What‘s Going On with SQ109 ?

LMUU

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TB Alliance Open Forum 2London, 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 Log10 CFU in Lung Log Decrease

2 WeeksUntreated 6.16 ± 0.02  

INH+RIF+EMB 4.64 ± 0.23 1.52INH+RIF+SQ109 4.46 ± 0.12 1.70

3 WeeksUntreated 6.34 ± 0.34  INH+RIF+EMB 4.38± 0.05 1.96INH+RIF+SQ109 3.80 ± 0.10 2.54

4 WeeksUntreated 6.42 ± 0.76  INH+RIF+EMB 3.86 ± 0.14 2.56INH+RIF+SQ109 3.26 ± 0.12 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

SQ109 10 mg/kg; RIF 20 mg/kg;

SQ109 reduced replication of Mtb and improved RIF activity (1/3 log10 CFU) by day 30

DrugLog10 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 6.54 ± 0.40 8.18 ± 0.11 +1.64 0

SQ109 6.54 ± 0.40 6.94 ± 0.20 +0.40 -1.24

RIF 6.54 ± 0.40 3.64 ± 0.15 -2.90 -4.54

SQ109+RIF 6.54 ± 0.40 3.34 ± 0.03 -3.20 -4.84

TB Alliance Open Forum 2London, 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 Log10 CFU over Time

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1

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8

Mean log10(c

fu)

/ml

0 1 2 4 6 8 10 12 14Day of administration of drug

300mg SQ109 RIF Monotherapy

-2.0

-1.5

-1.0

-0.5

0.0

0.5

log10(c

fu)/

ml, fitte

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hange fro

m b

aselin

e

0 2 4 6 8 10 12 14Day of administration of drug

75mg SQ109 150mg SQ109300mg SQ109 150mg SQ109 + RIF300mg SQ109 + RIF RIF Monotherapy

EBA with 95% confidence intervals

Fitted estimates of difference from mean baseline log10(CFU) /ml by visit and treatment allocation

Mixed Effects Model Assuming Linear Decline

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Fitte

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stim

ate

of lo

g10(c

fu)

/ml

0 2 4 6 8 10 12 14Day of administration of drug

75mg SQ109 150mg SQ109300mg SQ109 150mg SQ109 + RIF300mg SQ109 + RIF RIF Monotherapy

Individual Patient Log10 CFU over Time

0

1

2

3

4

5

6

7

8

Mean log10(c

fu)

/ml

0 1 2 4 6 8 10 12 14Day of administration of drug

300mg SQ109 RIF Monotherapy

• 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 MunichChief Investigator: Michael HoelscherPI: Andreas Diacon Co-PI: Rodney DawsonMicrobiology: Andeas Diacon, Amour VenterSponsor Medical Expert: Norbert HeinrichTrial Statistician (MRC): Patrick PhillipsChief 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: 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

• New Drug Combinations in MDR-TB, ACTG

• New Drug Combinations in DS-TB, ACTG

What‘s Next for SQ109

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