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Scientific Overview of Entasis Pipeline
Ruben Tommasi, PhDChief Scientific Officer, Entasis Therapeutics
Microbe
San Francisco, CA
June 22, 2019
2
Disclosures
• Full-time employee of Entasis Therapeutics
3
Robust Pipeline of Novel Antibiotics Addressing Antimicrobial Resistance
Product
CandidateIndication Preclinical Phase 1 Phase 2 Phase 3
Upcoming
Milestones
Commercial
RightsPartnerships
Sulbactam-
durlobactam
IV
Multi-drug resistant
Acinetobacter
infections
▪ Ongoing Phase 3
trial; data expected
2H 2020
Worldwide
excluding
Asia-Pacific(1)
Zoliflodacin
Oral
Uncomplicated
gonorrhea
▪ Initiate Phase 3 trial
in mid-2019
All developed
countries(2)
ETX0282CPDP
Oral
Complicated UTIs
(Enterobacteriaceae
including ESBL-
producing and CRE)
▪ Post Phase 1
formulation efforts
initiated in 2019
Worldwide
NBP
Program(3)
IV
Gram-negative
infections
(initially multi-drug
resistant
Pseudomonas)
▪ Select initial clinical
candidate in 2019 Worldwide
(1) Zai Lab has licensed Asia-Pacific rights to ETX2514SUL
(2) GARDP will fully fund the Phase 3 development program and has commercial rights in low-income and specified middle-income countries.
Entasis has retained commercial rights in all major markets in North America, Europe and Asia-Pacific.
(3) (3)Non-β-lactam inhibitors of the penicillin-binding protein.
4
High mortality rates and increasing incidence in MDR A. baumanniiβ-lactam resistance mediated by Class A, C and D β-lactamases(1)
β-lactamase content in MDR Acinetobacter(5)
Inhibition of β-lactamase classes A, C and D required for restoration of β-lactam activity in A. baumannii
Class C(extended spectrum)
38 (45.2%)A, C & D
7 (8.3%)A & D
33 (39.3%)esC & D
Class D(100%)
1(1.2%)
Class B & D
0%
10%
20%
30%
40%
50%
60%
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
20
11
20
12
20
13
20
14
Re
sist
ance
rat
e (
%)
U.S. Carbapenem Resistance Rates(2)
US carbapenem-resistance ~50%(3) Mortality rates close to ~50%(4)
1. Antimicrob Ag Chemother 2010;54(1):24-38 Lancet Infect Dis 2008;12(8):751-762.; J Glob Infect Dis 2010;2(3):291-304.2. CDDEP Antibiotic Resistance Map (resistancemap.cddep.org).3. IntechOpen, DOI: 10.5772/30379.4. Am J Respir Critical Care Med. 2011;184(12):1409-17; Int J Antimicrob Agents 2009;34:575–579.5. Whole-genome sequencing of 84 recent multi-drug resistant (MDR) A. baumannii strains. Derived from Nat Microbiol 2017;2:17104.
5
Durlobactam (ETX2514) is a β-lactamase inhibitor (BLI)Designed to expand coverage beyond Class A and C to include Class D
• Avibactam, a BLI, is largely inactive against Class D β-lactamases
(activity limited to inhibition of OXA-48)
• Durlobactam (ETX2514) designed to effectively bind all variants of
these enzymes, including OXA-23 -24/40, -51, -58 and other families
Overlay of ETX2514 and avibactam
AmpC co-crystal structures
Durlobactam (ETX2514) is the first clinical-stage BLI with broad-
spectrum activity against Class A, C and D β-lactamases
6
Sulbactam-durlobactam (ETX2514SUL) superior in vitro activity against MDR A. baumannii
In vitro activity of ETX2514SUL against 3,611 Acinetobacter isolates
MIC90
(mg/L)
CLSI
Breakpoint
(mg/L)
64 4(1)
2 NA
>8 2
>8 2
>64 16
2 2
0%
20%
40%
60%
80%
100%
0.0
31
25
0.0
62
5
0.1
25
0.2
5
0.5 1 2 4 8
16
32
% o
f S
train
s I
nh
ibit
ed
Concentration (mg/L)
Sulbactam
ETX2514SUL
Imipenem
Meropenem
Amikacin
Colistin
MIC90
(1) Based on the breakpoint for Unasyn™, the fixed-dose combination of sulbactam and ampicillin.(2) Sulbactam, ETX2514SUL, imipenem, and meropenem were tested against all 3,611 strains. Amikacin and colistin were tested against 3,003 of the 3,611 strains.
(2)
(2)
Sulbactam
Durlobactam (ETX2514)
See: McLeod et al P513-AAR09, 6/22 4-5PM
7
Rapid in vivo killing activity of ETX2514SUL translates to in vivo efficacy in mice (1)
Bacterial load suppression of XDR(2) Acinetobacter infections(3)
6.36
8.03 8.02
6.72
4.394.24
3.97 4.01 4.07
4.77
2
3
4
5
6
7
8
9
10
Pre
-tre
atm
ent
Ve
hic
le
2.5
/ 0
.625
5 / 1
.25
10 / 2
.5
20 / 5
30 / 7
.5
40 / 1
0
80 / 2
0
Colis
tin
40 m
g/k
g
Bacte
rial L
oa
d (
Lo
g C
FU
/g)
1-Log10
Reduction
Sulbactam / ETX2514 (mg/kg)
7.40
9.40
8.40
8.03
6.636.19
4.854.61
4.19
8.55
2
3
4
5
6
7
8
9
10
Pre
-tre
atm
ent
Ve
hic
le
2.5
/ 0
.625
5 / 1
.25
10 / 2
.5
20 / 5
30 / 7
.5
40 / 1
0
80 / 2
0
Colis
tin
40 m
g/k
g
Bacte
rial L
oa
d (
Lo
g C
FU
/g)
Sulbactam / ETX2514 (mg/kg)
1-Log10
Reduction
Lung
(1) ETX2514, sulbactam, and colistin were dosed subcutaneously. Colistin injected to maximum tolerated dose.(2) Extensively drug resistant (XDR) A. baumannii ARC3486 (OXA-72, OXA-66, TEM-1, AmpC): MIC(sulbactam) ≥ 32 mg/L, MIC(sulbactam/ETX2514) = 0.5 mg/L.(3) Nat Microbiol. 2017;2:17104
Thigh
See: O’Donnell et al AAR-LB-14 Session S339, 6/23 2:00-2:15and P579 –AAR late breakers 6/23 11:00-1:00
8
Robust Pipeline of Novel Antibiotics Addressing Antimicrobial Resistance
Product
CandidateIndication Preclinical Phase 1 Phase 2 Phase 3
Upcoming
Milestones
Commercial
RightsPartnerships
Sulbactam-
durlobactam
IV
Multi-drug resistant
Acinetobacter
infections
▪ Ongoing Phase 3
trial; data expected
2H 2020
Worldwide
excluding
Asia-Pacific(1)
Zoliflodacin
Oral
Uncomplicated
gonorrhea
▪ Initiate Phase 3 trial
in mid-2019
All developed
countries(2)
ETX0282CPDP
Oral
Complicated UTIs
(Enterobacteriaceae
including ESBL-
producing and CRE)
▪ Post Phase 1
formulation efforts
initiated in 2019
Worldwide
NBP
Program(3)
IV
Gram-negative
infections
(initially multi-drug
resistant
Pseudomonas)
▪ Select initial clinical
candidate in 2019 Worldwide
(1) Zai Lab has licensed Asia-Pacific rights to ETX2514SUL
(2) GARDP will fully fund the Phase 3 development program and has commercial rights in low-income and specified middle-income countries.
Entasis has retained commercial rights in all major markets in North America, Europe and Asia-Pacific.
(3) (3)Non-β-lactam inhibitors of the penicillin-binding protein.
9
Zoliflodacin: A novel single dose cure for gonorrhea
◼ A topoisomerase II inhibitor with distinct mode of action on the DNA gyrase/topoisomerase IV complex
◼ Oral monotherapy that serves as an alternative to intramuscular injection of ceftriaxone
− Strong antimicrobial activity against all strains of N.gonorrhoeae, including ESC and fluoroquinolone-resistant
− Has the potential to become a mainstay treatment option for uncomplicated gonorrhea
− Entering Phase 3 in 2019
◼ Developed in partnership with:
PDB:2XCT
Key interaction points for fluoroquinolones on Gyrase A
Zoliflodacin touch-points on Gyrase B
Nature Scientific Reports 5, 11827, 2015Front. Microbiol. 6, 1377, 2015Antimicrob. Agents Chemother. 59(3), 1478, 2015
See: John Mueller, S358, 6/23 2:30-3:15, Track Hub Booth 5053
10
Robust Pipeline of Novel Antibiotics Addressing Antimicrobial Resistance
Product
CandidateIndication Preclinical Phase 1 Phase 2 Phase 3
Upcoming
Milestones
Commercial
RightsPartnerships
Sulbactam-
durlobactam
IV
Multi-drug resistant
Acinetobacter
infections
▪ Ongoing Phase 3
trial; data expected
2H 2020
Worldwide
excluding
Asia-Pacific(1)
Zoliflodacin
Oral
Uncomplicated
gonorrhea
▪ Initiate Phase 3 trial
in mid-2019
All developed
countries(2)
ETX0282CPDP
Oral
Complicated UTIs
(Enterobacteriaceae
including ESBL-
producing and CRE)
▪ Post Phase 1
formulation efforts
initiated in 2019
Worldwide
NBP
Program(3)
IV
Gram-negative
infections
(initially multi-drug
resistant
Pseudomonas)
▪ Select initial clinical
candidate in 2019 Worldwide
(1) Zai Lab has licensed Asia-Pacific rights to ETX2514SUL
(2) GARDP will fully fund the Phase 3 development program and has commercial rights in low-income and specified middle-income countries.
Entasis has retained commercial rights in all major markets in North America, Europe and Asia-Pacific.
(3) (3)Non-β-lactam inhibitors of the penicillin-binding protein.
11
ETX0282CPDP: Potential Best-in-Class Oral Agent with Microbiological Activity
Comparable to IV Therapies
In vitro Activity of ETX0282CPDP(1) Against 54 Enterobacteriaceae Strains, Including CRE
MIC90
™
™
(1) ETX0282CPDP is an oral prodrug that is metabolized into ETX1317, the active BLI, and cefpodoxime. The in vitro activity is of ETX1317 + cefpodoxime.
(1)
MIC90
(mg/L)
1
>32
>32
0.5
4
0%
20%
40%
60%
80%
100%
0.0
31
0.0
62
5
0.1
25
0.2
5
0.5 1 2 4 8
16
32
64
% o
f S
train
s I
nh
ibit
ed
Concentration (mg/L)
ETX0282CPDP
Oral Agent 1 in Development
Oral Agent 2 in Development
Vabomere (IV)
Avycaz (IV)
Cefpodoxime Proxetil
ETX0282
See: McLeod et al, AAR-714 and Shapiro et al, AAR-715P588-AAR08 6/23 11:00-1:00
12
Oral Efficacy of CPDP/ETX0282 Combination Against MDR E. coli in Murine Thigh Infection
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)
J. O'Donnell, et al. Microbe 2017 Session 198, Poster 278,
13
Robust Pipeline of Novel Antibiotics Addressing Antimicrobial Resistance
Product
CandidateIndication Preclinical Phase 1 Phase 2 Phase 3
Upcoming
Milestones
Commercial
RightsPartnerships
Sulbactam-
durlobactam
IV
Multi-drug resistant
Acinetobacter
infections
▪ Ongoing Phase 3
trial; data expected
2H 2020
Worldwide
excluding
Asia-Pacific(1)
Zoliflodacin
Oral
Uncomplicated
gonorrhea
▪ Initiate Phase 3 trial
in mid-2019
All developed
countries(2)
ETX0282CPDP
Oral
Complicated UTIs
(Enterobacteriaceae
including ESBL-
producing and CRE)
▪ Post Phase 1
formulation efforts
initiated in 2019
Worldwide
NBP
Program(3)
IV
Gram-negative
infections
(initially multi-drug
resistant
Pseudomonas)
▪ Select initial clinical
candidate in 2019 Worldwide
(1) Zai Lab has licensed Asia-Pacific rights to ETX2514SUL
(2) GARDP will fully fund the Phase 3 development program and has commercial rights in low-income and specified middle-income countries.
Entasis has retained commercial rights in all major markets in North America, Europe and Asia-Pacific.
(3) (3)Non-β-lactam inhibitors of the penicillin-binding protein.
14*Reversibility of β-lactamase inhibition first exemplified with avibactam in: Ehmann D. et al., PNAS (2012) 109, 11663
Towards a Novel Class of Gram-negative Agents: Diazabicyclooctanone (DBO)
Tazobactam: hydrolyzed by -lactamases
ETX2514: stable to -lactamase hydrolysis hydrolysis
carbamoylation
reversible
acylation
irreversiblehydrolysis
X
-lactamase(active)
-lactamase(inactive)
-lactamase(active)
• In addition to acting as potent inhibitors of diverse β-lactamases, certain DBO analogs have intrinsic antibacterial activity
• Unique mechanism of inhibition and action of this class demonstrated by ETX2514*
• Several other DBO analogs have also exhibited PBP2 activity (e.g. nacubactam, zidebactam, NXL-105) but this feature has not yet been optimized
GOAL: Discover single I.V. DBO (no BLI required) to treat infections caused by P. aeruginosa, including MDR strains
15
Antibacterial Activity of ETX’054 is Unaffected by β-lactamases in a P. aeruginosa Isogenic Panel
• -lactams lose their activity in presence of -lactamases as depicted below for piperacillin, ceftazidime and imipenem
• In contrast, ETX’054 maintains activity in the presence of all 4 classes of -lactamases tested
• ETX’054 also retains activity against recent CAZ/AVI-resistant KPC-3 variants
MIC (mg/L) against P. aeruginosa isogenic strains expressing individual β-lactamases
parent Class A Class B Class C Class D
Compound PA01 CTX-M-15 KPC-2 SHV-2a TEM-1 NDM-1 VIM-1 VIM-2 AmpC P99 OXA-10 OXA-23 OXA-40 OXA-48 OXA-58
piperacillin 4 >256 >256 >256 >256 128 >256 128 256 128 >256 256 256 256 >256
ceftazidime 2 64 >64 32 4 >64 >64 >64 32 64 4 16 2 2 2
imipenem 1 1 32 1 1 16 64 64 1 1 1 16 32 64 8
ETX‘054 4 4 8 4 4 8 4 4 8 8 8 4 4 8 4
16
ETX’054 is Efficacious Against a P. aeruginosa Clinical Isolate in Murine Infection Model
In vivo efficacy of NXL-105 (PBP2) and ETX0462 (PBP3/1a) in neutropenic mouse thigh infection model*
* ARC6347 = MDR P. aeruginosa (OXA-486+, PDC-24+) Imipenem resistant (MIC>4 mg/L)
NXL-105 DBO-based PBP2 inhibitor has excellent in vitro potency (P.a. MIC90= 1 mg/L, N=302), it was devoid of in vivo efficacy despite dosing up to 100% fT/MIC
Using structure-based design, we have engineered strong PBP3 activity along with some PBP1a activity which translates into robust in vivo activity.
5.93
8.29 8.04
6.42 6.66
3.282
3
4
5
6
7
8
9
10
Pre-treatment vehicle only 6.25 50 250 levofloxacin 160mg/kg q24h (PO)
Log
(CFU
/g)
Stasis
PBP2 Inhibitor (mg/kg q3h)MIC = 0.25 mg/L
NXL-105
5.69
8.77
6.69
4.093.61
4.01
2
3
4
5
6
7
8
9
10
Pre-treatment vehicle only ETX'054 12.5mg/kg q3h
ETX'054 50mg/kg q3h
ETX'054 250mg/kg q3h
levofloxacin 160mg/kg q24h (PO)
ETX’054
Stasis
MIC = 0.25 mg/L
17
0 3 0 6 0 9 0 1 2 0 1 5 0
[ A r a b in o s e ] , M
Fo
ld-C
ha
ng
e i
n M
IC
E T X '9 9 1
E T X '6 7 8
E T X '0 5 4
1 6
8
4
2
0 3 0 6 0 9 0 1 2 0 1 5 0
[ A r a b in o s e ] , M
Fo
ld-C
ha
ng
e i
n M
IC
E T X '0 5 4
E T X '6 7 8
E T X '9 9 11 6
8
4
2
Porin-dependent effect
Porin has no effect
Generating Structure-Porin Permeation Relationships (SPPR) to Improve Cellular Potency
Compound ETX’054 ETX’678 ETX’991
Structure
Porin permeation none++,
multiple
+++,
multiple
P.a. PBP3 acylation
rate k(on) (M-1.s-1)582,000 610 230
OprDOprF
• Striking differences in biochemical activity and cellular uptake with simple structural modifications
• Hydrogen-bond donor appears required at R1 to effectively permeate several porins, but sub-optimal for PBP3 potency
• Optimization efforts underway to improve both.
18
Robust Pipeline of Novel Antibiotics Addressing Antimicrobial Resistance
Product
CandidateIndication Preclinical Phase 1 Phase 2 Phase 3
Upcoming
Milestones
Commercial
RightsPartnerships
Sulbactam-
durlobactam
IV
Multi-drug resistant
Acinetobacter
infections
▪ Ongoing Phase 3
trial; data expected
2H 2020
Worldwide
excluding
Asia-Pacific(1)
Zoliflodacin
Oral
Uncomplicated
gonorrhea
▪ Initiate Phase 3 trial
in mid-2019
All developed
countries(2)
ETX0282CPDP
Oral
Complicated UTIs
(Enterobacteriaceae
including ESBL-
producing and CRE)
▪ Post Phase 1
formulation efforts
initiated in 2019
Worldwide
NBP
Program(3)
IV
Gram-negative
infections
(initially multi-drug
resistant
Pseudomonas)
▪ Select initial clinical
candidate in 2019 Worldwide
(1) Zai Lab has licensed Asia-Pacific rights to ETX2514SUL
(2) GARDP will fully fund the Phase 3 development program and has commercial rights in low-income and specified middle-income countries.
Entasis has retained commercial rights in all major markets in North America, Europe and Asia-Pacific.
(3) (3)Non-β-lactam inhibitors of the penicillin-binding protein.
19
Acknowledgements
Pharmaron, JMI Laboratories, Neosome Life Sciences