ESCMID Online Lecture Library @ by Authoricaac (2007) F1-2110 TD-1792: Pros and Cons

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

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

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. Op. Pharmacol. (2014) 18:76–83 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 32 GSK2140944 – In vitro activity

Isolates Associated with Lower Respiratory Tract and Skin Infections

ESCMID Online Lecture Library

ICAAC (2013) F1216 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 33 GSK2140944 : pros and cons

• novel mode of action • broad spectrum • no cross-resistance • optimal dose still to be with FQ defined • broad spectrum • safety profile to be studied • bactericidal • oral and IV routes • no changes in ECG in Phase I ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 34 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2

company drug class status MRSA MDRSP VRE Phase II Melinta radezolid oxazolidinone CAPB / ABSSSI    aminomethyl Phase III Paratek omadacycline cyclines CAPB / ABSSSI    Phase III Cempra fusidic acid fusidane ABSSSI  Phase II Debiopharm Debio1452 FabI inhibitor S. aureus ABSSSI  Crystal- Phase II CG-400549 FabI inhibitor genomics ABSSSI / osteomyelitis  glycopeptide + Phase II completed Theravance TD-1792 cephalosporine cSSSI  

Phase II completed Nabriva lefamulin pleuromutilin ABSSSI /CABP/HA-VABP    defensin- Phase II completed CellceutixESCMID brilacidin Online Lecture Library mimetic ABSSSI   Constructed based on www.pewtrusts.org 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 35 radezolid vs linezolid

linezolid F O

N O

NO H N

heteroaryl biaryl substituant spacer H radezolid N F N N H N sparsomycin linezolid O

NO H protonable N aminated function O ESCMID Online Lecture Library

Zhou et al., J. Bioorg. Med. Chem. Lett. (2008) 18:6179-83 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 36 new oxazolidinones : pros and cons

• targeted spectrum • poorly or inactive on Gram(-) • still active on LZDR • bacteriostatic • tissue distribution • safety profile • active on intracell. organisms to be further documented • once daily administration • excellent oral bioavailability • less platelet toxicity ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 39 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2

Inactive if broad spectrum tigecycline efflux (P. aeruginosa)

omadacycline

ESCMID Online Lecture Library

Jenner et al., PNAS (2013) 110:3812-16 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 41 Omadacycline: pros and cons

• broad spectrum • broad spectrum -> monotherapy • inactive on P. aeruginosa • still active on TetR • bacteriostatic • tissue distribution • CI in children/pregnancy • once daily administration • safety to be documented • oral and IV formulation

ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 43 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2

Elongation factor G = GTP-ase Fusidic acid prevents EF-G release ~ translocation of tRNA-mRNA from the ribosome

ESCMID Online Lecture Library

Gao et al., Science (2009) 326:694-698 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 45 Fusidic acid: pros and cons

• active on CA-MRSA • resistance already spread • no cross resistance in some countries with other prot. • frequent target mutations synthesis inhibitors • bacteriostatic • oral formulation • substrate of CYP 3A4 [with loading dose] • tissue distribution • safety profile ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 47 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2

Debio1452 CG-400549

Fatty acid synthesis in bacteria

Specifically active on S. aureus ESCMID Online Lecture Library

Miesnel et al, Nature Rev. Gen. (2003) 4: 442-456 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 49 Debio (AFN) 1252 in vitro activity

ESCMID Online Lecture Library

Karlowsky et al, AAC (2009) 53: 3544-48 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 50 FabI inhibitors: pros and cons

• novel mode of action • bacteriostatic • restricted to S.aureus • restricted to S.aureus -> no effect on flora • oral formulation • tissue distribution

ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 51 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2

vancomycin

Cephalosporin (THRX-206852)

ESCMID Online Lecture Library

Long et al, J. Antibiot. (2008) 61:603-14 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 53 TD-1792 : in vitro activity

ESCMID Online Lecture Library @ by authorICAAC (2007) F1-2110 TD-1792: pros and cons

• bactericidal • no anti Gram(-) coverage • synergistic mode of action • no oral route • low MICs (incl. MRSA, VISA) • currently no sign of renal • Gram(+) spectrum toxicity [VAN] but more • once daily (IV) data needed • no metabolism (animals)

ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 57 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2

Antibiotic binding to peptidyl transferase center of 50S ribosome

lefamulin retapamulin

ESCMID Online Lecture Library

Schlünzen et al, Mol. Microbiol. (2004) 54: 1287–94 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 59 Lafamulin: pros and cons

• novel mode of action • cross resistance described • infrequent cross resistance with LZD (cfr, PTC mutations) with other classes • broad veterinary use of other • broad spectrum pleuromutilins • ELF penetration • not active on • accumulation in cells enterobacteriacae • first for systemic use in humans • topic, oral, IV ESCMID• no major CYP interactions Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 61 Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2

• membrane depolarisation ~ daptomycin • cytoplasmic protein misfolding  upregulation of chaperones and proteases (genes involved in stress response) ~ defensins ESCMID Online Lecture Library http://en.wikipedia.org/wiki/Antimicrobial_peptides 25/04/2015 Mensa et al, AAC (2014) 58:5136-45 @ by authorECCMID - anti-Gram positive pipeline 63 Brilacidin: phase II data

ESCMID Online Lecture Library

http://cellceutix.com 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 64 Brilacidin: pros and cons

• novel mode of action • IV administration

• rapidly bactericidal • small Vd • mimic human defenses • gender differences in PK • broad spectrum (Cl and body surface) • active on stationary • reversible adverse effects (paresthesia,  blood pressure and heart rate) phase bact. • short treatment (1-3 doses) ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - 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 (Phase III) are new derivatives in existing classes with improved properties (MIC – resistance – PK- safety)

ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - 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 dalbavancinESCMID 0.125 Online 0.125 Lecture0.125 Library rule in Europe !

25/04/2015@ by authorECCMID - 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

 Need to design superiority trials and to focus pricing and reimbursement for documented cases of infection by resistant organisms ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 68 Non-inferiority vs superiority trials ?

NON-INFERIORITY if NO evidence of spontaneous resolution rate (more effective than placebo) Indications (and delta): • Community-acquired pneumonia (-10%; more in PORT scores of IV-V) • Hospital-acquired pneumonia and ventilator-associated pneumonia (less than ≤ -12.5%) • Skin and soft tissue infections (-10%) DRUG/comparator • Intra-abdominal infections (-12.5%) trial • Urinary tract infections (-10 %)

SUPERIORITY if spontaneous resolution (placebo effective) • Acute bacterial maxillary sinusitis Placebo/ • Acute bacterial exacerbations of chronic bronchitis DRUG/comparator • Acute otitis media trial • Superficial skin infections (such as impetigo and minor wounds) • Inhaled antibacterial agents (excl. CF)

LIMITED TRIALS DRUG • RareESCMID MDR organisms Online Lecture Librarynon comparative • Few patients trial EMA/CHMP/351889/2013 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 69 Non-inferiority vs superiority trials ?

ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 70 What about the future ?

ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 71 Backup slides

ESCMID Online Lecture Library

25/04/2015@ by authorECCMID - anti-Gram positive pipeline 72 solithromycin: ongoing clinical trials

Study number & development Drugs and doses Study title Status Phase NCT01966055; Solithromycin; dose not specified Pharmacokinetics and Safety of Recruiting Phase I Solithromycin Capsules in Adolescents NCT01168713; Oral solithromycin (800 mg QD day 1; Efficacy and Safety Study of Oral CEM- Completed (2011) Phase II 400 mg QD days 2-5) ; comparator: oral 101 Compared to Oral Levofloxacin in levofloxacin (750 mg QD days 1-5) Treatment of Patients With Community- Acquired Bacterial Pneumonia NCT01591447; Single dose solithromycin 1000 mg by Safety and Efficacy Study of Single-Dose Completed (2013) Phase II oral route Oral CEM-101 in Patients With Uncomplicated Urogenital Gonorrhea NCT01968733; Solithromycin (intravenous with the Efficacy and Safety Study of Intravenous Recruiting Phase III potential step-down to oral); to Oral Solithromycin (CEM-101) comparator: moxifloxacin (intravenous Compared to Intravenous to Oral with the potential step-down to oral); Moxifloxacin in Treatment of Patients doses not specified With Community-Acquired Bacterial Pneumonia (SOLITAIRE-IV) NCT01756339; Solithromycin (800 mg orally on day 1 Efficacy and Safety Study of Oral Recruiting Phase III followed by 400 mg daily on days 2 Solithromycin (CEM-101) Compared to through 5, followed by placebo on days Oral Moxifloxacin in Treatment of 6 and 7); Patients With Community-Acquired comparator: moxifloxacin (400 mg Bacterial Pneumonia (SOLITAIRE-ORAL) ESCMIDorally on Day 1 to 7)Online Lecture Library

Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 73 solithromycin: ongoing clinical trials

Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 74 solithromycin : CABP Phase II data

ESCMID Online Lecture Library

Oldach et al, AAC (2013) 57:2526-34 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 75 new (fluoro)quinolones: in vitro activity

ESCMIDas or more Online active ~ moxifloxacin, Lecture but cross resistance Library

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 76 new (fluoro)quinolones: ongoing clinical trials

Study number & development Drugs and doses Study title Status Phase ZABOFLOXACIN NCT01081964; Zabofloxacin (400 mg orally QD for 3 Safety and Efficacy Study of Oral Completed (2012) Phase II or 5 days); Zabofloxacin in Community Acquired comparator: levofloxacin (500 mg Pneumonia orally QD for 7 days) NCT01658020; Zabofloxacin (400 mg orally QD); A Study to Evaluate Efficacy and Safety Ongoing, not Phase III comparator: moxifloxacin (400 mg Profile of Zabofloxacin Tablet 400mg and recruiting orally QD) Moxifloxacin Tablet 400mg (DW224-III-3) after Multi-dose Oral Administration in Patients With Acute Bacterial Exacerbation of Chronic Obstructive Pulmonary Disease.

ESCMID Online Lecture Library

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 77 new (fluoro)quinolones: ongoing clinical trials

Study number & development Drugs and doses Study title Status Phase NEMONOXACIN NCT00434291; Not provided Safety and Efficacy Comparison of TG- Not provided Phase II 873870 (Nemonoxacin) to Levofloxacin in Community-Acquired Pneumonia NCT00685698; Nemonoxacin 750 mg, oral Safety and Efficacy Study of TG-873870 Completed (2009) Phase II administration, once daily for 7±1 and (Nemonoxacin) in Diabetic Foot Infections 14±1 days NCT01537250; Nemonoxacin (750 mg orally 2 tablets Study to Assess the Efficacy and Safety of Completed (2010) Phase II or 500 mg orally 3 tablets) ; Nemonoxacin Malate in Treating Adult comparator: levofloxacin (500 mg Patients With Community-acquired orally QD + placebo) for 7 days Pneumonia (CAP) NCT01944774; Nemonoxacin (500 mg or 650 mg QD Study to Evaluate the Efficacy and Safety Recruiting Phase II IV for 7~14 days) ; of Intravenous Infusion With TG-873870 comparator: moxifloxacin (400 mg QD (nemonoxacin) Versus Moxifloxacin in IV for 7~14 days) Treating Adult Patients With Community Acquired Pneumonia (CAP) NCT01529476; Nemonoxacin (500 mg orally) ; Study to Evaluate the Efficacy and Safety Completed (2012) Phase III comparator levofloxacin (500 mg of Oral Administration With Nemonoxacin orally) for 7~14 days and Levofloxacin in Patients With ESCMID OnlineCommunity Lecture-acquired Pneumonia Library (CAP)

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 78 new (fluoro)quinolones: ongoing clinical trials

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 79 Nemonoxacin – CABP phase III data

ESCMID Online Lecture Library

Van Rensburg et al, AAC (2010) 54:4098-106 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 80 new (fluoro)quinolones: ongoing clinical trials

Study number & development Drugs and doses Study title Status Phase DELAFLOXACIN NCT00719810; Delafloxacin (300 mg or 450 mg IV BID) Safety and Efficacy Study of a Completed (2008) Phase II ; Fluoroquinolone to Treat Complicated Skin comparator: tigecycline (100 mg on Infections day 1 then 50 mg IV BID) NCT01283581; Delafloxacin (300mg IV BID) for 5-14 A Study to Assess Objective Endpoint Completed (2011) Phase II 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 NCT01811732; Delafloxacin (300 mg IV BID) for up 5- Delafloxacin Versus Vancomycin and Recruiting Phase III 14 days; Aztreonam for the Treatment of Acute comparator: vancomycin (15mg/kg IV) Bacterial Skin and Skin Structure Infections + aztreonam (2g) BID NCT01984684; Delafloxacin (300 mg IV BID 300mg iv Delafloxacin vs Vancomycin and Not yet recruiting Phase III 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) ESCMID+ aztreonam (2g) BID Online Lecture Library

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 81 Radezolid vs linezolid

ESCMID Online Lecture Library

Locke et al, AAC (2010) 54: 5337–43 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 82 Radezolid cellular pharmacokinetics in macrophages

N-acetyl--glucosaminidase lacticodehydrogenase (NAB) (LDH)

cytochrome C oxydase lysosome (CytOx) Cellular accumulation Subcellular distribution mitochondria 10 NAB 9 CytOx 30 8 RDZ 7 Radezolid 6 20 5  Q/

4  3 10 2 cellular accumulation cellular Linezolid 1

0 0 0 30 60 90 120 1.12 1.14 1.16 1.18 1.20 time (min) density ESCMID Onlineaccumulation in Lecture acidic vacuoles Library

Lemaire et al., AAC (2010) 54:2540-48 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 83 Omadacycline : CSSSI Phase II data

Omadacycline 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

ESCMID Online Lecture Library

Noel et al., AAC (2012) 56:5650-546 25/04/2015@ by authorECCMID - anti-Gram positive pipeline 84 TD-1792 : in vivo activity

ESCMID Online Lecture Library @ by authorICAAC (2007) TD-1792 : cSSSI Phase II data

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