epetraborole (AN3365) / AN2 Therap, Brii Biosci - LARVOL DELTA

Repurposing epetraborole to combat Neisseria gonorrhoeae and Chlamydia trachomatis infections. (PubMed, Antimicrob Agents Chemother) - "Ceftriaxone (CRO) is the only recommended treatment for gonococcal infections but has no activity against C. trachomatis. Azithromycin (AZM) or doxycycline (DOX) is recommended for C. trachomatis infections; however, N. gonorrhoeae has developed resistance to both agents...Finally, in an in vivo mouse model of CRO-resistant N. gonorrhoeae genital tract infection, EBO exhibited a 99.95% reduction in bacterial burden after 2 days of treatment. Collectively, our findings highlight EBO as a promising candidate for the treatment of sexually transmitted infections that warrants further investigation."

Journal • Infectious Disease • Nontuberculous Mycobacterial Disease • Respiratory Diseases

Preclinical evaluation of epetraborole in the hollow fibre system model of Mycobacterium abscessus lung disease. (PubMed, J Antimicrob Chemother) - "Epetraborole microbial kill is the best, thus far, achieved in the HFS-MAB, more than two times omadacycline's 123 cfu/mL below B0. We propose to test a novel combination regimen of epetraborole plus omadacycline plus a β-lactam versus GBT first in the HFS-MAB, followed by clinical trials."

Journal • Preclinical • Pulmonary Disease • Respiratory Diseases

Pharmacokinetics and in vivo efficacy of epetraborole against Burkholderia pseudomallei. (PubMed, Sci Rep) - "Notably, this study represents the first demonstration of in vivo efficacy against a panel of ten genetically and geographically diverse B. pseudomallei strains in a murine model. This unprecedented breadth of strain coverage provides strong evidence of EBO's robust and strain-independent therapeutic potential."

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

Epetraborole pharmacokinetics/pharmacodynamics in the hollow fiber system model of Mycobacterium tuberculosis. (PubMed, Antimicrob Agents Chemother) - "In the hollow fiber system model of tuberculosis (TB), the ratio of area under the concentration-time curve to MIC (AUC0-24/MIC) of 327.1 was identified as the epetraborole optimal exposure target for Mycobacterium tuberculosis kill. Monte Carlo simulation experiments showed that even the intravenous dose of 1,500 mg/twice daily would fail in the majority of patients, and the dose needed for good efficacy for TB may likely not be safe for patients."

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

Sulbactam-Durlobactam Plus Ceftriaxone Dosing and Novel Treatment Regimens for Mycobacterium abscessus Lung Disease. (PubMed, bioRxiv) - "Next, the sulbactam-durlobactam target exposure plus ceftriaxone was administered in the HFS-MAB inoculated with three different MAB isolates, as was the sulbactam-durlobactam-ceftriaxone combination with epetraborole and omadacycline (SDCEO). Sulbactam-durlobactam-ceftriaxone achieved the highest microbial kill encountered so far in the HFS-MAB. Sulbactam-durlobactam-ceftriaxone should be tested as the backbone for novel treatment shortening regimens."

Journal • Pulmonary Disease • Respiratory Diseases

Drug-target residence time and the post-antibiotic effect: Strategies to improve dosing regimens (ACS-Fall 2025) - "This includes ganfeborole and epetraborole which are benzoxaborole inhibitors of leucyl-tRNA synthetase (LeuRS), and inhibitors of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC). We have studied the residence time and PAE of these compounds and have determined that decreasing the resynthesis rate of LeuRS synthesis leads to an increase in PAE. We have also developed a high-throughput assay to screen the Escherichia coli Keio collection of ∼4000 deletion strains to identify genes that enhance the PAE caused by antibacterial compounds and have identified a molecular link between LpxC stability and synthesis of the LPS core antigen."

Infectious Disease

Genome-wide Screening of the Escherichia coli Keio Knockout Collection Identifies Genetic Determinants of Epetraborole Hypersusceptibility. (PubMed, Eur J Clin Microbiol Infect Dis) - "This study identifies novel genetic contributors to epetraborole susceptibility and provides a framework for exploring adjuvant therapies or resistance mechanisms to enhance its clinical utility against MDR infections."

Biomarker • Journal • Infectious Disease

Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease (clinicaltrials.gov) - P2/3 | N=177 | Terminated | Sponsor: AN2 Therapeutics, Inc | N=314 ➔ 177 | Active, not recruiting ➔ Terminated; EBO-301 truncated Phase 3 study (n=97) misses primary endpoint; results unable to confirm clinical efficacy observed in Phase 2 study.

Enrollment change • Trial termination • Pulmonary Disease • Respiratory Diseases

Time-Dependent Inhibition of Leucyl-tRNA-Synthetase (LeuRS): Insight into Target Vulnerability. (PubMed, ACS Infect Dis) - "The benzoxaboroles generated short PAEs (<1 h) in E. coli, however, the PAE values of AN3334 and epetraborole increased from 0.88 to 1.70-3 h when a sub-MIC concentration of the aminoglycoside tobramycin was included in the media. pSILAC revealed that the synthesis rate of ecLeuRS was reduced 1.6-fold in the presence of sub-MIC tobramycin, reinforcing the role that protein turnover plays in target vulnerability."

Journal

Repurposing drugs to advance the treatment of Buruli ulcer. (PubMed, Antimicrob Agents Chemother) - "Using a virulent reporter strain of M. ulcerans with intrinsic bioluminescence (MuAL), we compared the minimum inhibitory concentration (MIC) of moxifloxacin, bedaquiline, telacebec, tebipenem, omadacycline, and epetraborole with standard-of-care drugs-rifampin and clarithromycin. The MuAL strain is useful in the rapid screening of drugs' efficacy and potency against M. ulcerans. We should leverage the progress made in the tuberculosis drug development pipeline to repurpose the drugs for the rapid development of new therapeutic modalities for Buruli ulcer."

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

AN2 Provides Strategic Update for Phase 3 EBO-301 Trial in Treatment Refractory MAC Lung Disease (Businesswire) - "AN2 Therapeutics, Inc...today announced its submission of an amended statistical analysis plan to the FDA selecting the Quality of Life – Bronchiectasis (QOL-B) respiratory domain patient reported outcome (PRO) instrument as the primary efficacy endpoint for the Phase 3 part of the EBO-301 trial. The Company will evaluate whether the Phase 3 data supports the Phase 2 findings, where potential clinical proof-of-concept was shown...The Company intends to release topline Phase 3 results in the second quarter of 2025, subject to the timing of any potential FDA response."

Clinical protocol • P3 data: top line • Infectious Disease • Nontuberculous Mycobacterial Disease

In vitro susceptibility of 147 international clinical Mycobacterium abscessus isolates to epetraborole and comparators by broth microdilution. (PubMed, J Antimicrob Chemother) - "Epetraborole demonstrated potent in vitro activity against M. abscessus with MICs from 0.03 to 0.25 mg/L and consistent activity against all subspecies, resistance phenotypes and morphotypes. These data support clinical evaluation of epetraborole as a therapeutic option for M. abscessus disease."

Journal • Preclinical • Nontuberculous Mycobacterial Disease

Screening of the Pandemic Response Box library identified promising compound candidates against extensively drug-resistant Acinetobacter baumannii (ASTMH 2024) - "In this study, we assessed 400 structurally diverse compounds from the Medicines for Malaria Pandemic Response Box for their activity against two clinical isolates of A. baumannii: A. baumannii 5075, known for its extensive drug resistance, and A. baumannii QS17-1084, obtained from an infected wound in a Thai patient and displaying resistance to nearly all antimicrobial classes, including tetracycline. Our findings highlight gepotidacin, epetraborole, and eravacycline as promising candidates for further evaluation in murine wound infection models against multidrug-resistant A. baumannii. These compounds hold potential for addressing the critical need for effective antibiotics in the face of rising antimicrobial resistance."

Infectious Disease • Malaria

Management of Refractory Nontuberculous Mycobacterial Pulmonary Disease (KATRDIC 2024) - "Liposomal amikacin, for example, has shown an additional 20% bacterial conversion in refractory cases. Other new drugs, such as epetraborole, delpazolid, inhaled clofazimine, and omadacycline, have also been utilized for NTM-PD. When bacterial conversion is difficult, the treatment goal may shift to improving quality of life through appropriate antibiotic therapy. This presentation will comprehensively address the causes of treatment-refractory NTM-PD and outline appropriate management strategies."

Nontuberculous mycobacteria • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases

RECALCITRANT NONCAVITARY MYCOBACTERIUM AVIUM COMPLEX PULMONARY DISEASE WITH MYCOBACTERIUM ABSCESSUS COINFECTION (CHEST 2024) - "Management of refractory disease involves a multidisciplinary approach including maximizing airway clearance, re-assessing for antimicrobial susceptibility, changes to pharmacologic regimen (intermittent to daily dosing, clofazimine, amikacin liposome inhalation suspension (ALIS)), assessing for medication compliance, and absorption with therapeutic drug level monitoring...Four months later (eleven months into treatment), cultures continued to be positive, so rifampin was added...These revealed sub-therapeutic dosing for ethambutol and azithromycin... In this case, the addition of linezolid to an existing four drug regimen appears to have finally led to culture conversion. Continued monitoring and sputum testing will be needed. Additional research is crucial to assess treatment of refractory MAC with other currently available drugs such as bedaquiline, clofazimine, and oxazolidinones."

Bronchiectasis • Endocrine Disorders • Gastroesophageal Reflux Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease (clinicaltrials.gov) - P2/3 | N=314 | Active, not recruiting | Sponsor: AN2 Therapeutics, Inc | Trial completion date: Sep 2026 ➔ Dec 2024 | Trial primary completion date: Sep 2025 ➔ Dec 2024

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

Evaluation of MMV Pandemic Response Box compounds to identify potent compounds against clinically relevant bacterial and fungal clinical isolates in vitro. (PubMed, New Microbes New Infect) - "MMV1580854, MMV1579788, eravacycline and epetraborole inhibited both the bacterial test isolates...Five compounds from MMV Pandemic Box were found to be inhibiting colistin and ceftazidime resistant A. baumannii clinical isolate, also against colistin and β-lactam resistant P. aeruginosa clinical isolate...MMV1782110, Eberconazole, amorolfine and luliconazole exhibited potent anti-fungal activity. Further investigations are warranted to identify the targets and mechanism."

Journal • Preclinical • Infectious Disease • Malaria

Efficacy of epetraborole against Mycobacteroides abscessus in a mouse model of lung infection. (PubMed, Antimicrob Agents Chemother) - "Once-daily oral 100 mg/kg EBO was as effective as twice-daily 100 mg/kg imipenem injection. Our study suggests that EBO could address the unmet need for effective oral treatment options for Mab lung disease, given the high rates of Mab drug resistance and limited tolerable intravenous options."

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

Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease (clinicaltrials.gov) - P2/3 | N=314 | Active, not recruiting | Sponsor: AN2 Therapeutics, Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • Pulmonary Disease • Respiratory Diseases

In Vitro Evaluation of Drug-Drug Interaction Potential of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor. (PubMed, Pharmaceuticals (Basel)) - "At clinically relevant concentrations, neither EBO nor M3 inhibited major human efflux or uptake transporters. Based on these data, at clinically relevant concentrations of EBO and M3, there is a low risk of victim or perpetrator DDI."

Journal • Preclinical • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • CYP1A2 • CYP3A4

Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease (clinicaltrials.gov) - P2/3 | N=314 | Recruiting | Sponsor: AN2 Therapeutics, Inc

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

Screening of MMV pandemic response and pathogen box compounds against pan-drug-resistant Klebsiella pneumoniae to identify potent inhibitory compounds. (PubMed, New Microbes New Infect) - "MMV1580854 (94.60 ​%), MMV1579788 (94.65 ​%), MMV1578574 (eravacycline; 93.13 ​%), MMV1578566 (epetraborole; 95.29 ​%) and MMV1578564 (96.32 ​%) were able to exhibit a higher percentage of growth inhibition. Among the five, epetraborole andMMV1578564 were identified as highly potent based on the persister frequency and MICs. The pan-drug resistant clinical isolate used in this study was found to be acting differently from the reference or wild type strains against the test compounds in a previous study."

Journal • Infectious Disease • Malaria • Pneumonia • Respiratory Diseases

Epetraborole, a leucyl-tRNA synthetase inhibitor, demonstrates murine efficacy, enhancing the in vivo activity of ceftazidime against Burkholderia pseudomallei, the causative agent of melioidosis. (PubMed, PLoS Negl Trop Dis) - "In addition, adding epetraborole to ceftazidime significantly improved antimicrobial activity in this animal model. This work warrants further exploration of epetraborole as a candidate for treating melioidosis and substantiates LeuRS as a clinically relevant drug target in B. pseudomallei."

Journal • Preclinical • Infectious Disease

Study of Epetraborole in Patients With Treatment-refractory MAC Lung Disease (clinicaltrials.gov) - P2/3 | N=314 | Recruiting | Sponsor: AN2 Therapeutics, Inc | Trial completion date: May 2025 ➔ Sep 2026 | Trial primary completion date: May 2024 ➔ Sep 2025

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

Epetraborole (IDWeek 2023) - No abstract available

Infectious Disease