1. Daniel Everitt, MD; Erica Egizi MPH Global Alliance for TB Drug Development, New York Helen Winter, PhD University of Otago, New Zealand 2012 International AIDS Conference Washington, DC23 July 2012 Pharmacokinetic Interaction Between the Investigational Anti-Tuberculosis Agent TMC207 and Rifampicin or Rifapentine

2. Develop new, better treatments for TB Coordinate and act as catalyst for global TB drug activities Ensure that new regimens are Affordable, Adopted for use, and made widely Available (AAA strategy) TB Alliance Mission 2

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

4. 4 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 Microbiology and Development Bedaquiline – TMC207

5. 5 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 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 Bedaquiline – Clinical Characteristics

6. 6 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% Bedaquiline Previous Drug Interaction Studies

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

8. 8 N=32 subjects enrolled --29 completed No Serious Adverse Events 1 subject with skin reaction withdrew (rifapentine group) All AEs mild-moderate Interaction Study – Key Study Results Bedaquiline and Rifampicin or Rifapentine

9. 9 N=32 subjects enrolled --29 completed No Serious Adverse Events 1 subject with skin reaction withdrew (rifapentine group) All AEs mild-moderate Interaction Study – Key Study Results Bedaquiline and Rifampicin or Rifapentine Bedaquiline Alone With Rifapentine With Rifampicin Mean bedaquiline concentrations

10. 10 Geometric LS Means of Bedaquiline Confidence Intervals Treatment GroupParameterWith InducerAlone % Mean Ratio 90% Confidence Rifapentine Group 1 C max (ng/mL) 2077333962.2(53.4, 72.5) AUC (0-t) (ng*hr/mL) 276126453142.8(37.8, 48.5) Rifampicin Group 2 C max (ng/mL) 2240371860.2(52.0, 69.8) AUC (0-t) (ng*hr/mL) 253146120941.4(37.7, 45.4) Summary of Key Plasma PK Parameters

11. 11 Geometric LS Means of Bedaquiline Confidence Intervals Treatment GroupParameterWith InducerAlone % Mean Ratio 90% Confidence Rifapentine Group 1 C max (ng/mL) 2077333962.2(53.4, 72.5) AUC (0-t) (ng*hr/mL) 276126453142.8(37.8, 48.5) Rifampicin Group 2 C max (ng/mL) 2240371860.2(52.0, 69.8) AUC (0-t) (ng*hr/mL) 253146120941.4(37.7, 45.4) 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. 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. 13 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 Bedaquiline – Summary of Interaction with Rifamycins and Use in Patients with TB and HIV

14. Thank you!