Characterization of Baseline Pathogens and Microbiological ...

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