What

‘

s Going On with SQ109 ?

LMU

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 Regimen Log 10 CFU in Lung Log Decrease 2 Weeks

Untreated INH+RIF+EMB INH+RIF+SQ109

3 Weeks

Untreated INH+RIF+EMB INH+RIF+SQ109

4 Weeks

Untreated INH+RIF+EMB INH+RIF+SQ109 6.16 ± 0.02

4.64 ± 0.23

4.46 ± 0.12

6.34 ± 0.34

4.38

± 0.05

3.80 ± 0.10

1.52

1.70

1.96

2.54

6.42 ± 0.76

3.86 ± 0.14

3.26 ± 0.12

2.56

3.16

SQ109 10 mg/kg; INH 25 mg/kg; RIF 20 mg/kg; EMB 100 mg/kg

Nikonenko, et al. 2007. 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

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 Treatment SQ109 RIF SQ109+RIF

6.54 ± 0.40

6.54 ± 0.40

6.54 ± 0.40

6.54 ± 0.40

8.18 ± 0.11

6.94 ± 0.20

3.64 ± 0.15

3.34 ± 0.03

+1.64

+0.40

-2.90

-3.20

0 -1.24

-4.54

-4.84

SQ109 10 mg/kg; RIF 20 mg/kg; SQ109 reduced replication of Mtb and improved RIF activity (1/3 log 10 CFU) by day 30

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

6 5 8 7 1 0 4 3 2 0 1 2 4 6 8 Day of administration of drug 10 300mg SQ109 12 RIF Monotherapy 14

EBA with 95% confidence intervals

0.5

0.0

-0.5

-1.0

-1.5

-2.0

0 2 4 6 8 Day of administration of drug 10 75mg SQ109 300mg SQ109 300mg SQ109 + RIF 12 150mg SQ109 150mg SQ109 + RIF RIF Monotherapy 14

Mixed Effects Model Assuming Linear Decline

0.5

0.0

-0.5

-1.0

-1.5

-2.0

0 2 4 6 8 Day of administration of drug 10 75mg SQ109 300mg SQ109 300mg SQ109 + RIF 12 150mg SQ109 150mg SQ109 + RIF RIF Monotherapy 14 Fitted estimates of difference from mean baseline log 10 (CFU) /ml by visit and treatment allocation

Individual Patient Log 10 CFU over Time

6 5 8 7 1 0 4 3 2 0 1 2 4 6 8 Day of administration of drug 10 300mg SQ109 12 RIF Monotherapy 14

Safety/Tolerability of SQ109 in TB patients

• 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.

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

EBA Study Team Acknowledgments

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

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

What ‘ s Next for SQ109

• Registration trial in Russia for MDR-TB: ‒ OBT ± SQ109 ( 300 mg ) ‒ ‒ ICH guidelines Start: Q4 2012 • 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: Q4 2012 • Thorough QT (TQT) in healthy humans ‒ SQ109 (up to 450 mg) ± moxifloxicin

Infectex

• New Drug Combinations in MDR-TB, ACTG • New Drug Combinations in DS-TB, ACTG