This document summarizes a presentation on the need for new antibiotics and challenges in developing them. It discusses how antibiotic resistance is a growing public health crisis leading to increased illness and deaths. While all agree more antibiotics are urgently needed, pharmaceutical companies face significant challenges in funding clinical trials due to high costs and regulatory hurdles. Regulatory guidance has also made it difficult to gain approval for new oral antibiotics or expand indications for intravenous drugs. New approaches are needed to better incentivize antibiotic research and development.

1. HOW DO WE GET THE
ANTIBIOTICS WE NEED?
Opportunities and challenges
posed and lessons learned from
recent submissions
Dr. Flic Gabbay 24th Annual
Senior Partner
EuroMeeting
26-28 March 2012
TranScrip Partners LLP Copenhagen, Denmark

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3. 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
3

4. Why do we need new antibiotics?
4

5. 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

6. 6

7. 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?
7

8. 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
8

9. 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
9

10. 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
10

11. 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)
11

12. 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
12

13. • So everyone now agrees we need new
antibiotics…
• What is prohibiting the development of
new antibiotics?
13

14. New classes of antibiotics in
last 50y
14

15. 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
15

16. 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
16

17. The Antibacterial-Target Tree
s
Oxazolidinones Aminoglycosides Tetracyclines
ymixin in
Macrolides Pol tomyc
Chloramphenical PR
OT PROTEIN SYNTHESIS IC Dap
Lincosamides E
50S IN SY 30S ribosome OP LASM S
rib NTH CYT BRANE
oso
me ESIS MEM Vancomycin
Penicillins
CELL WALL Cephalosporins
Trimethoprim FOLATE SYNT Carbapenems
Sulphonamides
H ESIS
RNA POLYMERASE Rifampicin
Mupirocin tRNA SYNTHETASE Fidaxomycin
Metronidazole DNA SYNTHESIS Fluoroquinolones
DNA GYRASE Nitrofurantoin
White and Fairhead 2012
White and Fairhead 2012
17

18. 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 - allows narrower spectrum antibiotics
• Control of mobile genetic elements resistance (inhibition
of plasmids)
• Human Microbiome
• Vaccines, therapeutic vaccines
• Immunological approaches
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19. But they all need to pass the regulatory
hurdles
19

20. Regulatory submissions submitted
or reviewed since 2006 in EU or US
IV/IM or IV/oral Oral/topical/inhaled
2006 2006
• daptomycin • garenoxacin
2008 • faropenem
• telavancin • gemifloxacin
2007
• oritavancin
• retapamulin
• iclaprim 2009
• doripenem • Inhaled aztreonam
2009 • cethromycin
• ceftobiprole 2010
•fidaxomicin
2010
• ceftaroline
20

21. 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
21

22. Indications
Date of submission or review IV/parenteral Oral/topical
Comp SITL/ Sinus
2006 skin HAP VAP CAP Endo cUTI AI ERY Decol AECB itis decol
daptomycin P 6 P
faropenem O O O O
garenoxacin O O O O O O
gemifloxacin O O O
2008
telavancin PO PO PO
oritavancin O
iclaprim O
doripenem P P P
2007
retapamulin P 6 6
2009
ceftobiprole O 6 6 6
inhaled aztreonam P
cethromycin O
2010
ceftaroline P P
fidaxomicin P
O = submitted and failed
P =registered
6 =studied
22

23. 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
23

24. Why did the antibiotics fail?
Was this bad navigation?
24

25. 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
25

26. 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
26

27. So why are companies and agencies so
far adrift on benefit risk decisions at end of
Phase III
27

28. Detailed FDA Recent Guidance
since 2006
Note cUTI issued Feb 2012
28

29. 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?
29

30. 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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31. 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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32. 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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33. 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…
33

34. Just as a reminder that antibiotics
do make a difference…
Death Pre- Death With Change
Disease
Antibiotics Antibiotics in Death
Community Pneumonia ~35% ~10% -25%
1
Hospital Pneumonia 2 ~60% ~30% -30%
3
Heart Valve Infection ~100% ~25% -75%
Brain Infection
4
>80% ˂ 23% -60%
Skin Infection 5 11% ˂ 0.5% -10%
By comparison...treatment of myocardial infarction
-3%
with aspirin or streptokinase 6
1
IDSA 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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35. Thank you
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