1. The PanACEA trials High dose rifampicin (HR1 & HR2) PanACEA-MAMS-TB-01 Martin Boeree, MD, PhD Associate Professor Radboudumc Nijmegen Cape Town, December 5, 2015 Working Group on New TB drugs

2. Martin Boeree has no financial relationships with commercial entities to disclose.

3. The game plan for the evaluation of high dose rifampicin in PanACEA HR1 HR2 MAMS 1 MAMS 2 HR Phase III

4. HIGHRIF 1 (HR1) study design

5. Safety One control group with standard 10 mg/kg RIF (N=8) 5 consecutive arms of each 15 patients: – 20 mg RIF/kg – 25 mg RIF/kg – 30 mg RIF/kg – 35 mg RIF/kg – 40 mg RIF/kg All safe and well tolerated Boeree et al, AJRCCM, 191, 1058-65, 2015

6. PK

7. CFU

8. HighRIF2 – study design, N= 50 patients per arm

9. Results  No differences in safety and tolerabilty in the three groups 600, 900, 1200 mg  PK: successful increase  Bactericidal effect: no difference

10. High-Dose Rifampin, SQ109 and Moxifloxacin for Treating TB: The PanACEA MAMS-TB Trial Martin Boeree, Radboudumc, Nijmegen on behalf of the PanACEA consortium 25th February 2015, CROI, Seattle

11. Study Design: Randomisation All drugs at standard doses unless otherwise stated 8 weeks12 weeks26 weeks Control Isoniazid Rifampicin 10mg/kg Pyrazinamide Ethambutol Q Isoniazid Rifampicin 10mg/kg Pyrazinamide SQ109 20RQ Isoniazid Rifampicin 20mg/kgRifampicin 10mg/kg Pyrazinamide SQ109 20RM Isoniazid Rifampicin 20mg/kgRifampicin 10mg/kg Pyrazinamide Moxifloxacin 35R Isoniazid Rifampicin 35mg/kgRifampicin 10mg/kg Pyrazinamide Ethambutol

12. 1 Analysis has been adjusted for: HIV status; baseline GeneXpert CT; centre; baseline culture (using TTP). Time to stable culture conversion on MGIT liquid media over 12 weeks

13. Kaplan Meier curve for time to culture conversion in liquid MGIT media 1 treatment failure in the Q arm, relapse data are currently analyzed

14. Proportion of patients experiencing adverse events (AEs) *Hepatic AEs resulting in a change of treatment, pending final safety review. 4 (6%)

15. PK MAMS

16. Conclusion High-Dose Rifampicin is well tolerated 20 mg/kg is probably too low 35 mg/kg has an increased effect in culture conversion There is a difference in culture conversion in liquid and solid media In the MAMS trial the arms containing SQ109 had no increased effect in this design

17. Acknowledgements South Africa – Aurum, Tembisa: Gavin Churchyard, Solome Charalambous, Bob Wallis – CHRU, University of Witwatersrand, Johannesburg: Ian Sanne, Karla Mellet – TASK, University of Stellenbosch: Andreas Diacon, Jeannine Du Bois, Armour Venter – The Lung Institute, University of Cape Town: Rod Dawson, Kim Narunsky – Triclinium Tanzania – IHI, Bagamoyo: Klaus Reither, Lilian Tina Minja – KCRI, Moshi: Gibson Kibiki, Hadija Semvia, Stellah Magama, Charles Mthabo – MMRC, Mbeya: Nyanda Ntinginya, Leonard Maboko United States – Sequella inc. Carol Nacy United Kingdom – University of St Andrews, Stephen Gillespie – University of London, MRC CTU, Sunita Rehal, Patrick Phillips, Andrew Nunn – University of London, Tim Mc Hugh Germany – Ludwig Maximilian University, Munich: Michael Hoelscher, Norbert Heinrich, Anka Mekota, Sonja Henne The Netherlands – Radboudumc, Nijmegen: Rob Aarnoutse, Georgette Plemper van Balen, Marloes Weijers, Angela Colbers All other PanACEA site collaborators