Global Antibiotic Research and Development Partnership, Pasteur Institute, 29 February, 2016

Zoliflodacin (ETX0914) for Uncomplicated Gonorrhoea

Entasis Therapeutics - Introduction

• Entasis Therapeutics is developing a portfolio of innovative cures for serious drug-resistant bacterial infections

• Located in Waltham, MA, USA; established May 2015

• Strong financial position with $40 MM Series A financing

• First-in-class Phase 2 drug candidate to cure uncomplicated gonorrhoea

• Proprietary discovery platform with the potential to deliver additional novel drug candidates– Innovative chemistry, unique biological and mechanistic

insights

• Highly experienced team with an impressive scientific and managerial track record

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Entasis has a Highly Experienced Leadership Team

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Manos Perros, PhD, President and Chief Executive Officer• Head of Infection iMed and Site Head, AZ Boston• Director, Novartis Institute for Tropical Diseases• CSO, Antivirals, Pfizer; co-inventor of maraviroc , PhRMA Discovers Award 2010 & Prix Galien 2008

Michael Fitzgerald, Chief Financial Officer• SVP & CFO, Link Medicine Corp.• CFO, Hypnion Inc.

Robin Isaacs, MD, Chief Medical Officer• VP and Therapeutic Area Head, Vaccines/Infectious Diseases Clinical Development, Merck• Oversight of development and approval of numerous anti-infective, antiviral and vaccine products

John Mueller, PhD, Vice President – Program Management & Early Development• Senior Project Director, AstraZeneca Infection iMed• Senior Director & Biology Head, Antibacterial Research, Pfizer• Alexion Pharmaceuticals

Ruben Tommasi, PhD, Chief Scientific Officer• Executive Director, Infectious Disease Chemistry, AstraZeneca• Executive Director Infection Chemistry; Head, Hit to Lead Optimization & Chemogenetics, Novartis• Co-inventor tipranavir

Chris White, Chief Business Officer• CBO, AMAG Pharmaceuticals• Partner at management consulting firms A.T. Kearney and Accenture• Antibiotic product manager, Merck

Zoliflodacin (ETX0914) Overview

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• 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 for use by CDC since 2012

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

• A 2012 report from the WHO reported worldwide estimates of over 106MM new cases of gonorrhea in 2008, up from ~90MM new cases in 2005

• If untreated/poorly treated, gonorrhea can lead to pelvic inflammatory disease, infertility, and epididymitis

Gonorrhea is an Area of Significant Unmet Need

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

2010 2011 2012

China Japan Europe US

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1. CDC 2013 STD surveillance, susceptibility rates in the United States2. CDC Antibiotic Resistance Threats in the United States, 2013 3. Cole MJ, et al. Euro surveill 2014;19(45)

Cole MJ, et al. BMC Infect Dis 2015 4. Zheng H, et al. Japan J Infect Dis 2014;67:288-91

Hamasuna R, et al Japan J Infect Dis 203;19:571-8Gu et al. BMC Infect Dis 2014 14:731Hamasuna R, et al. J Infect Chemother 2015;21:1-6

CDC. STD Surveillance 2013.Atlanta, US Department of HHS 2014http://www.cdc.gov/std/gisp2013/default.htm* Includes oral cefixime and ceftriaxone

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

Cephalosporins3,*

Magnitude of Global Gonorrhoea Threat

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WHO Region

Incidence (per 1,000)

Incidence

(Millions of cases)Male Female

African 60.3 49.7 21.1

Americas 27.6 18.5 11.0

South-East Asia 37.0 16.2 25.4

European 7.0 8.3 3.4

Eastern Mediterranean 11.6 8.1 3.1

Western Pacific 49.9 34.9 42.0

Derived from WHO 2012

* Includes cefixime and ceftriaxone1 CDC 2013 STD surveillance, susceptibility rates in the US; CDC Antibiotic Resistance Threats in the US, 2013; Cole MJ, et al.

Euro Surveill 2014 19(45); 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 Chemo 2015 21:1-6

Resistance to extended-spectrum cephalosphorins is of great concern

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Territory% of N. gonorrhoeae Isolates with

Reduced Susceptibility to Extended-Spectrum Cephalosporins*, 1

USA 0.9%

Europe 4.5%

China 21%

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Drug Profile• First of a novel class of topoisomerase inhibitors against Neisseria

gonorrhoeae

Population

• CDC estimates 820,000 cases of gonorrhea per year• Concerns of growing resistance in available therapies• Zoliflodacin’s unique resistance profile, excellent tolerability and oral

dosing will differentiate it from other therapies

Label / Indications • One time oral therapy for eradication of infection

Data to Date• Phase 1: Linear PK and well tolerated up to 4 grams• Achieved exposures in excess of those required for efficacy

Status• Phase 2 conducted in partnership with NIAID; enrollment complete• FDA and MHRA endorsed Phase 2 and 3 endpoints

Next Steps• Phase 3 formulation development on track• Initiate thorough QT study/relative bioequivalence of Phase 3 formulation

Zoliflodacin for Uncomplicated Gonorrhea

Zoliflodacin is a “First-in-class” Antibiotic for the Treatment of Uncomplicated Gonorrhoea

• Current standard of care faces emerging resistance

– Threat of resistance rated as “Urgent” by CDC

• Zoliflodacin is from a novel class, no pre-existing resistance1

• Zoliflodacin is orally bioavailable

• Oral treatment could expedite partner therapy, increasing commercial potential

• Zoliflodacin is generally well-tolerated up to 4g

• Designated QIDP* and granted Fast Track status by the US FDA

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1. Responding to the challenge of untreatable gonorrhea: Zoliflodacin, a first-in-class agent with a distinct mechanism-of-action against bacterial Type II topoisomerases. Basarab, G. et al. Nature Scientific Reports; September, 2015

* Qualified Infectious Disease Product

Lack of Cross Resistance to Other Antibiotic ClassesMechanism Distinct from Fluoroquinolones

Zoliflodacin has the Best Microbiological Profile Against Contemporary Clinical Isolates of N. gonorrhoeae

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Susceptible Intermediate Resistant* The strains comprised 29 international gonococcal reference strains, including the 2008 WHO reference strains, 100 consecutive clinical Swedish gonococcal isolates obtained in 2013, and 121 isolates selected for their resistance phenotype. The collection included all of the currently described XDR gonococcal strains, additional isolates with in vitro and clinical ESC resistance, different types of ciprofloxacin resistance, and other high-level clinical resistance and multidrug resistance (MDR) to other antimicrobials previously used for treatment. (Jacobsson S. et al. Antimicrob. Agents Chemother. 2014. 58:9:5585-8)

Cumulative % at Each MIC (µg/mL)*

Compound ≤0.008 0.015 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 >32

Zoliflodacin 4.4 4.4 7.6 30 87.6 100

Ciprofloxacin 19.6 28.4 29.2 29.2 30.8 34.8 35.2 36.8 39.2 48 57.2 63.2 88.8 100

Azithromycin 0.4 3.6 8 16.4 32.4 54.8 83.2 88.8 92 94.8 97.2 98.4 100

Cefixime 29.6 60.4 71.2 80.4 89.2 95.6 98.4 98.8 98.8 99.6 100

Ceftriaxone 44 56 72.4 87.6 97.6 98.8 98.8 98.8 99.6 100

2015 2016 2017 2018 2019

Phase 2 Safety & Efficacy

Development Plan for Zoliflodacin

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NDA Prep, Submission &

Review

Approval & Launch

Phase 2 Read-out

Phase 3 Read-outPhase 3 Efficacy

Phase 3 Trial Design• Multi-center, randomized, open-label• Approximately 600 patients (2:1)• Non-inferiority vs. ceftriaxone 500mg I.M.• Primary endpoint: Microbiologic eradication• Partnering strategy being evaluated

Phase 3 Prep (TQT,

Rel. Bio)

Zoliflodacin offers a medical breakthrough in the management of uncomplicated gonorrhea

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Oral Therapy for Gonorrhea Eradication

Avoids painful intramuscular injections No need for crash cart or patient monitoring

following treatment Opportunity to treat both the patient & their partner

Novel Mechanism of Action

Lack of pre-existing clinical resistance limits concerns about treatment failure

One Time Treatment Single visit for treatment

Product’s Characteristics

Benefits

Entasis Therapeutics is seeking a partner to support the Phase 3 clinical development program of zoliflodacin

• Phase 2 study has completed enrollment

• Licensure in the US and in the EU will require a single Phase 3 study

– Approximately 600 patients

– Approximately 18-24 months from first patient enrolled to final clinical study report (approximately 13-months to enrol)

• Preliminary assessment does not predict significant ethnic sensitivity

– Results from clinical program in developed world should be directly relevant to low/middle-income areas

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Questions?

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