Seond Line TB Drugs in Combination with a Novel Drug Candidate SQ109

Second Line TB Drugs in Combination with Novel Drug Candidate SQ109

Lisa Beth Ferstenberg, MD Medical Director Drug Combinations Are Used to:

1. Exert activity on bacteria in different anatomical compartments (intracellular vs extracellular) 2. Work in concert in same anatomical compartment to prevent development of bacterial resistance 3. Work on different targets within the bacteria to ensure kill

In treatment of TB, an infection caused by a facultative intracellular pathogen, patients are always treated with multiple drugs delivered concurrently: – Combination therapy is used in both drug sensitive and drug resistant TB – Drugs with different mechanisms of action are used to eliminate bacteria in lung cavities (extracellular) and in macrophages and cells within granulomas (intracellular), prevent expansion of resistant strains, and shorten treatment time.

Thorough Knowledge of DDI is Essential for Efficacy Trial Design in TB

• Wherever there are drug combinations, there is potential for drug-drug interactions (DDI) • DDI can alter pharmacokinetics, resulting in ineffectual levels of critical drugs in a combination – If one drug increases effective exposure to another drug, toxicity may be potentiated – If one drug increases the metabolism of another drug, effective exposure may decrease resulting in lack of efficacy • CYP up-regulation • Decrease total AUC • DDI interactions may cause a safe and effective drug to be removed from development prematurely SQ109 In Vitro:

• Bactericidal • A new ethylenediamine-based antitubercular drug • MIC: 0.16-0.32 µg/ml (H37Rv); 0.16-0.64 µg/ml (18 clinical isolates)

• IC50: 14.5 µg/ml (HepG2) • Active against all TB (including EMBr, MDR, and XDR) • Acquired resistance rate (2.55x10-11) better than RIF (1.9x10-10) • Targets cell wall synthesis: mmpL3 (novel MOA) • Inhibits 99% of intracellular M. tuberculosis • Effective against non-replicating M. tuberculosis In Vivo Model of DDI Pharmacokinetics

• Female C57BL/6 mice • Single co-administration, PO or SC (based on standard delivery of drug) • SQ109 25 mg/kg plus – Cycloserine 150 mg/kg – Ethionamide 75 mg/kg – Kanamycin 150 mg/kg – Moxifloxacin 100 mg/kg – Para-amino salacylic acid 750 mg/kg • LC/MS/MS of drug(s) in plasma at various times

Results: Pharmacokinetics (PK)

• Cycloserine and kanamycin both decrease exposure to SQ109 by 2x • Co-administration of SQ109 and ethionamide – Increases AUC of SQ109 by 30% – Decreases AUC of ethionamide by 2x – Decreases T½ of ethionamide by 12x – Increases ethionamide Tmax from 15 to 30 min • PK profiles of SQ109 and moxifloxacin are not affected by co- administration • Co-administration of SQ109 and para-amino salacylic acid – Increase in AUC of SQ109 by 50% – Increase in T½ of PAS by 4x

IN Vivo Model of DDI: Drug Efficacy

• Standard mouse model of chronic TB – Female C57BL/6 mice – Inoculated with 0.2 ml suspensions of 10⁵ CFU H37Rv – Drug treatment initiated 3 weeks after infection – Animals sacrificed at 2 months – Spleen and lung homogenates at timed intervals plated for CFU counts • Drug combinations used in therapy: SQ109 25 mg/kg plus – Ethambutol 100 mg/kg – Ethionamide 75 mg/kg – Moxifloxacin 100 mg/kg – Pyrazinamide 150 mg/kg Results: Efficacy in Treating Murine TB

• SQ109 showed no antagonistic interactions with any of the 4 drugs tested

• Most efficacious: reduced CFU significantly better combined with SQ109 compared to drug alone

– SQ109 plus moxifloxicin (3.5 log10 CFU decrease; p=0.006)

• SQ109 plus ethionamide, pyrazimamide, and ethambutol showed modest additive effects (small sample size) on CFU reduction. Clinical Implications

• SQ109 plus moxifloxacin could be combined for increased efficacy and no adverse DDI

• SQ109 and ethionamide could also be combined:

– Modest increase in AUC of SQ109 would not increase toxicity – Decrease in ethionamide AUC and T1/2 could reduce toxicity

• SQ109 and Para-amino salacylic acid may be OK (efficacy unknown) – May be able to adjust SQ109 dose down and retain efficacy

• Cycloserine and kanamycin could decrease SQ109 efficacy

Conclusions

• Clinical trials using multiple drugs can be designed better if DDI data are available

• Safety and efficacy can be optimized by rational use of pharmacokinetic information and models of efficacy

• Human phase 1 pK data to confirm animal models are worth the time and effort before planning critical phase 2 studies