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

Transcription

1 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 2

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 3

4 Increasing drug resistance results in large unmet need. U.S.: 2 MM drug-resistant infections/year 1 >23,000 direct deaths 1 High mortality and morbidity CRE (carbapenem resistant Enterobacteriaceae) 75% mortality 2,3 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 antibiotics 4 Resistance trends increase the urgency of the medical need Resistance trends in Gram-negative bacteria 5 60% 50% 50% 44% 43% 40% 34% 30% 30% 27% 25% 23% 20% 20% 20% 20% 17% 13% 9% 10% 7% Entasis pipeline aims to effectively address medical need caused by each of these Gramnegative pathogens 0% Fluoroquinolone-resistant E. coli Carbapenem-resistant A. baumannii Carbapenem-resistant P. aeruginosa 1 Antibiotic Resistance Threats in the Unites States, 2013; Centers for Disease Control 2 Nat. Rev. Drug Discov. 12: Clin. Microbiol. 48: Expert Rev. Anti Infect. Ther. 10(8), (2012) 5 CDC Antibiotic Resistance Patient Safety ATLAS; Center for Disease Dynamics, Economics & Policy 4

5 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 5

6 Unique innovative platform sets foundation for repeated success Bacterial Genomics 0 No Rx After Rx Treatment ,522 Number of Mapped Reads Novel Therapeutics Structure-based Design Structure-based Design Medicinal Chemistry Molecular Dynamics 6

7 Urgent Community Critical Hospital Entasis Therapeutics Portfolio overview Product Discovery Preclinical Phase I Phase II Next Milestone ETX2514/ sulbactam Injectable ETX2514/ Imipenem Injectable Acinetobacter baumannii Infections Other Serious Hospital Gram-negative Infections Readout Phase 1 2Q-2017 ETX0282/ Cefpodoxime Oral Enterobacteriaceae incl. ESBL & CRE IND-enabling package 2H-2017 Zoliflodacin 1 (ETX0914) Oral Uncomplicated Gonorrhea Initiate TQT/RelBio Study Phase 2 completed in partnership with NIAID 2 In partnership 7

8 Urgent Community Critical Hospital Entasis Therapeutics Portfolio overview Product Discovery Preclinical Phase I Phase II Next Milestone ETX2514/ sulbactam Injectable ETX2514/ Imipenem Injectable Acinetobacter baumannii Infections Other Serious Hospital Gram-negative Infections Readout Phase 1 2Q-2017 ETX0282/ Cefpodoxime Oral Enterobacteriaceae incl. ESBL & CRE IND-enabling package 2H-2017 Zoliflodacin 1 (ETX0914) Oral Uncomplicated Gonorrhea Initiate TQT/RelBio Study Phase 2 completed in partnership with NIAID 2 In partnership 8

9 What is a b-lactamase inhibitor (BLI)? PBPs required for bacterial cell wall synthesis b-lactamases (BLs) expressed in periplasm b-lactam alone b b b b b BLs inactivate b-lactams No inhibition of cell wall synthesis b Bacterial growth BLI inhibits BLs, b-lactam inhibits PBPs MDR pathogen b-lactam + BLI b b b b b Inhibition of cell wall synthesis b b Dead bacteria 9

10 Entasis programs address unmet opportunity in b-lactamase inhibitors Originally marketed BLIs, generic Serine Enzymes b-lactamases Metallo-enzymes Class A KPC Carbapenemase Class C Class D Class B Emerging Threat Major new opportunity Acinetobacter & Pseudomonas ETX

11 ETX Sulbactam ETX imipenem Avycaz (AZ/Allergan) Zerbaxa (Merck) Carbavance (MedCo) Eravacycline (Tetraphase) Imipenem/ relebactam (Merck) Plazomicin (Ahcaogen) S (Shionogi) WCK 5999 (Wockhardt) ETX2514 combinations offer the broadest spectrum Gram-negative coverage amongst leading competitors ESBL Expressing Enterobacteriaceae +/ / 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?. 11

12 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 per year in EU5 1 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-lactams 3-5 About 63% of A. baumannii isolates are MDR 2 A. baumannii 1. Decision Resources 2. Am. J. Respir. Crit. Care Med ; Int. J. Antimicrob. Agents M.M. Ehlers, et. Al Prevalence of Carbapenemases in Acinetobacter baumannii, Antibiotic Resistant Bacteria A Continuous Challenge in the New Millennium, InTech, DOI: / Poirel, L Diversity, Epidemiology & Genetics of Class D b-lactamases. AAC. 54: Lancet ; J. Glob. Infect. Dis

13 ETX2514+sulbactam for Acinetobacter baumannii infections Drug Profile Market Opportunity Label / Indications Data to Date 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 A. baumannii infections associated with high mortality Resistance rates to one or more antibiotic >60% Demonstrated or suspected A. baumannii infection Multiple body sites I.V. infusion q6h 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

14 ETX sulbactam: A novel combination against multi-drug resistant A. baumannii ETX sulbactam maintains excellent activity over time MIC (mg/l) > N= N= N= N= * N=202 Cumul % Cumul % Cumul % Cumul % Cumul % MIC distributions for globally diverse A. baumannii clinical strains *2015 study performed at JMI ETX sulbactam activity remains unchanged in carbapenemresistant, colistin-resistant and multidrug resistant strains 14

15 Log(CFU/g) Log(CFU/g) ETX sulbactam exhibits excellent in vivo activity Strong bacterial load suppression of XDR* A. baumannii infections at clinically relevant doses 10 Thigh 10 Lung Stasis Stasis Pretreatment Pretreatment Vehicle 2.5 / / / / 5 30 / / / 20 sulbactam/etx2514 (mg/kg) q3h 2 Vehicle 2.5 / / / / 5 30 / / / 20 sulbactam/etx2514 (mg/kg) q3h Human dose projected to be mg/QID based on PK, efficacy and hollow fiber work * 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 15

16 % Susceptible Strains When combined with a carbapenem, ETX2514 has excellent microbiological potency against Pseudomonas Activity vs. 602 P. aeruginosa Strains JMI % 80% MIC 90 MIC 50 (mg/l) MIC 90 (mg/l) CLSI Breakpoint (mg/l) 60% 40% 20% Imipenem (IPM) IPM:ETX2514 Meropenem (MEM) MEM:ETX (IPM) (IPM) (MEM) (MEM) 0% MIC (mg/l) 16

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 17

18 Urgent Community Critical Hospital Entasis Therapeutics Portfolio overview Product Discovery Preclinical Phase I Phase II Next Milestone ETX2514/ sulbactam Injectable ETX2514/ Imipenem Injectable Acinetobacter baumannii Infections Other Serious Hospital Gram-negative Infections Readout Phase 1 2Q-2017 ETX0282/ Cefpodoxime Oral Enterobacteriaceae incl. ESBL & CRE IND-enabling package 2H-2017 Zoliflodacin 1 (ETX0914) Oral Uncomplicated Gonorrhea Initiate TQT/RelBio Study Phase 2 completed in partnership with NIAID 2 In partnership 18

19 Entasis programs address unmet opportunity in b-lactamase inhibitors Originally marketed BLIs, generic Serine Enzymes b-lactamases Metallo-enzymes Class A KPC Carbapenemase Class C Class D Class B Emerging Threat I.V. Gram-(avibactam) Oral ETX

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 Urinary Tract 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) * Spellberg, B. & Y. Doi. The Rise of Fluoroquinolone-Resistant Escherichia coli in the Community: Scarier Than We Thought. J Infect Dis (12):

21 ETX0282 with cefpodoxime is only oral BL/BLI combination with activity against ESBL and CRE bacteria Combination of ETX0282 with cefpodoxime-proxetil (prodrug of cefpodoxime) has excellent microbiological potency MIC 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 21

22 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 ) MIC 90 MIC 90 (mg/l) CLSI Breakpoint (mg/l) Cefpodoxime (CPD) >32 2 ETX ND CPD/ETX (CPD) Levofloxacin 32 2 Piperacillin/tazobactam >32 16 Note: BLIs tested at a fixed concentration of 4 mg/l in combinations. 22

23 Conc, ng/ml ETX0282 delivers high bioavailability in preclinical species Dog PK : Oral Bioavailability = 97% Rat PK : Oral Bioavailability = 98% ETX0282 PO ETX1317 IV Time, hr Time, hr Excellent bioavailability achieved in both rats and dogs PK profile similar to cefpodoxime proxetil 23

24 Urgent Community Critical Hospital Entasis Therapeutics Portfolio overview Product Discovery Preclinical Phase I Phase II Next Milestone ETX2514/ sulbactam Injectable ETX2514/ Imipenem Injectable Acinetobacter baumannii Infections Other Serious Hospital Gram-negative Infections Readout Phase 1 2Q-2017 ETX0282/ Cefpodoxime Oral Enterobacteriaceae incl. ESBL & CRE IND-enabling package 2H-2017 Zoliflodacin 1 (ETX0914) Oral Uncomplicated Gonorrhea Initiate TQT/RelBio Study Phase 2 completed in partnership with NIAID 2 In partnership 24

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-ofcare) 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 % of N. gonorrhoeae Isolates with Reduced Susceptibility to Extended-spectrum Cephalosporins 2,3,4 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% China Japan Europe US CDC 2013 STD surveillance, susceptibility rates in the United States 2 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 Includes oral cefixime and ceftriaxone 25

26 Zoliflodacin (ETX0914): Phase 2 POC Open-label, multi-center, randomized NIAID sponsored 3 study arms (N=180 total patients with gonorrhea) 2:2:1 ETX mg 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

27 Multiple near-term value generating milestones ETX nd Ph3 start 2H2019 Project 4 End of Ph1 4Q2020 ETX nd Ph3 DBL 2021 ETX2514 End of Ph1 2Q2017 ETX2514 Ph2 start 4Q2017 ETX2514 Ph3-ready 2Q2018 ETX2514 Ph3 start 3Q2018 Project 4 Ph1 start 4Q2019 ETX2514 DBL for NDA 1Q2020 ETX2514 NDA filing 3Q2020 ETX2514 Approval ETX0282 Ph1 start 1Q2018 ETX0282 End of Ph1 4Q2018 ETX0282 Ph2 start 1Q2019 ETX0282 POC 1Q2020 ETX0282 Ph3 start 4Q2020 zoliflodacin Ph3 start 2H2018 zoliflodacin end of Phase 3 1H2020 zoliflodacin Approval

28 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. 28

29 Thank you Patients & volunteers, their families Study investigators for zoliflodacin & ETX2514 Entasis employees and collaborators 29