NEW ANTIBACTERIAL DRUGS Drug pipeline for Gram-positive bacteria

Françoise Van Bambeke, PharmD, PhD Paul M. Tulkens, MD, PhD

Pharmacologie cellulaire et moléculaire Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium http://www.facm.ucl.ac.be

Based largely on presentations given at the 24th and 25th European Congress of Clinical Microbiology and Infectious Diseases and the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 1 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

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 2 Belgium

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 3 Belgium 10 millions inhabitants … 10 Nobel prizes (10/850)

• Peace - Institute of International Law, Ghent (1904) - Auguste Beernaert (1909) - Henri Lafontaine (1913) - Father Dominique Pire (1958) • Literature - Maurice Maeterlinck, Ghent (1911) • Medicine - Jules Bordet, Brussels (1919) - Corneille Heymans, Ghent (1938) - Christian de Duve, Louvain (1974) - Albert Claude, Brussels (1974) • Chemistry - Ilya Prigogyne, Brussels (1977) - Physics - François Englert, Brussels (2013)

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 4 The Catholic University of Louvain in brief (1 of 4)

• originally founded in 1425 in the city of Louvain (in French and English; known as Leuven in Flemish)

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 5 The Catholic University of Louvain in brief (2 of 4)

• It was one of the major University of the so-called "Low Countries" in the 1500 – 1800 period, with famous scholars and discoverers (Vesalius for anatomy, Erasmus for philosophy, …). Teaching was in Latin, Greek, and Hebrew (College of the 3 languages…)

The University in the 1500's Erasmus Vesalius

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 6 The Catholic University of Louvain in brief (3 of 4)

• In the 19th century, teaching was in French but in the early 1900's, a Flemish- speaking section was opened. Courses were given in both languages, attracting many students and celebrities…

Professor C. de Duve, Professor of Biochemistry, obtained the Nobel Prize (Physiology and Medicine) in 1974 for his work on Prof. G. Lemaitre, professor of Physics intracellular organelles and Mathematics at the University who, (lysosomes, peroxisomes…) in the 1930's, made the first suggestion of the continuous expansion of the (here in front of a centrifuge) Universe (“big bang”) (here in conversation with A. Einstein)

• in 1968, the University was divided into – a French-speaking Université catholique de Louvain – a Flemish-speaking Katholieke Universiteit Leuven…

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 7 The Catholic University of Louvain in brief (4 of 4)

• The Flemish-speaking Katholieke Universiteit Leuven has remained in Louvain (Leuven) and is named in English "Catholic Universiteit Leuven". • The French-speaking Université catholique de Louvain has moved about 25 km South in a place called "Louvain-la-Neuve, with the "Health Sciences Sector" located in Brussels (Woluwé)

Université catholique Katholieke de Louvain Universiteit Leuven http://www.uclouvain.be 10 km http://www.kuleuven.be

• Together, the two Universities have about 55,000 students

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 8 What do we do ?

• Teaching of Pharmacology and • Toxicity, medicinal chemistry, and Pharmacotherapy improved schedules of aminoglycosides • Post-graduate training on Drug Development • novel antibiotics • Launching of Clinical Pharmacy in Europe • beta-lactams (ceftaroline…) • Web-based courses on anti-infective • fluoroquinolones (finafloxacine…) Pharmacology • kétolides (solithromycin…) • 30 graduating students, doctoral fellows and • oxazolidinones (tedizolid …) post-graduate fellows working on anti- infective therapy (laboratory and clinical applications) www.facm.ucl.ac.be

• Editorial board of AAC and IJAA • Member of the General Committee of EUCAST (for ISC) and of its Steering committee (2008-10) • Member of the Belgian Antibiotic Policy Coordination Committee • Founder and Past President of the International Society of Antiinfective Pharmacology (ISAP)

A partial view of our University Clinic (900 beds) and the Education and Research buildings (5,000 students), in the outskirts of Brussels, Belgium www.isap.org

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 9 New antibiotics: what is your own view of the pipeline ?

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 10 New antibiotics: where are we ?

Approvals by FDA/EMA – systemic antibiotics

telavancin ceftaroline

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 11 New antibiotics: where are we ?

Approvals by FDA/EMA – systemic antibiotics

Shall we succeed ?

dalbavancin oritavancin tedizolid ceftazidime/avibactam ceftolozane/tazobactam

telavancin ceftaroline

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 12 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

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 13 Lipoglycopeptides

prolonged half-life

dimerization

• prolonged half-life • membrane anchoring

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

Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 14 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 15 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)

Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 16 Oritavancin: a unusual development …

N Engl J Med 2014;370:2180-90.

Participants underwent randomization in a 1:1 ratio to receive either • a single intravenous dose of 1200 mg of oritavancin followed by intravenously administered placebo, or • an intravenous dose of vancomycin (1 g, or 15 mg per kilogram of body weight) every 12 hours for 7 to 10 days

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 17 Oritavancin: a unusual development …

N Engl J Med 2014;370:2180-90.

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 18 Oritavancin: a unusual development …

N Engl J Med 2014;370:2180-90.

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 19 Oritavancin: a unusual development …

N Engl J Med 2014;370:2180-90.

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 20 oritavancin vancomycin Oritavancin: a unusual development …

N Engl J Med 2014;370:2180-90.

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 21 Tedizolid

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 22 Dong-A pharmaceuticals and tedizolid: step #1

Replacing the morpholinyl by a pyridinyl and adding a methyl-tetrazolyl moiety • increases activity • prolong half-life

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 23 Tedizolid has more interactions with the ribosome…

tedizolid

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 24 Tedizolid is systematically 3-4-x more active than linezolid against LSDS strains

O

O O N N H N O

F

O

N O N N OH N N N

F

potential role of the tetrazolyl moiety Lemaire et al. JAC 2009; 64:1035–1043

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 25 And even for S. aureus of different epidemiological origin…

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 26 Dong-A pharmaceuticals and tedizolid: step #2

O

N O N N OH N N N

F

2. replacing the acetamido by an hydroxyl maintains the increased activity vs. linezolid !

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 27 Tedizolid and linezolid resistance

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 28 Oxazolidinones: 1st mechanism of resistance

full to 16

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 29 Activity against Cfr+ resistant strains … (cfr+ bacteria)

Locke et al. AAC 2010;54:5337-5343

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 30 Why is tedizolid active against LZDR strains (cfr) ?

O

O O N N H N O

F LZD

O

N O N N OH N N N

F TR700

Locke et al. AAC 2010;54:5337-5343

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 31 R 5343 ) ? ) strains ( cfr Lockeet al. AAC2010;54:5337 - Why is tedizolidactive against LZD

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 32 Oxazolidinones: 2d mechanism of resistance

loses about 2 to 4-fold activity but still

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 33 Tedizolid and ribosomal mutations

TDZ MICs are 8x < than LZD but 2-4x > than for wild type bacteria

Locke et al. AAC 2010;54:5337-5343

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 34 Tedizolid vs Linezolid human pharmacokinetics: oral doses (200 mg TR-701 q24h vs 600 mg linezolid q12h for 21 days.

Tedizolid :

• mean t1/2 > 2 x greater than linezolid This allows for a once-a-day • longer initial presence at > 0.5 mg/L dosing (vs. 4 mg/L for linezolid). Muñoz et al. ECCMID 2010 P1594

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 35 Manipulating dosages and schedules

Louie et al. AAC 2011; 55:3453-3460

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 36 What do you see ?

The correlation with

f Cmax is not excellent

The correlation with f T > MIC is worse !

Louie et al. AAC 2011; 55:3453-3460

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 37 AUC24h and activity tedizolid

activity progresses as a function of the AUC/MIC, whatever the schedule

Louie et al. AAC 2011; 55:3453-3460

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 38 Tedizolid: a fast development…

JAMA. 2013;309(6):559-569 Design, Setting, and Patients: • Efficacy and Safety of • 6-day Oral Tedizolid (200 mg once- daily) vs • 10-day Oral Linezolid Therapy (600 mg twice daily) • Intent-to-treat analysis from 667 adults (tedizolid: n=332; linezolid: n=335).

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 39 Tedizolid: a fast development…

JAMA. 2013;309(6):559-569

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 40 Tedizolid: a fast development…

JAMA. 2013;309(6):559-569

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 41 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 42 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 43 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 44 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

CH H3C CH 3 CH3 increased 3 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 45 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 46 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 47 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 48 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 49 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 50 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 51 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 52 new (fluoro)quinolones: in vitro activity

as or more active ~ moxifloxacin, but cross resistance

Adapted from Van Bambeke, Ann. Med (2014) 46:512-29 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 53 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 54 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 55 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 56 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 57 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 58 GSK2140944 – topoisomerase inhibitor

+ H2N

N O

N GSK FQ O N N O

N

 No cross-resistance with fluoroquinolones

Ehmann & Lahiri, Cur. Op. Pharmacol. (2014) 18:76–83 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 59 GSK2140944 – In vitro activity

Isolates Associated with Lower Respiratory Tract and Skin Infections

ICAAC (2013) F1216 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 60 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 61 radezolid vs linezolid

linezolid F O

N O

O N H N

O

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

O N protonable H N aminated function

O

Zhou et al., J. Bioorg. Med. Chem. Lett. (2008) 18:6179-83 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 62 Radezolid vs linezolid

Locke et al, AAC (2010) 54: 5337–43 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 63 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 64 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 65 Omadacycline (PTK-0796) vs tigecycline

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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 66 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 67 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 68 Fusidic acid

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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 69 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 71 FabI (Enoyl-[acyl-carrier-protein] reductase) inhibitors

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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 72 Debio (AFN) 1252 in vitro activity

Karlowsky et al, AAC (2009) 53: 3544-48 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 73 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 74 TD-1792

vancomycin

Cephalosporin (THRX-206852)

Long et al, J. Antibiot. (2008) 61:603-14 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 75 TD-1792 : in vitro activity

ICAAC (2007) F1-2110 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram 76

TD-1792 : in vivo activity

ICAAC (2007) 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram 77

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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram 78

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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 79 Lefamulin (BC-3781) vs retapamulin

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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 80 Lefamulin: ABSSSI Phase II data

ICAAC (2012) L1-1660 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 81 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 22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 82 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 22/05/2015 Mensa et al, AAC (2014) 58:5136-45 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 83 Brilacidin: phase II data

http://cellceutix.com Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 84 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)

Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 85 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 ! Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 86 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

Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 87 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 Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 88 Non-inferiority vs superiority trials ?

Gause Institute for New Antibiotics: the anti-Gram 22/05/2015 positive pipeline 89 What about the future ?

22/05/2015 Gause Institute for New Antibiotics: the anti-Gram 90