What ‘ s Going On with SQ109 ? ULMUULMU Infectex

TB Alliance Open Forum 2 London, December 2006 “… each drug should be developed according to the specific characteristics of the drug itself, not form-fitted into a one-size-fits-all clinical development program…” [Nacy]

Timecourse for SQ109 Effects In Vivo Drug RegimenLog 10 CFU in LungLog Decrease 2 Weeks Untreated6.16 ± 0.02 INH+RIF+EMB4.64 ± INH+RIF+SQ ± Weeks Untreated6.34 ± 0.34 INH+RIF+EMB4.38± INH+RIF+SQ ± Weeks Untreated6.42 ± 0.76 INH+RIF+EMB3.86 ± INH+RIF+SQ ± SQ mg/kg; INH 25 mg/kg; RIF 20 mg/kg; EMB 100 mg/kg Nikonenko, et al Drug therapy of experimental tuberculosis (TB): improved outcome by combining SQ109, a new diamine antibiotic, with existing TB drugs. Antimicrob. Agents and Chemother 51: 1553.

Modeling EBA in the Mouse

Timecourse for SQ109 Effects In Vivo SQ mg/kg; RIF 20 mg/kg; SQ109 reduced replication of Mtb and improved RIF activity (1/3 log 10 CFU) by day 30 Drug Log 10 CFU in Lung Day 0 Day 30 Log Increase or Decrease From Day 0 Control Log Increase or Decrease From Day 30 Control Experiment: EBA No Treatment6.54 ± ± SQ ± ± RIF6.54 ± ± SQ109+RIF6.54 ± ±

TB Alliance Open Forum 2 London, December 2006 “… each drug should be developed according to the specific characteristics of the drug itself, not form-fitted into a one-size-fits-all clinical development program…” [Nacy] [TMC207 shows minimal activity in EBA] “…unfortunately, a right-of-passage in the TB community…” [Tibotec]

Individual Patient Log 10 CFU over Time

EBA with 95% confidence intervals

Fitted estimates of difference from mean baseline log 10 (CFU) /ml by visit and treatment allocation Mixed Effects Model Assuming Linear Decline

Individual Patient Log 10 CFU over Time

82 adverse events, of which 56% were gastrointestinal events One patient died during the 14 day follow-up period due to massive hemoptysis. This was deemed unrelated to study drug by the investigator. No other serious adverse events (SAEs). There were no ECG-related treatment discontinuations. There was no prolongation of QTcB or QTcF beyond 500ms, or an increase of more than 60ms as compared to baseline. Safety/Tolerability of SQ109 in TB patients

EBA Conclusions SQ109 is a safe and well tolerated drug. It‘s main side effect is nausea, which is more pronounced in the 300mg dose There were no systematic increases in QT in the SQ109 groups Steady state appears to be reached at ~day 7; the induction of CYP2C19 through Rif can be overcome with 300mg SQ109 SQ109 had no bactericidal effect in humans over 14 days; RIF had a 1-log effect in humans over 14 days. Mouse modeling data suggest that: - EBA data in humans mimics that seen in mouse - SQ109 effects are apparent the longer the drug is taken

Sponsor: Medical Center of the University of Munich Chief Investigator: Michael Hoelscher PI: Andreas Diacon Co-PI: Rodney Dawson Microbiology: Andeas Diacon, Amour Venter Sponsor Medical Expert: Norbert Heinrich Trial Statistician (MRC): Patrick Phillips Chief Medical Officer Sequella Inc.: Gary Horwith PanACEA Chief Investigators Group: M. Boeree, S. Gillespie, M. Hoelscher Funding: EDCTP, BMGF, BMBF, UK-MRC, Sequella, NIH EBA Study Team Acknowledgments

EBA Value-Add in TB Drug Development? Drugs effective in TB treatments that work poorly (or not at all) in EBA: Rifampicin Linezolid Clofazimine Pyrazinamide Bedaquiline SQ109

Registration trial in Russia for MDR-TB: ‒ OBT ± SQ109 ( 300 mg ) ‒ ICH guidelines ‒ Start: Q MAMS study in Africa in DS-TB: ‒ SQ109 ( 300 mg ) vs EMB in SOC ‒ SQ109 ( 300 mg ) vs EMB in SOC high-dose RIF ‒ Start: Q Thorough QT (TQT) in healthy humans ‒ SQ109 (up to 450 mg) ± moxifloxicin New Drug Combinations in MDR-TB, ACTG New Drug Combinations in DS-TB, ACTG What ‘ s Next for SQ109 Infectex