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Nuovi farmaci antimicrobici
Matteo Bassetti, MD, PhD
Infectious Diseases Division
Santa Maria Misericordia University
Hospital
Udine, Italy
Conflict of interest disclosure
 Research
grants
- Astellas, Pfizer, MSD, Gilead
 Advisor/consultant
- Astellas, Pfizer, MSD, Gilead, Angelini,
Vifor,Basilea, Roche, Cubist, Novartis
 Speaker/chairman
- Astellas, Pfizer, MSD, Gilead, Angelini, Vifor ,
Novartis, Bayer, Algorithm
The Situation in 2004
Infectious Disease Society of America.
Available at http://www.idsociety.org/badbugsnodrugs.html. Last accessed April 4, 2009.
Total no. of new antimicrobials
New Antibacterial Agents
Approved by the FDA
As Antibiotic Options Decline…
…the situation
worsens
IDSA Public Policy. Clin Infect Dis. 2011;52(Suppl 5):S397-S428.
The Situation TenYears
Later

Bad Bugs, No Drugs: No ESKAPE1
- Enterococcus faecium (E), Staphylococcus aureus (S),
Klebsiella pneumoniae (K), Acinetobacter baumannii (A),
Pseudomonas aeruginosa (P), and Enterobacter spp. (E)

The late-stage clinical development pipeline remains
unacceptably lean2
- Some important molecules for problematic pathogens such
as MRSA
- Few novel molecules for other ESKAPE pathogens
- No new drugs for infection due to MDR Gram-negative bacilli
(e.g., A baumannii and P. aeruginosa)
- None represent more than an incremental advance over
currently available therapies
1Rice
2Boucher
LB. J Infect Dis. 2008;197:1079-1081.
HW, et al. Clin Infect Dis. 2009;48:1-12.
Between 1962 and 2000, no major
classes of antibiotics were introduced
Fischbach MA and Walsh CT Science 2009
The Current Pipeline
IV antibiotics
currently in clinical
development as of
2014
Phase 1
Phase 2
Phase 3
Theuretzbacher U. Curr Opin Pharmacol. 2011;11:433-38.
GRAM +
GRAM -
Why the decrease?

Reasons for decreased antibiotic development over
the last ten years:
- Economic
 Low price
 Short-term treatment
 Small markets for narrow spectrum antibiotics
- Regulatory
 Precedence of bigger studies
 Shift to indication and non-inferiority
- Science
 Espertises lost in R&D and commercial groups
Consideration…….
“WE’RE WILLING TO PAY $50,000 FOR A
COURSE OF CANCER CHEMOTHERAPY THAT
PROLONGS LIFE AN AVERAGE OF FOUR
WEEKS, BUT WE DON’T LIKE TO
PAY MORE THAN $50 FOR A SEVEN-DAY
COURSE OF ANTIBIOTICS THAT CURES THE
DISEASE AND HAS THE POTENTIAL TO ADD
DECADES OF LIFE”.
Brad Spellberg, Los Angeles Biomedical Research Institute
Antibiotics show little opportunity compared
with other therapeutic categories
Summary of unmet needs

Broad and narrow spectrum drugs active aganist MDR
Gram-negative rods (enterobacteriaceae, pseudomonas,
and acinetobacter)
- Including those that produce carbapenemase where the only
active agents are tigecycline and colistin (anticipated to increase
over the next decade)
- Oral formulation in addition to IV is a plus


Gram-positive drugs active against MRSA and Coag neg
Staph show improved efficacy in more difficult to treat
infections like osteo, endocarditis and PJI, particularly
drugs taht are more effective, safer and /or more
convenient than current drugs
Drugs for MDR TB; MDR gonorrhea
DRUGS HERE AND THOSE COMING
Staphylococcus aureus
Drug Here
Agent
Ceftaroline
Drug On The Way
Route
IV
Agent
BC-3781
Class
Route
pleuromutilin
IV-PO
Clindamycin
IV-PO
Ceftobiprole
ceph
IV
Daptomycin
IV
Dalbavancin
glycopeptide
IV
Linezolid
IV-PO
Delafloxacin
FQ
IV-PO
Rifampin
IV-PO
JNJ-Q2
FQ
IV-PO
SMX/TMP
IV-PO
Oritavancin
Glycopeptide
IV
Televancin
IV
PTK-0796
Tetracycline
IV-PO
Tigecycline
IV
Brilacidin
defensin-mimetics
IV
Vancomycin
IV
Tedizolid
oxazolidinone
IV-PO
Tetracycline
IV
Teicoplanin
IV, IM
TP-434
DRUGS HERE AND THOSE COMING
Gram-Negative Bacilli
Narrow Spectrum
Broad Spectrum
Agent
Class
Route
Sponsor
Agent
Class
Route
Sponsor
POL-7080
Mim
IV
Polyphor
KPI-10-RIP
FQ
IV-PO
Kalidex
ACHN-975
LpxC
IV
Achaogen
GSK-052-RIP
Leucyl-tRNA
synthetase
IV
GSK
Eravacycline
TET
IV
Tetraphase
TP-2758
TET
IV
Tetraphase
BAL-30072
BL
IV
Basilea
Aztreonam-Avibactam
BL/BLI
IV
AZ
Ceftaroline-Avibactam
BL/BLI
IV
AZ/Forrest
Ceftazidime-Avibactam
BL/BLI
IV
AZ
Ceftolazane-tazobactam
BL/BLI
IV
Cubist
Biapenem-RPX-7009
BL/BLI
IV
Rempex
Imipenem-MK-7655
BL/BLI
IV
Merck
Plazomicin
AG
IV
Achaogen
DRUGS COMING
Gram-Negative Bacilli
Inhalation Antibiotics On The Way
Agent
Class
Route
Sponsor
Amikacin (liposomal)
AG
Inhaled
Insmed
Ciprofloxacin (dry powder)
FQ
Inhaled
Bayer
Ciprofloxacin (liposomal)
FQ
Inhaled
Aradigm
Levofloxacin
FQ
Inhaled
Aptalis
Tobramycin (dry powder)
AG
Inhaled
Novartis
Late-Stage Pipeline: Phase 3
Compound
Drug Class
Spectrum
Potential Indication
Cephalosporin and novel
beta lactamase inhibitor
C. difficile -associated
diarrhoea
Complicated UTI, acute
Broad spectrum,
pyelonephritis, IAI, HAP,
(mainly, gram-negative)
VAP
Delafloxacin
Fluoroquinolone
Broad spectrum
Eravacycline
Tetracycline
Broad spectrum
Plazomicin
Aminoglycoside
Solithromycin
Macrolide (ketolide)
Broad spectrum
CAP
Surotomycin
Lipopeptide
Gram-positive
C. difficile-associated
diarrhea
Cadazolid
Ceftazidime +
avibactam
Sources: see notes section
Quinolonyl-oxazolidinone
Gram-positive
ABSSSI, Uncomplicated
Gonorrhea
Complicated IAI,
Complicated UTI
BSI, nosocomial
pneumonia caused by
Gram-negative + MRSA
carbapenem resistant
enterobacteriaeceae
Ceftolozane

Ceftolozane demonstrated excellent activity in vitro against a panel of
>900 Pa strains, including cephalosporin- and carbapenem-resistant
isolates
% Susceptiblea
Agent
US
5 EU
Ceftolozane/tazobactamb
97.7
97.0
Cefepime
80.7
83.5
Ceftazidime
80.9
78.0
Meropenem
78.3
77.6
Doripenem
82.7
81.1
Piperacillin/tazobactam
74.6
73.9
Data for 973 P. aeruginosa from 2011 PACTS surveillance program (JMI laboratories)
a. Criteria as published by CLSI [2012]
b. MIC ≤ 8ug/mL
5 EU = UK, France, Germany, Italy, and Spain
Gram-Negative Therapeutics: New Data on
Ceftolozane/ tazobactam (CFT) for Complicated
IAI or UTI
cIAI
N=993
R
CFT (IV, 1.5g q8h) + metronidazole
(MTZ)(IV, 0.5g q8h)
Meropenem (MER) (IV, 1g q8h)
Days 4-10 (EOT)
Time
Microbiologic
eradication
Microbiologically
evaluable patients
N=800
R
CFT (IV, 1.5g q8h)
Levofloxacin (LVFX)(IV, 750mg QD)
Primary endpoint
(26-30 d after SoT)
CFT+MZT (%)
MER (%)
Gram(-) AE
96.3c
95.4
Gram(-) ANE
98.2
Gram(+) AE
Gram(+) ANE
Clinical cure
cUTI
Primary endpoint
(5-9 d after EoT)
Time
Microbiologically
evaluable patients
CFT (%)
LVFX (%)
84.7a
75.1
97.8
Microbiological
eradication (ME)
92.9
94.6
Clinical cure (CC)
95.9
93.2
100
93.9
ME+ CC
83.3
75.4
94.2
94.7
Eckmann C et al. 24th ECCMID. Barcelona, Spain 10-13 May 2014.
Wagenlehner F et al. 24th ECCMID. Barcelona, Spain 10-13 May 2014
Ceftolozane/tazobactam
Penetrates Well Into Lung
Concentrations in ELF
Mean Concentration
(ug/mL)
CXA-101
25
20
 Penetration 48%
15
 63% Time above
target MIC of 8ug/mL
10
Proposed breakpoint
5
 Penetration of
Piperacillin 26%
0
0
2
4
Time (hr)
6
8
5th Generation Cephalosporins
Ceftobiprole1-3

Ceftaroline4-6
 Broad-spectrum

Broad-spectrum cephalosporin
cephalosporin
 Enhanced
gram-positive
spectrum including MRSA,
VISA, and EF

 Bactericidal

Bactericidal
 IV

IV with q8h – q12h dosing

t1/2 = 2 – 3 h

Elimination: renal

MIC range 0.5 – 2 mg/L
with q8h – q12h dosing
 t1/2
=3–4h
 Elimination:
 MIC
renal
range 0.5 – 2 mg/L
Enhanced gram-positive
spectrum, including MRSA,
VISA, and EF
1. Chambers. Clin Microbiol Infect. 2006;12:17-22.
2. Appelbaum. Clin Microbiol Infect. 2006;12:3-10.
3. Lodise et al. Presented at: ECCMID 2006; Nice, France. Abstract 1524.
4. Ge et al. Presented at: 46th ICAAC, 2006; San Francisco, CA. Abstract 1935.
5. Ge et al. Presented at: 46th ICAAC, 2006; San Francisco, CA. Abstract 1937.
6. Ge et al. Presented at: 46th ICAAC, 2006; San Francisco, CA. Abstract 1939.
Ceftaroline fosamil

Parenteral, bactericidal, advanced generation cephalosporin

First beta-lactam with anti-MRSA activity, along with activity against
other common Gram-positive and -negative bacteria in cSSTI
- Like other cephalosporins, no activity against ESBLs and
P. aeruginosa
‡

CLSI designates ceftaroline fosamil as a member of a new class of
beta-lactam antibiotic, ‘cephalosporin with MRSA activity’

In the EU, ceftaroline fosamil was approved in August 2012 and is
indicated for the treatment of cSSTI and CAP in adults‡*
Important note: in the CAP indication, there is no clinical evidence to support the activity of ceftaroline against MRSA and available clinical data cannot substantiate
efficacy against PNSP; * Consideration should be given to official guidance on the appropriate use of antibacterial agents
Lodise TP & Low DE. Drugs 2012;72:1473–93.
CAP, community-acquired pneumonia; CLSI, Clinical and Laboratory Standards Institute; ESBL, extended-spectrum beta-lactamase; PNSP, penicillin nonsusceptible
S. pneumoniae
Ceftaroline
Advantages
- Excellent activity against MRSA, VRSA, PRSP
- 2/3 generation cephalosporin-type activity against
Enterobacteriaceae
- Safety profile of cephalosporin
Disadvantages
- Marginal activity against P. aeruginosa and
nonfermentors
- No activity against ESBL-producing
Enterobacteriaceae
- Not adeguate comparator in CAP
Telavancin is a novel lipoglycopeptide
antibacterial agent
OH
Me
N
O
H
Me
O
O
OH
CI
O
O
HO
O
NH
N
H
O
O
OH
OH O
HN
OH
O
O
H
N
N
H
O H2N
HO2C
HO
OH
OH
O
CI
N
HH H
O
P
Lipophilic side-chain
Membrane anchoring
• Improved potency
• Rapid cidality
N
H
OH
OH
Leadbetter et al. J Antibiot 2004
N
H
Unique dual mechanism of action
H
N
–
Me
–
Bacterial cell wall inhibition: preventing
polymerisation and crosslinking
Bacterial cell membrane disruption
Me
Me
Hydrophilic side-chain
Favourable PK-ADME properties
• Long half-life
• Renal clearance
Comparative activity of telavancin
against MRSA
Susceptibility of MRSA (n=1629)
MIC (µg/ml)
Cumulative % at MIC
100
90%
80
Telavancin
60
40
20
0
MIC (g/ml)
2005 Telavancin US and Europe Surveillance (Focus Bio-Inova). Data on file.
Range
0.5
0.06–1
Daptomycin
1
0.12–>1
Vancomycin
1
0.5–4
Linezolid
2
≤0.5–>4
Telavancin concentration in alveolar
macrophages (AM) and epithelial lining fluid
(ELF) from BAL samples
Mean ratios of ELF and AM concentrations to MIC90 for S. aureus
at the 4 BAL sampling times
ELF/MIC90
AM/MIC90
100
Concentration Ratio
Concentration Ratio
10
8
6
4
2
75
50
25
0
0
4
8
12
Time (h)
Gotfried et al. ICAAC 2005; Poster A-14
24
4
8
12
Time (h)
24
ATTAIN 1 and 2: Primary endpoint –
clinical cure at test of cure visit
Vancomycin Telavancin
% cure
% cure
(n/N)
(n/N)
AT population
(N=1,503)
59.5
(449/754)
58.9
(441/749)
CE population
(N=654)
80.7
(276/342)
82.4
(257/312)
ME population
(N=480)
76.8
(182/237)
79.0
(192/243)
–5.6 –0.7
4.3
–4.3
1.7
–5.2
–15
–10
–5
Favours VAN
7.7
2.2
0
9.7
5
10
15
Favours TLV
Difference in success rates
(TLV–VAN, %) with 95% CI
Rubinstein et al. Clin Infect Dis 2011
Data from pooled retrospective analysis;
AT, all-treated; CE, clinically evaluable; ME, microbiologically evaluable.
Dalbavancin Penetration into Bone and
Related Structures
Concentration (mg/L)
What we need
Plasma
Bone
100
10
1
2
3
4
5
Time (study day)
6
7
8
Gram-Positive Therapeutics: Latest Data on IV
Antibiotics Awaiting Approval for ABSSSI
Oritavancin (ORI)
Dalbavancin (DAL)
Phase 3 Study
SOLO 1 and 2 pooled analysis
DISCOVER 2
Infection
ABSSSI
ABSSSI
N
1959
739
Evaluated
IV dose of ORI or vancomycin
(VAN) for 7-10 days
Early Clinical
PTE Clinical
a,c
Response (%)
Cure (%)b
ORI
VAN
ORI
VAN
Wound
88.0
85.1
83.4
78.3
Cellulitis
76.0
75.5
76.0
78.8
Major
cutaneous
abscess
81.5
84.3
85.7
84
Similar safety profile
IV dose of DAL days 1 and 8 or IV VAN for
≥3 days; option to switch to oral linezolid
Clinical status
Early response
endpoint EOT
endpointa (%)
(D14) (%)
All ABSSSI
DAL
VAN
DAL
VAN
76.8
78.3
93.5
92.7
Similar safety profile
Corey GR et al. 24th ECCMID Barcelona, Spain 10-13 May 2014. poster_113642
Wilcox M et al. ICAAC 2013. Denver, Colorado. 10-13 September 2013. Poster L-202
Tedizolid
Chemical structure
Bush K, Curr Opin Pharmacol, 2012
Tedizolid: Novel Oxazolidinone
• Proposed indication: treatment of acute
bacterial skin and skin structure infections
(ABSSSI)
– NDA submission October 2013; MAA
submission Q1 2014
• Clinical development program
– ABSSSI
• Under regulatory review
– Hospital-acquired/ventilator associated bacterial
pneumonia (HABP/VABP)
• Late stage development
NDA=new drug application; IV=intravenous; HAP=hospital-acquired pneumonia; VAP=ventilator-associated pneumonia.
1. www.Cubist.com ; assessed December 17, 2013.
Phase 3 Program: 2 Studies
ESTABLISH-1 (TR701-112)1

A Phase 3 Randomized, Double-blind, Multicenter Study Comparing the Efficacy and
Safety of 6-Day Oral Tedizolid Phosphate FA and 10-Day Oral Linezolid for the
Treatment of Acute Bacterial Skin and Skin Structure Infections
Key endpoints
•
Early clinical response at the 48- to 72-hour assessment (defined as: no increase in lesion area
from baseline and afebrile, confirmed by second temperature measurement within 24 hours)
•
Investigator-assessed clinical response at PTE
ESTABLISH-2 (TR701-113)2,3

A Phase 3 Randomized, Double-blind, Multicenter Study Comparing the Efficacy and
Safety of IV to Oral 6-Day Tedizolid Phosphate FA and IV to Oral 10-Day Linezolid for the
Treatment of ABSSSI
Key endpoints
•
Early clinical response at the 48- to 72-hour assessment (defined as: at least 20% decrease in
lesion area from baseline)
•
Investigator-assessed clinical response at PTE
FA=free acid; PTE = post therapy evaluation; IV=intravenous; ABSSSI=acute bacterial skin and skin structure infections.
1. Prokocimer P, et al. JAMA. 2013;309(6):559-569; 2. http://www.clinicaltrials.gov/ct2/show/NCT01421511; 3. Fang E, et al. Efficacy and safety results from the
ESTABLISH-2 ABSSSI study comparing IV and oral tedizolid phosphate and linezolid. Poster presented at: 23rd European Congress of Clinical Microbiology and Infectious
Diseases (ECCMID); April 27-30, 2013; Berlin, Germany. (LB2964).
Gram-Positive Therapeutics: Latest Data on
Oral Antibiotics Awaiting Approval for ABSSSI
Tedizolid (TED)1
Phase 3 Study
ESTABLISH-1
Infection
ABSSSI
N
667
Evaluated
6-day oral tedizolid vs 10-day oral linezolid
therapy
Early Clinical Responsea
(%)
TED
LIN
TED
LIN
Wound
85.6
83.7
84.5
89.8
Cellulitis
74.8
71.9
88.1
82.0
80
85.7
83.0
87.8
Major cutaneous
abscess
TEAEs
a
PTEb Clinical Success
(%)
Based on the
observed minimum
inhibitory
concentrations,
tedizolid was fourto eight-fold more
active than
linezolid against
Staphylococcus spp
including MRSA,
and
Streptococcus spp.
Similar rates
Early clinical evaluation or response endpoints occurred at 48-72 hours after treatment initiation b Post therapy evaluation (PTE) occurred at 714 days after end of therapy .
1.. Prokocimer P et al. JAMA. 2013;309(6):559-69
Platelet Counts– Pooled Phase 3
Studies
Patients With TEAEs (%)
At any
post-baseline assessment through last
20
dose of study druga
P=.0002
15
12.6
10
P=.0175
5
6.4
4.5
2.1
0
Below LLN
6-Day TZP 200 mg once daily
Substantially Abnormal (<75% of LLN)
10-Day LZD 600 mg twice daily
TEAE=treatment-emergent adverse events; GI=gastrointestinal; LLN=lower limit of normal; TZP=tedizolid; LZD=linezolid.
aPlatelet
counts were collected on Study Day 7-9, Study Day 11-13, and after the last dose of study drug.
1. DeAnda C, et al. Integrated results from 2 phase 3 studies comparing tedizolid phosphate 6 days vs. linezolid 10 days in patients with ABSSSI. Poster presented at: 53rd Interscience
Congress on Antimicrobial Agents and Chemotherapy (ICAAC); September 10-13, 2013; Denver, CO. (L-203).
Pharmacokinetic and relative penetration ratios for
single doses of tedizolid and linezolid in the murine
pneumonia model under various conditions
Blood fAUCb
Drug
Model
Tedizolid
Immunocomp
4.7 (0.1)c
etent
Linezolid
ELF AUC
ELF
penetration
ratio
43.9 (2.8)c
9.34
Neutropenic
3.35 (0.1)c
35.6 (0.2)c
10.63
Uninfected
2.77 (0.1)c
17.0 (0.1)c
6.14
Immunocomp
115.9 (44.0)d
etent
155.8 (14.2)d
1.34
Neutropenic
53.4 (4.7)
61.4 (17.9)
1.15
Uninfected
36.3 (0.9)
62.5 (17.7)
1.72
Keel RA et al. Antimicrob. Agents Chemother 2012; 56: 3420-3422
Oritavancin: Mechanisms of Action
Three
mechanisms of action:
-
Inhibits two key steps of cell wall synthesis:
 Transglycosylation
 Transpeptidation
-
Disrupts bacterial membrane integrity
Differentiated
from vancomycin
-
Increased in vitro potency and expanded Gram-positive spectrum
-
Concentration-dependent killing
-
Long elimination half-life
Mendes RE et al. Clinical Infectious Diseases 2012; 54(S3):S203-S213
Zhanel GG et al. Clinical Infectious Diseases 2012; 54(S3):S214-S219
Ambrose PG et al. Clinical Infectious Diseases 2012; 54(S3):S220-S228
Belley et al 2013. AAC 57:205-211
Potency Against Important Gram Positive
Organisms
MIC90 (µg/mL)
Pathogen (n)
Oritavancin
Vancomycin
Daptomycin
Linezolid
0.06
1
0.5
2
MSSA (7,800)
0.06
1
0.5
2
MRSA (5,536)
0.06
1
0.5
1
β streptococci (2,281)
0.12
0.5
0.25
1
E. faecalis (2,132)
0.06
2
1
2
E. faecium (1,237)
0.06
>16
2
2
S. aureus (13,336)
US and European isolates collected between 2010-2012
Oritavancin Phase III Clinical Studies
Randomized
double blind trial design with 60 day safety follow
up
Safety Evaluation
n=1959
Day 10
IV IV IV IV IV IV IV IV IV IV
Day 1
1 x 1200mg
IV IV IV IV IV IV IV IV IV IV
Day 7
Oritavancin
Vancomycin
IV IV IV IV IV IV IV IV IV IV
7-10 days
(1g or 15mg/kg BID)
IV IV IV IV IV IV IV IV IV IV
Post-Treatment Evaluations
ECE
(48-72 hrs)
Primary
endpoint
FDA
Legend:
IV
Active drug
PTE
Secondary
endpoint
EMA
IV
Placebo
Note: Infusions on days 7-10 were administered at the investigators’ discretion
60-day
Safety
Oritavancin Phase III Clinical Studies
Single Dose Oritavancin Similar Efficacy to 7-10 Days of
Vancomycin
Key Efficacy Endpoints: n=1959
0,2%
Composite
endpoint at ECE
Early
48-72 h
Post Rx
7-14 d
-3,3%
3,7%
2,3%
≥20% reduction
in lesion size
-0,9%
-0,1%
Investigator
Assessed
Clinical Cure at
PTE
4,5%
-2,5%
-10%
-5%
Vancomycin
better
ICAAC 2013
5,4%
0%
5%
Oritavancin
better
10%
15%
NXL-104
(Avibactam)

NXL-104 (Novexel, now AstraZeneca) is a
non-β-lactam β-lactamase inhibitor .

It restores β-lactam activity against
Enterobacteriaceae producing:
- class A enzymes (including many ESBLs)
- class C enzymes (derepressed AmpC)
- some class D enzymes

NXL-104 is not active against class-B enzyme
producers.
NXL-104
(Avibactam)
Alone, NXL-104 is endowed with
limited antibacterial activity.
It is being studied in combination
with two cephalosporins:
1.
2.
3.
ceftaroline
Ceftazidime
Aztreonam
Ceftazidime-avibactam
Pathogen
Ceftazidime
Ceftazidime-avibactam
32
0.5
K. pneumoniae ESBL
> 32
2
K. pneumoniae NS to
carbapenem
> 32
2
E. cloacae CeftazidimeR
> 32
2
Enterobacteriaceae
> 256
4
32
8
E. coli ESBL
P. aeruginosa
Shlaes DM, Ann NY Acad Sci, 2013
Plazomicin
In vitro activity against MDR entorobacteria
MIC50
MIC90
Range
K. pneumoniae
Plazomicin
Amikacin
Gentamicin
1
32
4
2
> 32
>8
≤ 0.5 – 4
≤ 8 – > 32
≤2–>8
E. coli
Plazomicin
Amikacin
Gentamicin
1
≤8
8
2
> 32
>8
≤ 0.25 – 2
≤ 8 – > 32
≤2–>8
Enterobacter spp.
Plazomicin
Amikacin
Gentamicin
1
16
2
1
> 32
4
≤ 0.5 – 2
≤ 8 – > 32
≤2–>8
Galani I et al., J Chemother, 2012
Eravacycline
• Novel tetracycline chemistry platform
• Synthetic strategy enables chemical
synthesis of previously inaccessible
analogs
Charest et al., Science 2005, 308, 395-398
Eravacycline
• Broad spectrum activity excluding Pseudomonas
– Similar potency to Tigecycline
• Phase 1 single and multiple dose PK studies complete
– Suggests 1.5 mg/kg QD or 1.0 mg/kg BID adequate to cover target
pathogens
– Above doses to be examined in Phase 2 cIAI study
• Oral bioavailability (~30%) reported
Hunt et al ICAAC 2010, Poster F1-2157
Yue et al ICAAC 2010, Poster A1-028
ERAVACYCLINE
Profile of a Well Differentiated Gram (–) Antibiotic
FEATURE
Broad-spectrum antibiotic activity
• Covers Gram-negative, Gram-positive, anaerobes and atypicals
• Active against difficult-to-treat MDR Gram-negative pathogens
Convenient dosing
•
Potential for IV-to-oral therapy in cUTI
•
Broad spectrum coverage allows for monotherapy
Successful Phase 2 study in cIAI
• Demonstrated clinical efficacy
• Well tolerated; minimal GI side effects
• Activity against MDR pathogens
46
P2 cIAI Summary

Eravacycline IV demonstrated high cure rates at both doses
- Efficacy in complex multi-pathogen infections
- Eravacycline showed effectiveness in patients with MDR pathogens

Including pathogens resistant to two or more antibiotic classes

1.0 mg/kg bid &1.5 mg/kg qd eravacycline doses were safe and well
tolerated
- Low rates of gastrointestinal side effects
- No discontinuations due to drug

Phase 3 dose selections
- cIAI: 1.0 mg/kg bid selected as the Phase 3 cIAI dose
- cUTI: 1.5 mg/kg qd selected as the Phase 3 cUTI dose
Conclusions

There is, and will continue to be, a need for new antibiotics

Market dynamics and the regulatory structure have created an environment
in which manufacturers are discouraged from developing the drugs that are
urgently needed.

EMA, FDA and drug developers are committed to working together to strike
the right balance between assessing the safety and efficacy of new drugs
requirements, and better diagnostics may help by reducing the cost of
clinical trials

The actual pipeline is encouraging in theory, but more clinical data in
advanced phases are absolutely needed
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