22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
NEW ANTIBACTERIAL DRUGSDrug pipeline
for Gram-positive bacteriaFrançoise Van Bambeke, PharmD, PhD
Paul M. Tulkens, MD, PhD
Pharmacologie cellulaire et moléculaireLouvain Drug Research Institute, Université catholique de Louvain,
Brussels, Belgiumhttp://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
1
Disclosures
Gause Institute for New Antibiotics: the anti-Gram positive pipeline 2
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
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 3
Belgium
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 4
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 5
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 6
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 7
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…
• in 1968, the University was divided into – a French-speaking Université catholique de Louvain– a Flemish-speaking Katholieke Universiteit Leuven…
Prof. G. Lemaitre, professor of Physics and Mathematics at the University who, in the 1930's, made the first suggestion of the continuous expansion of the Universe (“big bang”) (here in conversation with A. Einstein)
Professor C. de Duve, Professor of Biochemistry, obtained the Nobel Prize (Physiology and Medicine) in 1974 for his work on intracellular organelles (lysosomes, peroxisomes…)
(here in front of a centrifuge)
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 8
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)
• Together, the two Universities have about 55,000 students
Universitécatholiquede Louvain
http://www.uclouvain.be
KatholiekeUniversiteit
Leuvenhttp://www.kuleuven.be10 km
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 9
What do we do ?
• Teaching of Pharmacology and Pharmacotherapy
• Post-graduate training on Drug Development• Launching of Clinical Pharmacy in Europe • Web-based courses on anti-infective
Pharmacology• 30 graduating students, doctoral fellows and
post-graduate fellows working on anti-infective therapy (laboratory and clinical applications)
• Toxicity, medicinal chemistry, and improved schedules of aminoglycosides
• novel antibiotics• beta-lactams (ceftaroline…)• fluoroquinolones (finafloxacine…)• kétolides (solithromycin…)• oxazolidinones (tedizolid …)
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)
www.isap.orgA partial view of our University Clinic (900 beds) and the Education and Research buildings (5,000 students), in the outskirts of Brussels, Belgium
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 ?
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
telavancinceftaroline
Approvals by FDA/EMA – systemic antibiotics
11
New antibiotics: where are we ?
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
telavancinceftaroline
Approvals by FDA/EMA – systemic antibiotics
dalbavancin
oritavancintedizolidceftazidime/avibactamceftolozane/tazobactam
Shall we succeed ?
12
Anti Gram-positive recently approved drugs
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class indications MRSA MDRSP VRE
Theravance Telavancin lipoglyco-peptide
cSSSI / HABP/VABP VanB
only
Durata Ther. Dalbavancin lipoglyco-peptide ABSSSI VanB
only
The MedCo Oritavancin lipoglyco-peptide ABSSSI
MSD Tedizolid oxazolidinone ABSSSI Forrest
Astra-Zeneca Ceftaroline β-lactam ABSSSI / CABP
Basilea Ceftobiprole* β-lactam CAP / HAP * licensed in 13 countries: AT, BE, CH, DE, DK, ES, FI, FR, IT, LU, NO, SE, UK;
reimbursement and pricing authorization ongoing in most of them
13
Lipoglycopeptides
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
prolonged half-life
• prolonged half-life
• membrane anchoring
dimerization
decreased half-life
Van Bambeke, Cur. Op. Pharmacol.
2004, 4:471–478
14
Lipoglycopeptides: dual mode of action
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
X
oritavancin (lipoglycopeptide)
O O
NH
HN
NH
HN
NH
O
ClO
O
O
O
HOOH
ONHCH3
HN
HOOC
OH
CONH2
Cl
O OH
HOHO
OO
H3C
CH3HNOH
Cl
O
H2N
CH3O
HOH3C
O
OH
transpeptidase
transglycosylase
D-AlaD-AlaL-LysD-GluL-AlaN-acetylmuramic acid -
N-acetylglucosamine
Lipid II
PyrophosphateLipid carrier
Van Bambeke et al, TIPS 2008, 29:124-134
• highly bactericidal• activity on VR strains
15
Lipoglycopeptides: pharmacokinetics
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
parameter VAN ORI TLV TEC DAL
Dosage 15 mg/kg 1200 mg 10 mg/kg 6 mg/kg 1000 mg
Cmax(mg/L)
20-50 138 93 43 287
AUC(mg.h/L)
260 1110 (24h)2800 (tot) 668 600 3185 (24h)
23443 (tot)
(%) prot. binding 55 85 95 88-94 99
T ½ (h)1 (β)
3-9 (γ)14 (β)245 (γ)
810 (β)168 (γ)
346 (γ)
single dose treatment
once-a-week dose treatment (2 doses)
16
Oritavancin: a unusual development …
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 17
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
Oritavancin: a unusual development …
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 18
N Engl J Med 2014;370:2180-90.
Oritavancin: a unusual development …
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 19
N Engl J Med 2014;370:2180-90.
Oritavancin: a unusual development …
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 20
N Engl J Med 2014;370:2180-90.
Oritavancin: a unusual development …
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 21
N Engl J Med 2014;370:2180-90.
oritavancin vancomycin
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 22
Tedizolid
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 23
Dong-A pharmaceuticals and tedizolid: step #1
Replacing the morpholinyl by a pyridinyl and adding amethyl-tetrazolyl moiety
• increases activity• prolong half-life
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 24
Tedizolid has more interactions with the ribosome…
tedizolid
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 25
Tedizolid is systematically 3-4-x more active than linezolid against LSDS strains
potential role of the tetrazolyl
moiety
O
NO
OH
F
NN
N
N
N
O
NO
HN
F
NO
O
Lemaire et al. JAC 2009; 64:1035–1043
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 26
And even for S. aureus of different epidemiological origin…
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 27
Dong-A pharmaceuticals and tedizolid: step #2
O
NO
OH
F
NN
N
N
N
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 28
Tedizolid and linezolid resistance
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 29
Oxazolidinones: 1st mechanism of resistance
full to 16
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 30
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 31
Why is tedizolid active against LZDR strains (cfr) ?
LZD
TR700
O
NO
HN
F
NO
O
O
NO
OH
F
NN
N
N
N
Locke et al. AAC 2010;54:5337-5343
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 32
Why
is te
dizo
lid a
ctiv
e ag
ains
t LZD
R
stra
ins
(cfr
) ?
Lock
e et
al.
AAC
201
0;54
:533
7-53
43
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 33
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 34
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 35
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• longer initial presence at > 0.5 mg/L
(vs. 4 mg/L for linezolid).Muñoz et al. ECCMID 2010 P1594
This allows for a once-a-day
dosing
Manipulating dosages and
schedules
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 36
Louie et al. AAC 2011; 55:3453-3460
What do you see ?
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 37
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 38
AUC24h and activity tedizolid
Louie et al. AAC 2011; 55:3453-3460
activity progresses as a function of the AUC/MIC, whatever the schedule
Tedizolid: a fast development…
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 39
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).
Tedizolid: a fast development…
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 40
JAMA. 2013;309(6):559-569
Tedizolid: a fast development…
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline 41
JAMA. 2013;309(6):559-569
ceftaroline and ceftobiprole
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Otero et al, PNAS (2013) 110:16808–13
Resistance toβ-lactamases Binding to
PBP2a
OO
NS
S
O
HN
S
N
O
N
OEt
N N
S
NH2
H
NCH3
N
N
S
HN
NOH
O
NO
S
N
O
NH2
HH2N
H
OO
ceftaroline
ceftobiprole
ceftaroline & PBP2a
allosteric site
catalytic site
42
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Cempra solithromycin ketolidePhase III
CAPB
Melinta delafloxacin fluoroquinolone Phase IIIABSSSI
TaiGen nemonoxacin fluoroquinolone Phase IIICAPB / ABSSSI
Dong zabofloxacin fluoroquinolonePhase III
CAPB
Activis avarofloxacin fluoroquinolone Phase II completedCAPB / ABSSSI
MerLion finafloxacin fluoroquinolone Phase IIABSSSI
GSK GSK2140944 topoisomeraseinhibitor
Phase IIrespiratory / ABSSSI
Constructed based on www.pewtrusts.org43
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Cempra solithromycin ketolidePhase III
CAPB
Melinta delafloxacin fluoroquinolone Phase IIIABSSSI
TaiGen nemonoxacin fluoroquinolone Phase IIICAPB / ABSSSI
Dong zabofloxacin fluoroquinolonePhase III
CAPB
Activis avarofloxacin fluoroquinolone Phase II completedCAPB / ABSSSI
MerLion finafloxacin fluoroquinolone Phase IIABSSSI
GSK GSK2140944 topoisomeraseinhibitor
Phase IIrespiratory / ABSSSI
Constructed based on www.pewtrusts.org44
solithromycin vs telithromycin
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Adapted from Van Bambeke, Ann. Med (2014) 46:512-29
O
O
O
N
OCH3
O
O
CH3
O
OOH
NH+(CH3)2
CH3
N
CH3
F
CH3
CH2CH3
CH3
O
CH3
NN
NH2
lower interactionwith nicotinic receptor
increased activity
45
O
O
O
N
OCH3
O
O
H3C
O
OHO
(H3C)2+HN
CH3
N
H3C
CH3
H3C
H3CH2C
CH3
O
CH3
N N
absence of inducibility of MLSB resistance
increased activity
• binding to ribosomal domain II• poor recognition by pneumococci efflux pumps
telithromycinsolithromycin
telithromycin : structure-toxicity relationship
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Adapted from Bertrand et al, AAC (2010) 54:5399-4246
neuro-muscularjunction
ciliary ganglion (eye)
vagus nerve (liver)
liver failure
visual disturbance
myastenia gravisexacerbation
Inhibition of acetycholine nicotinic receptors Role of telithromycin metabolites
MetabolitesNOT present for solithromycin
solithromycin: ongoing clinical trials
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Van Bambeke, Ann. Med (2014) 46:512-2947
Study number & development
PhaseDrugs and doses Study title Status
NCT01966055; Phase I
Solithromycin; dose not specified Pharmacokinetics and Safety of Solithromycin Capsules in Adolescents
Recruiting
NCT01168713; Phase II
Oral solithromycin (800 mg QD day 1; 400 mg QD days 2-5) ; comparator: oral levofloxacin (750 mg QD days 1-5)
Efficacy and Safety Study of Oral CEM-101 Compared to Oral Levofloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia
Completed (2011)
NCT01591447; Phase II
Single dose solithromycin 1000 mg by oral route
Safety and Efficacy Study of Single-Dose Oral CEM-101 in Patients With Uncomplicated Urogenital Gonorrhea
Completed (2013)
NCT01968733; Phase III
Solithromycin (intravenous with the potential step-down to oral); comparator: moxifloxacin (intravenous with the potential step-down to oral); doses not specified
Efficacy and Safety Study of Intravenous to Oral Solithromycin (CEM-101) Compared to Intravenous to Oral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SOLITAIRE-IV)
Recruiting
NCT01756339; Phase III
Solithromycin (800 mg orally on day 1 followed by 400 mg daily on days 2 through 5, followed by placebo on days 6 and 7); comparator: moxifloxacin (400 mg orally on Day 1 to 7)
Efficacy and Safety Study of Oral Solithromycin (CEM-101) Compared to Oral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SOLITAIRE-ORAL)
Recruiting
solithromycin: ongoing clinical trials
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Van Bambeke, Ann. Med (2014) 46:512-2948
Study number & development
PhaseDrugs and doses Study title Status
NCT01966055; Phase I
Solithromycin; dose not specified Pharmacokinetics and Safety of Solithromycin Capsules in Adolescents
Recruiting
NCT01168713; Phase II
Oral solithromycin (800 mg QD day 1; 400 mg QD days 2-5) ; comparator: oral levofloxacin (750 mg QD days 1-5)
Efficacy and Safety Study of Oral CEM-101 Compared to Oral Levofloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia
Completed (2011)
NCT01591447; Phase II
Single dose solithromycin 1000 mg by oral route
Safety and Efficacy Study of Single-Dose Oral CEM-101 in Patients With Uncomplicated Urogenital Gonorrhea
Completed (2013)
NCT01968733; Phase III
Solithromycin (intravenous with the potential step-down to oral); comparator: moxifloxacin (intravenous with the potential step-down to oral); doses not specified
Efficacy and Safety Study of Intravenous to Oral Solithromycin (CEM-101) Compared to Intravenous to Oral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SOLITAIRE-IV)
Recruiting
NCT01756339; Phase III
Solithromycin (800 mg orally on day 1 followed by 400 mg daily on days 2 through 5, followed by placebo on days 6 and 7); comparator: moxifloxacin (400 mg orally on Day 1 to 7)
Efficacy and Safety Study of Oral Solithromycin (CEM-101) Compared to Oral Moxifloxacin in Treatment of Patients With Community-Acquired Bacterial Pneumonia (SOLITAIRE-ORAL)
Recruiting
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Cempra solithromycin ketolidePhase III
CAPB
Melinta delafloxacin fluoroquinolone Phase IIIABSSSI
TaiGen nemonoxacin fluoroquinolone Phase IIICAPB / ABSSSI
Dong zabofloxacin fluoroquinolonePhase III
CAPB
Activis avarofloxacin fluoroquinolone Phase II completedCAPB / ABSSSI
MerLion finafloxacin fluoroquinolone Phase IIABSSSI
GSK GSK2140944 topoisomeraseinhibitor
Phase IIrespiratory / ABSSSI
Constructed based on www.pewtrusts.org49
new (fluoro)quinolones
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Van Bambeke, Ann. Med (2014) 46:512-29
N N
+H2N
ON
F
N
O
O-
O
zabofloxacin
N
O
N
N
F
O
O-
O
+H2N
finafloxacin
N
O
O
N
F
O
O-
F
NH3+ avarofloxacin
N
O
O
N
O
O-
+H3N
nemonoxacin delafloxacin
N
O
O-
O
N
HO
F
ClN
F
F
H2N
des-fluoro
non zwitterionic
50
BAY35-3377
JNJ-Q2 DW-224a
WQ-3034; ABT-492; RX-3341TG-873870
Delafloxacin, the first “non-zwitterionic” quinolone
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 51
2 3 4 5 6 7 8 9 1 00
2 0
4 0
6 0
8 0
1 0 0
p H
mic
ros
pe
cie
s d
istr
ibu
tio
n
a n io n icn e u tra l
an io n icn e u tra l
c a tion ic
c a tion ic
D E L A F L O X A C IN
2 3 4 5 6 7 8 9 1 00
2 0
4 0
6 0
8 0
1 0 0
p H
mic
ros
pe
cie
s d
istr
ibu
tio
n
a n io n icc a tion ic
an io n ic
z w itte rio n icc a tion ic
z w itte rio n ic
M O X IF L O X A C IN
Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-58
Delafloxacin, the first “non-zwitterionic” quinolone
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Van Bambeke, Future Microbiol. (in press); Lemaire et al, AAC (2011) 55:649-5852
2 3 4 5 6 7 8 9 1 00
2 0
4 0
6 0
8 0
1 0 0
p H
mic
ros
pe
cie
s d
istr
ibu
tio
n
a n io n icn e u tra l
an io n icn e u tra l
c a tion ic
c a tion ic
D E L A F L O X A C IN
2 3 4 5 6 7 8 9 1 00
2 0
4 0
6 0
8 0
1 0 0
p H
mic
ros
pe
cie
s d
istr
ibu
tio
n
a n io n icc a tion ic
an io n ic
z w itte rio n icc a tion ic
z w itte rio n ic
M O X IF L O X A C IN
5.5 6.0 6.5 7.0 7.50
100
200
300
400
500
600
* *
** **
moxifloxacindelafloxacin
**
fluor
oqui
nolo
ne a
ccum
ulat
ion
(ng
. mg
prot
-1/ µ
g . m
l-1)
5.5 6.0 6.5 7.0 7.5
delafloxacinmoxifloxacin
-5
-4
-3
-2
-1
0
1
2
fold difference in MIC
relative to pH 7.4 (log
2 )
pH of broth
Increased• uptake by bacteria• activity at acidic pH
new (fluoro)quinolones: in vitro activity
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Adapted from Van Bambeke, Ann. Med (2014) 46:512-2953
as or more active ~ moxifloxacin, but cross resistance
new (fluoro)quinolones: ongoing clinical trials
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Adapted from Van Bambeke, Ann. Med (2014) 46:512-2954
Study number & development
PhaseDrugs and doses Study title Status
ZABOFLOXACINNCT01081964; Phase II
Zabofloxacin (400 mg orally QD for 3 or 5 days); comparator: levofloxacin (500 mg orally QD for 7 days)
Safety and Efficacy Study of Oral Zabofloxacin in Community Acquired Pneumonia
Completed (2012)
NCT01658020; Phase III
Zabofloxacin (400 mg orally QD); comparator: moxifloxacin (400 mg orally QD)
A Study to Evaluate Efficacy and Safety Profile of Zabofloxacin Tablet 400mg and Moxifloxacin Tablet 400mg (DW224-III-3) after Multi-dose Oral Administration in Patients With Acute Bacterial Exacerbation of Chronic Obstructive Pulmonary Disease.
Ongoing, not recruiting
new (fluoro)quinolones: ongoing clinical trials
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Adapted from Van Bambeke, Ann. Med (2014) 46:512-2955
Study number & development
PhaseDrugs and doses Study title Status
NEMONOXACINNCT00434291; Phase II
Not provided Safety and Efficacy Comparison of TG-873870 (Nemonoxacin) to Levofloxacin in Community-Acquired Pneumonia
Not provided
NCT00685698; Phase II
Nemonoxacin 750 mg, oral administration, once daily for 7±1 and 14±1 days
Safety and Efficacy Study of TG-873870 (Nemonoxacin) in Diabetic Foot Infections
Completed (2009)
NCT01537250; Phase II
Nemonoxacin (750 mg orally 2 tablets or 500 mg orally 3 tablets) ; comparator: levofloxacin (500 mg orally QD + placebo) for 7 days
Study to Assess the Efficacy and Safety of Nemonoxacin Malate in Treating Adult Patients With Community-acquired Pneumonia (CAP)
Completed (2010)
NCT01944774; Phase II
Nemonoxacin (500 mg or 650 mg QD IV for 7~14 days) ; comparator: moxifloxacin (400 mg QD IV for 7~14 days)
Study to Evaluate the Efficacy and Safety of Intravenous Infusion With TG-873870 (nemonoxacin) Versus Moxifloxacin in Treating Adult Patients With Community Acquired Pneumonia (CAP)
Recruiting
NCT01529476; Phase III
Nemonoxacin (500 mg orally) ; comparator levofloxacin (500 mg orally) for 7~14 days
Study to Evaluate the Efficacy and Safety of Oral Administration With Nemonoxacinand Levofloxacin in Patients With Community-acquired Pneumonia (CAP)
Completed (2012)
new (fluoro)quinolones: ongoing clinical trials
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Adapted from Van Bambeke, Ann. Med (2014) 46:512-2956
Study number & development
PhaseDrugs and doses Study title Status
NEMONOXACINNCT00434291; Phase II
Not provided Safety and Efficacy Comparison of TG-873870 (Nemonoxacin) to Levofloxacin in Community-Acquired Pneumonia
Not provided
NCT00685698; Phase II
Nemonoxacin 750 mg, oral administration, once daily for 7±1 and 14±1 days
Safety and Efficacy Study of TG-873870 (Nemonoxacin) in Diabetic Foot Infections
Completed (2009)
NCT01537250; Phase II
Nemonoxacin (750 mg orally 2 tablets or 500 mg orally 3 tablets) ; comparator: levofloxacin (500 mg orally QD + placebo) for 7 days
Study to Assess the Efficacy and Safety of Nemonoxacin Malate in Treating Adult Patients With Community-acquired Pneumonia (CAP)
Completed (2010)
NCT01944774; Phase II
Nemonoxacin (500 mg or 650 mg QD IV for 7~14 days) ; comparator: moxifloxacin (400 mg QD IV for 7~14 days)
Study to Evaluate the Efficacy and Safety of Intravenous Infusion With TG-873870 (nemonoxacin) Versus Moxifloxacin in Treating Adult Patients With Community Acquired Pneumonia (CAP)
Recruiting
NCT01529476; Phase III
Nemonoxacin (500 mg orally) ; comparator levofloxacin (500 mg orally) for 7~14 days
Study to Evaluate the Efficacy and Safety of Oral Administration With Nemonoxacinand Levofloxacin in Patients With Community-acquired Pneumonia (CAP)
Completed (2012)
new (fluoro)quinolones: ongoing clinical trials
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline
Adapted from Van Bambeke, Ann. Med (2014) 46:512-2957
Study number & development
PhaseDrugs and doses Study title Status
DELAFLOXACINNCT00719810; Phase II
Delafloxacin (300 mg or 450 mg IV BID) ; comparator: tigecycline (100 mg on day 1 then 50 mg IV BID)
Safety and Efficacy Study of a Fluoroquinolone to Treat Complicated Skin Infections
Completed (2008)
NCT01283581; Phase II
Delafloxacin (300mg IV BID) for 5-14 days; comparators: linezolid (600mg IV BID) and vancomycin(15mg/kg, up to 1250 mg, IV BID) for 5-14 days
A Study to Assess Objective Endpoint Measurements of Response in Bacterial Skin Infections
Completed (2011)
NCT01811732; Phase III
Delafloxacin (300 mg IV BID) for up 5-14 days; comparator: vancomycin (15mg/kg IV) + aztreonam (2g) BID
Delafloxacin Versus Vancomycin and Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections
Recruiting
NCT01984684; Phase III
Delafloxacin (300 mg IV BID 300mg iv BID for 3 days) followed by 450mg oral BID for up 5-14 days total; comparator: vancomycin (15mg/kg IV) + aztreonam (2g) BID
Delafloxacin vs Vancomycin and Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections
Not yet recruiting
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 1/2
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Cempra solithromycin ketolidePhase III
CAPB
Melinta delafloxacin fluoroquinolone Phase III
TaiGen nemonoxacin fluoroquinolone Phase IIICAPB / ABSSSI
Dong zabofloxacin fluoroquinolonePhase III
CAPB
Activis avarofloxacin fluoroquinolone Phase II completedCAPB / ABSSSI
MerLion finafloxacin fluoroquinolone Phase IIABSSSI
GSK GSK2140944 topoisomeraseinhibitor
Phase IIrespiratory / ABSSSI
Constructed based on www.pewtrusts.org58
GSK2140944 – topoisomerase inhibitor
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 59
GSKFQ
Ehmann & Lahiri, Cur. Op. Pharmacol. (2014) 18:76–83
N
N
NO O
N
+H2N
NO
No cross-resistance with fluoroquinolones
GSK2140944 – In vitro activity
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 60
ICAAC (2013) F1216
Isolates Associated with Lower Respiratory Tract and Skin Infections
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Melinta radezolid oxazolidinone Phase IICAPB / ABSSSI
Paratek omadacycline aminomethylcyclines
Phase IIICAPB / ABSSSI
Cempra fusidic acid fusidane Phase IIIABSSSI
Debiopharm Debio1452 FabI inhibitor Phase II S. aureus ABSSSI
Crystal-genomics CG-400549 FabI inhibitor Phase II
ABSSSI / osteomyelitis
Theravance TD-1792 glycopeptide + cephalosporine
Phase II completedcSSSI
Nabriva lefamulin pleuromutilin Phase II completedABSSSI /CABP/HA-VABP
Cellceutix brilacidin defensin-mimetic
Phase II completedABSSSI
Constructed based on www.pewtrusts.org
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2
61
radezolid vs linezolid
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 62
heteroarylsubstituantbiaryl
spacer
O
NOHN
F
N
O
O
O
NOHN
F
O
NH
HN
N
N
protonableaminated function
linezolid
radezolid
sparsomycin linezolid
Zhou et al., J. Bioorg. Med. Chem. Lett. (2008) 18:6179-83
Radezolid vs linezolid
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 63
Locke et al, AAC (2010) 54: 5337–43
Radezolid cellular pharmacokinetics in macrophages
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 64
Lemaire et al., AAC (2010) 54:2540-48
1.12 1.14 1.16 1.18 1.200
10
20
30
NABCytOxRDZ
density
∆Q
/ ∆ρ
0 30 60 90 1200123456789
10
Linezolid
Radezolid
time (min)
cellu
lar a
ccum
ulat
ion
accumulation in acidic vacuoles
Cellular accumulation Subcellular distribution
lysosome
mitochondria
cytochrome C oxydase(CytOx)
N-acetyl-β-glucosaminidase(NAB)lacticodehydrogenase
(LDH)
lysosome
mitochondria
cytochrome C oxydase(CytOx)
N-acetyl-β-glucosaminidase(NAB)lacticodehydrogenase
(LDH)
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Melinta radezolid oxazolidinone Phase IICAPB / ABSSSI
Paratek omadacycline aminomethylcyclines
Phase IIICAPB / ABSSSI
Cempra fusidic acid fusidane Phase IIIABSSSI
Debiopharm Debio1452 FabI inhibitor Phase II S. aureus ABSSSI
Crystal-genomics CG-400549 FabI inhibitor Phase II
ABSSSI / osteomyelitis
Theravance TD-1792 glycopeptide + cephalosporine
Phase II completedcSSSI
Nabriva lefamulin pleuromutilin Phase II completedABSSSI /CABP/HA-VABP
Cellceutix brilacidin defensin-mimetic
Phase II completedABSSSI
Constructed based on www.pewtrusts.org
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2
65
Omadacycline (PTK-0796) vs tigecycline
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 66
minocycline
tigecycline
N
OH O OH
H HN
OH
NH2
OOOH
H3C CH3 H3C CH3
N
OH O OH
H HN
OH
NH2
OOOH
H3C CH3 H3C CH3
NH
HN
O
N
OH O OH
H HN
OH
NH2
OOOH
H3C CH3 H3C CH3
HN
omadacycline
Jenner et al., PNAS (2013) 110:3812-16
Active if• ribosomal protection• Tet-mediated efflux
Inactive if broad spectrumefflux (P. aeruginosa)
Omadacycline : CSSSI Phase II data
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 67
Noel et al., AAC (2012) 56:5650-546
Omadacycline 100 mg [i.v.] QD; possible transition to 200 mg [p.o.] QDlinezolid 600 mg [i.v.] BID; possible transition to 600 mg [p.o.]y BID
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Melinta radezolid oxazolidinone Phase IICAPB / ABSSSI
Paratek omadacycline aminomethylcyclines
Phase IIICAPB / ABSSSI
Cempra fusidic acid fusidane Phase IIIABSSSI
Debiopharm Debio1452 FabI inhibitor Phase II S. aureus ABSSSI
Crystal-genomics CG-400549 FabI inhibitor Phase II
ABSSSI / osteomyelitis
Theravance TD-1792 glycopeptide + cephalosporine
Phase II completedcSSSI
Nabriva lefamulin pleuromutilin Phase II completedABSSSI /CABP/HA-VABP
Cellceutix brilacidin defensin-mimetic
Phase II completedABSSSI
Constructed based on www.pewtrusts.org
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2
68
Fusidic acid
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 69
HOOC
O
O
CH3
H
CH3
CH3
HO
CH3
HCH3
HO
CH3H3C
H
Elongation factor G = GTP-ase~ translocation of tRNA-mRNA
Fusidic acid prevents EF-G release from the ribosome
Gao et al., Science (2009) 326:694-698
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Melinta radezolid oxazolidinone Phase IICAPB / ABSSSI
Paratek omadacycline aminomethylcyclines
Phase IIICAPB / ABSSSI
Cempra fusidic acid fusidane Phase IIIABSSSI
Debiopharm Debio1452 FabI inhibitor Phase II S. aureus ABSSSI
Crystal-genomics CG-400549 FabI inhibitor Phase II
ABSSSI / osteomyelitis
Theravance TD-1792 glycopeptide + cephalosporine
Phase II completedcSSSI
Nabriva lefamulin pleuromutilin Phase II completedABSSSI /CABP/HA-VABP
Cellceutix brilacidin defensin-mimetic
Phase II completedABSSSI
Constructed based on www.pewtrusts.org
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2
71
FabI (Enoyl-[acyl-carrier-protein] reductase) inhibitors
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 72
Miesnel et al, Nature Rev. Gen. (2003) 4: 442-456
O
N
O
N NH
O
NNH2
O
S
O
CG-400549Debio1452
Specifically active on S. aureus
Fatty acid synthesis in bacteria
Debio (AFN) 1252 in vitro activity
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 73
Karlowsky et al, AAC (2009) 53: 3544-48
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Melinta radezolid oxazolidinone Phase IICAPB / ABSSSI
Paratek omadacycline aminomethylcyclines
Phase IIICAPB / ABSSSI
Cempra fusidic acid fusidane Phase IIIABSSSI
Debiopharm Debio1452 FabI inhibitor Phase II S. aureus ABSSSI
Crystal-genomics CG-400549 FabI inhibitor Phase II
ABSSSI / osteomyelitis
Theravance TD-1792 glycopeptide + cephalosporine
Phase II completedcSSSI
Nabriva lefamulin pleuromutilin Phase II completedABSSSI /CABP/HA-VABP
Cellceutix brilacidin defensin-mimetic
Phase II completedABSSSI
Constructed based on www.pewtrusts.org
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2
74
TD-1792
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 75
Long et al, J. Antibiot. (2008) 61:603-14
vancomycin
Cephalosporin(THRX-206852)
TD-1792 : in vitro activity
ICAAC (2007) F1-211022/05/2015 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
Stryjewski et al, AAC (2012) 56:5476-83
TD-1792 : 2 mg/kg once daily vs vancomycin 1 g twice daily
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram
78
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Melinta radezolid oxazolidinone Phase IICAPB / ABSSSI
Paratek omadacycline aminomethylcyclines
Phase IIICAPB / ABSSSI
Cempra fusidic acid fusidane Phase IIIABSSSI
Debiopharm Debio1452 FabI inhibitor Phase II S. aureus ABSSSI
Crystal-genomics CG-400549 FabI inhibitor Phase II
ABSSSI / osteomyelitis
Theravance TD-1792 glycopeptide + cephalosporine
Phase II completedcSSSI
Nabriva lefamulin pleuromutilin Phase II completedABSSSI /CABP/HA-VABP
Cellceutix brilacidin defensin-mimetic
Phase II completedABSSSI
Constructed based on www.pewtrusts.org
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2
79
Lefamulin (BC-3781) vs retapamulin
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 80
Schlünzen et al, Mol. Microbiol. (2004) 54: 1287–94
retapamulinlefamulin
Antibiotic binding to peptidyl transferase center of 50S ribosome
OH
HO
O
O
SN
OH
HO
O
O
S
OH
H2N
Lefamulin: ABSSSI Phase II data
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 81
ICAAC (2012) L1-1660
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram positive pipeline
company drug class status MRSA MDRSP VRE
Melinta radezolid oxazolidinone Phase IICAPB / ABSSSI
Paratek omadacycline aminomethylcyclines
Phase IIICAPB / ABSSSI
Cempra fusidic acid fusidane Phase IIIABSSSI
Debiopharm Debio1452 FabI inhibitor Phase II S. aureus ABSSSI
Crystal-genomics CG-400549 FabI inhibitor Phase II
ABSSSI / osteomyelitis
Theravance TD-1792 glycopeptide + cephalosporine
Phase II completedcSSSI
Nabriva lefamulin pleuromutilin Phase II completedABSSSI /CABP/HA-VABP
Cellceutix brilacidin defensin-mimetic
Phase II completedABSSSI
Constructed based on www.pewtrusts.org
Anti Gram-positive antibiotics in the pipeline (phases II/III) – 2/2
82
Brilacidin
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 83
http://en.wikipedia.org/wiki/Antimicrobial_peptides
• membrane depolarisation ~ daptomycin• cytoplasmic protein misfolding
upregulation of chaperones and proteases(genes involved in stress response)
~ defensins
Mensa et al, AAC (2014) 58:5136-45
Brilacidin: phase II data
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 84
http://cellceutix.com
Antibiotic pipeline: did you change your mind ?
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 85
• 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)
Antibiotic pipeline: some work ahead
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 86
• Susceptibility Breakpoint harmonization
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
An example with MRSA …
rule in Europe !
Antibiotic pipeline: can we do better ?
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 87
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
• Equivalence to current options in comparative clinical trials
Non-inferiority vs superiority trials ?
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 88
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%)• Intra-abdominal infections (-12.5%)• Urinary tract infections (-10 %)
SUPERIORITY if spontaneous resolution (placebo effective)• Acute bacterial maxillary sinusitis • Acute bacterial exacerbations of chronic bronchitis • Acute otitis media • Superficial skin infections (such as impetigo and minor wounds)• Inhaled antibacterial agents (excl. CF)
LIMITED TRIALS• Rare MDR organisms• Few patients
EMA/CHMP/351889/2013
DRUG/comparatortrial
Placebo/DRUG/comparator
trial
DRUG non comparative
trial
Non-inferiority vs superiority trials ?
22/05/2015Gause Institute for New Antibiotics: the anti-Gram
positive pipeline 89
22/05/2015 Gause Institute for New Antibiotics: the anti-Gram
90
What about the future ?