Contribution of different oxazolidinones to the efficacy of novel regimens containing bedaquiline and pretomanid in murine models of TB

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1 Contribution of different oxazolidinones to the efficacy of novel regimens containing bedaquiline and pretomanid in murine models of TB Rokeya Tasneen 1, Fabrice Betoudji 1, Véronique Dartois, Tian Yang 3, Khisimuzi E. Mdluli 3, Eric L. Nuermberger 1 1 Johns Hopkins University School of Medicine, Baltimore, MD, Public Health Research Institute and New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ; 3 Global Alliance for TB Drug Development, New York, NY

2 Unmet need in TB treatment A short-course oral regimen that is active against virtually all circulating strains of DR-TB is safe and well-tolerated has no serious drug-drug interactions produces cure rates at least comparable to the first-line regimen for drug susceptible TB prevents selection of mutants resistant to component drugs

3 Background The novel combo of bedaquiline+pretomanid (JPa) plus sutezolid (U) has sterilizing activity superior to the 1 st -line regimen (RHZ) in BALB/c mice As linezolid (L) & tedizolid (T) are marketed agents, and AZD 57 is in Phase II, these oxies warrant evaluation in this combo. Further study of these combos in C3HeB/FeJ mice which, unlike BALB/c mice, develop caseous lesions will be useful to confirm their efficacy. R Tasneen et al, AAC 15; 59:19

4 Oxazolidinone plasma AUC in BALB/c mice (JHU) and humans, with reference to MIC vs. M. tb Drug Species Dose AUC -h (µg-h/ml) MIC* (µg/ml) Linezolid Mouse 1 mpk.5-1. Human 1 mg 15-9 Sutezolid Mouse 5 mpk Mouse (M1) 5 mpk Human 1 mg 7.13 Human (M1) 1 mpk 3. Tedizolid Mouse 1 mpk..5 mpk 77.7 Human mg - AZD 57 Mouse 15 mpk Human mg bid 1. *MIC 5, geometric mean or median values from the literature

5 Addition of a linezolid (L) or sutezolid (U) increases the bactericidal activity of bedaquiline+pretomanid (JPa) in BALB/c mice weeks Doses tested J = 5 mpk Pa = 1 mpk L = 5-1 mpk U = 5 mpk weeks Lung log 1 CFU Lung log 1 CFU D JPa JPaU JPaL 5 JPaL 1 D RHZ JPa JPaU JPaL 5 1. Both oxies increased the bactericidal activity of the JPa combo.. The JPaOxie combos were superior to RHZ at wks. 3. U was superior to L at either dose.. Halving the L dose or duration did not significantly affect results at weeks. JPaL 1 1JPaL 1, 1JPa

6 Addition of a linezolid (L) or sutezolid (U) increases the sterilizing activity of bedaquiline+pretomanid (JPa) in BALB/c mice Proportion relapsing after treatment for: Regimen months 3 months RHZ/RH /1 (57%) JPa 3/1 (1%) JPaU 1/1 (7%) 3JPaL 1 /15 (%) *p =.11 vs. JPa; p.1 vs. RHZ by 1-tailed Fisher exact test /1* (%) /15* (%) 1. JPaU and JPaL were superior to RHZ at 3 months, but JPa was not. Limiting the duration of L 1 to the first month modestly reduced sterilizing activity

7 L u n g lo g 1 C F U L u n g lo g 1 C F U AZD 57 (AZD) and tedizolid (T) increase the activity of JPa in BALB/c mice, but not as much as U or L w e e k s w e e k s D J P a J P a U J P a L 1 J P a L 5 J P a A Z D J P a T D R H Z J P a J P a U J P a L 1 J P a L 5 J P a A Z D J P a T At wks: all oxies add to JPa except T (p<.1 for U, L, RWJ; p<.5 for AZD) At wks: all oxies add to JPa (p<.1 for U, L, RWJ; p<.1 for AZD; p<.5 for T) Drug doses (in mpk): U 5; L5-1; AZD 15; T 1 (as pro-drug)

8 L u n g lo g 1 C F U L u n g lo g 1 C F U Sutezolid and linezolid increase the bactericidal activity of JPa in C3HeB/FeJ mice w e e k s w e e k s 1 1 D R H Z J P a J P a U J P a L J P a A z D R H Z J P a J P a U J P a L J P a A z At wks: all oxies but AZD add to JPa At wks: no oxie adds to JPa (p<.1)

9 L u n g lo g 1 C F U L o g 1 C F U /L u n g JPa + oxies in C3HeB/FeJ mice, nd expt C o m b o e x p t 1 ( w k s ) D o s e -ra n g in g e x p t ( w k s ) 1 1 D R H Z J P a J P a U J P a L J P a A z D O J P a J P a U J P a L 5 J P a L 5 J P a L 1 J P a A Z D Only U and L1 add to JPa (p<.1 and p<.5) 1. JPaU and JPaL1 were superior to JPa. L had dose-dependent additive effects. At 1 mpk, activity is comparable to U.

10 Tedizolid also has dose-dependent effects in combination with JPa in C3HeB/FeJ mice BALB/c C3HeB/FeJ 1 1 Lung log 1 CFU Log 1 CFU/Lung D JPa JPaL 5 JPaL 1 JPaT1 DO JPa JPaL5 JPaL5 JPaL1 JPaT1 JPaT 1. JPaT was not statistically superior to JPa alone. T at 1 and mpk had effects similar to L at 5 and 5 mpk, respectively

11 L o g 1 C F U /lu n g Sterilizing activity of oxazolidinones in combination with JPa in C3HeB/FeJ Mice (Relapse Expt) 1 Lung CFU counts after months D O R H Z J P a J P a U J P a L Doses (in mpk): U (5), L (1), T () J P a T Relapses after 3 months of treatment % relapsing vs. RHZ vs. JPa Regimen RHZ 91% NA NA JPa % * NA JPaU 7% *** * JPaL 9% ** NS JPaT 1% *** NS *p<.5, **p<.1, ***p<.1 Relapses after.5 months of treatment % relapsing vs. RHZ vs. JPa Regimen RHZ 1% NA NA JPa % NA JPaU % NS JPaL % NS JPaT % NS p=.7 1. JPaOxie combos reduced the treatment duration by ~1.5 months vs. RHZ. Only U added sterilizing activity to the JPa combination in a stat. significant fashion 3. In this nd expt in C3HeB/FeJ mice, T was at least as potent as L1 11

12 Comparative single-dose PK in BALB/c and C3HeB/FeJ mice Table 1, Pharmacokinetic parameters after single dose oral administration of Sutezolid, Linezolid, and Tedizolid in BALB/C mice. Compound (dose, mg/kg) t1/ Tmax Cmax AUC-hr AUC- hr/dose Cavg,-hr hr hr ng/ml hr*ng/ml hr*ng/ml/mg ng/ml Sutezolid Mean SD Sutezolid M1 Mean SD Linezolid Mean SD Tedizolid Mean SD Tedizolid Mean SD Table, Pharmacokinetic parameters after single dose oral administration of Sutezolid, Linezolid, and Tedizolid in Kramnik mice. AUC- Compound t1/ Tmax Cmax AUC-hr hr/dose Cavg, -hr dose, mg/kg hr hr ng/ml hr*ng/ml hr*ng/ml/mg ng/ml Sutezolid Mean SD Sutezolid M1 Mean SD Linezolid Mean SD Tedizolid Mean SD NAME OF PRESENTATION 1

13 Conclusions JPa + an oxazolidinone has potential for short-course oral regimens for all forms of TB, justifying evaluation of JPaL in the Nix-TB trial Sutezolid was the most active oxie in the combo in BALB/c mice, but was not clearly superior to linezolid, tedizolid in C3HeB/FeJ However, the L and T exposures produced in the C3HeB/FeJ relapse expt were higher relative to U than in BALB/c mice, and exceeded the average human exposure at the highest approved doses Additional work is needed to confirm whether lower L and T exposures contribute sterilizing activity in C3HeB/FeJ mice Relapse results after months of treatment may help to understand if early mortality in JPa-containing groups may have biased the efficacy results in their favor

14 Acknowledgements Colleagues Faculty and staff of the JHU Center for TB Research Matt Zimmerman (Rutgers) Colleagues at the TB Alliance Omar Vandal (Gates Foundation) Anne Lenaerts and colleagues (Colorado St.) Funding Gates Foundation (OPP13717 & OPP199) TB Alliance NIAID (R1-AI11199, R1-AI9)