Oral oxaborole MRX-5 exhibits efficacy against pulmonary Mycobacterium abscessus in mouse

Abstract

Mycobacterium abscessus (Mab) is an opportunistic pathogen common in patients with lung comorbidities and immunosuppression. There are no FDA-approved treatments, and current treatment has a failure rate exceeding 50%. The intravenous oxaborole MRX-6038 is active against Mab. This study evaluated MRX-5, the oral prodrug, against five Mab isolates in a mouse lung infection model. MRX-5 showed dose-dependent efficacy, with 15 and 45 mg/kg doses comparable to the standard of care, supporting progression to clinical trial.

Keywords: MRX-5; Mycobacterium abscessus.

Fig 1

MRX-6038 pharmacokinetics profile in C3HeB/FeJ mice. (A) Mean (± standard deviation) of plasma concentrations of MRX-6038 vs sampling time points following oral administration of 5, 15, and 45 mg/kg bolus is shown. Dose linearity of the area under the plasma concentration vs time curve from time 0 to 12 h post dosing (AUC_0-12) (B) and C_max (C), and linearity correlation coefficient are shown.

Fig 2

(A) Schematic of drug efficacy assessment in a mouse model of Mab lung infection. The day on which antibiotic administration was initiated is considered reference and designated “week 0.” One week prior, all mice were simultaneously infected by exposing them to aerosol of a Mab culture. Mab burden in the lungs of mice was enumerated at weeks −1, 0, +1, +2, and +4 (n = 5 per group at weeks −1, 0, +1, and +2, and n = 10 per group at week +4). M. abscessus burden in the lungs of mice infected with isolates M9501 (B), M9507 (C), M9530 (D), and M9510 (E). The week −1 time point corresponds to 24 h post-infection with Mab via aerosol. The week 0 time point marks 1 week post-infection and the beginning of treatment. The time points at weeks +1, +2, and +4 correspond to the conclusion of 1, 2, and 4 weeks of treatment, respectively, with the following regimens: once-daily sterile DI water (H₂O), twice-daily subcutaneous imipenem at 100 mg/kg (IMI), once-daily oral MRX-5 at 5 mg/kg (MRX5-5), 15 mg/kg (MRX5-15), and 45 mg/kg (MRX5-45). The graph shows the mean Mab burden in the lungs along with the standard error for each group at each time point (n = 5 at weeks −1, 0, +1, and +2; n = 10 at week +4).