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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 2019; Resistance. The study analysed to what extent antibacterial and antimycobacterial drugs for systemic human use as 19: e40–50 well as oral non-systemic antibacterial drugs for Clostridium difficile infections were active against pathogens included Published Online in the WHO priority pathogen list and their innovativeness measured by their absence of cross-resistance (new class, October 15, 2018 http://dx.doi.org/10.1016/ target, mode of action). As of July 1, 2018, 30 new chemical entity (NCE) antibacterial drugs, ten biologics, ten NCEs S1473-3099(18)30513-9 against Mycobacterium tuberculosis, and four NCEs against C difficile were identified. Of the 30 NCEs, 11 are expected Center for Anti-Infective to have some activity against at least one critical priority pathogen expressing carbapenem resistance. The clinical Agents, Vienna, Austria pipeline is dominated by derivatives of established classes and most development candidates display limited (U Theuretzbacher PhD); innovation. New antibacterial drugs without pre-existing cross-resistance are under-represented and are urgently Biovision Foundation for Ecological Development, Zurich, needed, especially for geographical regions with high resistance rates among Gram-negative bacteria and Switzerland (S Gottwalt); M tuberculosis. Essential Medicines and Health Products, WHO, Geneva, Background potential inno vation, and clinical value globally. This Switzerland (P Beyer PhD); University of Queensland Centre Although improved preventive measures have reduced analysis, in con junction with the WHO PPL, supports the for Clinical Research, Royal resistance in some pathogens, antibacterial drug resistance identification of research and development gaps from a Brisbane and Women’s Hospital, has increased worldwide, posing an enormous clinical and public health perspective and allows for better focused Herston, QLD, Australia public health burden.1–3 This is not surprising given the public research and development investment. As drug (M Butler PhD); Chemical Biology Ventures Ltd, Abingdon, UK strong selection pressure caused by extensive antibacterial development is subject to rapid changes, the analysis will (L Czaplewski PhD); Global TB drug use in humans, animals, agriculture, and the food be annually updated and the data made openly available at Programme, WHO, Geneva, chain, which has also led to considerable environmental the WHO Global Observatory on Health Research and Switzerland (C Lienhardt PhD); pollution. In contrast to the first decades of the antibiotic Development.5 Unité Mixte Internationale TransVIHMI, Institut de era, the rise in resistance has not been sufficiently Recherche pour le countered by the development of new antibiotics. Ever Methods Développement, Montpellier, rising resistance rates have increased society’s awareness We did a systematic review of the antibacterial drugs in the France (C Lienhardt); Essential of this issue, which has prompted political commitment clinical pipeline with exhaustive efforts to identify all Medicines and Health Products, WHO, Geneva, Switzerland and global initiatives. The 68th World Health Assembly, antibacterial drugs under study. We carefully evaluated (L Moja PhD); Infectious Diseases Geneva endorsed the Global Action Plan on Antimicrobial evidence to identify limitations on specific antibacterial Institute, Rambam Health Care Resistance in 2015 and the United Nations General effects. All identified molecules and detailed assessment Campus, Haifa, Israel (M Paul MD); Essential Medicines Assembly, New York reinforced these commitments in were transparently reported to inform decision making. and Health Products, WHO, 2016 at a high-level meeting on antimicrobial resistance. Publicly available information concerning antibacterial Geneva, Switzerland This public health issue is on the agenda of the G7 and the drugs in clinical development was identified by scrutinising (S Paulin PhD); F2G Ltd, G20, which both supported actions to encourage the existing pipeline reviews,6–8 including the Stop TB Wellesley Hills, MA, USA (J H. Rex MD); LL Silver development of new antibacterial treatments. Partnership (https://www.newtbdrugs.org), international Consulting, Springfield, NJ, USA One of the strategic objectives of the Global Action Plan (L L Silver PhD); Global Alliance is to increase research and development for new for TB Drug Development, New antibacterial drugs to ensure the sustained availability of Key messages York, NY, USA (M Spigelman MD); Oxford University Clinical treatment options. The WHO Priority Pathogen List (PPL) • The current clinical pipeline contains 30 new antibacterial Research Unit, Ho Chi Minh City, for antibiotic research and development identifies the drugs with activity against priority pathogens and is Vietnam priorities on which research and development of new dominated by derivatives of established classes (Prof G E Thwaites FRCP); Global antimicrobials should be focused.4 This effort was Antibiotic R&D Partnership, • New antibacterial drugs to address the problem of Geneva, Switzerland complemented with a comprehensive analysis of the global extensively or even pan-drug resistant Gram-negative (J-P Paccaud PhD); WHO clinical pipeline of antibacterial and antimycobacterial bacteria without pre-existing cross-resistance to existing Collaborating Centre on Patient drugs (hereinafter, collectively referred to as antibacterial). drug classes are under-represented and are urgently needed Safety, Geneva University This review presents a catalogue of all antibacterial drugs in Hospitals, Geneva, Switzerland • Extensive efforts to develop new classes of antibacterial (Prof S Harbarth MD); and clinical development and assesses both their potential drugs, especially against Gram-negative bacteria, have Faculty of Medicine, Geneva, activity against PPL pathogens including Mycobacterium not yet been translated into clinical development Switzerland (Prof S Harbarth) tuberculosis and Clostridium difficile as well as their degree of • The clinical pipeline analysis highlights the continued Correspondence to: innovation. Unlike earlier clinical pipeline reviews of need for innovative antibacterial drugs against the WHO Dr U Theuretzbacher, Center for antibacterial drugs, this analysis focuses on the assessment Anti-Infective Agents, critical priority pathogens and Mycobacterium tuberculosis 1180 Vienna, Austria of the pipeline against global public health needs, its [email protected] www.thelancet.com/infection Vol 19 February 2019 e40 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 the used to treat bacterial infections and have
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