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HOW DO WE GET THE
ANTIBIOTICS WE NEED?
Opportunities and challenges
posed and lessons learned from
recent submissions
Dr. Flic Gabbay
Senior Partner
TranScrip Partners LLP
24th Annual
EuroMeeting
26-28 March 2012
Copenhagen, Denmark
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How do we get the antibiotics we
need?
• Why do we need new antibiotics?
• What is prohibiting the development of
new antibiotics?
– discovery
– funding
– regulatory hurdles
– successful launch and stewardship
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Why do we need new antibiotics?
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Crisis in Treatment of Bacterial
Infection
• Infectious Diseases Society of America
• US senate, GAIN act
• ECDC and EMA
• Focus of World Health Day 2011; April 7th
5
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Why do we not hear more about
antibiotic resistance?
• If it was important the media would tell us
about it wouldn’t they?
– Superbugs –
• MRSA is getting under control
• C.difficile is still worrying but being addressed
– Other diseases are perceived to be much
more important
• AIDs, malaria, coronary heart disease and cancer
So why are all these organisations worried?
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Incidence of disease (millions)
based on WHO 2004
Diarrhoea
0-4y children – 5% mortality
European figures
LRTI
CAP – up to 5% mortality
HAP – up to 20% mortality
COPD and AECB, ranked
4th in deaths in US not
measurable by incidence
alone
a US alone, b JAMA 2007, c CDC annual, d 10 countries only
2010 EU Kock et al, e ECDC annual
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We have been through a period of believing
antibiotics are not needed for respiratory infections
• Many serious respiratory infections are perceived to be
caused by viruses alone, however…..
– there is an increasing recognition of the interplay
between viral infections and bacterial infection both
needing to be treated (e.g. exacerbations of COPD
and asthma)
• Resistance to antibiotics is perceived by some to be
controlled by antibiotic stewardship alone…
– it has now been shown this is not possible for
established resistance
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Incidence of disease (millions)
based on WHO 2004
MRSA – up to 20% mortality
Healthcare associated
infection – up to 5%
mortality
a US alone, b JAMA 2007, c CDC annual, d 10 countries only
2010 EU Kock et al, e ECDC annual
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MRSA and E.coli resistance
Data: 1293 hospitals in 31 countries in Europe
MRSA: 5,503 excess deaths associated with resistance
E.Coli: 2712 excess deaths associated with resistance
Trends estimate that 97,000 resistant bloodstream
infections and 17,000 associated deaths could occur in
2015.
‘…. despite anticipated gains in the control of MRSA, the persistently
increasing number of infections caused by third-generation
cephalosporin-resistant Gram-negative pathogens is likely to outweigh
this achievement ….‘
de Kraker MEA, Davey PG, Grundmann H, BURDEN study group (2011)
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And it is not just MRSA and E.coli it
includes pneumococcus
In the US S.pneumonia has >40% resistance to macrolides, 15% to
penicillin and 30% to quinolones
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• So everyone now agrees we need new
antibiotics…
• What is prohibiting the development of
new antibiotics?
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New classes of antibiotics in last
50y
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Lack of antibiotics in R&D
• 2009 analyses by IDSA & ECDC/EMA
– Only 15-16 antibiotics in clinical development
– Only 8 have activity against key G-ve bacteria
– Of these, NONE has activity against bacteria resistant
to all currently available drugs
• 2011
– show only 10 compounds in clinical development
against G-ves
– and no trials running in HAP/VAP and still NONE has
activity against bacteria resistant to all currently
available drugs
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Why is pharma not researching
more new antibiotics?
• Challenges to find novel targets
• Return on investment for pharma companies is less
attractive than other therapeutic areas due to the “acute”
nature of the disease and the current risk and cost of a
regulatory programme
• Even if products are generated from discovery in small
or big pharma it is hard to convince companies to fund
drugs beyond Phase I
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The Antibacterial-Target Tree
Oxazolidinones
Macrolides
Chloramphenical
Lincosamides
Aminoglycosides
PROTEIN SYNTHESIS
30S ribosome
CELL WALL
Trimethoprim
Sulphonamides
Mupirocin
Tetracyclines
tRNA SYNTHETASE
Metronidazole
DNA SYNTHESIS
Vancomycin
Penicillins
Cephalosporins
Carbapenems
RNA POLYMERASE
DNA GYRASE
Rifampicin
Fidaxomycin
Fluoroquinolones
Nitrofurantoin
White and Fairhead 2012
White and Fairhead 2012
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Novel targets…
• Novel versions of existing mechanisms
• Except non specific bacterial DNA inhibition (SASP)
which is universally effective but the vector is bacteria
specific
• Faster diagnostics - to allow narrower spectrum
antibiotics
• Control of mobile genetic elements resistance (inhibition
of plasmids)
• Human Microbiome
• Vaccines, therapeutic vaccines
• Immunological approaches
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But they all need to pass the regulatory
hurdles
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Regulatory submissions submitted or
reviewed since 2006 in EU or US
IV/IM or IV/oral
2006
• daptomycin
2008
• telavancin
• oritavancin
• iclaprim
• doripenem
2009
• ceftobiprole
2010
• ceftaroline
Oral/topical/inhaled
2006
• garenoxacin
• faropenem
• gemifloxacin
2007
• retapamulin
2009
• Inhaled aztreonam
• cethromycin
2010
• fidaxomicin
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Key points US and EU registration
• Approvals:
– 7/14 (50%) total antibiotics
– 1/5 (20%) oral antibiotics*
– 4/7 ( 57%) parenteral antibiotics
– 2/2 (100%) approvals for topical/inhaled
antibiotics
*fidaxomicin was gained both EU and FDA approval for C.difficile
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Indications
Date of submission or review
2006
daptomycin
faropenem
garenoxacin
gemifloxacin
2008
telavancin
oritavancin
iclaprim
doripenem
2007
retapamulin
2009
ceftobiprole
inhaled aztreonam
cethromycin
2010
ceftaroline
fidaxomicin
IV/parenteral
Comp
skin
HAP
P
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VAP
CAP Endo cUTI
AI
O
O
O
O
O
O
AECB
Sinus
itis decol
O
O
O
O
O
O
PO PO
P
P
P
P
O
Decol
P
O
PO
O
O
Oral/topical
SITL/
ERY
6
6
6
6
6
P
O
P
P
P
O
P
6
= submitted and failed
=registered
=studied
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Key issues – changing environment
• Most antibiotics attempted registration in US first
• Until 2006 most antibiotics were submitted for multiple
indications but since 2007 maximum indications has
been 3
• Daptomycin was the first antibiotic to submitted for a
single specific indication (cSSTI)
• Three of the 5* successful antibiotic submissions in last
5 years were for cSSTI
• Doripenem achieved, HAP, cAIS, cUTI
• Telavancin got cSSTI in US and NP in Europe
*excluding topical and inhaled
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Why did the antibiotics fail?
Was this bad navigation?
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Oral antibiotics
• Change in regulatory attitude
– Non inferiority changed to superiority over placebo
AECB, sinusitis etc
– Few investigators will do these studies
– Most products didn’t reach EMA
– This has paralysed development of new oral
antibiotics
• Safety issues
– garenoxacin – rare but unexplained hypotension
– gemifloxacin – rash in 0.8% subjects
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IV Antibiotics registration failure
• Four submissions failed in complicated SSTI
– telavancin (EU) (based on benefit-risk)
– oritavancin (lack of evidence of outcome (MRSA))
– iclaprim (study designs inadequate)
– ceftobiprole (GCP issues)
• One failed in HAP
– telavancin (FDA) based on failure to meet new
endpoint guidance of 28 day mortality
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So why are companies and agencies so
far adrift on benefit risk decisions at end of
Phase III
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Detailed FDA Recent Guidance
since 2006
Note cUTI issued Feb 2012
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EU guidance
“Guideline on the evaluation of medicinal
products indicated for treatment of bacterial
infections”
15 December 2011 CPMP/EWP/558/95 rev 2 Committee for Medicinal
Products for Human Use (CHMP)
More generic and flexible… Is this the way
to go?
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Current FDA guidance
• Predominantly requires two large studies per indication
based on non inferiority guidance introduced in the
early1990s
– Non inferiority was ironically introduced to reduce the
size of studies!
• Indications have been subdivided to such an extent that
no company can afford to register a drug for more than
two or three indications making the return on investment
limited.
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Successful launch and stewardship
• Companies are concerned that restrictions on
cost and use of antibiotics will struggle to cover
the cost of the substantial drug development
programmes
• Thus it will be difficult to get large pharmas to
register and launch antibiotics
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In summary
• The need for new antibiotics is critical
• Governments and charity money are available in
recognition of this but mainly pre-clinical
• The lack of funding for Phase II/III will kill off novel
compounds in Phase I
• Regulatory guidance has been mainly US based and has
driven large expensive studies based on principles put in
place 20y ago
– can we think differently?
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Finally
WHO quote:
• “Antibiotic resistance is becoming a public health
emergency of yet unknown proportions”
IDSA quote
• We could revert to infection mortality not seen
since pre 1950s – we must find ways of
developing and registering new antibiotics…
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Just as a reminder that antibiotics
do make a difference..
Disease
Death PreAntibiotics
Death With
Antibiotics
Change
in Death
Community Pneumonia
~35%
~10%
-25%
Hospital Pneumonia 2
~60%
~30%
-30%
Heart Valve Infection 3
~100%
~25%
-75%
Brain Infection 4
>80%
˂23%
-60%
1
11%
˂0.5%
Skin Infection 5
By comparison...treatment of myocardial infarction
with aspirin or streptokinase
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1 IDSA
-10%
-3%
Position Paper ’08 Clin Infect Dis 47 (S3): S249-65; 2IDSA/ACCP/ATS/SCCM Position Paper ’10 Clin Infect Dis In
Press; 3Kerr AJ. Subacute Bacterial Endocarditis. Springfield IL: Charles C. Thomas, 1955 & Lancet 1935 226:383-4; 4
Lancet ’38 231:733-4 & Waring et al. ’48 Am J Med 5:402-18; 5 Spellberg et al. ’09 Clin Infect Dis 49:383-91 & Madsen ’73
Infection 1:76081
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Thank you
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