Antimicrobial Drug Development:
a crisis?
Alasdair MacGowan
Bristol Centre for Antimicrobial Research & Evaluation
University of Bristol/North Bristol NHS Trust
18th October, 2005
Topics
Antibacterial drugs in development (past, present, future)
The antibacterial market; drivers and inhibitors of
development
The response to antibacterial resistance
Are there new targets?
Conclusions
th
20
Century
• Golden age of antibiotics
– Discovery
– Development
– Clinical exploitation
• Arguably the most significant medical
advance of the century
• Considerable pharmaceutical investment
– 11 distinct antibiotic classes
– >270 antibiotics in clinical use
21st Century
•
•
•
•
Prospects of a post-antibiotic era?
Evolving resistance with antibiotic use
Emergence of superbugs
Unmet needs of the hospital treatment
market
An external perspective on industry:
short-term/fiscally driven?
• All pharmaceutical companies are under continual pressure by
shareholders to maximise returns and sustain strong growth rates
– Chronic care medications > acute care medications
– Innovation > me-too’s
– Specialised hospital products > GP products (profitability)
• Pressures to maximise sales and profitability do not necessarily
align with the appropriate use, promotion, or consumption, of
antibiotics
• Recognition of antibiotics as a finite strategic resource is rarely
compatible with corporate commercial aspirations
• Industry responsibility in the management of bacterial resistance is
rarely if ever acknowledged, yet industry may be the most critical
player in this dynamic
Past
FDA approved antibacterial agents 1983-2002
5 year periods
1983-87
1988-92
1993-97
1998-02
antibacterials
approved
16
14
10
6
Past
New drugs approved since 1998 - USA & EU
agent
year
FDA
EMA
rifapentine
synercid
moxifloxacin
gatifloxacin
linezolid
cefditoren
ertapenem
gemifloxacin
daptomycin
telithromycin
tigecycline
doripenem
1998
1999
1999
1999
2000
2001
2001
2003
2003
2004
2005
2005






















x
x
Novel
mechanism
no
maybe
no
no
yes
no
no
no
yes
maybe
maybe
no
Past
Antibacterials vs other anti infectives 1998-03
9 antibacterials licenced (4 in EU)
2 antifungals licenced (caspofungin; voriconazole)
2 antiparasitic agents
9 antivirals (5 HIV specific plus 3 more since ‘03)
Present/future
Drugs in development
 large pharma
 smaller pharma
 biotechnology sector
largest 15 companies have accounted for 93% of
licenced new antibacterials since 1980
Present
New molecular entities (NME) in publically disclosed
R&D by largest 15 companies
therapeutic area
cancer
inflammation/pain
metabolic/endocrine
pulmonary
infection
neurological
vaccines
psychiatric
cardiac
haematology
gastro intestinal
genito urinary
ocular
dermatology
number
NME
67
33
34
32
31
24
18
16
15
12
13
12
4
4
315
%
share
21
10
11
10
10
7.5
6
5
5
4
4
4
1
1
Present
New molecular entities in infection
area
anti HIV
other antiviral
anti bacterial
anti parasite
anti fungal
topical
number
NME
12
5
5 (1.5% all NME)
5
3
1
Present
New molecular entities from 7 largest biotechnology
companies
therapeutic area
inflammation/immunomodulator
metabolic/endocrine
cancer
inherited enzyme deficiencies
cardiovascular
haematological
dermatological
renal
neurology
pulmonary
antibacterials
number
NME
24
15
13
9
6
3
3
3
2
2
1
Present
Antibacterials in development (PI II/III
company
BMS
Abbott
J+J/Basilea
Wyeth
Cubist
Pfizer
Arpida
Roche
Theravance
GSK
Oscient
Peninsula
Ranbaxy
Iseganan
product
garenoxacin
ABT-773
ABT-493
BAL 5788
Tigecycline
daptomycin
dalbavancin
Iclaprim
Ro-49/CS-023
telavancin
SB-275833
GSKI
ramoplanin
doripenem
vanbezolid
peptides
class
FQ
macro
FQ
lactam
tetra
new
glyco
dihydro
Blactam
glyco
new
new
new
Blactam
oxa
new
status
Ph3 complete
Ph3 complete
unknown
Ph3
at EMEA
at EMEA
Ph3
?Ph2
Ph2/3
Ph2/3
Ph2/3
?pre clinical
Ph2/3
licence in US
PhI
3
Future
community iv/po mainly RTI
4
(2005-2007)
injectable antigram positive
8
(2005-2010)
uncertain
topical/non absorbable
2
2
antigram negative
0
Trends in antibacterial development
number of newly licenced products in decline
few agents under development compared to other
therapeutic areas in all sectors
drugs in late development still focused on community
RTI sector
drugs in earlier development focused on hospital
multiresistant Gram-positive indications
no agents for Gram-negative infection
The worldwide anti infective market - 2002
total value
$26 billion
split:
USA; EU; Japan; ROW
48%; 22%; 13%; 17%
antibacterials
antivirals
2:1 HIV : non HIV
biologicals
antifungals
proportion by
sales
62%
expected
growth
+6%
18%
13%
7%
+22%
+14%
+10%
Market for antibacterial drugs USD (billion) in 2002
drug class
cephalosporins
fluoroquinolones
macrolides
other lactams
penicillins
carbapenems
aminoglycosides
glycopeptides
oxazolidinones
streptogramins
total
sales
4.44
3.62
2.96
2.17
1.03
0.45
0.32
0.28
0.15
0.03
nosocomial
infection
0.43
0.17
0.14
0.22
0.04
0.25
0.05
0.03
Data from the seven major pharmaceutical markets
(USA, France, Germany, Italy, Spain, UK, Japan)
Expected changes in antibacterial market
(www.datamonitor.com)
Global market 2002 $26 billion (+1.8% growth
until 2011)
company
GSK
Pfizer
market share
2002
2011
21.1
9.4
18.1
17.8
Bayer
12.8
11.8
Abbott
11.6
11.3
J+J
7.9
2.9
comment
loss of augmentin
loss of azithromycin
retain linezolid
loss of ciprofloxacin
retain moxifloxacin
loss of clarithromycin
?gain ABT-773; ABT-492
loss of levofloxacin
?gain ceftobiprole
Anti-infectives have grown significantly less than all other
segments, mainly due to lack of launches, genericisation, and
pricing pressure
Worldwide Pharmaceutical Sales
30%
Last Year
(2002–2003)
Last Four Years
(1999–2003)
20%
Source: IMS MIDAS, PADDS
Antibiotics
AI
Antifungals
CV
Metabolics
Allergies
Antivirals
CNS
Allergies
Antibiotics
AI
CV
Metabolics
Antivirals
0%
CNS
0%
Antifungals
10%
Urology
10%
Cancer
Total Pharma
Market = 10%
Urology
Total Pharma
Market = 10%
CAGR
20%
Cancer
Annual Growth Rate
30%
Factors determining antibacterial drug development
ageing population
new therapeutic interventions
infection control interventions
highly saturated market (many agents)
few novel agents
increasing generic competition (price)
increasingly conservative prescribers
short course therapy
increasing regulatory needs
manufacture/safety/efficacy
cost containment (governments in EU, MCO in USA)
less attractive than other therapeutic areas (chronic
therapy; lifestyle)
antimicrobial resistance
Death of the blockbuster: antibacterial market
dynamics do not promote investment
• Highly saturated with many
similar products
• Novel product success reliant
on significant innovation and/or
differentiation
Market
saturation
• Community physicians tend to
stick with 2–3 products with
which they are very familiar
Acute nature of
disease
LIMITED
INVESTMENT
• Pharmaceuticals prefer to target
chronic diseases, e.g. cancer, viral
infections, CNS & CV
• Makes it difficult for new
branded drugs to compete in
terms of price
Increasing
generics
• Resistance means hospital
physicians are reluctant to
prescribe new drugs
• Infections are acute, with short
treatment duration
• Results in lower revenue per
patient
• Increasing level of generic
competition
Increasing
resistance
• Instead, only use them
when alternative treatments
have been exhausted
Development based on  assessment of unmet need (patients to treat)
 how new product can be differentiated from others to
treat similar patients
 price structures, required investment, R&D costs
 regulatory environment
Use “Net present value” or rNPV or maximum peak
sales $200-$500
Net present value (NPV)
• A technique for evaluating the viability of an investment
decision
• Widely used in the pharmaceutical industry to determine
both the viability of specific products and to compare
investment strategies
• Enables economic costs and benefits of a development
programme to be estimated at current values
• Describes the relationship between the projected costs
of the project and the potential in terms of cash flow
• An NPV > 0 means that the project will benefit the
company
Antibiotics and NPV
• Antibiotic R&D is at the fringe of economic
viability
• Antibiotics perform poorly compared with drugs
for chronic conditions
–
–
–
–
Antibiotic – NPV 100
Anti-cancer drug – NPV 300
Neurological drug – NPV 720
Muscular-skeletal drug – NPV 1150
• Any drug with an NPV < 100 is unlikely to be
developed
Bartlett JG, 2003, available from: http://www.medscape.com/viewarticle/461620
What impacts NPV?
• Antibiotic restrictions
– Reduce potential profit and thus NPV
• Increased regulatory hurdles
– Increases risk / costs
– May move acceptable projects in to more marginal
projects
• Length of patent protection
– Life-cycle extensions for successful antibiotics can be
profitable
• Resistance
– Agent to which resistance develops rapidly will have a
shorter useful clinical lifespan
Antibiotic Resistance
Emergence of resistance to newly introduced antibacterials
penicillin
streptomycin
tetracycline
vancomycin
methicillin
nalidixic acid
gentamicin
cefotaxime
year
approved
year
1943
1947
1952
1952
1960
1964
1967
1981
ciprofloxacin
linezolid
daptomycin
1988
2000
2003
agent
resistance
first reported
1940
1947
1956
1987
1961
1966
1969
1981 (Ampc)
1983 (ESBL)
1987
1999
-
Present resistance in the UK
(www.bsacsurv.org : bacteraemia)
Staphylococci
MRSA
95%
84%
30%
23%
10%
2%
ciprofloxacin resistant
erythromycin resistant
trimethoprim resistant
clindamycin resistant
gentamicin resistant
tetracycline resistant
MRCoNS
83%
75%
73%
61%
35%
31%
trimethoprim resistant
gentamicin resistant
erythromycin resistant
tetracycline resistant
teicoplanin resistant
clindamycin resistant
Streptococci and Enterococci
(www.bsacsurv.org)
S.pneumoniae
17%
8%
2%
erythromycin resistant
penicillin non-susceptible
clindamycin resistant
E.faecalis
43%
high level gentamicin resistant
E.faecium
86%
32%
20%
15%
ampicillin resistant
HL gentamicin resistant
vancomycin resistant
teicoplanin resistant
Gram-negative rods
(www.bsacsurv.org)
E.coli
59%
24%
11%
10%
7%
3%
3%
ampicillin resistant
co-amoxiclav resistant
gentamicin resistant
cefuroxime resistant
ciprofloxacin resistant
ceftazidime resistant
pip/tazobactam resistant
Serratia spp
97%
96%
92%
90%
21%
20%
14%
4%
cefotaxime resistant
cefuroxime resistant
ampicillin resistant
co-amoxiclav resistant
pip/tazobactam resistant
ciprofloxacin resistant
gentamicin resistant
ceftazidime resistant
Potential (extreme) consequences of policies/strategies
to manage resistance
Resistance
threat to antibacterial utility and
health outcomes
medical/political concern
policies/strategies
changed
withdrawal from
antibacterial R&D
threat to antibacterial utility &
health outcomes
sustainable
antibacterials R&D
ensure future availability of antibacterials,
maintains/improves health outcomes
Modified - A White
Resistance and NPV
Turnover antibiotic A
Resistance to antibiotic A
Turnover antibiotic B
Resistance to antibiotic B
90
90
80
NPV = 163.1
70
70
60
60
50
50
NPV = 198.9
40
40
30
30
20
20
10
10
0
0
2003
2004
2005
2006
2007
2008
Year
2009
2010
2011
2012
2013
Resistance (%)
Turnover (US$ million)
80
Antibacterial
need
Antibacterial
productivity
?
Policies &
Regulation
past
1920-40
1960-80
now
1990-2010
future
A White
Are there new targets?
indication
genes
680
essential
single
genes
200-300
essential
gene
complexes
120
Gram +
pathogens
Gram –
pathogens
530
150-300
70
RTI pathogens
200-300
150-300
70
complete broad
spectrum
130
100
80
from Labischinski
target area
DNA replication
division
transcription
translation
fatty acid synthesis
cell wall synthesis
nucleotid synthesis
co-enzyme synthesis
number of known
essential genes
19
5
6
54
7
11
8
4
number of market
antibacterials
targeting
3
0
1
7
1
2
0
2
Labischinski
 large number of targets known; many not
exploited
Antibacterial discovery - post genomics
 genomics has revolutionised antibacterial discovery
 it provides targets, not drugs
 now unprecedented number of novel antibacterial
strategies
 optimisation of clinical candidates is very challenging
 lack of pipeline compounds
 belief genomes, high throughput screening and
combinational chemistry have not delivered
 wish to reduce future R&D spend in antibacterials
Strengths and weaknesses in antibiotic drug
discovery - commercial
•
for hospital indications iv formulation - i.e. aqueous solvability
essential
•
specific and potent inhibitor needed to kill bacteria and not host
•
targets need to be protein families to provide spectrum
•
target less accessible due to permeability/efflux
•
emergence of resistance more common with single targets
•
chemistry is complex, i.e. solubility, polarity
•
animal/other models predictive compared to other therapeutic
areas
•
antibacterials have short development times in clinical and high
success rates but usually require at least 3 indications
•
novel antibiotics may be niched and cost restricted
Academic based research almost exclusively focused on
alternative strategies
• phage therapy
• pathogenicity/virulence
• immunology
defensins
antibodies
vaccines
From target to drug
1) Research Phase
Exploratory Research
molecular
target
screen
Strategic Project
development
candidates
lead
compound
success rate
60%
time 2-3 years
20%
50%
From target to drug
2) Development Phase
pre clinical
Ph1
MICology
pharmacokinetics
pharmacodynamics
mechanism of activity
mechanism of resistance
Ph2
Ph3
exposure
in 200-300
patients
(no
dose
ranging)
RCT vs comparitors
for each indication
(2 studies required)
2000-4000
patient exposures
Duration 5-6 years cost $800-950 million
Success rate (%)
Success rate first human dose
to market
100
90
80
70
60
50
40
30
20
10
0
80 75 80
75
75
47
43
33
32
6 6
9 8
1
First human dose to
market
Anti-infective
14
2
First patient dose to
market
Cardiovascular
First pivotal dose to
market
Anticancer
Submission to market
Nervous system
Attractiveness: in A-I early POP and high likelihood of technical success
Source: CMR International 2003
Proposed actions to address present situation
•
governmental support for basic science research in
chemotherapy and orphan drugs
(i.e. NIH cancer programme)
•
combined academic/industry programmes
•
legislative change
 streamline approvals
dose escalation, single RCT, delta issue
 responsibilities of Generics Houses
•
economic incentives
 rapid price setting
 price comparability, USA, Canada, EU
 wild card exclusivity
 extended patient lives
Summary
probably fewer antibacterials in development than historically
drugs still focused on RTI, hospital Gram + markets, compared to
Gram -/broad spectrum
antibacterial market is large and growing
but
not as fast as other sectors
few new blockbusters expected
antibacterial R&D not attractive compared to other therapy areas in
terms of rNPV
antibacterial resistance remains a problem
numerous new antibacterial targets identified
drug optimisation appears very difficult
poor academia/industry linkages and synergies
regulation has increased
development costs approach $1billion