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
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
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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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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
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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
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
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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
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.