Optimisation of Therapy in Gram-Negative Infections

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

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 New antibiotics: what is your own view of the pipeline ?

25/04/2015 ECCMID - anti-Gram positive pipeline 3 New antibiotics: where are we ?

Approvals by FDA/EMA – systemic antibiotics

telavancin ceftaroline

25/04/2015 ECCMID - 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

telavancin ceftaroline

25/04/2015 ECCMID - 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

25/04/2015 ECCMID - anti-Gram positive pipeline 6 Lipoglycopeptides

prolonged half-life

dimerization

• prolonged half-life • membrane anchoring

Van Bambeke, decreased Cur. Op. Pharmacol. half-life 2004, 4:471–478

25/04/2015 ECCMID - 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

Van Bambeke et al, TIPS 2008, 29:124-134 25/04/2015 ECCMID - 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 (β) 14 (β) 10 (β) T ½ (h) 8 346 (γ) 3-9 (γ) 245 (γ) 168 (γ)

single dose once-a-week dose treatment treatment (2 doses)

25/04/2015 ECCMID - anti-Gram positive pipeline 9 tedizolid vs linezolid

linezolid

F O

N O

O N H N

N N N F N tedizolid N O

O N HO

Binding of tedizolid Locke et al, AAC (2010) 54: 5337–43 to methylated ribosomes 25/04/2015 ECCMID - anti-Gram positive pipeline 10 ceftaroline and ceftobiprole ceftaroline ceftaroline & PBP2a NH2 S N N catalytic

H H N S site N N

OEt O N O S S N O O CH3 Resistance to β-lactamases Binding to PBP2a allosteric site S N O H2N N H H HN S N OH N N NH2 O O O O ceftobiprole

Otero et al, PNAS (2013) 110:16808–13 25/04/2015 ECCMID - 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  

Constructed based on www.pewtrusts.org 25/04/2015 ECCMID - 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  

Constructed based on www.pewtrusts.org 25/04/2015 ECCMID - anti-Gram positive pipeline 13 solithromycin vs telithromycin

lower interaction • binding to ribosomal domain II with nicotinic receptor • poor recognition by pneumococci efflux pumps

N N N N

N O N O

H C CH 3 CH3 3 CH3 increased NH2 O OCH3 O OCH3 activity

H3C N CH3 CH3 N CH3 + + (H3C)2 HN NH (CH3)2 H3C O CH3 O HO OH H3CH2C O O CH2CH3 O O O CH3 O CH3

O O O O absence of inducibility F CH3 of MLS resistance increased B activity

solithromycin telithromycin

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - 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 visual disturbance NOT present for solithromycin

Adapted from Bertrand et al, AAC (2010) 54:5399-42 25/04/2015 ECCMID - anti-Gram positive pipeline 15 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) orally on Day 1 to 7)

Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-Gram positive pipeline 16 solithromycin: ongoing clinical trials

Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-Gram positive pipeline 17 solithromycin : CABP Phase II data

Oldach et al, AAC (2013) 57:2526-34 25/04/2015 ECCMID - anti-Gram positive pipeline 18 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 effects

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 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  

Constructed based on www.pewtrusts.org 25/04/2015 ECCMID - anti-Gram positive pipeline 20 new (fluoro)quinolones

O O

F - O

+ N N H2N N finafloxacin O BAY35-3377

O O O O F - F - O O

O N N N N N N O

+H N F 2

+ avarofloxacin zabofloxacin NH3 JNJ-Q2 DW-224a

des-fluoro O O O O

F - - O non zwitterionic O

N N N N

F O HO Cl N

+ H3N H2N nemonoxacin delafloxacin F TG-873870 WQ-3034; ABT-492; RX-3341

Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-Gram positive pipeline 21 Delafloxacin, the first “non-zwitterionic” quinolone

DELAFLOXACIN MOXIFLOXACIN

cationic neutral anionic cationic zw itterionic anionic

100 100 anionic neutral cationic zw itterionic 80 80

60 60

40 40

20 20 microspecies distribution microspecies cationic distribution microspecies anionic 0 0 2 3 4 5 6 7 8 9 10 2 3 4 5 6 7 8 9 10 pH pH

Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-58 25/04/2015 ECCMID - anti-Gram positive pipeline 22 Delafloxacin, the first “non-zwitterionic” quinolone

DELAFLOXACIN MOXIFLOXACIN

cationic neutral anionic cationic zw itterionic anionic

100 100 anionic neutral cationic zw itterionic 80 80

60 60

40 40

20 20 microspecies distribution microspecies cationic distribution microspecies anionic 0 0 2 3 4 5 6 7 8 9 10 2 3 4 5 6 7 8 9 10 pH pH

moxifloxacin moxifloxacin 2 ) 600 -1

delafloxacin relative to pH 7.4 (log delafloxacin 1 fold difference in MIC 500 ** 0

/ µg . ml **

-1 400 Increased -1 • uptake by bacteria 300 * * -2 • activity at acidic pH 200 -3 2 (ng . mg prot mg . (ng -4 ) 100 fluoroquinolone accumulation fluoroquinolone ** -5 0 5.5 6.0 6.5 7.0 7.5 5.5 6.0 6.5 7.0 7.5

pH of broth Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-58 25/04/2015 ECCMID - anti-Gram positive pipeline 23 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 24 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.

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-Gram positive pipeline 25 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 Community-acquired Pneumonia (CAP)

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-Gram positive pipeline 26 new (fluoro)quinolones: ongoing clinical trials

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-Gram positive pipeline 27 Nemonoxacin – CABP phase III data

Van Rensburg et al, AAC (2010) 54:4098-106 25/04/2015 ECCMID - anti-Gram positive pipeline 28 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) + aztreonam (2g) BID

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 25/04/2015 ECCMID - anti-Gram positive pipeline 29 new (fluoro)quinolones : pros and cons

• broad spectrum • broad spectrum • low MICs • cross resistance with other FQ • highly bactericidal • AB class possibly showing • tissue distribution rare/serious side effects • also active on • CI in children/pregnancy intracell. organisms • once daily administration • oral or IV

• delafloxacin / finafloxacin highly active at acidic pH

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 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  

Constructed based on www.pewtrusts.org 25/04/2015 ECCMID - anti-Gram positive pipeline 31 GSK2140944 – topoisomerase inhibitor

+ H2N

N O

N GSK FQ O N N O

 No cross-resistance with fluoroquinolones

Ehmann & Lahiri, Cur. Op. 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 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

25/04/2015 ECCMID - 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 Cellceutix brilacidin mimetic ABSSSI   Constructed based on www.pewtrusts.org 25/04/2015 ECCMID - anti-Gram positive pipeline 35 radezolid vs linezolid

linezolid F O

N O

O N H N

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

O N protonable H N aminated function

Zhou et al., J. Bioorg. Med. Chem. Lett. (2008) 18:6179-83 25/04/2015 ECCMID - anti-Gram positive pipeline 36 Radezolid vs linezolid

Locke et al, AAC (2010) 54: 5337–43 25/04/2015 ECCMID - anti-Gram positive pipeline 37 Radezolid cellular pharmacokinetics in macrophages

N-acetyl-β-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 ∆ρ Q/

4 ∆ 3 10 2 cellular accumulation Linezolid 1

0 0 0 30 60 90 120 1.12 1.14 1.16 1.18 1.20 time (min) density

accumulation in acidic vacuoles

Lemaire et al., AAC (2010) 54:2540-48 25/04/2015 ECCMID - anti-Gram positive pipeline 38 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

25/04/2015 ECCMID - anti-Gram positive pipeline 39 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  

H3C CH3 H3C CH3 minocycline N N H H Active if OH • ribosomal protection

NH2 • Tet-mediated efflux OH OH O OH O O Inactive if broad spectrum tigecycline efflux (P. aeruginosa) H3C CH3 H3C CH3 N N H H OH O H N NH2 N H OH OH O OH O O

omadacycline

H3C CH3 H3C CH3 N N H H OH

H N NH2 OH OH O OH O O

Jenner et al., PNAS (2013) 110:3812-16 25/04/2015 ECCMID - anti-Gram positive pipeline 41 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

Noel et al., AAC (2012) 56:5650-546 25/04/2015 ECCMID - anti-Gram positive pipeline 42 Omadacycline: pros and cons

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

25/04/2015 ECCMID - anti-Gram positive pipeline 43 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  

H3C CH3

HOOC

H HO O CH3

CH3 CH3 O

H CH3 HO H CH3

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

Gao et al., Science (2009) 326:694-698 25/04/2015 ECCMID - 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

25/04/2015 ECCMID - anti-Gram positive pipeline 47 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  

O O

NH2 S N N

O O N N O H Debio1452 CG-400549

Fatty acid synthesis in bacteria

Specifically active on S. aureus

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

Karlowsky et al, AAC (2009) 53: 3544-48 25/04/2015 ECCMID - 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

25/04/2015 ECCMID - anti-Gram positive pipeline 51 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  

vancomycin

Cephalosporin (THRX-206852)

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

ICAAC (2007) F1-2110 TD-1792 : in vivo activity

ICAAC (2007) TD-1792 : cSSSI Phase II data

TD-1792 : 2 mg/kg once daily vs vancomycin 1 g twice daily

Stryjewski et al, AAC (2012) 56:5476-83 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)

25/04/2015 ECCMID - anti-Gram positive pipeline 57 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  

Antibiotic binding to peptidyl transferase center of 50S ribosome

lefamulin retapamulin

OH O OH O OH S H S H O N O

H2N

O O Schlünzen et al, Mol. Microbiol. (2004) 54: 1287–94 25/04/2015 ECCMID - anti-Gram positive pipeline 59 Lefamulin: ABSSSI Phase II data

ICAAC (2012) L1-1660 25/04/2015 ECCMID - anti-Gram positive pipeline 60 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 • no major CYP interactions

25/04/2015 ECCMID - anti-Gram positive pipeline 61 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  

• membrane depolarisation ~ daptomycin • cytoplasmic protein misfolding  upregulation of chaperones and proteases (genes involved in stress response) ~ defensins

http://en.wikipedia.org/wiki/Antimicrobial_peptides 25/04/2015 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 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)

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 (Phase III) 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

 Need 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 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 • Rare MDR organisms non comparative • Few patients trial EMA/CHMP/351889/2013 25/04/2015 ECCMID - anti-Gram positive pipeline 69 Non-inferiority vs superiority trials ?

25/04/2015 ECCMID - anti-Gram positive pipeline 70 What about the future ?

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