TBAJ-876 / Global Alliance for TB Drug Development - LARVOL DELTA

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

Phase 2 Trial Assessing TBAJ876 or Bedaquiline, with Pretomanid and Linezolid in Adults with Drug-sensitive Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=309 | Active, not recruiting | Sponsor: Global Alliance for TB Drug Development | Recruiting ➔ Active, not recruiting

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

Pharmacokinetics and safety of TBAJ-876, a novel antimycobacterial diarylquinoline, in healthy subjects. (PubMed, Antimicrob Agents Chemother) - "TBAJ-876, a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile compared with bedaquiline, is under development for the treatment of drug-susceptible and drug-resistant tuberculosis (TB). With co-administration of TBAJ-876, the AUC0-inf of midazolam was unchanged and the Cmax was reduced by 14%; the AUC0-last of digoxin was increased by 51%, and the Cmax was increased by 18%. These results support further investigation of TBAJ-876 for the treatment of tuberculosis."

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

Relative contributions of the novel diarylquinoline TBAJ-876 and its active metabolite to the bactericidal activity in a murine model of tuberculosis. (PubMed, J Infect Dis) - "These findings emphasize the need to consider metabolites and their potentially distinct exposure and activity profiles compared to parent drugs to enhance the translational value of mouse model-driven predictions."

Journal • Preclinical • 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

Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=300 | Recruiting | Sponsor: Global Alliance for TB Drug Development | Not yet recruiting ➔ Recruiting

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

The heme oxygenase-1 metalloporphyrin inhibitor stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model. (PubMed, Antimicrob Agents Chemother) - "Here, we evaluated the adjunctive HDT activity of a novel HO-1 inhibitor, stannsoporfin (SnMP), in combination with a novel MDR-TB regimen comprising a next-generation diarylquinoline, TBAJ-876 (S), pretomanid (Pa), and a new oxazolidinone, TBI-223 (O) (collectively, SPaO), in Mtb-infected BALB/c mice. SnMP was well tolerated and did not significantly alter gross or histological lung pathology. SnMP is a promising HDT candidate requiring further study in combination with regimens for drug-resistant TB."

IO biomarker • Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD38 • HMOX1

GaMF1.39's antibiotic efficacy and its enhanced antitubercular activity in combination with clofazimine, Telacebec, ND-011992, or TBAJ-876. (PubMed, Microbiol Spectr) - "In this study, we present the GaMF1.39 antimycobacterial compound, targeting the rotary subunit γ of the biological engine. The compound is bactericidal, inhibits infection ex vivo, and displays enhanced anti-tuberculosis activity in combination with ETC inhibitors, which promises new strategies to shorten tuberculosis chemotherapy."

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

Phase 2 Trial Assessing TBAJ876 or Bedaquiline, With Pretomanid and Linezolid in Adults With Drug-sensitive Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=300 | Not yet recruiting | Sponsor: Global Alliance for TB Drug Development

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

A tale of two inhibitors: diarylquinolines and squaramides. (PubMed, EMBO J) - "The diarylquinoline bedaquiline (BDQ) is an FDA-approved drug for the treatment of multidrug-resistant tuberculosis that targets the mycobacterial adenosine triphosphate (ATP) synthase, a key enzyme in cellular respiration. In a recent study, Courbon et al (2023) examine the interaction between Mycobacterium smegmatis ATP synthase with the second generation diarylquinoline TBAJ-876 and the squaramide inhibitor SQ31f, showing that both drugs prevent the rotatory motions needed for enzymatic function."

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

Mechanism of mycobacterial ATP synthase inhibition by squaramides and second generation diarylquinolines. (PubMed, EMBO J) - "The diarylquinoline bedaquiline (BDQ), a mycobacterial ATP synthase inhibitor, is an important medication for treatment of drug-resistant tuberculosis but suffers from off-target effects and is susceptible to resistance mutations. Remarkably, BDQ, TBAJ-876, and SQ31f all induce similar conformational changes in ATP synthase, suggesting that the resulting conformation is particularly suited for drug binding. Further, high concentrations of the diarylquinolines uncouple the transmembrane proton motive force while for SQ31f they do not, which may explain why high concentrations of diarylquinolines, but not SQ31f, have been reported to kill mycobacteria."

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

An Alternative Approach to Tablet Splitting and Grinding for Medication Administration. (PubMed, Int J Pharm Compd) - "We developed a new device comprised of a flexible receptacle, a tight-fitting cap, and a suction cup bottom to convert tablets into liquid preparations. Tuberculosis treatment drugs, TBAJ-876 and TBI-223, were dispersed within the device utilizing water and commonly available suspending vehicles...The effectiveness of the device was also evaluated using commercially available tablets of acetaminophen, amlodipine, glimepiride, metformin, and valsartan...Aliquots for partial dose delivery can be withdrawn accurately. These findings demonstrate that XTEMP-R can be used to accurately deliver doses of suspensions for patients who cannot swallow tablets."

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

A Phase 1, Drug-Drug Interaction Study of TBAJ-876 in Healthy Adults (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: Global Alliance for TB Drug Development | Recruiting ➔ Completed | N=44 ➔ 28 | Trial completion date: Jan 2023 ➔ Aug 2022

Enrollment change • Trial completion • Trial completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CYP3A4

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

Evaluate Safety, Tolerability, PK of TBAJ-876 in Healthy Adults (clinicaltrials.gov) - P1 | N=107 | Completed | Sponsor: Global Alliance for TB Drug Development | Active, not recruiting ➔ Completed | Trial completion date: Mar 2022 ➔ Nov 2022 | Trial primary completion date: Mar 2022 ➔ Jun 2022

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

Binding properties of the anti-TB drugs bedaquiline and TBAJ-876 to a mycobacterial F-ATP synthase. (PubMed, Curr Res Struct Biol) - "We further calculate the binding free energy of both drugs bound to their target and predict an increased affinity of TBAJ-876 for the F domain. This approach will be useful in future efforts to design new and highly potent DARQ analogs targeting F-ATP synthases of Mtb, nontuberculosis mycobacteria (NTM) as well as the M. leprosis complex."

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

A Phase 1, Drug-Drug Interaction Study to Evaluate Safety, Tolerability, and Induction Potential of TBAJ-876 on CYP3A4 and P-glycoprotein and Inhibition Potential of TBAJ-876 on P-glycoprotein in Healthy Adults (clinicaltrials.gov) - P1 | N=44 | Recruiting | Sponsor: Global Alliance for TB Drug Development

New P1 trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CYP3A4