ETX0282, a Novel Oral Agent Against Multidrug-Resistant Enterobacteriaceae

Thomas Durand-Réville

02 June 2017 - ASM Microbe 2017 (Session #113)

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Disclosures

• Thomas Durand-Réville: Full-time Employee; Self; Entasis Therapeutics.

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The cefpodoxime proxetil/ETX0282 combination addresses a significant unmet medical need

Unmet need: Lack of effective, oral agents for treatment of MDR UTIs

• There is an unmet need for new treatments due to increasing incidence of UTI due to MDR Gram-negative

bacteria not covered by available oral therapies (fluoroquinolones, TMP-SMX)

• Uncomplicated UTI patients (typically treated in the community) require hospitalization for I.V. treatment

when infected with MDR strains

• 95% of community UTIs are caused by Enterobacteriaceae, ~75% by E. coli

• Oral and BID administration providing well tolerated and

convenient dosing

• Outpatient setting: First-line treatment for UTI and avoid

hospitalization

• Hospital setting: Oral step-down resulting in a reduced length

of hospitalization

Our vision: An oral BL/BLI combination to treat MDR Enterobacteriaceae

Prodrug Active Agent

β-lactamase inhibitor (BLI)

ETX0282 ETX1317

β-lactam (BL)Cefpodoxime

proxetil (CPDP)Cefpodoxime

(CPD)* Foxman, B. Urinary Tract Infection Syndromes: Occurrence, Recurrence, Bacteriology, Risk Factors, and Disease Burden. Infect. Dis. Clin. N. Am. 2014, (28): 1-13

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MDR Gram-negative uropathogens are rapidly emerging and spreading globally

72.4%

13.3%

3.0%

2.0%

1.8%

7.5%

E. coli

Klebsiella spp.

Proteus spp.

P. aeruginosa

Enterobacter spp.

Other

E. coli

Klebsiella spp.

Proteus spp.

P. aeruginosa

Enterobacter spp.

Other

* Zowawi, H.M., et al. The emerging threat of multidrug-resistant Gram-negative bacteria in urology. Nat. Rev. Urol. 2015, 12(12): 570-584.

N = 216,645 global UTI isolates (2009-2014)A new orally-bioavailable, broad spectrum BLI is needed

CDDEP Resistance Map, CDC Antibiotic Resistance Atlas

% Resistance (HAIs, 2011-2014, USA)

ESBL CRE FQ-R MDR

E. coli 13.4 0.7 33.0 7.5

Klebsiella spp. 20.0 8.7 ND 14.2

Enterobacter spp. 28.5 4.1 ND 7.9

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ETX2514 (IV)Class A, C and D BLI

Restores β-lactam activity in A. baumannii, P. aeruginosa,

Enterobacteriaceae

Diazabicyclooctenones: the next generation β-lactamase inhibitors

ETX1317Class A, C and D BLI

Restores β-lactam activity in Gram-negative bacteria

Optimize β-lactamase inhibition and MIC by exploring substitutions around core and activating groups

ETX0282 (PO)Oral prodrug

Optimize ADME properties and oral bioavailability

In vivo activation

(liver)

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Compound

β-lactamase inhibition (IC50, µM)

Class A Class C Class D

CTX-M-15 SHV-5 KPC-2 TEM-1AmpC

P. aeruginosaP99 OXA-24/40 OXA-48

avibactam 0.009 0.23 0.18 6.9 0.52 0.12 32 0.88

ETX2514 0.001 0.004 0.002 0.001 0.006 0.001 0.28 0.005

ETX1317 0.002 0.036 0.043 0.003 0.16 0.024 0.54 0.077

ETX1317 displays broad spectrum inhibition of serine β-lactamases and E. coli PBP2

0 10µM 100µM 100µM 100µM

ETX1317

1a1b

2

3

4

AZT MEC PEN

AZT: aztreonam, MEC: mecillinam, PEN: penicillin G

E. coli W3110 (ΔampC)

total cell membrane extract (competition with Bocillin FL)

• ETX1317 is a broad spectrum serine β-lactamase inhibitor• ETX1317 inhibits E. coli PBP2 which results in intrinsic antibacterial activity

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ETX1317 Cefpodoxime Cefuroxime Tigemonam Faropenem Cefixime Loracarbef

K. pneumoniaeSHV-18, OXA-2,

OKP-6(ATCC 700603)

32 16 0.25 32 4 32 0.5 8 0.5 8 ≤0.06 32 0.125

ETX1317 restores activity of multiple β-lactams against K. pneumoniae strain

• A series of β-lactams from different chemical subclasses were tested in combination with ETX1317• Cefpodoxime selected as partner based on microbiological data, PK profile and dosage

*ETX1317 tested at a fixed concentration of 4 mg/L in combinations

+ ETX1317* + ETX1317* + ETX1317* + ETX1317* + ETX1317* + ETX1317*

MIC (mg/L) for single agents and combinations

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CPD/ETX1317 has excellent microbiological profile against Enterobacteriaceae

Compound

MIC50

(mg/L)

MIC90

(mg/L)

CLSI Breakpoint(mg/L)

CPD >32 >32 2

ETX1317 2 32 ND

CPD/ETX1317* ≤0.015 0.03 ND

LVX 16 32 2

TZP* 16 >32 16

*BLIs tested at a fixed concentration of 4 mg/L in combinationsLVX: levofloxacin; TZP: piperacillin/tazobactam

Session 198 - AAID11, “New Antimicrobial Agents: New Beta-lactams and New Beta-lactamase Inhibitors”SATURDAY – Poster 279, S. McLeod, et al.

Activity vs. ~900 global, diverse, ESBL-enriched Enterobacteriaceae isolates

(from UTI in 2013-2015)

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β-lactamase class

All Not

classifiedNone or

OSBLESBL KPC OXA-48-like

wildtype AmpC

De-repressed AmpC

Plasmid AmpC

MBL

N 911 7 15 621 18 30 98 69 25 28

MIC50(mg/L) ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015 ≤0.015

MIC90(mg/L) 0.03 0.03 0.03 0.03 0.03 0.06 0.03 0.06 0.06 >32

Bacterial species

All E. coli K. pneumoniae K. oxytoca Citrobacter spp. E. aerogenes E. cloaceae Proteus spp.

N 911 301 253 53 120 40 51 93

MIC50 (mg/L) ≤0.015 ≤0.015 ≤0.015 ≤0.015 0.06 ≤0.015 ≤0.015 ≤0.015

MIC90(mg/L) 0.03 ≤0.015 0.03 0.125 0.06 0.06 0.25 0.12

Consistent CPD/ETX1317 activity across the different Enterobacteriaceae pathogens and different serine β-lactamases

Activity vs. ~900 global, diverse, ESBL-enriched Enterobacteriaceae isolates (from UTI in 2013-2015)

Session 198 - AAID11, “New Antimicrobial Agents: New Beta-lactams and New Beta-lactamase Inhibitors”SATURDAY – Poster 279, S. McLeod, et al.

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Liver S9 incubations demonstrate consistent conversion of ETX0282 to ETX1317 in vitro

in vitro S9 stability (T1/2 in minutes, 37oC)

BufferpH 7.4

Rat Intestinal (RI)S9

Rat Liver (SL)S9

Dog Intestinal (DI)S9

Dog Liver (DL)S9

Human Intestinal (HI)S9

Human Liver (HL)S9

ETX0282 186 240 32 186 30 163 39

Session 198 - AAID11, “New Antimicrobial Agents: New Beta-lactams and New Beta-lactamase Inhibitors”SATURDAY – Poster 278, J. O'Donnell, et al.

• ETX0282 is predominantly stable in the presence of buffer and intestinal S9

• More rapid conversion of ETX0282 into ETX1317 by rat, dog and human liver S9 enzymes

ETX1317 formationHL

DL

RL

HI

DI

RI

Buffer

Co

nce

ntr

atio

n, µ

M

Time, min

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ETX0282 delivers high bioavailability in preclinical species

1

10

100

1000

10000

100000

0 5 10

Time, hr

1

10

100

1000

10000

100000

0 5 10 15

Time, hr

Rat Dog

Species(n=3)

Dose Eq.(mg/kg)

Cmax

(µg/mL)AUC

(µg.h/mL)T1/2

(hr)Oral Bioavailability

F%

Rat 10 5.8 ± 0.2 7.0 ± 0.6 1.1 ± 0.3 98

Dog 1 1.27 ± 0.02 2.7 ± 0.2 1.3 ± 0.6 97

ETX0282 PO Pharmacokinetics (ETX1317 concentrations)

• Excellent bioavailability achieved in both rats and dogs

• PK profile similar to cefpodoxime proxetil

Session 198 - AAID11, “New Antimicrobial Agents: New Beta-lactams and New Beta-lactamase Inhibitors”SATURDAY – Poster 278, J. O'Donnell, et al.

Co

nce

ntr

atio

n, n

g/m

L

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CPDP/ETX0282 combination is orally efficacious against MDR E. coli in murine studies

6.63

10.8610.24

9.56

5.77 5.59 5.52 5.17

Log(

CFU

/g)

Neutropenic mouse thigh model (PO)

Stasis

• In vivo oral efficacy also observed for CPDP/ETX0282 combination against 4 other MDR Enterobacteriaceaeisolates (including K. pneumoniae CRE strain where ETX1317 MIC > 32 mg/L)

ETX0282 + CPDP 50 mg/kg

MDR E. coli (AmpC, CTX-M-14):• Levofloxacin resistant (MIC > 4 mg/L)• Cefpodoxime resistant (MIC > 64 mg/L)• Meropenem (MIC = 0.03 mg/L)• ETX1317 (MIC = 0.5 mg/L)• Cefpodoxime/ETX1317 (MIC ≤ 0.03 mg/L)

Session 198 - AAID11, “New Antimicrobial Agents: New Beta-lactams and New Beta-lactamase Inhibitors”SATURDAY – Poster 278, J. O'Donnell, et al.

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CPDP/ETX0282 represents the first, new oral BL/BLI combination for the treatment of MDR Gram-negative uropathogens in decades

• ETX1317 potently restores the activity of CPD against ESBL-producing, carbapenem-resistant, fluoroquinolone-resistant and colistin-resistant Enterobacteriaceae

• The prodrug ETX0282 demonstrates high bioavailability of ETX1317 following oral administration in preclinical species with similar ADME attributes as CPDP

• The promising activity of CPDP/ETX0282 in vitro and in vivo warrants further preclinical evaluation of the combination

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Acknowledgements

• Pharmaron• IHMA, Inc.• NeoSome Life Sciences, LLC