Telacebec for Ultrashort Treatment of Buruli Ulcer in a Mouse Model

Abstract

Telacebec (Q203) is a new antitubercular drug with extremely potent activity against Mycobacterium ulcerans Here, we explored the treatment-shortening potential of Q203 alone or in combination with rifampin (RIF) in a mouse footpad infection model. The first study compared Q203 at 5 and 10 mg/kg doses alone and with rifampin. Q203 alone rendered most mouse footpads culture negative in 2 weeks. Combining Q203 with rifampin resulted in a relapse-free cure 24 weeks after completing 2 weeks of treatment, compared to a 25% relapse rate in mice receiving RIF with clarithromycin, the current standard of care, for 4 weeks. The second study explored the dose-ranging activity of Q203 alone and with RIF, including the extended activity of Q203 after treatment discontinuation. The bactericidal activity of Q203 persisted for ≥ 4 weeks beyond the last dose. All mice receiving just 1 week of Q203 at 2 to 10 mg/kg were culture negative 4 weeks after stopping treatment. Mice receiving 2 weeks of Q203 at 0.5, 2, and 10 mg/kg were culture negative 4 weeks after treatment. RIF did not increase the efficacy of Q203. A pharmacokinetics substudy revealed that Q203 doses of 2 to 10 mg/kg in mice produce plasma concentrations similar to those produced by 100 to 300 mg doses in humans, with no adverse effect of RIF on Q203 concentrations. These results indicate the extraordinary potential of Q203 to reduce the duration of treatment necessary for a cure to ≤ 1 week (or 5 doses of 2 to 10 mg/kg) in our mouse footpad infection model and warrant further evaluation of Q203 in clinical trials.

Keywords: Buruli ulcer; Mycobacterium ulcerans; Q203; Telacebec.

FIG 1

Footpad swelling grade of infected mouse footpads in response to treatment in study 1. Treatment was initiated 6 weeks after infection when swelling approached swelling grade 2.5. Swelling grade 0 corresponds to no clinically visible pathology, grade 1 infers redness of the footpad, grade 2 represents edematous swelling of the footpad, and grade 3 infers ascending swelling of the leg and impending necrosis. Data points represent medians per treatment group. Data were normalized to day 0 (beginning of treatment) by subtracting from the median swelling grade of all mice at D0 and assuming the total median as group mean for that time point. All Q203-containing regimens rapidly reduced swelling grade compared with R₁₀C₁₀₀ controls. By the end of 1 week of treatment, all Q203-containing regimens, except the lowest dose of Q203, 5 mg/kg, had reduced the swelling to below grade 1, while no change was seen in the RC treatment controls. By the end of 2 weeks, all mice treated with Q203-containing regimens had only residual swelling left; the median swelling grade was 0.25. Numbers in subscripts after drugs indicate doses in mg/kg. D, day; R, rifampin; C, clarithromycin; Q, Q203/Telacebec.

FIG 2

Microbiological outcome in study 1. Mice were infected with 2.71 ± 0.93 log₁₀ CFU/footpad of M. ulcerans into both hind footpads. After 6 weeks of incubation, treatment was initiated (D0). At this time point, the CFU mean (± standard deviation [SD]) equaled 5.42 (±0.56). Groups of mice were sacrificed at week 1, week 2, and week 4, and footpads (n = 6) were dissected, minced, and plated on 7H11 selective agar for colony counting and CFU analysis. For statistical analysis, all test regimens were compared to R₁₀C₁₀₀ controls. (A) After 1 week of treatment, all Q203-containing regimens, except Q₁₀ given alone, were significantly better than controls, with R₁₀Q₁₀ (P < 0.0001) and R₂₀Q₁₀ (P < 0.001) showing the best activity. (B) At week 2, most footpads in mice treated with Q203-containing regimens were culture negative and significantly better than R₁₀C₁₀₀ (P ≤ 0.0008). At week 4, none of the mice in the combination treatment groups, including R₁₀C₁₀₀ controls, were culture positive (data not shown). Monotherapy regimens were not tested at this time point. Numbers in subscript after drugs indicate doses in mg/kg. D, day; UT, untreated; R, rifampin; C, clarithromycin; Q, Q203/Telacebec; NT, not tested. Dashed line indicates the pretreatment CFU at D0. Horizontal lines indicate median values.

FIG 3

Single-dose PK for Q203. Mice were dosed with either 0.5 mg/kg (green circle), 2 mg/kg (red squares), or 10 mg/kg (blue triangles) of Q203 and the blood collected for plasma concentrations at the indicated time points. Median PK parameters shown in the inset indicate dose-proportional exposures.

FIG 4

Footpad swelling grade of infected mouse footpads in response to treatment in study 2. Treatment was initiated 6 weeks after infection when the median swelling grade approached 2. Data points represent medians per treatment group. (A and B) Swelling results in mice treated for 1 week. (C and D) Swelling results in mice treated for 2 weeks. Monotherapy groups are shown in panels A and C, while combination treatment groups are shown in panels B and D. R₁₀C₁₀₀ is the standard treatment control. Solid lines represent change in footpad swelling during treatment, while that after stopping treatment is shown by dashed lines. All Q203-containing regimens reduced footpad swelling after just 1 week of treatment and continued to show response after stopping treatment. Most footpads were at baseline levels after 2 to 3 weeks. RIF alone produced a slight decline in swelling after peaking at 1 week. The footpads never reached a median grade of 1 after 4 weeks of follow-up. As with 1 week of treatment, 2 weeks of Q203-containing regimens rapidly rendered footpads swelling free. In comparison, the RC-treated controls showed gradual decreases in footpad swelling. Numbers in subscripts after drugs indicate doses in mg/kg. D, day; UT, untreated; R, rifampin; C, clarithromycin; Q, Q203/Telacebec.

FIG 5

Microbiological outcome in study 2. (A and B) Response to treatment for 1 week. (C and D) Response to treatment for 2 weeks. Panels A and C show results for monotherapy, and panels B and D show combination treatment groups. Solid lines indicate fall in mean CFU (±standard error of the mean [SEM]) during treatment, and dashed lines show reduction after stopping treatment. After 1 week of treatment, Q203-containing regimens showed a marked dose response, and although CFU counts at week 1 were not significantly different than RC controls, more dramatic reductions occurred during the 4-week follow-up period after stopping treatment. All Q203-containing regimens except Q_0.5 were significantly better after 1 week of treatment than RC treatment for 2 weeks. After 2 weeks of treatment, all Q203-containing regimens were significantly better than RC control after 2 weeks and rendered footpads negative at follow-up 2 weeks after stopping treatment.