Breakthrough medicines targeting the growing global medicines targeting the growing global health...

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

3

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

4

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

7

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

tica

l Ho

spit

alU

rgen

t C

om

mu

nit

y

ETX2514/sulbactamInjectable

ETX0282/ Cefpodoxime

Oral

IND-enabling package2H-2017

1 Phase 2 completed in partnership with NIAID2 In partnership

Enterobacteriaceaeincl. ESBL & CRE

8

Entasis TherapeuticsPortfolio overview

Product Discovery Preclinical Phase I Phase IINext

Milestone

Uncomplicated Gonorrhea

ETX2514/ ImipenemInjectable

Zoliflodacin1

(ETX0914)Oral

Initiate TQT/RelBio Study 20172

Acinetobacter baumannii Infections

Other Serious Hospital Gram-negative Infections

Cri

tica

l Ho

spit

alU

rgen

t C

om

mu

nit

y

ETX2514/sulbactamInjectable

1 Phase 2 completed in partnership with NIAID2 In partnership

ETX0282/ Cefpodoxime

Oral

IND-enabling package2H-2017

Readout Phase 12Q-2017

Enterobacteriaceaeincl. ESBL & CRE

9

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

10

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

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26

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no

gi)

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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

17

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

18

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

tica

l Ho

spit

alU

rgen

t C

om

mu

nit

y

ETX2514/sulbactamInjectable

1 Phase 2 completed in partnership with NIAID2 In partnership

ETX0282/ Cefpodoxime

Oral

IND-enabling package2H-2017

Enterobacteriaceaeincl. ESBL & CRE

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

20

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

23

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

24

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

tica

l Ho

spit

alU

rgen

t C

om

mu

nit

y

ETX2514/sulbactamInjectable

1 Phase 2 completed in partnership with NIAID2 In partnership

ETX0282/ Cefpodoxime

Oral

IND-enabling package2H-2017

Enterobacteriaceaeincl. ESBL & CRE

25

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

27

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

ETX0282Ph1 start1Q2018

ETX25142nd Ph3 start

2H2019

ETX25142nd Ph3 DBL

2021

ETX2514Approval

2021

Project 4Ph1 start4Q2019

zoliflodacinApproval

2021

Multiple near-term value generating milestones

2021

zoliflodacinPh3 start2H2018

ETX0282Ph2 start1Q2019

ETX0282Ph3 start4Q2020

Project 4End of Ph1

4Q2020

ETX2514Ph2 start4Q2017

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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.

29

Thank you

• Patients & volunteers, their families

• Study investigators for zoliflodacin & ETX2514

• Entasis employees and collaborators