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Antibiotics in the Clinical Pipeline in October 2019 The Journal of Antibiotics (2020) 73:329–364 https://doi.org/10.1038/s41429-020-0291-8 REVIEW ARTICLE Antibiotics in the clinical pipeline in October 2019 1 1 Mark S. Butler ● David L. Paterson Received: 17 December 2019 / Revised: 30 January 2020 / Accepted: 30 January 2020 / Published online: 10 March 2020 © The Author(s), under exclusive licence to the Japan Antibiotics Research Association 2020 Abstract The development of new and effective antibacterial drugs to treat multi-drug resistant (MDR) bacteria, especially Gram- negative (G−ve) pathogens, is acknowledged as one of the world’s most pressing health issues; however, the discovery and development of new, nontoxic antibacterials is not a straightforward scientific task, which is compounded by a challenging economic model. This review lists the antibacterials, β-lactamase/β-lactam inhibitor (BLI) combinations, and monoclonal antibodies (mAbs) first launched around the world since 2009 and details the seven new antibiotics and two new β-lactam/ BLI combinations launched since 2016. The development status, mode of action, spectra of activity, lead source, and administration route for the 44 small molecule antibacterials, eight β-lactamase/BLI combinations, and one antibody drug conjugate (ADC) being evaluated in worldwide clinical trials at the end of October 2019 are described. Compounds discontinued from clinical development since 2016 and new antibacterial pharmacophores are also reviewed. There has been 1234567890();,: 1234567890();,: an increase in the number of early stage clinical candidates, which has been fueled by antibiotic-focused funding agencies; however, there is still a significant gap in the pipeline for the development of new antibacterials with activity against β-metallolactamases, orally administered with broad spectrum G−ve activity, and new treatments for MDR Acinetobacter and gonorrhea. Introduction to capture a snapshot of what is happening today and compare it to previous years. This review provides an Since their development in the 1940s, antibacterial drugs update to previous reviews in this series in 2015 [1], 2013 have become lifesaving medicines that are integral to [2] and 2011 [3], which are complementary to recent human health. Unfortunately, antibacterial drug resistance reviews that describe the pre-clinical [4] and clinical pipe- is widespread amongst pathogenic bacteria, which sig- line [5–11]. There have also been several important reviews nificantly reduces the medical effectiveness of currently that analyze the lead discovery and development of anti- marketed drugs. These drug-resistant and multi-drug resis- biotics [12–22], antibiotic alternatives [23–25], β-lactam/ tant (MDR) bacteria have been acknowledged by Govern- β-lactamase inhibitors [26, 27], and antibiotic conjugate and ments and scientists as one of the world’s most pressing prodrug strategies [28]. There has also been reviews that health issues; however, the discovery and development of discuss issues with antibiotic stewardship, resistance and, new antibiotics and antibiotic-alternatives to treat these the commercialization challenge [29–41]. infections is not straightforward. As a consequence, it is This review details antibacterials launched since 2009 important to analyze the antibacterial development pipeline (Table 1; Table S1 from 2000 to 2009) and analyzes new antibacterials approved (Figs. 1–3)sincetheprevious 2015 review [1]. Small molecule antibacterials, BLI combinations, and antibody drug conjugates (ADC) that Supplementary information The online version of this article (https:// are being evaluated in phase-I, -II, or -III clinical trials doi.org/10.1038/s41429-020-0291-8) contains supplementary and under pre-approval regulatory evaluation as of 31 material, which is available to authorized users. October 2019 (Tables 2–5,Figs.4–12) are reviewed * Mark S. Butler highlighting their development status, mode of action, [email protected] spectra of activity, historical discovery, and origin of the lead compound’s pharmacophore. The clinical trial 1 Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane and Women’s Hospital Complex, codes, which are predominantly from ClinicalTrials.gov Herston, Brisbane, QLD 4072, Australia (NCT), are listed in parentheses for each antibacterial, 330 M. S. Butler, D. L. Paterson Table 1 Antibiotics, β-lactamase inhibitor (BLI) combinations, and monoclonal antibodies (mAb) launched from January 2009 to October 2019, their antibiotic class, activity spectra, country of first approval, and lead source Year Drug namea,b Class Country of first Lead source approved approval Small molecule antibacterials 2009 Tebipenem pivoxil Carbapenem Japan NP 2009 Telavancin Glycopeptide USA NP 2009 Antofloxacin Fluoroquinolone China S 2009 Besifloxacinc Fluoroquinolone USA S 2010 Ceftaroline fosamil Cephalosporin USA NP 2011 Fidaxomicinb Tiacumicin USA NP 2012 Bedaquilineb Diarylquinoline USA S 2012 Perchlozone Thiosemicarbazone Russia S 2014 Delamanid Nitroimidazole Europe S 2014 Dalbavancin Glycopeptide USA NP 2014 Oritavancin Glycopeptide USA NP 2014 Tedizolid phosphate Oxazolidinone USA S 2014 Nemonoxacin Quinolone Taiwan S 2014 Morinidazole (1)e Nitroimidazole People’s Republic S of China 2014 Finafloxacinc Fluoroquinolone USA S 2015 Zabofloxacin (2) Fluoroquinolone Republic of Korea S 2017 Delafloxacin (3) Fluoroquinolone USA S 2018 Plazomicin (4) Aminoglycoside USA NP 2018 Eravacycline (5) Tetracycline Europe NP 2018 Omadacycline (6) Tetracycline USA NP 2018 Sarecycline (7)c Tetracycline USA NP 2019 Pretomanid (8) Nitroimidazole USA S 2019 Lefamulin (9) Pleuromutilin USA NP 2019 Lascufloxacin (10) Fluoroquinolone Japan S 2019 Cefiderocol (11) Cephalosporin siderophore USA NP BLI combinations 2014 Zerbaxa: ceftolozane + β-Lactam + BLI USA NP + NP tazobactamd 2015 Avycaz: avibactamb + DBO BLI + β-lactam USA S + NP ceftazidimed 2017 Vabomere: vaborbactamb Boronate BLI + β-lactam USA S + NP (12) + meropenemd (13) 2019 Recarbrio: relebactam (14) DBO BLI + β-lactam + renal USA S + NP + S + imipenem (15)d + dehydropeptidase inhibitor cilastatin (16)d mAbs 2012 Raxibacumab mAb USA mAb 2016 Obiltoxaximab mAb USA mAb 2016 Bezlotoxumab mAb USA mAb BLI β-lactamase inhibitor, DBO diazabicyclooctane, mAb monoclonal antibody, NP natural product-derived, S synthetic, USA United States of America aThe structures of the antibiotics approved from 2000 to 2014 can be found in our previous reviews [1–3] bFirst member of a new antibiotic or β-lactamase inhibitor class approved for human therapeutic use cApproved for topical use dFirst launches: tazobactam in 1992, ceftazidime in 1983, meropenem (13) in 1998, and imipenem (15) + cilastatin (16) in 1985 eAlso approved for the treatment of amebiasis and trichomoniasis Antibiotics in the clinical pipeline in October 2019 331 8 while non-registered trials are referenced at least by a Existing classes 7 New classes Press Release or peer-reviewed publication. A list of on- 6 line clinical trial databases can be found in the Supple- 5 mentary information. Repurposed drugs that have not previously been approved as antibacterials have been 4 included in this analysis. Pro-drugs are grouped together 3 with their active metabolites, while ongoing trials of 2 antibacterial drugs that already approved anywhere in the Number of antibiotics launched Number of 1 world are not discussed but are listed in Table S2. Com- 0 pounds for which no development activity has been reportedsince2017arelistedinTable6. The anti- Year bacterials in clinical development have been further ana- Fig. 1 New antibacterial and BLI classes January 2000 to October lyzed by phase and source derivation (Fig. 13) and to the 2019 with new classes highlighted previous 2011 [3], 2013 [2], and 2015 [1]reviews Fig. 2 Structures of the recently launched antibacterial drugs 332 M. S. Butler, D. L. Paterson Fig. 3 Structures of the recently β-lactam/β-lactamase inhibitor (BLI) combinations (Fig. 14). An analysis of new antibacterial pharmaco- obiltoxaximab [46], help reduce the effects of anthrax phores (Table 7,Figs.15 and 16) and administration toxins but further work is required to fully establish their routes (Figs. S1 and S2) has also been undertaken. efficacy in preclinical and clinical studies [47]. Bezlotox- Data in this review were obtained by analyzing the umab is a mAb that binds and neutralizes Clostridioides scientific literature and internet resources such as com- difficile (formally Clostridium difficile [48]) toxin B, pany web pages, clinical trial registers, The Pew Chari- which is approved to help reduce the occurrence of C. table Trusts (Philadelphia, PA, USA) [42, 43]andWorld difficile infections (CDI) in patients undergoing anti- Health Organization (WHO) (Geneva, Switzerland) bacterial drug treatments [49, 50]. pipeline analyses [5] and biotechnology newsletters. Every effort has been undertaken to ensure that these data are accurate; however, it is possible compounds in the Description of antibacterial drugs launched earlier stages of clinical development have been over- since 2016 looked as there is limited information available in the public domain. An overview of the drug development and Since the 2016, seven new antibacterials (Fig. 2)andtwonew approval process, antibiotic clinical trial categories and β-lactam/BLI combinations (Fig. 3) have been approved abbreviations can be found in the Supplementary around the world. These new approvals are discussed, along information. with morinidazole (1) and zabofloxacin
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