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