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Analysis of the Clinical Antibacterial and Antituberculosis Pipeline Review Analysis of the clinical antibacterial and antituberculosis pipeline Ursula Theuretzbacher, Simon Gottwalt, Peter Beyer, Mark Butler, Lloyd Czaplewski, Christian Lienhardt, Lorenzo Moja, Mical Paul, Sarah Paulin, John H Rex, Lynn L Silver, Melvin Spigelman, Guy E Thwaites, Jean-Pierre Paccaud, Stephan Harbarth This analysis of the global clinical antibacterial pipeline was done in support of the Global Action Plan on Antimicrobial Lancet Infect Dis 2018 Resistance. The study analysed to what extent antibacterial and antimycobacterial drugs for systemic human use as Published Online well as oral non-systemic antibacterial drugs for Clostridium difficile infections were active against pathogens included October 15, 2018 in the WHO priority pathogen list and their innovativeness measured by their absence of cross-resistance (new class, http://dx.doi.org/10.1016/ S1473-3099(18)30513-9 target, mode of action). As of July 1, 2018, 30 new chemical entity (NCE) antibacterial drugs, ten biologics, ten NCEs Center for Anti-Infective against Mycobacterium tuberculosis, and four NCEs against C difficile were identified. Of the 30 NCEs, 11 are expected Agents, Vienna, Austria to have some activity against at least one critical priority pathogen expressing carbapenem resistance. The clinical (U Theuretzbacher PhD); pipeline is dominated by derivatives of established classes and most development candidates display limited Biovision Foundation for innovation. New antibacterial drugs without pre-existing cross-resistance are under-represented and are urgently Ecological Development, Zurich, Switzerland (S Gottwalt); needed, especially for geographical regions with high resistance rates among Gram-negative bacteria and Essential Medicines and Health M tuberculosis. Products, WHO, Geneva, Switzerland (P Beyer PhD); Background potential inno vation, and clinical value globally. This University of Queensland Centre for Clinical Research, Royal Although improved preventive measures have reduced analysis, in con junction with the WHO PPL, supports the Brisbane and Women’s Hospital, resistance in some pathogens, antibacterial drug resistance identification of research and development gaps from a Herston, QLD, Australia has increased worldwide, posing an enormous clinical and public health perspective and allows for better focused (M Butler PhD); Chemical Biology public health burden.1–3 This is not surprising given the public research and development investment. As drug Ventures Ltd, Abingdon, UK (L Czaplewski PhD); Global TB strong selection pressure caused by extensive antibacterial development is subject to rapid changes, the analysis will Programme, WHO, Geneva, drug use in humans, animals, agriculture, and the food be annually updated and the data made openly available at Switzerland (C Lienhardt PhD); chain, which has also led to considerable environmental the WHO Global Observatory on Health Research and Unité Mixte Internationale pollution. In contrast to the first decades of the antibiotic Development.5 TransVIHMI, Institut de Recherche pour le era, the rise in resistance has not been sufficiently Développement, Montpellier, countered by the development of new antibiotics. Ever Methods France (C Lienhardt); Essential rising resistance rates have increased society’s awareness We did a systematic review of the antibacterial drugs in the Medicines and Health Products, of this issue, which has prompted political commitment clinical pipeline with exhaustive efforts to identify all WHO, Geneva, Switzerland (L Moja PhD); Infectious Diseases and global initiatives. The 68th World Health Assembly, antibacterial drugs under study. We carefully evaluated Institute, Rambam Health Care Geneva endorsed the Global Action Plan on Antimicrobial evidence to identify limitations on specific antibacterial Campus, Haifa, Israel Resistance in 2015 and the United Nations General effects. All identified molecules and detailed assessment (M Paul MD); Essential Medicines and Health Products, WHO, Assembly, New York reinforced these commitments in were transparently reported to inform decision making. Geneva, Switzerland 2016 at a high-level meeting on antimicrobial resistance. Publicly available information concerning antibacterial (S Paulin PhD); F2G Ltd, This public health issue is on the agenda of the G7 and the drugs in clinical development was identified by scrutinising Wellesley Hills, MA, USA G20, which both supported actions to encourage the existing pipeline reviews,6–8 including the Stop TB (J H. Rex MD); LL Silver Consulting, Springfield, NJ, USA development of new antibacterial treatments. Partnership (https://www.newtbdrugs.org), international (L L Silver PhD); Global Alliance One of the strategic objectives of the Global Action Plan for TB Drug Development, New is to increase research and development for new York, NY, USA (M Spigelman antibacterial drugs to ensure the sustained availability of Key messages MD); Oxford University Clinical Research Unit, Ho Chi Minh City, treatment options. The WHO Priority Pathogen List (PPL) • The current clinical pipeline contains 30 new antibacterial Vietnam for antibiotic research and development identifies the drugs with activity against priority pathogens and is (Prof G E Thwaites FRCP); Global priorities on which research and development of new dominated by derivatives of established classes Antibiotic R&D Partnership, antimicrobials should be focused.4 This effort was Geneva, Switzerland • New antibacterial drugs to address the problem of (J-P Paccaud PhD); WHO complemented with a comprehensive analysis of the global extensively or even pan-drug resistant Gram-negative Collaborating Centre on Patient clinical pipeline of antibacterial and antimycobacterial bacteria without pre-existing cross-resistance to existing Safety, Geneva University drugs (hereinafter, collectively referred to as antibacterial). drug classes are under-represented and are urgently needed Hospitals, Geneva, Switzerland This review presents a catalogue of all antibacterial drugs in (Prof S Harbarth MD); and • Extensive efforts to develop new classes of antibacterial Faculty of Medicine, Geneva, clinical development and assesses both their potential drugs, especially against Gram-negative bacteria, have Switzerland (Prof S Harbarth) activity against PPL pathogens including Mycobacterium not yet been translated into clinical development Correspondence to: tuberculosis and Clostridium difficile as well as their degree of • The clinical pipeline analysis highlights the continued Dr U Theuretzbacher, Center for innovation. Unlike earlier clinical pipeline reviews of need for innovative antibacterial drugs against the WHO Anti-Infective Agents, antibacterial drugs, this analysis focuses on the assessment 1180 Vienna, Austria critical priority pathogens and Mycobacterium tuberculosis [email protected] of the pipeline against global public health needs, its www.thelancet.com/infection Published online October 15, 2018 http://dx.doi.org/10.1016/S1473-3099(18)30513-9 1 Review For more information on the Approved Antibiotic class Route of Indication Expected activity against Innovation Stop TB Partnership see https:// by (date) administration priority pathogens www.newtbdrugs.org (market authorisation holder) CRAB CRPA CRE OPP NCR CC T MoA Delafloxacin FDA Fluoroquinolone IV + oral (Melinta) ABSSSI (CAP, Ph3) - - - A ∙∙ ∙∙ ∙∙ ∙∙ (Baxdela) (6/2017) Vaborbactam + FDA Boronate BLI + IV (Melinta) cUTI (Escherichia coli, - - A* na ID ∙∙ ∙∙ meropenem (8/2017) carbapenem Klebsiella pneumoniae, (Vabomere) Enterobacter cloacae) Plazomicin FDA Aminoglycoside IV (Achaogen) cUTI - - A na ∙∙ ∙∙ ∙∙ ∙∙ (Zemdri) (6/2018) See Table 2 for definitions. ABSSSI=acute bacterial skin and skin structure infection. cUTI=complicated urinary tract infection.*Active against Klebsiella pneumoniae carbapenemase (KPC) but not metallo-β-lactamase-producing Enterobacteriaceae. Table 1: Antibiotics and combinations containing a new chemical entity that are being developed against priority pathogens, approved by FDA 2017/2018 trial registry platforms (Clinical Trials; WHO trial registry advisory board was reached during the advisory group platform), the commercial database Adis Insight meetings. Potential conflicts of interest were managed (http://adis.springer.com), a patent database (the Lens; following the World Health Organization Handbook for https://www.lens.org), conference abstracts, publications, Guideline Development.9,10 Members of the advisory group and press releases. These sources were supplemented by who had conflicts of interest with respect to a particular searches through PubMed for peer-reviewed journal drug were excluded from the discussion on that drug. articles in all languages and Google for grey literature. The Experts’ feedback informed all evaluation steps and final search cutoff date was July 1, 2018. Additional details about decisions were incorporated into the pipeline evaluation. the search strategy and selection criteria are described in Our analysis included new therapeutic entities that the WHO report.9 were in clinical development for systemic human use, For some agents, some data sources reported different had publicly available information, and did not yet have phases of development in different countries. In that regulatory approval anywhere in the world for human situation, both or the most advanced development phase use. The review was restricted to agents that could be reported has been listed. The dataset retrieved through
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