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

Semi-Mechanistic Joint Population Pharmacokinetic Modeling of the Novel Antituberculosis Drug Sorfequiline and Its Metabolite M3 in Healthy Volunteers. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "Food reduced the fraction of sorfequiline dose absorbed as M3, likely due to limited gut first-pass metabolism. The developed model provides an initial platform for future pharmacokinetic/pharmacodynamic analyses and simulation of both analytes' exposures under drug-drug interaction scenarios."

Clinical • Journal • PK/PD data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CYP3A4

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

Sorfequiline-based Regimens in Adults With Newly Diagnosed Drug-sensitive Pulmonary TB (clinicaltrials.gov) - P2 | N=100 | Recruiting | Sponsor: Global Alliance for TB Drug Development | Not yet recruiting ➔ Recruiting

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

Sorfequiline-based Regimens in Adults With Newly Diagnosed Drug-sensitive Pulmonary TB (clinicaltrials.gov) - P2 | N=100 | Not yet recruiting | Sponsor: Global Alliance for TB Drug Development

New P2 trial • 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=309 | Active, not recruiting | Sponsor: Global Alliance for TB Drug Development | Trial completion date: Jun 2026 ➔ Feb 2027

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

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

Structural insights of mycobacterial ATP synthase and recent updates on molecular recognition of Mtb ATP synthase inhibitors: a review. (PubMed, Future Med Chem) - "The discovery of Bedaquiline in 2012 has validated mycobacterial ATP synthase as a substantial target to combat resistance developed in mycobacterial strains...It also highlights its distinguished features from similar enzymes present in eukaryotes, fungi, and other bacterial species. Additionally, the present work reviews recent updates on various heterocyclic active chemical compounds designed as mycobacterial ATP synthase inhibitors for the treatment of tuberculosis till 2025."

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

Cardiodynamic evaluation of sorfequiline (TBAJ-876): results from a first-in-human study. (PubMed, Antimicrob Agents Chemother) - P2 | "Concentration-QTc modeling showed a shallow, non-significant slope. The predicted mean effect on ΔΔQTcF at the maximum geometric mean Cmax of sorfequiline's M3 metabolite was -1.1 ms (90% CI -9.5 to 7.4).CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT06058299."

First-in-human • Journal • P1 data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Potential correlations between the energies at the solid/liquid interfaces and the physical stability of pharmaceutical suspensions. (PubMed, Int J Pharm) - "Some surfactant-drug compound combinations, such as polysorbate 20 with naproxen or TBAJ-876, showed contact angles near 0°, potentially indicating superspreading behavior...While some correlations between low work of adhesion and poor stabilizer performance were noted - such as vitamin E TPGS with bedaquiline and poloxamer 188 with haloperidol - no consistent trend was observed across all surfactants and drug compounds. Most data clustered closely, with outliers offering limited predictive value between interfacial measurements and particle size profiles. These findings therefore suggested that although interfacial energy measurements provided valuable insight into surfactant behavior and solid-liquid interactions, they were not sufficient as standalone predictors of physical stability in pharmaceutical suspensions."

Journal

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