What s next in the antibiotic pipeline?

What s next in the antibiotic pipeline? Jennifer Tieu, Pharm.D., BCPS Clinical Pearls OSHP Spring Meeting Mercy Hospital April 13, 2018 Objective 2 Describe the drug class and mechanism of action of antibiotics in the pipeline

Pre-Assessment Question 3 What is the drug class and mechanism of action of cefiderocol? A. Siderophore cephalosporin / chelates iron ions B. Siderophore cephalosporin / binds 50S ribosome C. Pleuromutilin / inhibits PBP D. Diaminopyrimidine / inhibits dihydrofolate reductase World Health Organization Priority Pathogens List 4 Created February 2017 to guide research and development of new antibiotics Critical Acinetobacter baumannii, carbapenem-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant & 3 rd generation cephalosporin-resistant High Enterococcus faecium, vancomycin-resistant Staphylococcus aureus, methicillin-resistant, vancomycin-intermediate and resistant Helicobacter pylori, clarithromycin-resistant Campylobacter, FQ-resistant Salmonella spp., FQ-resistant Neisseria gonorrhoeae, 3 rd generation cephalosporin-resistant, FQ-resistant Medium Streptococcus pneumoniae, PCN-non-susceptible Haemophilus influenzae, ampicillin-resistant Shigella spp., FQ-resistant http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/. FQ = Fluoroquinolone PCN = Penicillin

5 https://www.fda.gov/downloads/drugs/resourcesforyou/consumers/ucm284393.pdf. Review of FDA Drug Approval Process (Cont d) 6 https://www.fda.gov/downloads/drugs/resourcesforyou/consumers/ucm284393.pdf.

Recently Approved Antibiotics 7 Delafloxacin (Baxdela ) Approved: June 19, 2017 Class: Fluoroquinolone MOA: inhibits bacterial type II topoisomerase FDA Indication: acute bacterial skin and skin structure infections Antibiotic spectrum Gram (+) including MRSA, Streptococcus spp., and Enterococcus faecalis Gram (-) including Enterobacteriaceae and Pseudomonas Anaerobes Meropenem/vaborbactam (Vabomere ) Approved: August 30, 2017 Class: -lactam (carbapenem) + -lactamase inhibitor MOA: inhibits PBP and -lactamase FDA Indication: complicated UTI, including pyelonephritis Antibiotic spectrum: meropenem coverage, gram negative organisms including ESBL and KPC http://melinta.com/pipeline/baxdela/ https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208610s000,208611s000lbl.pdf https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209776lbl.pdf MRSA = Methicillin-resistant Staphylococcus aureus UTI = Urinary Tract Infection PBP = Penicillin-Binding Protein KPC = Klebsiella pneumoniae Carbapenemase Plazomicin 8 NDA submitted October 2017 Class: Aminoglycoside MOA: inhibits 30S subunit of bacterial ribosome Proposed Indications Complicated UTI (including pyelonephritis) EPIC Trial Bloodstream infections CARE Trial Dosage form: IV Notable antibiotic spectrum: MDR Enterobacteriaceae including ESBL and CRE Activity is preserved due to protection from enzymatic modifications from bacteria Kish T. PT 2018 Feb;43(2):116-120 http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development http://www.achaogen.com/plazomicin/ NDA = New Drug Application UTI = Urinary Tract Infection MDR = Multi-drug Resistant CRE = Carbapenem-Resistant Enterobacteriaceae

Tetracyclines Omadacycline NDA submitted Aminomethylcycline MOA: binds 30S bacterial ribosome Potential indications: acute bacterial skin and skin structure infection, CABP IV & PO formulation Notable spectrum: MRSA, MDRSP, VRE, ESBL, anaerobes, atypical bacteria Eravacycline 9 NDA submitted for ciai MOA: binds 30S bacterial ribosome Potential indications: ciai (cuti??) IV formulation Notable spectrum: MRSA, CRE, ESBL http://paratekpharma.com/science/omadacycline/ http://investor.paratekpharma.com/phoenix.zhtml?c=253770&p=irol-newsarticle&id=2324587 http://www.contagionlive.com/news/paratek-submits-ndas-for-oral-and-iv-formulations-of-omadacycline http://ir.tphase.com/news-releases/news-release-details/tetraphase-announces-top-line-results-ignite3-phase-3-clinical ciai = complicated intra-abdominal infection cuti = complicated UTI CABP = Community-acquired Bacterial Pneumonia MRSA = Methicillin-resistant Staphylococcus aureus MDRSP = Multi-drug resistant Streptococcus pneumoniae VRE = Vancomycin-resistant Enterococcus CRE = Carbapenem-Resistant Enterobacteriaceae Phase 3 Antibiotics

Imipenem/cilastatin/relebactam 11 Undergoing Phase 3 studies Class: -lactam (carbapenem) + -lactamase inhibitor MOA: inhibits PBP and -lactamase Potential indications Hospital-acquired infections caused by MDR gram negative bacteria (includes complicated UTI, complicated IAI, and pneumonia) Dosage form: IV Notable antibiotic spectrum: Enhanced activity against Klebsiella pneumoniae and Pseudomonas aeruginosa; activity against ESBL and CRE enzymes Kish T. PT 2018 Feb;43(2):116-120 http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development PBP = Penicillin-Binding Protein MDR = Multi-drug resistant UTI = Urinary Tract Infection IAI = Intra-abdominal Infection CRE = Carbapenem-Resistant Enterobacteriaceae Sulopenem 12 Undergoing Phase 3 studies, NDA planned for 2019 Class: -lactam (carbapenem) MOA: inhibits PBP Potential indications Uncomplicated & complicated UTI, complicated IAI Dosage form: IV & PO Notable antibiotic spectrum: Enterobacteriaceae, including ESBL https://www.prnewswire.com/news-releases/iterum-announces-sulopenem-in-development-for-treatment-of-gram-negative-multi-drug-resistantinfections-300386218.html http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development NDA = New Drug Application PBP = Penicillin-Binding Protein UTI = Urinary Tract Infection IAI = Intra-abdominal Infection

Cefiderocol Undergoing Phase 3 studies, NDA planned for 2018 Class: -lactam (siderophore cephalosporin) MOA: chelates iron ions within the bacteria which are essential to the organism s survival Potential indications: cuti, nosocomial pneumonia Dosage form: IV & PO Notable antibiotic spectrum: CRE, MDR P. aeruginosa and A. baumannii, Stenotrophomonas maltophilia, and Burkholderia cepacia Does not have any gram positive activity 13 Kish T. PT 2018 Feb;43(2):116-120 http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development NDA = New Drug Application CRE = Carbapenem-Resistant Enterobacteriaceae cuti = complicated urinary tract infection MDR = Multi-drug resistant Fosfomycin (Zolyd TM ) 14 Undergoing Phase 3 studies, NDA submission anticipated to be early 2018 Bactericidal gram negative and gram positive agent MOA: inhibits mura Potential indications Dosage form: IV Notable antibiotic spectrum: MDR organisms, including ESBL; potential synergistic activity in combination with other agents https://www.zavante.com/#pipeline MDR = Multi-drug resistant

Lefamulin 15 Undergoing Phase 3 studies Class: pleuromutilin MOA: binds 50S bacterial ribosome Potential indications Dosage form: IV & PO Notable antibiotic spectrum: MRSA, S. pneumoniae, H. influenzae, M. catarrhalis, N. gonorrhoeae (including MDR strains) https://www.nabriva.com/pipeline-research https://www.nabriva.com/news MRSA = Methicillin-resistant Staphylococcus aureus Iclaprim 16 Undergoing Phase 3 studies, NDA submission planned for second quarter of 2018 Class: diaminopyrimidine MOA: inhibits dihydrofolate reductase Potential indications: ABSSSI,HABP, VABP, S. aureus lung infections in CF patients Dosage form: IV Notable antibiotic spectrum: gram (+); MRSA No therapeutic drug monitoring https://www.motifbio.com/iclaprim/ ABSSSI = Acute Bacterial Skin and Skin Structure Infection HABP = Hospital-acquired Bacterial Pneumonia VABP = Ventilator-associated Bacterial Pneumonia CF = Cystic Fibrosis MRSA = Methicillin-resistant Staphylococcus aureus

Summary 17 WHO expert panel released a priority pathogens list guiding research and development of new antibiotics NDAs have been submitted for three new antibiotics (plazomicin, omadacycline, and eravacycline) and are undergoing review by the FDA A new class of antibiotic, pleuromutilin, is in the pipeline, which acts by binding the 50S bacterial ribosome Post-Assessment Question 18 What is the drug class and mechanism of action of cefiderocol? A. Siderophore cephalosporin / chelates iron ions B. Siderophore cephalosporin / binds 50S ribosome C. Pleuromutilin / inhibits PBP D. Diaminopyrimidine / inhibits dihydrofolate reductase

What s next in the antibiotic pipeline? Jennifer Tieu, Pharm.D., BCPS Clinical Pearls OSHP Spring Meeting Mercy Hospital April 13, 2018