify Bactericidal Compounds against Vulnerable Targets in Drug-Tolerant M. tuberculosis found in Caseum. (PubMed, mBio) - "By screening drug candidates in the surrogate model, we determined that the bedaquiline analogs TBAJ876 and TBAJ587, currently in clinical development, exhibit superior bactericidal against caseum-resident Mtb, both alone and as substitutions for bedaquiline in the bedaquiline-pretomanid-linezolid regimen approved for the treatment of multidrug-resistant TB. The assay is well suited to screen for bactericidal compounds against caseum-resident Mtb in a medium-throughput format, allowing for reduced reliance on resource intensive animal models that present large necrotic lesions and cavities. Importantly, this approach will aid the identification of vulnerable targets in caseum Mtb and can accelerate the development of novel TB drugs with treatment-shortening potential."

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

Next-Generation Diarylquinolines Improve Sterilizing Activity of Regimens with Pretomanid and the Novel Oxazolidinone TBI-223 in a Mouse Tuberculosis Model. (PubMed, Antimicrob Agents Chemother) - "Replacing linezolid or TBI-223 with sutezolid in combination with TBAJ-587 and pretomanid significantly reduced the proportion of mice relapsing. In combination with pretomanid and TBI-223, TBAJ-876 at 6.25 mg/kg was equipotent to TBAJ-587 at 25 mg/kg. We conclude that replacement of bedaquiline with these more efficacious and potentially safer diarylquinolines and replacement of linezolid with potentially safer and at least as efficacious oxazolidinones in the clinically successful BPaL regimen may lead to superior regimens capable of treating both drug-susceptible and drug-resistant TB more effectively and safely."

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

Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults (clinicaltrials.gov) - P1 | N=106 | Active, not recruiting | Sponsor: Global Alliance for TB Drug Development | Recruiting ➔ Active, not recruiting

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

Discovery of Anti-tubercular Analogues of Bedaquiline with Modified A-, B- and C-Ring Subunits. (PubMed, ChemMedChem) - "To date, the clinical use of the anti-tubercular therapy bedaquiline has been limited due to safety concerns. Recent investigations determined that modification of the B- and C-ring units of bedaquiline delivered new compounds (for example TBAJ-587) with potent anti-tubercular activity yet an improved safety profile due to reduced affinity for the hERG channel. Building on our recent discovery that substitution of bedaquiline's quinoline motif (the A-ring subunit) for C5-aryl pyridine groups led to retention of anti-tubercular activity, we investigated the concurrent modification of A-, B- and C-ring units within bedaquiline variants. These investigations led to the discovery that 4-trifluoromethoxyphenyl and 4-chlorophenyl pyridyl analogues of TBAJ-587 retained relatively potent anti-tubercular activity and delivered a significant reduction in hERG inhibition relative to bedaquiline, demonstrating that modifications of the A-, B- and C-ring..."

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

The pipeline of new molecules and regimens against drug-resistant tuberculosis. (PubMed, J Clin Tuberc Other Mycobact Dis) - "The clinical development and regulatory approval of bedaquiline, delamanid and pretomanid over the last decade brought about significant progress in the management of drug-resistant tuberculosis, providing all-oral regimens with favorable safety profiles...Investigational drugs in clinical development that target clinically validated mechanisms, such as second generation oxazolidinones (sutezolid, delpazolid, TBI-223) and diarylquinolines (TBAJ-876 and TBAJ-587) promise improved potency and/or safety compared to the first-in-class drugs. Compounds with novel targets involved in diverse bacterial functions such as cell wall synthesis (DrpE1, MmpL3), electron transport, DNA synthesis (GyrB), cholesterol metabolism and transcriptional regulation of ethionamide bioactivation pathways have advanced to early clinical studies with the potential to enhance antibacterial activity when added to new or established anti-TB drug regimens. Clinical validation of preclinical in vitro..."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: Global Alliance for TB Drug Development

Clinical • New P1 trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis