Epetraborole in Patients With Mycobacterium Abscessus Lung Disease

Non-tuberculous mycobacterial lung disease (NTM-LD) is a chronic, debilitating disease that can cause significant morbidity and mortality, and reduces quality of life. The primary intervention to treat NTM-LD is antibiotic treatment to eliminate the causative pathogen and thereby prevent progression of NTM-associated lung destruction and respiratory compromise. Among NTM organisms causing pulmonary infection, Mycobacterium abscessus complex (MABc) LD requires particularly complicated, prolonged and onerous intravenous treatment regimens that are burdensome to patients. New therapeutic options, especially those that can be administered orally, represent a high unmet need. Epetraborole (EBO), a boron-containing heterocycle also possessing amine and hydroxyl functional groups, blocks bacterial protein synthesis by inhibiting bacterial LeuRS. Epetraborole is active against Mycobacterium abscessus complex (MABc) organisms in vitro, including against isolates resistant to drugs commonly used to treat MABc-Lung Disease (LD) (e.g., clarithromycin and amikacin). To date, no clinical efficacy data are available for use of EBO in humans with MABc-LD. However, available nonclinical and PK data support the potential efficacy of EBO in MABc-LD. A Phase 1 human lung PK study in healthy volunteers showed that the exposure of EBO in alveolar (lung) macrophages, lung cells that are primarily infected with mycobacteria in NTM-LD, was approximately 5-fold higher than in plasma. EBO exposure in pulmonary epithelial lining fluid (ELF) is approximately 53% of that in plasma. Because NTM organisms may also be found in ELF, adequate EBO concentrations in that space are potentially important to achieve therapeutic success. Furthermore, PK/PD modeling data support the potential efficacy of EBO for treatment of MABc-LD. Since the EBO MIC90 for MABc isolates is \~256-fold lower than that observed for MAC isolates from the truncated EBO-301 Phase 2/3 study in treatment-refractory Mycobacterium avium complex lung disease, treatment outcomes in MABc-LD are expected to be favorable. The molecule therefore has the potential to address the unmet need in MABc-LD patients with limited treatment options. For this study, two oral EBO dose regimens will be studied in patients with MABc-LD compared to placebo: 500 mg daily and 750 mg daily.