Transcript PRESENTATION

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
Log10 CFU in Lung
Log Decrease
2 Weeks
Untreated
6.16 ± 0.02
INH+RIF+EMB
4.64 ± 0.23
INH+RIF+SQ109
4.46 ± 0.12
1.52
1.70
3 Weeks
Untreated
6.34 ± 0.34
INH+RIF+EMB
4.38± 0.05
INH+RIF+SQ109
3.80 ± 0.10
1.96
2.54
4 Weeks
Untreated
6.42 ± 0.76
INH+RIF+EMB
3.86 ± 0.14
INH+RIF+SQ109
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
Log10 CFU in Lung
Log
Increase or
Decrease
From Day 0
Control
Log
Increase or
Decrease
From Day 30
Control
Day 0
Day 30
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
Experiment: EBA
SQ109 10 mg/kg; RIF 20 mg/kg;
SQ109 reduced replication of Mtb and improved RIF activity (1/3 log10 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 Log10 CFU over Time
8
7
6
5
4
3
2
1
0
0
1
2
4
10
8
6
Day of administration of drug
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
10
Day of administration of drug
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
10
8
6
Day of administration of drug
75mg SQ109
300mg SQ109
300mg SQ109 + RIF
12
14
150mg SQ109
150mg SQ109 + RIF
RIF Monotherapy
Fitted estimates of difference from mean baseline log10(CFU) /ml by visit and
treatment allocation
Individual Patient Log10 CFU over Time
8
7
6
5
4
3
2
1
0
0
1
2
4
10
8
6
Day of administration of drug
300mg SQ109
12
RIF Monotherapy
14
Safety/Tolerability of SQ109 in TB patients
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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:
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Rifampicin
Linezolid
Clofazimine
Pyrazinamide
Bedaquiline
SQ109
What‘s Next for SQ109
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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
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New Drug Combinations in MDR-TB, ACTG
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New Drug Combinations in DS-TB, ACTG
Infectex