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
1
Entasis has a Highly Experienced Leadership Team
2
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
3
• 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
4
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
5
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
6
Territory% of N. gonorrhoeae Isolates with
Reduced Susceptibility to Extended-Spectrum Cephalosporins*, 1
USA 0.9%
Europe 4.5%
China 21%
7
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
8
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
9
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
10
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
11
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
12
Questions?
13