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ETX0282, a Novel Oral Agent Against Multidrug-Resistant Enterobacteriaceae
Thomas Durand-Réville
02 June 2017 - ASM Microbe 2017 (Session #113)
2
Disclosures
• Thomas Durand-Réville: Full-time Employee; Self; Entasis Therapeutics.
3
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
12
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
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