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Characterization of Baseline Pathogens and Microbiological
Eradication in a Phase 2 trial for Treatment of Complicated
Intra-abdominal Infections Comparing Eravacycline (TP-434)
to Ertapenem
1
C. Fyfea, J. Deaneb, T. Grossmana, P. Horna, G.
Moorea, D. Sahmb, J. Studenya, S. Walpolea, and J.
Sutcliffea
aTetraphase Pharmaceuticals, Inc. (Watertown, MA,
USA) and bEurofins Medinet Global Central
Laboratory (Chantilly, VA, USA)
Broad Spectrum Coverage Against Gram-Negative Aerobes
APRIL 2013 2
In Vitro MIC90 Comparison
EravacyclineTigecyclineCarbapenemFluoroquinolone3rd Gen CephAminoglycosidePip/Tazo0
4
8
12
16
20
24
28
32
MIC
90 in
g/
mL
Strong Potency Against Gram-Positive Pathogens
3
In Vitro MIC90 Comparison
EravacyclineTigecyclineDaptomycinLinezolidVancomycinFluoroquinoloneMacrolide0
2
4
6
8
MIC
90 in
µg/
mL
APRIL 2013
Broad Spectrum and Potency vs. Anaerobes
4
In Vitro MIC90 Comparison
Eravacycline
Tigecycline
CarbapenemMetronidazoleVancomycin
0
4
8
12
16
20
24
28
32
MIC
90 in
µg/
mL
APRIL 2013
Phase 2 cIAI Trial Design
143 Patients with cIAI Randomized (2:2:1)
Eravacycline (ERV 1.5)
1.5 mg/kg IV q24h
N=54
MITT Population
Eravacycline (ERV 1.0)
1.0 mg/kg IV q12h
N=56
MITT Population
Ertapenem (ERT)
1.0 g IV q24h
N=29
MITT Population
5 APRIL 2013
Baseline Pathogen Identified
m-MITT
N=45
Baseline Pathogen Identified
m-MITT
N=47
Baseline Pathogen Identified
m-MITT Population
N=27
Microbiologically Evaluable
N=42
Microbiologically Evaluable
N=41
Microbiologically Evaluable
N=26
Primary Efficacy Analysis:
Clinical Response at TOC (ME)
95% CI 80.5 – 98.5 91.4 – 100 74.9 – 99.1
6 APRIL 2013
92.9%
100%
92.3%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
ERV 1.5 ERV 1.0 ERT
Pe
rce
nt
Clin
ical
Cu
re
Bacterial Pathogens in m-MITT Population
Heavy in Enterobacteriaceae
7
Average of 1.8 isolates/patient (212 isolates/119 patients)
60.4% (128/212) Enterobacteriaceae; 7.6% (16/212) gram-negative non-fermenters
Escherichia coli, 44.3%
Klebsiella spp., 9.9%
Other Enterobacteriaceae,
6.1%
GN Non-fermenters, 7.5%
Streptococcus spp., 9.0%
Enterococcus spp., 7.5%
Staphylococcus spp., 6.1%
Other Gram-positive spp., 0.9%
Anaerobes, 8.5%
APRIL 2013
144 (67.9%) Gram-negative aerobes
– 25.0 % (36/144) contain an ESBL(s)
– 11.1% (16/144) of the isolates were carbapenem-resistant
• 2.1% (3/144) were Enterobacteriaceae
• 9.0% (13/144) were Gram-negative non-fermenters
– 30.6% (44/144) were tetracycline-resistant
29.4% (15/51) of Gram-positive aerobes were tetracycline-
resistant
ESBL and Carbapenemase Producers in m-MITT
Population
8 APRIL 2013
MIC Comparisons Among Gram-Negative Aerobes
in m-MITT Population
Species No.
isolates
MIC range (g/ml)
Eravacycline Ertapenem
Range MIC50 MIC90 Range MIC50 MIC90
A. baumannii 4 0.06 –0.5 -- -- >16 - >16 -- --
Acinetobacter spp. 1 0.06 -- -- 0.008 -- --
E. coli 94 0.12 – 1 0.25 0.5 ≤0.002 - >16 0.004 0.06
Klebsiella spp. 21 0.25 - 2 0.5 1 ≤0.002 – 16 0.008 0.06
Other Enterobacteriaceae
13 0.03 - 2 1 2 0.004 – 2 0.008 0.25
GN Non-fermenters 11 ≤0.015 – 16 0.5 16 ≤0.002->16 16 >16
9 APRIL 2013
MIC Comparisons Among Gram-Positive Aerobes
in m-MITT Population
10
Species No.
MIC Range (g/ml)
MIC50/MIC90
ERV ERT LEV GEN TET PTZ DAP LIN VAN
Bacillus spp. 1 ≤0.015
NA/NA
≤0.03
NA/NA
0.12
NA/NA
0.5
NA/NA
0.5
NA/NA
≤0.12
NA/NA
4
NA/NA
1
NA/NA
2
NA/NA
Enterococcus
spp. 16
≤0.015 –0.12
0.06/0.06
2 - >16
8/16
0.5 - >4
2/>4
0.5 – 8
>8/>8
≤0.06 - >32
16/>32
2 - >8
8/>8
0.05 – 4
1/ 2
≤0.5 – 2
1/ 2
≤0.25 – 2
0.5/1
Leuconostoc
spp. 1
0.015
NA/NA
0.25
NA/NA
4
NA/NA
ND
NA/NA
2
NA/NA
1
NA/NA
0.25
NA/NA
1
NA/NA
>1
NA/NA
Staphylococcus
spp. 13
≤0.015 – 0.12
0.06/0.12
0.06 – >16
0.5/4
0.06 - >4
0.12/0.25
≤0.06 - >8
0.25/0.5
≤0.06 – 32
0.25/32
≤0.12 - >8
1/>8
≤0.12 – 0.5
0.5/0.5
≤0.5 – 2
1/ 2
≤0.25 – 1
0.5/1
Streptococcus
spp. 19
≤0.008 – 0.06
0.015/0.03
≤0.015 – 1
0.12/0.5
≤0.25 - >4
0.5/1 ND
≤0.06 - >4
0.25/>4
≤0.015 – 4
0.12/0.5
≤0.03 – 1
0.25/0.5
≤0.25 – 1
1/1
0.25 – 1
0.5/1
ERV = eravacycline; ERT = ertapenem; LEV = levofloxacin; GEN = gentamicin; TET = tetracycline; PTZ = piperacillin/tazobactam; TGC = tigecycline; DAP = daptomycin;
LIN = linezolid; VAN = vancomycin
APRIL 2013
Resistance in Enterobacteriaceae and Gram-
Negative Non-Fermenter Isolates in ME population
Multidrug resistance was seen, including 15.8% of Enterobacteriaceae (n=18/114) with resistance to ≥3 antibiotic classes, 15 of which were ESBL-producers.
11
Resistancesa Number of Enterobacteriaceae
Isolates (n = 23) with Phenotype
Number of Gram-Negative Non-
Fermenters (n=14) with Phenotype NONE 3
TET LEV 1
CEF LEV 3
GEN LEV 1
ERT CEF 1
TET CEF LEV 3
TET GEN LEV 1
CEF PTZ LEV 3
ERT CEF LEV 1
ERT TET CEF 3
TET GEN CEF LEV 3
TET CEF PTZ LEV 3
TET GEN CEF PTZ LEV 2
ERT GEN CEF PTZ LEV 2
ERT TET GEN CEF LEV 2
ERT TET CEF PTZ LEV 2
ERT TET GEN CEF PTZ LEV 1 2
a TET = tetracycline; LEV = levofloxacin; CEF = either ceftazidime or cefotaxime; ERT = ertapenem; PTZ = piperacillin/tazobactam; GEN = gentamicin
APRIL 2013
Eravacycline Covers the Toughest Gram-Negative Aerobes,
Including ESBL+ Pathogens
12
Pathogen(s) Presumed Eradicated No.
A. baumannii 2
E. coli 13
K. pneumoniae 1
MDR phenotypes include combinations of ESBL(s), FQR, TetR, ErtaR, Pip/Tazo-R
Cures Only in Combined Eravacycline Cohorts in ME Population
Eravacycline
ErtapenemCeftazidime
TetracyclineLevofloxacin
GentamicinPiperacillin/Tazobactam
0
2
4
6
8
10
12
14
16
Nu
mb
er
of
Iso
late
s
MIC (μg/ml)
APRIL 2013
Data from Phase 2 cIAI, on file, Tetraphase Pharmaceuticals, Inc.
Isolates in the ME Population at the TOC that are
ESBL-positive ± Carbapenem-Resistant
SEPTEMBER 2012 CONFIDENTIAL 13
24% (31/129) of the isolates of the gram-negative aerobes in the ME
population ) had ESBLs/carbapenemases
22 ESBL/carbapenem genes/gene families were screened by PCR and
confirmed by gene sequencing
Isolates were found to have one or more ESBLs or carbapenemases
– Class A enzymes: CTXM
– Class B enzymes: NDM-1, NDM-4
– Class C enzymes: CMY, ADC
– Class D enzymes: OXA, AIM
Favorable Clinical/Microbiological Responses (n/N*) at the TOC in Patients from the ME Population with Drug Resistance (ESBL-positive ± Carbapenem-Resistant)
14
Pathogen
Eravacycline (1.5mg/kg q24h)
X=10**
Eravacycline (1.0mg/kg q12h)
X=10
Ertapenem (1.0 g q24h)
X=4
A. baumannii 1/1 1/1 2/2
E. coli 5/6 6/6 1/1
K. pneumoniae 0/1 1/1 -
Pantoea spp. - - 1/1
P. aeruginosa 3/4 1/1 -
S. maltophilia - 1/1 -
*n/N = Favorable clinical response/No. patients with pathogen **X = Total number of patients; some patients had greater than one ESBL pathogen
APRIL 2013
Eravacycline: Profile of a Well-Differentiated
Antibiotic
15
Feature
Broad Spectrum Antibiotic
- covers Gram –ve, Gram +ve, anaerobes and atypicals
- active against difficult-to-treat MDR Gram –ve pathogens
Demonstrated clinical efficacy
Convenient dosing
- monotherapy
- once daily dosage supported
Safe and well tolerated in patients
- minimal GI side effects
Potential for oral step down therapy
APRIL 2013