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Daniel Everitt, MD; Erica Egizi MPH Global Alliance for TB Drug Development, New York

Pharmacokinetic Interaction Between the Investigational Anti-Tuberculosis Agent TMC207 and Rifampicin or Rifapentine. 2012 International AIDS Conference Washington, DC 23 July 2012. Daniel Everitt, MD; Erica Egizi MPH Global Alliance for TB Drug Development, New York Helen Winter, PhD

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Daniel Everitt, MD; Erica Egizi MPH Global Alliance for TB Drug Development, New York

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  1. Pharmacokinetic Interaction Between the Investigational Anti-Tuberculosis Agent TMC207 and Rifampicin or Rifapentine 2012 International AIDS Conference Washington, DC 23 July 2012 Daniel Everitt, MD; Erica Egizi MPH Global Alliance for TB Drug Development, New York Helen Winter, PhD University of Otago, New Zealand

  2. TB Alliance Mission

  3. The Context:Approach to TB Drug/Regimen Development Phase II  Phase III Single Compound Preclinical Development  Phase I  EBA Compound 1 Drug Candidate Pool Compound 2 Regimen A Compound 3 Regimen B Compound 4 Regimen C Compound 5 Regimen Identification in Mice Identification of New Drug Candidates Selection of Potential New Regimens Tackling TB Through Technology Discovery and Development Process

  4. Bedaquiline – TMC207 Microbiology and Development • Bedaquiline – a diarylquinoline • An MTB ATP synthase inhibitor – unique MOA against TB • Bactericidal against dormant and actively dividing bacteria • MIC range 0.030 – 0.120 ug/mL • Active against Drug Sensitive and Resistant strains • Joint development between the TB Alliance and Janssen Pharmaceutical Companies of Johnson & Johnson • Janssen has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for the use of the TMC207 as an oral treatment, to be used as part of combination therapy for pulmonary, MDR-TB in adults. – June, 2012

  5. Bedaquiline – Clinical Characteristics • Well tolerated by healthy subjects and patients with pulmonary TB • PK with tri-phasic elimination • Effective T1/2 of 24 hours; long terminal elimination half-life • Food Effect – approximate 2-fold increase in exposure • Metabolism • Primarily oxidative metabolism to M2 metabolite by CYP3A$ • No in vitro induction or inhibition of metabolism by bedaquiline • Efficacy • Early Bactericidal Activity (EBA) demonstrated over 2 weeks in patients • Phase 2 studies have demonstrated significantly greater reduction in the time to culture conversion for TMC207 versus placebo when added to an standardized background TB regimen • 80% culture conversion rate at 24 weeks when TMC207 is added to an individualized background regimen

  6. BedaquilinePrevious Drug Interaction Studies • Nevirapine • Steady state NVP did not significantly influence bedaquiline exposure • Lopinavir/ritonavir • Exposure of bedaquiline increased by 22% and M2 exposure decreased by 41% • Efavirenz (See: Dooley KE, et al. J Acquir Immune Defic Syndr 2012; 59:455-60) • Exposure of bedaquiline decreased by 18% with 14 days of daily efavirenz in healthy volunteers • Bedaquiline exposure decrease may be greater with repeat dosing • Ketoconazole – potent inhibitor of CYP3A4 • Exposure of bedaquiline increased by 22%; no difference in M2 • Rifampin – potent inducer of CYP3A4 • Exposure of bedaquiline decreased by 52% after 7 days rifampicin • Exposure of M2 decreased by 25%

  7. Interaction Study Bedaquiline and Rifampicin or Rifapentine Period 2 Period 1 • Rifapentine a rifamycin • In vitro and in vivo studies suggested induction potential of CYP 3A4 may be less than rifampin TMC207 SD 400 mg day 1 Rifapentine 600 mg qd days 20-41 + TMC207 SD day 29 Group 1 N = 16 4 weeks TMC207 SD 400 mg day 1 Rifampicin 600 mg qd days 20-41 + TMC207 SD day 29 Group 2 N = 16 4 weeks

  8. Interaction Study – Key Study ResultsBedaquiline and Rifampicin or Rifapentine

  9. Interaction Study – Key Study ResultsBedaquiline and Rifampicin or Rifapentine Mean bedaquiline concentrations Bedaquiline Alone With Rifapentine With Rifampicin

  10. Summary of Key Plasma PK Parameters

  11. Summary of Key Plasma PK Parameters • Effects of both inducers on PK of M2 were similar • Cmax higher by 82-97%; AUC lower by 37 – 45%

  12. Upcoming Study with bedaquiline in Regimens: NC-003 • A two week EBA study to evaluate bactericidal activity in patients with newly diagnosed pulmonary TB • H-R-Z-E (Rifafour®) compared to various combinations of: • Bedaquiline • PA-824 • Clofazimine • Pyrazinamide • Study to start in S. Africa September, 2012

  13. Bedaquiline – Summary of Interaction with Rifamycins and Use in Patients with TB and HIV • Unique MOA and marked bactericidal effect on both drug sensitive and drug resistant TB infection • Metabolized by hepatic CYP3A4 enzymes (but does note induce or inhibit these enzymes) • Both Rifampicin and Rifapentine are strong “inducers” and markedly increase the clearance of bedaquiline • TB regimens with bedaquiline to treat HIV coinfected patients should avoid use of rifampicin and rifapentine • Expected to have minimal interactions of clinical importance with most anti-retroviral therapy • Not expected to affect the exposure/efficacy of ART • Care should be taken in use with ritonavir combinations until further experience, with PK in patients, is documented

  14. Thank you!

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