NEW ANTIBACTERIAL DRUGS Drug pipeline for Gram-positive bacteria Françoise Van Bambeke, PharmD, PhD Pharmacologie cellulaire et moléculaire Louvain Drug Research Institute Université catholique de Louvain, Brussels, Belgium <www.facm.ucl.ac.be> ESCMID Online Lecture Library 25/04/2015@ by authorECCMID - anti-Gram positive pipeline F. Van Bambeke’s disclosures Research grants for work on investigational compounds discussed in this presentation from • Cempra Pharmaceuticals • Cerexa • GSK • Melinta therapeutics • The Medicine Company • MerLion Pharmaceuticals • Theravance • Trius ESCMID Online Lecture Library @ by authorECCMID - anti-Gram positive pipeline 2 New antibiotics: what is your own view of the pipeline ? ESCMID Online Lecture Library 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 3 New antibiotics: where are we ? Approvals by FDA/EMA – systemic antibiotics ESCMID Online Lecturetelavancin Library ceftaroline 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 4 New antibiotics: where are we ? Approvals by FDA/EMA – systemic antibiotics Shall we succeed ? dalbavancin oritavancin tedizolid ceftazidime/avibactam ceftolozane/tazobactam ESCMID Online Lecturetelavancin Library ceftaroline 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 5 Anti Gram-positive recently approved drugs company drug class indications MRSA MDRSP VRE lipoglyco- cSSSI / VanB Theravance Telavancin peptide HABP/VABP only lipoglyco- VanB Durata Ther. Dalbavancin ABSSSI peptide only lipoglyco- The MedCo Oritavancin ABSSSI peptide MSD Tedizolid oxazolidinone ABSSSI Forrest Ceftaroline β-lactam ABSSSI / CABP Astra-Zeneca Basilea Ceftobiprole* β-lactam CAP / HAP * licensed in 13 countries: AT, BE, CH, DE, DK, ES, FI, FR, IT, LU, NO, SE, UK; reimbursement and pricing authorization ongoing in most of them ESCMID Online Lecture Library 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 6 Lipoglycopeptides prolonged half-life dimerization • prolonged half-life • membrane anchoring ESCMID Online LectureVan Bambeke, Library decreased Cur. Op. Pharmacol. half-life 2004, 4:471–478 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 7 Lipoglycopeptides: dual mode of action Cl D-Ala oritavancin (lipoglycopeptide) Lipid II D-Ala L-Lys D-Glu HO HO L-Ala O OH O O HN CH3 N-acetylmuramic acid - H2N O Cl HO OH N-acetylglucosamine H3C O O H3C O Pyrophosphate CH3 O OH Lipid carrier Cl O O O H H N N N N NH H H HN O O NHCH3 CONH2O HOOC OH HO OH transpeptidase • highly bactericidal transglycosylaseX • activity on VR strains ESCMID Online Lecture Library Van Bambeke et al, TIPS 2008, 29:124-134 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 8 Lipoglycopeptides: pharmacokinetics parameter VAN ORI TLV TEC DAL Dosage 15 mg/kg 1200 mg 10 mg/kg 6 mg/kg 1000 mg Cmax 20-50 138 93 43 287 (mg/L) AUC 1110 (24h) 3185 (24h) 260 668 600 (mg.h/L) 2800 (tot) 23443 (tot) (%) prot. 55 85 95 88-94 99 binding 1 () 14 () 10 () T ½ (h) 8 346 () 3-9 () 245 () 168 () single dose once-a-week dose ESCMID Onlinetreatment Lecture Librarytreatment (2 doses) 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 9 tedizolid vs linezolid linezolid tedizolid ESCMID Online Lecture Library Binding of tedizolid Locke et al, AAC (2010) 54: 5337–43 to methylated ribosomes 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 10 ceftaroline and ceftobiprole ceftaroline ceftaroline & PBP2a catalytic site Resistance to -lactamases Binding to PBP2a allosteric site ceftobiproleESCMID Online Lecture Library Otero et al, PNAS (2013) 110:16808–13 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 11 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2 company drug class status MRSA MDRSP VRE Phase III Cempra solithromycin ketolide CAPB Phase III Melinta delafloxacin fluoroquinolone ABSSSI Phase III TaiGen nemonoxacin fluoroquinolone CAPB / ABSSSI Phase III Dong zabofloxacin fluoroquinolone CAPB Phase II completed Activis avarofloxacin fluoroquinolone CAPB / ABSSSI Phase II MerLion finafloxacin fluoroquinolone ABSSSI topoisomerase Phase II GSK GSK2140944 inhibitor respiratory / ABSSSI ESCMID Online Lecture Library Constructed based on www.pewtrusts.org 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 12 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2 company drug class status MRSA MDRSP VRE Phase III Cempra solithromycin ketolide CAPB Phase III Melinta delafloxacin fluoroquinolone ABSSSI Phase III TaiGen nemonoxacin fluoroquinolone CAPB / ABSSSI Phase III Dong zabofloxacin fluoroquinolone CAPB Phase II completed Activis avarofloxacin fluoroquinolone CAPB / ABSSSI Phase II MerLion finafloxacin fluoroquinolone ABSSSI topoisomerase Phase II GSK GSK2140944 inhibitor respiratory / ABSSSI ESCMID Online Lecture Library Constructed based on www.pewtrusts.org 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 13 solithromycin vs telithromycin lower interaction • binding to ribosomal domain II with nicotinic receptor • poor recognition by pneumococci efflux pumps increased activity absence of inducibility of MLS resistance increased B activity ESCMIDsolithromycin Online Lecturetelithromycin Library Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 14 telithromycin : structure-toxicity relationship Inhibition of acetycholine nicotinic receptors Role of telithromycin metabolites vagus nerve neuro-muscular (liver) junction liver failure myastenia gravis exacerbation ciliary ganglion (eye) Metabolites ESCMIDvisual disturbance Online LectureNOT present Library for solithromycin Adapted from Bertrand et al, AAC (2010) 54:5399-42 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 15 Solithromycin : pros and cons • low MIC incl. MLR • substrate of CYP3A4 • tissue distribution • low cidal effect • also active on • moderate activity intracell. organisms against H. influenzae • once daily administration • IV/oral • low interaction with nicotinic receptors • potent anti-inflammatory ESCMID effects Online Lecture Library 25/04/2015 @ by authorECCMID - anti-Gram positive pipeline 19 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2 company drug class status MRSA MDRSP VRE Phase III Cempra solithromycin ketolide CAPB Phase III Melinta delafloxacin fluoroquinolone ABSSSI Phase III TaiGen nemonoxacin fluoroquinolone CAPB / ABSSSI Phase III Dong zabofloxacin fluoroquinolone CAPB Phase II completed Activis avarofloxacin fluoroquinolone CAPB / ABSSSI Phase II MerLion finafloxacin fluoroquinolone ABSSSI topoisomerase Phase II GSK GSK2140944 inhibitor respiratory / ABSSSI ESCMID Online Lecture Library Constructed based on www.pewtrusts.org 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 20 new (fluoro)quinolones BAY35-3377 JNJ-Q2 DW-224a ESCMID Online Lecture Library TG-873870 WQ-3034; ABT-492; RX-3341 Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 21 Delafloxacin, the first “non-zwitterionic” quinolone DELAFLOXACIN MOXIFLOXACIN c a tio n ic O O n e u tra l O O a n io n ic O O c a tio n ic zwitterionic a n io n ic F F F OH OH O O O O O O O F F N N F O N N N N OH O Cl F Cl F HO HO HO Cl F N N HN N N N N H N N N H N 2 HN 2 OCH3 OCH OCH3 3 H2N H2N H2N F F F 1 0 0 1 0 0 a n io n ic n e u tra l c a tio n ic zwitterionic 8 0 8 0 6 0 6 0 4 0 4 0 2 0 2 0 microspecies distribution c a tio n ic microspecies distribution a n io n ic 0 0 2 3 4 5 6 7 8 9 1 0 2 3 4 5 6 7 8 9 1 0 p H p H ESCMID Online Lecture Library Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-58 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 22 Delafloxacin, the first “non-zwitterionic” quinolone DELAFLOXACIN MOXIFLOXACIN c a tio n ic O O n e u tra l O O a n io n ic O O c a tio n ic zwitterionic a n io n ic F F F OH OH O O O O O O O F F N N F O N N N N OH O Cl F Cl F HO HO HO Cl F N N HN N N N N H N N N H N 2 HN 2 OCH3 OCH OCH3 3 H2N H2N H2N F F F 1 0 0 1 0 0 a n io n ic n e u tra l c a tio n ic zwitterionic 8 0 8 0 6 0 6 0 4 0 4 0 2 0 2 0 microspecies distribution c a tio n ic microspecies distribution a n io n ic 0 0 2 3 4 5 6 7 8 9 1 0 2 3 4 5 6 7 8 9 1 0 p H p H moxifloxacin moxifloxacin 2 ) 600 -1 delafloxacin relative to pH 7.4 (log delafloxacin 1 fold difference in MIC 500 ** 0 / µg . ml . µg / ** -1 400 Increased -1 • uptake by bacteria 300 * * -2 • activity at acidic pH 200 -3 2 (ng . mg protmg . (ng -4 ) 100 fluoroquinolone accumulation fluoroquinolone ** -5 0 ESCMID Online5.5 6.0 6.5 7.0 Lecture7.5 5.5 6.0 6.5 7.0 7.5Library pH of broth Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-58 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 23 new (fluoro)quinolones : pros and cons • broad spectrum • broad spectrum • low MICs • cross resistance with other FQ • tissue distribution • AB class possibly showing • also active on rare/serious side effects intracell. organisms • CI in children/pregnancy • highly bactericidal • once daily administration • oral or IV ESCMID• delafloxacin / finafloxacin Online Lecture Library highly active at acidic pH 25/04/2015 @ by authorECCMID - anti-Gram positive pipeline 30 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2 company drug class status MRSA MDRSP VRE Phase III Cempra solithromycin ketolide CAPB Melinta delafloxacin fluoroquinolone Phase III Phase III TaiGen nemonoxacin fluoroquinolone CAPB / ABSSSI Phase III Dong zabofloxacin fluoroquinolone CAPB Phase II completed Activis avarofloxacin fluoroquinolone CAPB / ABSSSI Phase II MerLion finafloxacin fluoroquinolone ABSSSI topoisomerase Phase II GSK GSK2140944 inhibitor respiratory / ABSSSI ESCMID Online Lecture Library Constructed based on www.pewtrusts.org 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 31 GSK2140944 – topoisomerase inhibitor GSK FQ ESCMID Online No Lecture cross-resistance withLibrary fluoroquinolones Ehmann & Lahiri, Cur.