Antibacterial Drug R&D

03/11/2017

BioInfect, Alderley Park 2017 Resistance in Gram-negative bacteria

Antibacterial Drug R&D Medical Need and Public Support

U. Theuretzbacher – Center for Anti-Infective Agents, Vienna, Austria

who priority pathogens list Critical Priority Pathogens

Prioritization: Multi‐criteria decision analysis

© Ursula Theuretzbacher http://www.who.int/medicines/publications/WHO‐PPL‐Short_Summary_25Feb‐ET_NM_WHO.pdf © Ursula Theuretzbacher http://www.who.int/medicines/areas/rational_use/PPLreport_2017_09_19.pdf

Critical Priority Pathogens Critical Priority Pathogens

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Innovation Clinical pipelines - WHO critical priority pathogens

ß‐lactams, ß‐lactam‐inhibitor combinations Scientific definition

Ph Class Compound Pathogen activity WHO critical priority pathogens No cross‐resistance to existing antibiotics CR‐E | CR‐PA| CR‐AB Carbapenem resistant  . Innovation • New class/target/MoA Carbapenems Vaborbactam/merop CR‐E: Enterobacteriaceae CR‐PA: Pseudomonas aeruginosa • Substantial improvement of existing class 3 Relebactam/imip CR‐AB: Acinetobacter baumannii group without cross‐resistance 1 VNRX‐5133/merop 3 Sulopenem Activity Improved antibiotics from existing classes 1 Cephalosporins Zidebactam/cefep Unclear . Novelty • Reduced class‐specific resistance 1 Nacubactam/cefep No or insufficient activity 2 AAI‐101/cefep 1 Tazo/cefep Improved features, e.g. 1 C‐Scape New App • Oral formulation 3 Ceph‐siderophore Cefiderocol . Usefulness • Improved pharmacokinetics 2 Monobactams Avibactam/aztreon 1 LYS228 Definition not uniformly agreed! 1BLIs ETX‐2514SUL KPC|NDM Pipeline: Specific solutions for specific patients for specific situations in specific regions

U. Theuretzbacher Antibiotic innovation for future public health needs. Clin Microbiol Infect. 2017 Jun 24. U. Theuretzbacher: New drugs – will they solve the problem of resistance to antibiotics? Clin Microbiol Infect. 2017 August 19 Based on the WHO pipeline analysis 2017 © Ursula Theuretzbacher © Ursula Theuretzbacher

Clinical pipelines - WHO critical priority pathogens Preclinical pipelines, n=254

WHO critical priority pathogens CR‐E|CR‐PA|CR‐AB  Delafloxacin Fluoroquinolone  3 Sulopenem Carbapenem ESBL Carbapenem resistant CARB‐X submissions 2016, n=254 CR‐E: Enterobacteriaceae 3 Plazomicin Aminoglycoside CR‐PA: Pseudomonas aeruginosa 60 200 3 Lascufloxacin Fluoroquinolone  CR‐AB: Acinetobacter baumannii 150 3 Eravacycline Tetracycline group 50 100 3 Omadacycline Tetracycline   40 50 3 Solithromycin Macrolide Activity  3 Iclaprim DHFR‐inhibitor Unclear 30 0 3 Lefamulin Pleuromutilin*  No or insufficient activity 2/3 MRX‐I/MRX‐IV Oxazolidinone  20 2 Gepotidacin NBTI (Triazaacenaphthylene)  2 Zoliflodacin NBTI (Spiropyrimidenetrione)  10 2 Murepavidn Novel membrane targeting AB Mostly developed by 0 2 Brilacidin Novel membrane targeting AB  companies with <500 New chemical or functional class 2 Afabicin FabI inhibitor  employees (most companies <100) 2 Nafithromycin Macrolide  2 Finafloxacin Fluoroquinolone 1 SPR‐741 + antibiotic? Polymyxin + antibiotic? Biologics, C. diff. 1 TP‐271 Tetracycline  drugs, combinations 1 TP‐6076 Tetracycline or off‐patent drugs 1 KBP‐7072 Tetracycline  not included 1 TNP‐2092 Rifamycin‐quinolone hybrid  U. Theuretzbacher et al: Innovation potential of the preclinical antibiotic pipeline. Nature Reviews Drug Discovery. Oct 2017 Gram‐pos

DRIVE-AB’s recommended models Push mechanisms ICO

Priority grants Increase, Coordinate, Optimise resources • Address drug discovery and early development

Basic Science Preclinical Phase I Phase II Phase III Market Generic market hurdles: scientific and financial • Global coordination hub Discovery

Optimisation Grants Discovery grants improve the entry rates Pipeline Coordinator Preclinical dev. into the preclinical phase, improve the effect of pull mechanisms MER Continuity Phase 1 Phase 2 Additional annual push funding ~200‐500 million Phase 3

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Market Entry Reward – Simulation Summary

. Medical need is not reflected in the clinical pipelines . The preclinical pipelines are encouraging but not robust enough . More innovation is required . Need for support is apparent

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