2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT an overview and analysis 2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT an overview and analysis 2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT an overview and analysis 2020 Antibacterial agents in clinical and preclinical development: an overview and analysis ISBN 978-92-4-002130-3 (electronic version) ISBN 978-92-4-002131-0 (print version) © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization (http://www.wipo.int/amc/en/mediation/rules/). Suggested citation. 2020 Antibacterial agents in clinical and preclinical development: an overview and analysis. Geneva: World Health Organization; 2021. Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Design and layout by Phoenix Design Aid Contents Acknowledgements vi Abbreviations and acronyms vii Executive summary viii 1. INTRODUCTION 1 2. AGENTS THAT OBTAINED MARKET AUTHORIZATION SINCE 1 JULY 2017 2 3. CLINICAL ANTIBACTERIAL PIPELINE 4 3.1 Antibiotics being developed against WHO priority pathogens 5 3.1.1 β-Lactams 7 3.1.2 Tetracyclines 10 3.1.3 Aminoglycosides 10 3.1.4 Topoisomerase inhibitors 11 3.1.5 FabI inhibitor 11 3.1.6 FtsZ inhibitor 12 3.1.7 Oxazolidinones 12 3.1.8 Macrolides and ketolides 12 3.1.9 Antibiotic hybrids 13 3.1.10 Polymyxins 13 3.2 Agents in development for treating TB infections 13 3.3 Agents in development for treating C. difficile infections 15 3.4 Non-traditional antibacterials 17 3.4.1 Antibodies 18 3.4.2 Bacteriophages and phage-derived enzymes 20 3.4.3 Microbiome-modulating agents 20 3.4.4 Immunomodulating agents 22 3.4.5 Miscellaneous 22 3.5 Agents that are not under active development or for which there is no recent information 23 4. PRECLINICAL ANTIBACTERIAL PIPELINE 24 4.1 Individual entities developing preclinical projects 25 4.2 Categorization of preclinical agents 26 2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT: AN OVERVIEW AND ANALYSIS iii 5. DISCUSSION 28 5.1 New agents mainly derivatives of existing classes 28 5.2 The clinical “traditional” pipeline is still insufficient against priority pathogens 28 5.3 Innovation remains a challenge for Gram-negatives 29 5.4 Diversity in non-traditional approaches 29 5.5 A dynamic preclinical pipeline database 30 5.6 The pipeline outlook is slightly improved but remains unfavourable 30 6. METHODS 31 6.1 Clinical pipeline analysis 31 6.1.1 Scope and inclusion/exclusion criteria 31 6.1.2 Search strategy 32 6.1.3 Assessment of activity against priority pathogens and innovation 32 6.2 Preclinical pipeline review 33 6.2.1 Scope and inclusion/exclusion criteria 33 6.2.2 Data collection 34 6.3 Methodological considerations 34 6.3.1 Variable data quality 34 6.3.2 Limitations 34 7. REFERENCES 36 Annex 1. Declaration of interests of advisory group members 41 Annex 2. Background information on Phase 3 antibacterial products 43 1. Sulopenem 43 2. Durlobactam (ETX-2514) + sulbactam 47 3. Taniborbactam (VNRX-5133) + cefepime 49 4. Enmetazobactam (AAI-101) + cefepime 51 5. Zoliflodacin 53 6. Gepotidacin 55 7. Ridinilazole 57 iv 2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT: AN OVERVIEW AND ANALYSIS Table 1. Antibiotics that gained market authorization between 1 July 2017 and 1 September 2020 3 Table 2. Antibiotics being developed against WHO priority pathogens 5 Table 3. Expected activity of β-lactams and β-lactam/BLI combinations against common β-lactamases 7 Table 4. Antibiotics for the treatment of TB and non-tuberculous mycobacteria in clinical development 14 Table 5. Antibiotics (small molecules) for the treatment of C. difficile infections in clinical development 16 Table 6. Non-traditional antibacterial agents in clinical development 17 Table 7. Agents not under active development or for which there is no recent information 23 Table 8. Distribution of preclinical programmes by mode of action and development stages 26 Table 9. Structure and development goals of traditional and non-traditional antibacterials 31 Fig. 1. Traditional and non-traditional antibacterials in clinical development (Phases 1–3) x Fig. 2. Geographical distribution of the 162 developers 25 Fig. 3. Categorization of entities that responded to the 2020 data call 26 Fig. 4. Distribution of preclinical programmes by antibacterial agent and vaccine category 26 Fig. 5. Pathogens targeted by a single pathogen target product 27 Fig. 6. Summary of antibiotics in the clinical pipeline targeting WHO priority pathogens 29 Fig. 7. Summary of non-traditional antibacterials in the clinical pipeline 30 Fig. 8. Traditional drug development phases showing the preclinical phases included in this report in red 33 2020 ANTIBACTERIAL AGENTS IN CLINICAL AND PRECLINICAL DEVELOPMENT: AN OVERVIEW AND ANALYSIS v Acknowledgements This publication was prepared by Sarah Paulin (WHO, Antimicrobial Resistance Division) with support from Mark Butler (WHO Consultant), Hatim Sati (WHO Consultant), Richard Alm (WHO Consultant) and Laila Al-Sulaiman (WHO Intern) under the direct supervision of Peter Beyer (WHO, Antimicrobial Resistance Division) and the overall direction of Haileyesus Getahun (WHO, Antimicrobial Resistance Division). Administrative support was provided by Sandra Kotur Corliss (WHO, Antimicrobial Resistance Division). We would like to thank the members of the advisory group, which met virtually on 23–24 November 2020 to discuss and assess the antibacterial agents included this report. The advisory group consisted of: • Cesar Arias, Professor, University of Texas Health Science Center, Houston, United States of America, and Founder and Scientific Advisor, Molecular Genetics and Antimicrobial Resistance Unit/International Center for Microbial Genomics, Universidad El Bosque, Colombia. • Lloyd Czaplewski, Director, Chemical Biology Ventures, United Kingdom of Great Britain and Northern Ireland. • Prabha Fernandes, Chair of the Scientific Advisory Committee, Global Antibiotic Research and Development Partnership (GARDP), Switzerland, and independent consultant. • François Franceschi, Project Leader, Asset Evaluation and Development, GARDP, Switzerland (observer). • Stephan Harbarth, Full Professor, Division of Infectious Diseases and Infection Control Programme, Geneva University Hospitals, WHO Collaborating Centre, Switzerland. • Jennie Hood, Global AMR R&D Hub, Germany (observer). • Roman Kozlov, Rector, Smolensk State Medical University, Russian Federation. • Christian Lienhardt, Research Director, Institute for Research on Sustainable Development and University of Montpellier, France. • Norio Ohmagari, Director, Disease Control and Prevention