Breakthrough medicines targeting the growing global medicines targeting the growing global health threat of antibiotic resistance Jefferies Healthcare Conference June 2017 June 2017

Breakthrough medicines targeting the growing global health threat of antibiotic resistance

Jefferies Healthcare Conference

June 2017

June 2017

2

Our Mission

To build an enduring biopharmaceutical company focused on medicines that target the growing global threat of drug-resistant

bacterial infections affecting millions of people worldwide

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Building an enduring antibacterial company

• Multi-product, Gram-negative infectious disease discovery and development company, with 2 clinical-stage assets and a 3rd entering the clinic by 1Q 2018

• Highly-differentiated products targeting drug resistant pathogens with high medical need and significant revenue potential

• All products wholly-owned

• Discovery engine capable of delivering continued pipeline

• Experienced team with deep expertise in antibiotic discovery and development

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7%

20%

27%30%

34%

9%

23%

44% 43%

50%

13%

17%20%

25%

20%

0%

10%

20%

30%

40%

50%

60%

2000 2005 2010 2012 2014

Fluoroquinolone-resistant E. coli

Carbapenem-resistant A. baumannii

Carbapenem-resistant P. aeruginosa

Resistance trends in Gram-negative bacteria5

Increasing drug resistance results in large unmet need….

• U.S.: 2 MM drug-resistant infections/year1

– >23,000 direct deaths1

• High mortality and morbidity

– CRE (carbapenem resistant Enterobacteriaceae) 75% mortality2,3

– Acinetobacter baumannii mortality 43%4 and 63% multi-drug resistant (MDR)2,3

– 14%5 of Pseudomonas aeruginosa are MDR, occasional reports of resistance to last resort antibiotics4

• Resistance trends increase the urgency of the medical need

• Entasis pipeline aims to effectively address medical need caused by each of these Gram-negative pathogens

1 Antibiotic Resistance Threats in the Unites States, 2013; Centers for Disease Control2 Nat. Rev. Drug Discov. 12:963.3 Clin. Microbiol. 48:2271. 4 Expert Rev. Anti Infect. Ther. 10(8), 917-934 (2012)5 CDC Antibiotic Resistance Patient Safety ATLAS; Center for Disease Dynamics, Economics & Policy

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Which has prompted a global call to action

• Non-dilutive funding for R&D– NIAID, BARDA, DARPA, CARB-X(US)– IMI (Europe)

• New regulatory pathways, accelerated approvals

• QIDP & fast track designations• Improved biological insights• Rapid molecular diagnostics

• Next generation antibiotics – Tailored to target key pathogens – Highly effective– Well tolerated– Priced to reflect value-add

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Unique innovative platform sets foundation for repeated success

Structure-based Design

Novel TherapeuticsStructure-based Design

No Rx

After RxTreatment

0

24

1150

0

128

44,522

Nu

mb

er of

Map

ped

Read

s

Bacterial Genomics

Molecular Dynamics

Medicinal Chemistry

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Entasis TherapeuticsPortfolio overview

Product Discovery Preclinical Phase I Phase IINext

Milestone

Uncomplicated Gonorrhea

Readout Phase 12Q-2017ETX2514/

ImipenemInjectable

Zoliflodacin1

(ETX0914)Oral

Initiate TQT/RelBio Study 20172

Acinetobacter baumannii Infections

Other Serious Hospital Gram-negative Infections

Cri

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ETX2514/sulbactamInjectable

ETX0282/ Cefpodoxime

Oral

IND-enabling package2H-2017

1 Phase 2 completed in partnership with NIAID2 In partnership

Enterobacteriaceaeincl. ESBL & CRE

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Milestone


ETX2514/ ImipenemInjectable

Zoliflodacin1

(ETX0914)Oral




Cri

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Oral


Readout Phase 12Q-2017


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What is a b-lactamase inhibitor (BLI)?

PBPs required

for bacterial cell

wall synthesis

BLs inactivate b-lactams

No inhibition of

cell wall synthesis

Bacterial growth

MDR

pathogen

BLI inhibits BLs,

b-lactam inhibits PBPs

Deadbacteria

b-lactamalone

b

b-lactam

+ BLI

b Inhibition of

cell wall synthesisb

b

b

b

b

b

b

b

b

b

b

b-lactamases (BLs)

expressed in periplasm

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Emerging Threat

Entasis’ programs address unmet opportunity in b-lactamase inhibitors

Class C Class D Class B

b-lactamases

Metallo-enzymesSerine Enzymes

Originally marketed BLIs, generic

Major new opportunity Acinetobacter &

PseudomonasETX2514

KPCCarbapenemase

Class A

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ETX2514 combinations offer the broadest spectrum Gram-negative coverage amongst leading competitors

ETX

25

14

+

Sulb

acta

m

ETX

25

14

+

imip

en

em

Avy

caz

(AZ/

All

erg

an)

Zerb

axa

(Me

rck)

Car

bav

ance

(Me

dC

o)

Erav

acyc

line

(Te

trap

has

e)

Imip

en

em

/ re

leb

acta

m(M

erc

k)

Pla

zom

icin

(Ah

cao

gen

)

S-6

49

26

6(S

hio

no

gi)

WC

K 5

99

9(W

ock

har

dt)

ESBL ExpressingEnterobacteriaceae +/- + + +/- + + + + + +

Carbapenem-Resistant Enterobacteriaceae

+/- + +/- - + + + + + +

Pseudomonas - ++ + ++ + - + - + -

Acinetobacter ++ +/- - - - +* - +/- +/- +/-

* Activity measured in vitro, concerns about plasma exposure in vivo

Source: Tetraphase Needham Investor presentation, Karen Bush “Has the Antibiotic Pipeline been Sufficiently Replenished?”.

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Multi-Drug Resistant Acinetobacter baumannii is growing in prevalence and is associated with high mortality

• Between 60,000 and 100,000 infections per year in the US, ~100,000-140,000 per year in EU51

– forecast to grow over the next decade

• A. baumannii causes infections among critically ill patients. Mortality rates as high as 43%2

• Class D b-lactamases in A. baumannii are responsible for failure of many b-lactams3-5

• About 63% of A. baumannii isolates are MDR2

1. Decision Resources2. Am. J. Respir. Crit. Care Med. 2011.1409; Int. J. Antimicrob. Agents 2009.5753. M.M. Ehlers, et. Al. 2012. Prevalence of Carbapenemases in Acinetobacter baumannii, Antibiotic Resistant Bacteria – A Continuous Challenge in the New Millennium,

InTech, DOI: 10.5772/303794. Poirel, L. 2010. Diversity, Epidemiology & Genetics of Class D b-lactamases. AAC. 54: 24-38.5. Lancet 2008.751; J. Glob. Infect. Dis. 2010.291

A. baumannii

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ETX2514+sulbactam for Acinetobacter baumannii infections

Drug Profile

• Novel I.V. antibiotic to treat serious A. baumannii infections• b-lactamase inhibitor with novel mode-of-action and expanded

spectrum, including Class D b-lactamases

Market Opportunity

• A. baumannii infections associated with high mortality• Resistance rates to one or more antibiotic >60%

Label / Indications

• Demonstrated or suspected A. baumannii infection• Multiple body sites • I.V. infusion q6h

Data to Date• Pre-clinical safety and DMPK complete• Extensive PK/PD to project clinical exposure and safety

Status • Phase 1 initiated October 2016

Next Steps • Readout Phase 1 2Q-2017, Phase 2 start 4Q-2017

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ETX2514 + sulbactam: A novel combination against multi-drug resistant A. baumannii

• ETX2514 + sulbactam maintains excellent activity over time

• ETX2514 + sulbactam activity remains unchanged in carbapenem-resistant, colistin-resistant and multidrug resistant strains

MIC (mg/L) ≤0.06 0.12 0.25 0.5 1 2 4 8 16 32 >64

2011N=195

Cumul % 1 3.1 13.8 41.5 65.6 89.7 96.9 97.9 99.5 100 100

2012 N=209

Cumul % 0 0.5 2.9 20.1 46.9 79 98.6 100 100 100 100

2013N=207

Cumul % 0 0 4.3 15.9 43.4 73.8 96.5 97.5 99 99 100

2014N=1131

Cumul % 1 1.6 7.8 27.9 63.7 88.9 99.6 99.6 99.7 100 100

2015*N=202

Cumul % 0 1.0 7.4 43.1 78.7 97.0 99.5 99.5 100 100 100

MIC distributions for globally diverse A. baumannii clinical strains

*2015 study performed at JMI

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ETX2514 + sulbactam exhibits excellent in vivo activity

Strong bacterial load suppression of XDR* A. baumannii infections at clinically relevant doses

7.40

9.40

8.408.03

6.636.19

4.854.61

4.19

2

3

4

5

6

7

8

9

10

Pre-treatment

Vehicle 2.5 /0.625

5 / 1.25 10 / 2.5 20 / 5 30 / 7.5 40 / 10 80 / 20

Log(

CFU

/g)

Lung

Stasis

sulbactam/ETX2514 (mg/kg) q3h

6.36

8.03 8.02

6.72

4.39 4.243.97 4.01 4.07

2

3

4

5

6

7

8

9

10

Pre-treatment

Vehicle 2.5 /0.625

5 / 1.25 10 / 2.5 20 / 5 30 / 7.5 40 / 10 80 / 20

Log(

CFU

/g)

Thigh

Stasis

sulbactam/ETX2514 (mg/kg) q3h

* Extensively drug resistant A. baumannii ARC3486 (OXA-72, OXA-66, TEM-1, AmpC) in neutropenic mice; MIC(sulbactam) ≥ 32 mg/L, MIC(sulbactam/ETX2514) = 0.5 mg/L

Human dose projected to be 500-1000mg/QID based on PK, efficacy and hollow fiber work

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When combined with a carbapenem, ETX2514 has excellent microbiological potency against Pseudomonas

MIC50

(mg/L)MIC90

(mg/L)

CLSI Breakpoint

(mg/L)

1 16 2 (IPM)

0.25 1 2 (IPM)

0.5 16 8 (MEM)

0.25 8 8 (MEM)

Activity vs. 602 P. aeruginosa StrainsJMI 2013-2015

0%

20%

40%

60%

80%

100%

% S

us

ce

pti

ble

Str

ain

s

MIC (mg/L)

Imipenem (IPM)

IPM:ETX2514

Meropenem (MEM)

MEM:ETX2514

MIC90

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ETX2514: Rapid and broad development strategy

• Currently in Phase 1– Compelling preclinical safety and toleration profile

– SAD, MAD, drug-drug interaction studies with multiple partners completed

– Data will be prepared for presentation at upcoming ID conference

• Phase 2 will be initiated by the end of 2017, pivotal trials in 2018

• Anticipate NDA filing against A. baumannii in 2020– Rapid path to licensure reflects high medical need

• Opportunity to expand label to additional pathogens/indications

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Milestone



ImipenemInjectable

Zoliflodacin1

(ETX0914)Oral




Cri

tica

l Ho

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Oral



19

Emerging Threat

Entasis’ programs address unmet opportunity in b-lactamase inhibitors

Class C Class D Class B

b-lactamases

Metallo-enzymesSerine Enzymes

Originally marketed BLIs, generic

KPCCarbapenemase

Class A

I.V. Gram-(avibactam)Oral ETX0282

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ETX0282 in combination with cefpodoxime addresses a significant unmet medical need

• MDR community urinary tract infections (UTIs) are a major concern in the medical community

• Category has been subject to an increase in resistance to SOCs (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

Our vision: To create an oral agent for MDR Enterobacteriaceae (Class A and C)

• Outpatient setting (PCP or ER): Treatment for MDR cystitis, pyelonephritis patients who failed initial oral therapy (prevent hospitalization)

• Hospital setting: Oral step-down from IV - extend utility well beyond UTI (early discharge)

Urinary Tract

* Spellberg, B. & Y. Doi. The Rise of Fluoroquinolone-Resistant Escherichia coli in the Community: Scarier Than

We Thought. J Infect Dis. 2015. 212(12):1853-5..

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• Combination of ETX0282 with cefpodoxime-proxetil (prodrug of cefpodoxime) has excellent microbiological potency– MIC90 ≤ 0.5 µg/ml against a panel of relevant Enterobacteriaceae clinical

isolates, including ESBL and CRE

• Favorable ADME, robust oral efficacy in neutropenic mouse thigh infection model– PK/PD requirements defined for projected clinical efficacy

• Excellent safety profile in non-GLP toxicology

ETX0282 with cefpodoxime is only oral BL/BLI combination with activity against ESBL and CRE bacteria

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Our novel combination provides best-in-class coverage of contemporary clinical UTI isolates

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

(from UTI in 2013-2015)

MIC90

(mg/L)

CLSI Breakpoint

(mg/L)

Cefpodoxime (CPD) >32 2

ETX1317 32 ND

CPD/ETX1317 0.03 2 (CPD)

Levofloxacin 32 2

Piperacillin/tazobactam >32 16

Note: BLIs tested at a fixed concentration of 4 mg/L in combinations.

MIC90

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ETX0282 delivers high bioavailability in preclinical species

Rat PK : Oral Bioavailability = 98% Dog PK : Oral Bioavailability = 97%

1

10

100

1000

10000

100000

0 5 10

Time, hr

1

10

100

1000

10000

100000

0 5 10 15

Co

nc,

ng/

mL

Time, hr

ETX0282 PO

ETX1317 IV

• Excellent bioavailability achieved in both rats and dogs

• PK profile similar to cefpodoxime proxetil

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Milestone



ImipenemInjectable

Zoliflodacin1

(ETX0914)Oral




Cri

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Oral



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Gonorrhea is an area of significant unmet need

• N. gonorrhoeae is an immediate public health threat

– Highly contagious with low rates of resistance sufficient to drive new treatment recommendations

– Resistance to cefixime (oral cephalosporin) >1%1; not recommended since 2012

– Resistance to ceftriaxone (injectable cephalosporin, current standard-of-care) is growing

– Cluster of MDR infections recently reported in Hawaii, but already an everyday reality in Europe and Asia

• In 2013, 333,000 cases of gonorrhea were reported, but CDC estimates that more than 820,000 cases occur annually in the U.S.3

1 CDC 2013 STD surveillance, susceptibility rates in the United States2 Cole MJ, et al. Euro surveill 2014;19(45) ; 3 Zheng H, et al. Japan J Infect Dis 2014;67:288-91; Hamasuna R, et al Japan J Infect Dis 203;19:571-8; Hamasuna R, et al. J Infect

Chemother 2015;21:1-6; CDC. STD Surveillance 2013.Atlanta, US Department of HHS 2014

http://www.cdc.gov/std/gisp2013/default.htm4 Includes oral cefixime and ceftriaxone

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

2009 2010 2011

China Japan Europe US

% of N. gonorrhoeae Isolates with Reduced Susceptibility to Extended-spectrum

Cephalosporins2,3,4

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Zoliflodacin (ETX0914): Phase 2 POC

Open-label, multi-center, randomized

• NIAID sponsored

• 3 study arms (N=180 total patients with gonorrhea)– 2:2:1 ETX0914 2000mg or 3000mg once, or ceftriaxone 500mg I.M. once

– ETX0914 dosed as an oral suspension

Zoliflodacin has achieved POC

• Microbiological eradication and clinical cure in urogenital and anal infections comparable to high-dose ceftriaxone (100% at high dose)

• Potentially numerically slightly inferior in pharyngeal infections (4/6 and 7/9 respectively) but small numbers

• Generally well tolerated, no drug-related SAEs

Progression to Phase 3

• Relative bioavailability and TQT required prior to initiation of Phase 3

• Phase 3 initiation planned in 2H-2018

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2017 2018 2019 2020

ETX2514End of Ph1

2Q2017

ETX2514Ph3-ready

2Q2018

ETX2514Ph3 start3Q2018

ETX2514DBL for NDA

1Q2020

ETX0282End of Ph1

4Q2018

ETX0282POC

1Q2020

ETX2514NDA filing3Q2020

zoliflodacinend of Phase 3

1H2020


ETX25142nd Ph3 start

2H2019

ETX25142nd Ph3 DBL

2021

ETX2514Approval

2021

Project 4Ph1 start4Q2019

zoliflodacinApproval

2021

Multiple near-term value generating milestones

2021

zoliflodacinPh3 start2H2018



Project 4End of Ph1

4Q2020


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Building an enduring antibacterial company

Building value with a differentiated pipeline and favorable

clinical and regulatory strategy

Two clinical programs and a compelling preclinical pipeline

addressing critical unmet medical needs

Proven team and strong investors

Upcoming Milestones

ETX2514 ETX0282 Zoliflodacin

Phase 2 initiates 4Q2017 Phase 1 initiates 1Q2018 Initiate TQT/RelBio study in 2017*

* Dependent on partner funding.

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Thank you

• Patients & volunteers, their families

• Study investigators for zoliflodacin & ETX2514

• Entasis employees and collaborators

Documents

Breakthrough medicines targeting the growing global medicines targeting the growing global health threat of antibiotic resistance Jefferies Healthcare Conference June 2017 June 2017