what ‘ s going on with sq109 ? ulmuulmu infectex
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What‘s Going On with SQ109 ?
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Infectex
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
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
-2.0
-1.5
-1.0
-0.5
0.0
0.5
log10(c
fu)/
ml, fitte
d c
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
d e
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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