Antimicrobial Drug Development:

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Antimicrobial Drug Development a crisis?
Alasdair MacGowanBristol Centre for
Antimicrobial Research EvaluationUniversity of
Bristol/North Bristol NHS Trust 18th October,
2005
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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
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20th 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
• gt270 antibiotics in clinical use

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21st Century

• Prospects of a post-antibiotic era?
• Evolving resistance with antibiotic use
• Emergence of superbugs
• Unmet needs of the hospital treatment market

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An external perspective on industry short-term/fi
scally driven?

• All pharmaceutical companies are under continual
  pressure by shareholders to maximise returns and
  sustain strong growth rates
• Chronic care medications gt acute care medications
• Innovation gt me-toos
• Specialised hospital products gt 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

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PastFDA approved antibacterial agents 1983-2002
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PastNew drugs approved since 1998 - USA EU
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PastAntibacterials 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)
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Present/futureDrugs in development
? large pharma ? smaller pharma ? biotechnology
sector
largest 15 companies have accounted for 93 of
licenced new antibacterials since 1980
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PresentNew molecular entities (NME) in
publically disclosed RD by largest 15 companies
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PresentNew molecular entities in infection
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PresentNew molecular entities from 7 largest
biotechnology companies
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PresentAntibacterials in development (PI II/III
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Future
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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
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The worldwide anti infective market - 2002 total
value 26 billion split USA EU Japan
ROW 48 22 13 17
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Market for antibacterial drugs USD (billion) in
2002
Data from the seven major pharmaceutical markets
(USA, France, Germany, Italy, Spain, UK, Japan)
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Expected changes in antibacterial
market(www.datamonitor.com) Global market
2002 26 billion (1.8 growth until 2011)
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Anti-infectives have grown significantly less
than all other segments, mainly due to lack of
launches, genericisation, and pricing pressure
Worldwide Pharmaceutical Sales
Last Year (20022003)
Last Four Years (19992003)
Total Pharma Market 10
Total Pharma Market 10
CAGR
Annual Growth Rate
Source IMS MIDAS, PADDS
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Factors determining antibacterial drug
development ageing populationnew therapeutic
interventionsinfection control
interventionshighly saturated market (many
agents)few novel agentsincreasing generic
competition (price)increasingly conservative
prescribersshort course therapyincreasing
regulatory needs manufacture/safety/efficacycost
containment (governments in EU, MCO in USA)less
attractive than other therapeutic areas (chronic
therapy lifestyle)antimicrobial resistance
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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
• Community physicians tend to stick with 23
  products with which they are very familiar

• Increasing level of generic competition
• Makes it difficult for new branded drugs to
  compete in terms of price

Market saturation
Acute nature of disease
Increasing generics
LIMITED INVESTMENT

• Resistance means hospital physicians are
  reluctant to prescribe new drugs
• Instead, only use them when alternative
  treatments have been exhausted

• Infections are acute, with short treatment
  duration
• Results in lower revenue per patient
• Pharmaceuticals prefer to target chronic
  diseases, e.g. cancer, viral infections, CNS CV

Increasing resistance
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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, RD
costs ? regulatory environment
Use Net present value or rNPV or maximum peak
sales 200-500
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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 gt 0 means that the project will benefit
  the company

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Antibiotics and NPV

• Antibiotic RD 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 lt 100 is unlikely to be
  developed

Bartlett JG, 2003, available from
http//www.medscape.com/viewarticle/461620
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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

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Antibiotic Resistance Emergence of resistance to
newly introduced antibacterials
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Present resistance in the UK(www.bsacsurv.org
bacteraemia) Staphylococci
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Streptococci and Enterococci(www.bsacsurv.org)
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Gram-negative rods(www.bsacsurv.org)
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Potential (extreme) consequences of
policies/strategies to manage resistance
Resistance
threat to antibacterial utility and health
outcomes
medical/political concern
policies/strategieschanged
withdrawal from antibacterial RD
sustainable antibacterials RD
threat to antibacterial utility health outcomes
ensure future availability of antibacterials,
maintains/improves health outcomes
Modified - A White
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Resistance and NPV
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Antibacterial need
Antibacterial productivity
?
Policies Regulation
past
now
future
1920-40
1960-80
1990-2010
A White
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Are there new targets?
from Labischinski
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Labischinski
? large number of targets known many not
exploited
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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 RD spend in
antibacterials
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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

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Academic based research almost exclusively
focused on alternative strategies

• phage therapy
• pathogenicity/virulence
• immunology defensins antibodies vaccines

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From target to drug
1) Research PhaseExploratory Research Strategic
Project
molecular target
screen
development candidates
lead compound
success rate
60
20
50
time 2-3 years
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From target to drug
2) Development Phase
Duration 5-6 years cost 800-950 million
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Success rate first human dose to market
Attractiveness in A-I early POP and high
likelihood of technical success
Source CMR International 2003
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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 approvalsdose 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
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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 growingbutnot as fast as other sectors few
new blockbusters expected antibacterial RD 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