EW ATIBACTERIAL 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> 25/04/2015 ECCMID - 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 ECCMID - anti-gram positive pipeline 2
ew antibiotics: what is your own view of the pipeline? 25/04/2015 ECCMID - anti-gram positive pipeline 3
ew antibiotics: where are we? Approvals by FDA/EMA systemic antibiotics 25/04/2015 ECCMID - anti-gram positive pipeline telavancin ceftaroline 4
ew antibiotics: where are we? Approvals by FDA/EMA systemic antibiotics 25/04/2015 ECCMID - anti-gram positive pipeline telavancin ceftaroline Shall we succeed? dalbavancin oritavancin tedizolid ceftazidime/avibactam ceftolozane/tazobactam 5
Anti Gram-positive recently approved drugs company drug class indications MRSA MDRSP VRE Theravance Telavancin Durata Ther. Dalbavancin The MedCo ritavancin lipoglycopeptide lipoglycopeptide lipoglycopeptide csssi / 25/04/2015 ECCMID - anti-gram positive pipeline HABP/VABP ABSSSI VanB only VanB only ABSSSI MSD Tedizolid oxazolidinone ABSSSI Forrest Astra-Zeneca Ceftaroline β-lactam ABSSSI / CABP Basilea Ceftobiprole* β-lactam CAP / HAP * licensed in 13 countries: AT, BE, CH, DE, DK, ES, FI, FR, IT, LU,, SE, UK; reimbursement and pricing authorization ongoing in most of them 6
dimerization prolonged half-life membrane anchoring decreased half-life Lipoglycopeptides 25/04/2015 ECCMID - anti-gram positive pipeline Van Bambeke, Cur. p. Pharmacol. 2004, 4:471 478 prolonged half-life 7
Cl Lipoglycopeptides: dual mode of action HC H oritavancin (lipoglycopeptide) H H H CH 3 H 2 H H H 3 C H 3 C CH 3 Cl H H H highly bactericidal activity on VR strains H H H H 25/04/2015 ECCMID - anti-gram positive pipeline Cl H CH 2 H H HCH 3 X transglycosylase Lipid II transpeptidase Van Bambeke et al, TIPS 2008, 29:124-134 D-Ala D-Ala L-Lys D-Glu L-Ala -acetylmuramic acid - -acetylglucosamine Pyrophosphate Lipid carrier 8
Lipoglycopeptides: pharmacokinetics parameter VA RI TLV TEC DAL Dosage 15 mg/kg 1200 mg 10 mg/kg 6 mg/kg 1000 mg Cmax (mg/l) AUC (mg.h/l) (%) prot. binding T ½ (h) 20-50 138 93 43 287 260 1110 (24h) 2800 (tot) 25/04/2015 ECCMID - anti-gram positive pipeline 668 600 3185 (24h) 23443 (tot) 55 85 95 88-94 99 1 () 3-9 () 14 () 245 () single dose treatment 8 10 () 168 () 346 () once-a-week dose treatment (2 doses) 9
linezolid tedizolid tedizolid vs linezolid Locke et al, AAC (2010) 54: 5337 43 25/04/2015 ECCMID - anti-gram positive pipeline Binding of tedizolid to methylated ribosomes 10
ceftaroline Resistance to -lactamases ceftobiprole ceftaroline and ceftobiprole Binding to PBP2a 25/04/2015 ECCMID - anti-gram positive pipeline allosteric site ceftaroline & PBP2a tero et al, PAS (2013) 110:16808 13 catalytic site 11
Anti Gram-positive antibiotics in the pipeline (phases II/III) 1/2 company drug class status MRSA MDRSP VRE Cempra solithromycin ketolide Melinta delafloxacin fluoroquinolone TaiGen nemonoxacin fluoroquinolone Dong zabofloxacin fluoroquinolone Activis avarofloxacin fluoroquinolone MerLion finafloxacin fluoroquinolone GSK GSK2140944 topoisomerase inhibitor 25/04/2015 ECCMID - anti-gram positive pipeline CAPB ABSSSI CAPB / ABSSSI CAPB completed CAPB / ABSSSI ABSSSI Constructed based on www.pewtrusts.org respiratory / ABSSSI 12
Anti Gram-positive antibiotics in the pipeline (phases II/III) 1/2 company drug class status MRSA MDRSP VRE Cempra solithromycin ketolide Melinta delafloxacin fluoroquinolone TaiGen nemonoxacin fluoroquinolone Dong zabofloxacin fluoroquinolone Activis avarofloxacin fluoroquinolone MerLion finafloxacin fluoroquinolone GSK GSK2140944 topoisomerase inhibitor 25/04/2015 ECCMID - anti-gram positive pipeline CAPB ABSSSI CAPB / ABSSSI CAPB completed CAPB / ABSSSI ABSSSI Constructed based on www.pewtrusts.org respiratory / ABSSSI 13
increased activity solithromycin vs telithromycin lower interaction with nicotinic receptor Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline binding to ribosomal domain II poor recognition by pneumococci efflux pumps increased activity absence of inducibility of MLS B resistance solithromycin telithromycin 14
telithromycin : structure-toxicity relationship Inhibition of acetycholine nicotinic receptors vagus nerve (liver) liver failure ciliary ganglion (eye) visual disturbance neuro-muscular junction myastenia gravis exacerbation Adapted from Bertrand et al, AAC (2010) 54:5399-42 25/04/2015 ECCMID - anti-gram positive pipeline Role of telithromycin metabolites Metabolites T present for solithromycin 15
Solithromycin : pros and cons low MIC incl. ML R tissue distribution also active on intracell. organisms once daily administration IV/oral low interaction with nicotinic receptors potent anti-inflammatory effects substrate of CYP3A4 low cidal effect moderate activity against H. influenzae 25/04/2015 ECCMID - anti-gram positive pipeline 19
Anti Gram-positive antibiotics in the pipeline (phases II/III) 1/2 company drug class status MRSA MDRSP VRE Cempra solithromycin ketolide Melinta delafloxacin fluoroquinolone TaiGen nemonoxacin fluoroquinolone Dong zabofloxacin fluoroquinolone Activis avarofloxacin fluoroquinolone MerLion finafloxacin fluoroquinolone GSK GSK2140944 topoisomerase inhibitor 25/04/2015 ECCMID - anti-gram positive pipeline CAPB ABSSSI CAPB / ABSSSI CAPB completed CAPB / ABSSSI ABSSSI Constructed based on www.pewtrusts.org respiratory / ABSSSI 20
new (fluoro)quinolones JJ-Q2 Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline BAY35-3377 DW-224a WQ-3034; ABT-492; RX-3341 TG-873870 21
Delafloxacin, the first non-zwitterionic quinolone H c a tio n ic F m icrospecies distributio n 1 0 0 8 0 6 0 4 0 2 0 Cl H H 2 F F c a tio n ic H n e u tra l H D E L A F L X A C I n e u tra l F Cl H2 F 0 2 3 4 5 6 7 8 9 1 0 p H F H H a n io n ic F Cl H 2 F a n io n ic F 25/04/2015 ECCMID - anti-gram positive pipeline 22 m icrospecies distributio n c a tio n ic 1 0 0 8 0 c a tio n ic Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-58 H 2 F CH 3 H H2 M X IF L X A C I zw itterionic F CH 3 a n io n ic zw itterionic 6 0 4 0 2 0 a n io n ic 0 2 3 4 5 6 7 8 9 1 0 p H H F CH 3
Delafloxacin, the first non-zwitterionic quinolone H c a tio n ic F m icrospecies distributio n 1 0 0 8 0 6 0 4 0 2 0 Cl H H 2 c a tio n ic n e u tra l H n e u tra l Increased uptake by bacteria activity at acidic ph F F H D E L A F L X A C I F Cl H2 F 0 2 3 4 5 6 7 8 9 1 0 p H F fluoroquinolone accumulation (ng. mg prot -1 / µg. ml -1 ) H 600 500 400 300 200 100 0 H a n io n ic a n io n ic Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-58 25/04/2015 ECCMID - anti-gram positive pipeline F ** ** Cl H 2 ** F F * * moxifloxacin delafloxacin 5.5 6.0 6.5 7.0 7.5 H 2 m icrospecies distributio n c a tio n ic F 1 0 0 8 0 6 0 4 0 2 0 CH 3 c a tio n ic H H2 M X IF L X A C I zw itterionic F CH 3 0 2 3 4 5 6 7 8 9 1 0 moxifloxacin delafloxacin p H a n io n ic H zw itterionic ph of broth 5.5 6.0 6.5 7.0 7.5 2 1 0-1 -2-3 -4-5 fold difference in MIC relative to ph 7.4 (log 2 ) F CH 3 a n io n ic 23
new (fluoro)quinolones : pros and cons broad spectrum low MICs tissue distribution also active on intracell. organisms highly bactericidal once daily administration oral or IV delafloxacin / finafloxacin highly active at acidic ph broad spectrum cross resistance with other FQ AB class possibly showing rare/serious side effects CI in children/pregnancy 25/04/2015 ECCMID - anti-gram positive pipeline 30
Anti Gram-positive antibiotics in the pipeline (phases II/III) 1/2 company drug class status MRSA MDRSP VRE Cempra solithromycin ketolide 25/04/2015 ECCMID - anti-gram positive pipeline CAPB Melinta delafloxacin fluoroquinolone TaiGen nemonoxacin fluoroquinolone Dong zabofloxacin fluoroquinolone Activis avarofloxacin fluoroquinolone MerLion finafloxacin fluoroquinolone GSK GSK2140944 topoisomerase inhibitor CAPB / ABSSSI CAPB completed CAPB / ABSSSI ABSSSI Constructed based on www.pewtrusts.org respiratory / ABSSSI 31
FQ GSK2140944 topoisomerase inhibitor GSK o cross-resistance with fluoroquinolones Ehmann & Lahiri, Cur. p. Pharmacol. (2014) 18:76 83 25/04/2015 ECCMID - anti-gram positive pipeline 32
GSK2140944 In vitro activity Isolates Associated with Lower Respiratory Tract and Skin Infections ICAAC (2013) F1216 25/04/2015 ECCMID - anti-gram positive pipeline 33
novel mode of action no cross-resistance with FQ broad spectrum bactericidal oral and IV routes no changes in ECG in Phase I GSK2140944 : pros and cons broad spectrum optimal dose still to be defined safety profile to be studied 25/04/2015 ECCMID - anti-gram positive pipeline 34
company drug class status MRSA MDRSP VRE Melinta radezolid oxazolidinone Paratek omadacycline aminomethyl cyclines Cempra fusidic acid fusidane Debiopharm Debio1452 FabI inhibitor Theravance CG-400549 TD-1792 FabI inhibitor glycopeptide + cephalosporine abriva lefamulin pleuromutilin Cellceutix Anti Gram-positive antibiotics in the pipeline (phases II/III) 2/2 brilacidin Crystalgenomics defensinmimetic 25/04/2015 ECCMID - anti-gram positive pipeline CAPB / ABSSSI CAPB / ABSSSI ABSSSI S. aureus ABSSSI ABSSSI / osteomyelitis completed Constructed based on www.pewtrusts.org csssi completed ABSSSI /CABP/HA-VABP completed ABSSSI 35
linezolid H biaryl spacer radezolid H F F radezolid vs linezolid H heteroaryl substituant H protonable aminated function sparsomycin linezolid Zhou et al., J. Bioorg. Med. Chem. Lett. (2008) 18:6179-83 25/04/2015 ECCMID - anti-gram positive pipeline 36
new oxazolidinones : pros and cons targeted spectrum still active on LZD R tissue distribution active on intracell. organisms once daily administration excellent oral bioavailability less platelet toxicity poorly or inactive on Gram(-) bacteriostatic safety profile to be further documented 25/04/2015 ECCMID - anti-gram positive pipeline 39
company drug class status MRSA MDRSP VRE Melinta radezolid oxazolidinone Paratek omadacycline aminomethyl cyclines Cempra fusidic acid fusidane Debiopharm Debio1452 FabI inhibitor Theravance CG-400549 TD-1792 FabI inhibitor glycopeptide + cephalosporine abriva lefamulin pleuromutilin Cellceutix Anti Gram-positive antibiotics in the pipeline (phases II/III) 2/2 brilacidin Crystalgenomics defensinmimetic 25/04/2015 ECCMID - anti-gram positive pipeline CAPB / ABSSSI CAPB / ABSSSI ABSSSI S. aureus ABSSSI ABSSSI / osteomyelitis completed Constructed based on www.pewtrusts.org csssi completed ABSSSI /CABP/HA-VABP completed ABSSSI 40
minocycline tigecycline omadacycline madacycline (PTK-0796) vs tigecycline Active if ribosomal protection Tet-mediated efflux Inactive if broad spectrum efflux (P. aeruginosa) Jenner et al., PAS (2013) 110:3812-16 25/04/2015 ECCMID - anti-gram positive pipeline 41
madacycline: pros and cons broad spectrum -> monotherapy still active on Tet R tissue distribution once daily administration oral and IV formulation broad spectrum inactive on P. aeruginosa bacteriostatic CI in children/pregnancy safety to be documented 25/04/2015 ECCMID - anti-gram positive pipeline 43
company drug class status MRSA MDRSP VRE Melinta radezolid oxazolidinone Paratek omadacycline aminomethyl cyclines Cempra fusidic acid fusidane Debiopharm Debio1452 FabI inhibitor Theravance CG-400549 TD-1792 FabI inhibitor glycopeptide + cephalosporine abriva lefamulin pleuromutilin Cellceutix Anti Gram-positive antibiotics in the pipeline (phases II/III) 2/2 brilacidin Crystalgenomics defensinmimetic 25/04/2015 ECCMID - anti-gram positive pipeline CAPB / ABSSSI CAPB / ABSSSI ABSSSI S. aureus ABSSSI ABSSSI / osteomyelitis completed Constructed based on www.pewtrusts.org csssi completed ABSSSI /CABP/HA-VABP completed ABSSSI 44
Fusidic acid Elongation factor G = GTP-ase ~ translocation of tra-mra Fusidic acid prevents EF-G release from the ribosome Gao et al., Science (2009) 326:694-698 25/04/2015 ECCMID - anti-gram positive pipeline 45
active on CA-MRSA no cross resistance with other prot. synthesis inhibitors oral formulation [with loading dose] tissue distribution safety profile Fusidic acid: pros and cons resistance already spread in some countries frequent target mutations bacteriostatic substrate of CYP 3A4 25/04/2015 ECCMID - anti-gram positive pipeline 47
company drug class status MRSA MDRSP VRE Melinta radezolid oxazolidinone Paratek omadacycline aminomethyl cyclines Cempra fusidic acid fusidane Debiopharm Debio1452 FabI inhibitor Theravance CG-400549 TD-1792 FabI inhibitor glycopeptide + cephalosporine abriva lefamulin pleuromutilin Cellceutix Anti Gram-positive antibiotics in the pipeline (phases II/III) 2/2 brilacidin Crystalgenomics defensinmimetic 25/04/2015 ECCMID - anti-gram positive pipeline CAPB / ABSSSI CAPB / ABSSSI ABSSSI S. aureus ABSSSI ABSSSI / osteomyelitis completed Constructed based on www.pewtrusts.org csssi completed ABSSSI /CABP/HA-VABP completed ABSSSI 48
Debio1452 FabI (Enoyl-[acyl-carrier-protein] reductase) inhibitors Specifically active on S. aureus Fatty acid synthesis in bacteria Miesnel et al, ature Rev. Gen. (2003) 4: 442-456 25/04/2015 ECCMID - anti-gram positive pipeline 49 CG-400549
Debio (AF) 1252 in vitro activity Karlowsky et al, AAC (2009) 53: 3544-48 25/04/2015 ECCMID - anti-gram positive pipeline 50
novel mode of action restricted to S.aureus -> no effect on flora oral formulation tissue distribution FabI inhibitors: pros and cons bacteriostatic restricted to S.aureus 25/04/2015 ECCMID - anti-gram positive pipeline 51
company drug class status MRSA MDRSP VRE Melinta radezolid oxazolidinone Paratek omadacycline aminomethyl cyclines Cempra fusidic acid fusidane Debiopharm Debio1452 FabI inhibitor Theravance CG-400549 TD-1792 FabI inhibitor glycopeptide + cephalosporine abriva lefamulin pleuromutilin Cellceutix Anti Gram-positive antibiotics in the pipeline (phases II/III) 2/2 brilacidin Crystalgenomics defensinmimetic 25/04/2015 ECCMID - anti-gram positive pipeline CAPB / ABSSSI CAPB / ABSSSI ABSSSI S. aureus ABSSSI ABSSSI / osteomyelitis completed Constructed based on www.pewtrusts.org csssi completed ABSSSI /CABP/HA-VABP completed ABSSSI 52
Cephalosporin (THRX-206852) TD-1792 Long et al, J. Antibiot. (2008) 61:603-14 vancomycin 25/04/2015 ECCMID - anti-gram positive pipeline 53
TD-1792 : in vitro activity ICAAC (2007) F1-2110
bactericidal synergistic mode of action low MICs (incl. MRSA, VISA) Gram(+) spectrum once daily (IV) no metabolism (animals) TD-1792: pros and cons no anti Gram(-) coverage no oral route currently no sign of renal toxicity [VA] but more data needed 25/04/2015 ECCMID - anti-gram positive pipeline 57
company drug class status MRSA MDRSP VRE Melinta radezolid oxazolidinone Paratek omadacycline aminomethyl cyclines Cempra fusidic acid fusidane Debiopharm Debio1452 FabI inhibitor Theravance CG-400549 TD-1792 FabI inhibitor glycopeptide + cephalosporine abriva lefamulin pleuromutilin Cellceutix Anti Gram-positive antibiotics in the pipeline (phases II/III) 2/2 brilacidin Crystalgenomics defensinmimetic 25/04/2015 ECCMID - anti-gram positive pipeline CAPB / ABSSSI CAPB / ABSSSI ABSSSI S. aureus ABSSSI ABSSSI / osteomyelitis completed Constructed based on www.pewtrusts.org csssi completed ABSSSI /CABP/HA-VABP completed ABSSSI 58
lefamulin Lefamulin (BC-3781) vs retapamulin Antibiotic binding to peptidyl transferase center of 50S ribosome Schlünzen et al, Mol. Microbiol. (2004) 54: 1287 94 retapamulin 25/04/2015 ECCMID - anti-gram positive pipeline 59
novel mode of action infrequent cross resistance with other classes broad spectrum ELF penetration accumulation in cells first for systemic use in humans topic, oral, IV no major CYP interactions Lafamulin: pros and cons cross resistance described with LZD (cfr, PTC mutations) broad veterinary use of other pleuromutilins not active on enterobacteriacae 25/04/2015 ECCMID - anti-gram positive pipeline 61
company drug class status MRSA MDRSP VRE Melinta radezolid oxazolidinone Paratek omadacycline aminomethyl cyclines Cempra fusidic acid fusidane Debiopharm Debio1452 FabI inhibitor Theravance CG-400549 TD-1792 FabI inhibitor glycopeptide + cephalosporine abriva lefamulin pleuromutilin Cellceutix Anti Gram-positive antibiotics in the pipeline (phases II/III) 2/2 brilacidin Crystalgenomics defensinmimetic 25/04/2015 ECCMID - anti-gram positive pipeline CAPB / ABSSSI CAPB / ABSSSI ABSSSI S. aureus ABSSSI ABSSSI / osteomyelitis completed Constructed based on www.pewtrusts.org csssi completed ABSSSI /CABP/HA-VABP completed ABSSSI 62
25/04/2015 Brilacidin membrane depolarisation ~ daptomycin cytoplasmic protein misfolding upregulation of chaperones and proteases (genes involved in stress response) ~ defensins http://en.wikipedia.org/wiki/antimicrobial_peptides Mensa et al, AAC (2014) 58:5136-45 ECCMID - anti-gram positive pipeline 63
Brilacidin: phase II data http://cellceutix.com 25/04/2015 ECCMID - anti-gram positive pipeline 64
novel mode of action rapidly bactericidal mimic human defenses broad spectrum active on stationary phase bact. short treatment (1-3 doses) Brilacidin: pros and cons IV administration small V d gender differences in PK (Cl and body surface) reversible adverse effects (paresthesia, blood pressure and heart rate) 25/04/2015 ECCMID - anti-gram positive pipeline 65
Antibiotic pipeline: did you change your mind? Large number of molecules in clinical development much more in preclinical development More advanced molecules () are new derivatives in existing classes with improved properties (MIC resistance PK- safety) 25/04/2015 ECCMID - anti-gram positive pipeline 66
Antibiotic pipeline: some work ahead Susceptibility Breakpoint harmonization An example with MRSA antibiotic EUCAST CLSI/FDA S R > S R rifampicin 0.06 0.5 1 4 azithromycin 1 2 2 8 doxycycline 1 2 4 16 vancomycin 2 2 2 16 linezolid 4 4 4 8 ceftaroline 1 1 0.5 2 telavancin 0.125 0.125 0.125 dalbavancin 0.125 0.125 0.125 rule in Europe! 25/04/2015 ECCMID - anti-gram positive pipeline 67
Antibiotic pipeline: can we do better? Equivalence to current options in comparative clinical trials This will raise issues for reimbursement, especially against the generics of the comparators used in these studies eed to design superiority trials and to focus pricing and reimbursement for documented cases of infection by resistant organisms 25/04/2015 ECCMID - anti-gram positive pipeline 68
on-inferiority vs superiority trials? -IFERIRITY if evidence of spontaneous resolution rate (more effective than placebo) Indications (and delta): Community-acquired pneumonia (-10%; more in PRT scores of IV-V) Hospital-acquired pneumonia and ventilator-associated pneumonia (less than -12.5%) Skin and soft tissue infections (-10%) Intra-abdominal infections (-12.5%) Urinary tract infections (-10 %) SUPERIRITY if spontaneous resolution (placebo effective) Acute bacterial maxillary sinusitis Acute bacterial exacerbations of chronic bronchitis Acute otitis media Superficial skin infections (such as impetigo and minor wounds) Inhaled antibacterial agents (excl. CF) LIMITED TRIALS Rare MDR organisms Few patients EMA/CHMP/351889/2013 DRUG/comparator trial Placebo/ DRUG/comparator trial DRUG non comparative trial 25/04/2015 ECCMID - anti-gram positive pipeline 69
on-inferiority vs superiority trials? 25/04/2015 ECCMID - anti-gram positive pipeline 70
What about the future? 25/04/2015 ECCMID - anti-gram positive pipeline 71
Backup slides 25/04/2015 ECCMID - anti-gram positive pipeline 72
Study number & development Phase CT01966055; Phase I CT01168713; CT01591447; CT01968733; CT01756339; solithromycin: ongoing clinical trials Drugs and doses Study title Status Solithromycin; dose not specified ral solithromycin (800 mg QD day 1; 400 mg QD days 2-5) ; comparator: oral levofloxacin (750 mg QD days 1-5) Single dose solithromycin 1000 mg by oral route Solithromycin (intravenous with the potential step-down to oral); comparator: moxifloxacin (intravenous with the potential step-down to oral); doses not specified Solithromycin (800 mg orally on day 1 followed by 400 mg daily on days 2 through 5, followed by placebo on days 6 and 7); comparator: moxifloxacin (400 mg orally on Day 1 to 7) Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline Pharmacokinetics and Safety of Solithromycin Capsules in Adolescents Efficacy and Safety Study of ral CEM- 101 Compared to ral Levofloxacin in Treatment of Patients With Community- Acquired Bacterial Pneumonia Safety and Efficacy Study of Single-Dose ral CEM-101 in Patients With Uncomplicated Urogenital Gonorrhea Efficacy and Safety Study of Intravenous to ral Solithromycin (CEM-101) Compared to Intravenous to ral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SLITAIRE-IV) Efficacy and Safety Study of ral Solithromycin (CEM-101) Compared to ral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SLITAIRE-RAL) Recruiting Completed (2011) Completed (2013) Recruiting Recruiting 73
Study number & development Phase CT01966055; Phase I CT01168713; CT01591447; CT01968733; CT01756339; solithromycin: ongoing clinical trials Drugs and doses Study title Status Solithromycin; dose not specified ral solithromycin (800 mg QD day 1; 400 mg QD days 2-5) ; comparator: oral levofloxacin (750 mg QD days 1-5) Single dose solithromycin 1000 mg by oral route Solithromycin (intravenous with the potential step-down to oral); comparator: moxifloxacin (intravenous with the potential step-down to oral); doses not specified Solithromycin (800 mg orally on day 1 followed by 400 mg daily on days 2 through 5, followed by placebo on days 6 and 7); comparator: moxifloxacin (400 mg orally on Day 1 to 7) Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline Pharmacokinetics and Safety of Solithromycin Capsules in Adolescents Efficacy and Safety Study of ral CEM- 101 Compared to ral Levofloxacin in Treatment of Patients With Community- Acquired Bacterial Pneumonia Safety and Efficacy Study of Single-Dose ral CEM-101 in Patients With Uncomplicated Urogenital Gonorrhea Efficacy and Safety Study of Intravenous to ral Solithromycin (CEM-101) Compared to Intravenous to ral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SLITAIRE-IV) Efficacy and Safety Study of ral Solithromycin (CEM-101) Compared to ral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SLITAIRE-RAL) Recruiting Completed (2011) Completed (2013) Recruiting Recruiting 74
solithromycin : CABP data ldach et al, AAC (2013) 57:2526-34 25/04/2015 ECCMID - anti-gram positive pipeline 75
new (fluoro)quinolones: in vitro activity as or more active ~ moxifloxacin, but cross resistance Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline 76
Study number & development Phase ZABFLXACI CT01081964; CT01658020; new (fluoro)quinolones: ongoing clinical trials Drugs and doses Study title Status Zabofloxacin (400 mg orally QD for 3 or 5 days); comparator: levofloxacin (500 mg orally QD for 7 days) Zabofloxacin (400 mg orally QD); comparator: moxifloxacin (400 mg orally QD) Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline Safety and Efficacy Study of ral Zabofloxacin in Community Acquired Pneumonia A Study to Evaluate Efficacy and Safety Profile of Zabofloxacin Tablet 400mg and Moxifloxacin Tablet 400mg (DW224-III-3) after Multi-dose ral Administration in Patients With Acute Bacterial Exacerbation of Chronic bstructive Pulmonary Disease. Completed (2012) ngoing, not recruiting 77
Study number & development Phase EMXACI CT00434291; CT00685698; CT01537250; CT01944774; CT01529476; new (fluoro)quinolones: ongoing clinical trials ot provided Drugs and doses Study title Status emonoxacin 750 mg, oral administration, once daily for 7±1 and 14±1 days emonoxacin (750 mg orally 2 tablets or 500 mg orally 3 tablets) ; comparator: levofloxacin (500 mg orally QD + placebo) for 7 days emonoxacin (500 mg or 650 mg QD IV for 7~14 days) ; comparator: moxifloxacin (400 mg QD IV for 7~14 days) emonoxacin (500 mg orally) ; comparator levofloxacin (500 mg orally) for 7~14 days Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline Safety and Efficacy Comparison of TG- 873870 (emonoxacin) to Levofloxacin in Community-Acquired Pneumonia Safety and Efficacy Study of TG-873870 (emonoxacin) in Diabetic Foot Infections Study to Assess the Efficacy and Safety of emonoxacin Malate in Treating Adult Patients With Community-acquired Pneumonia (CAP) Study to Evaluate the Efficacy and Safety of Intravenous Infusion With TG-873870 (nemonoxacin) Versus Moxifloxacin in Treating Adult Patients With Community Acquired Pneumonia (CAP) Study to Evaluate the Efficacy and Safety of ral Administration With emonoxacin and Levofloxacin in Patients With Community-acquired Pneumonia (CAP) ot provided Completed (2009) Completed (2010) Recruiting Completed (2012) 78
Study number & development Phase EMXACI CT00434291; CT00685698; CT01537250; CT01944774; CT01529476; new (fluoro)quinolones: ongoing clinical trials ot provided Drugs and doses Study title Status emonoxacin 750 mg, oral administration, once daily for 7±1 and 14±1 days emonoxacin (750 mg orally 2 tablets or 500 mg orally 3 tablets) ; comparator: levofloxacin (500 mg orally QD + placebo) for 7 days emonoxacin (500 mg or 650 mg QD IV for 7~14 days) ; comparator: moxifloxacin (400 mg QD IV for 7~14 days) emonoxacin (500 mg orally) ; comparator levofloxacin (500 mg orally) for 7~14 days Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline Safety and Efficacy Comparison of TG- 873870 (emonoxacin) to Levofloxacin in Community-Acquired Pneumonia Safety and Efficacy Study of TG-873870 (emonoxacin) in Diabetic Foot Infections Study to Assess the Efficacy and Safety of emonoxacin Malate in Treating Adult Patients With Community-acquired Pneumonia (CAP) Study to Evaluate the Efficacy and Safety of Intravenous Infusion With TG-873870 (nemonoxacin) Versus Moxifloxacin in Treating Adult Patients With Community Acquired Pneumonia (CAP) Study to Evaluate the Efficacy and Safety of ral Administration With emonoxacin and Levofloxacin in Patients With Community-acquired Pneumonia (CAP) ot provided Completed (2009) Completed (2010) Recruiting Completed (2012) 79
emonoxacin CABP phase III data Van Rensburg et al, AAC (2010) 54:4098-106 25/04/2015 ECCMID - anti-gram positive pipeline 80
Study number & development Phase DELAFLXACI CT00719810; CT01283581; CT01811732; CT01984684; new (fluoro)quinolones: ongoing clinical trials Drugs and doses Study title Status Delafloxacin (300 mg or 450 mg IV BID) Safety and Efficacy Study of a Completed (2008) ; comparator: tigecycline (100 mg on Fluoroquinolone to Treat Complicated Skin Infections day 1 then 50 mg IV BID) Delafloxacin (300mg IV BID) for 5-14 A Study to Assess bjective Endpoint Completed (2011) days; Measurements of Response in Bacterial comparators: linezolid (600mg IV BID) Skin Infections and vancomycin (15mg/kg, up to 1250 mg, IV BID) for 5-14 days Delafloxacin (300 mg IV BID) for up 5- Delafloxacin Versus Vancomycin and Recruiting 14 days; Aztreonam for the Treatment of Acute comparator: vancomycin (15mg/kg IV) Bacterial Skin and Skin Structure Infections + aztreonam (2g) BID Delafloxacin (300 mg IV BID 300mg iv Delafloxacin vs Vancomycin and ot yet recruiting BID for 3 days) followed by 450mg oral Aztreonam for the Treatment of Acute BID for up 5-14 days total; Bacterial Skin and Skin Structure Infections comparator: vancomycin (15mg/kg IV) + aztreonam (2g) BID Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-gram positive pipeline 81
Radezolid vs linezolid Locke et al, AAC (2010) 54: 5337 43 25/04/2015 ECCMID - anti-gram positive pipeline 82
cellular accumulation 10 9 8 7 6 5 4 3 2 1 Radezolid cellular pharmacokinetics in macrophages Cellular accumulation Radezolid Linezolid 0 0 30 60 90 120 time (min) Q/ 30 20 10 0 Subcellular distribution AB Cytx RDZ 1.12 1.14 1.16 1.18 1.20 density accumulation in acidic vacuoles Lemaire et al., AAC (2010) 54:2540-48 lacticodehydrogenase (LDH) cytochrome C oxydase lysosome mitochondria 25/04/2015 ECCMID - anti-gram positive pipeline 83 (Cytx) -acetyl--glucosaminidase (AB)
madacycline : CSSSI data madacycline 100 mg [i.v.] QD; possible transition to 200 mg [p.o.] QD linezolid 600 mg [i.v.] BID; possible transition to 600 mg [p.o.]y BID oel et al., AAC (2012) 56:5650-546 25/04/2015 ECCMID - anti-gram positive pipeline 84
TD-1792 : in vivo activity ICAAC (2007)
TD-1792 : csssi data TD-1792 : 2 mg/kg once daily vs vancomycin 1 g twice daily Stryjewski et al, AAC (2012) 56:5476-83
Lefamulin: ABSSSI data ICAAC (2012) L1-1660 25/04/2015 ECCMID - anti-gram positive pipeline 87