Antimicrobial Drug Development:

a crisis?

Alasdair MacGowanBristol Centre for Antimicrobial Research & EvaluationUniversity 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

• 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

20th Century

• Prospects of a post-antibiotic era?

• Evolving resistance with antibiotic use

• Emergence of superbugs

• Unmet needs of the hospital treatment market

21st Century

• 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

An external perspective on industry:short-term/fiscally driven?

PastFDA approved antibacterial agents 1983-2002

5 year periods antibacterialsapproved

1983-87 161988-92 141993-97 101998-02 6

PastNew drugs approved since 1998 - USA & EU

agent year FDA EMA Novel

mechanism rifapentine 1998 no synercid 1999 maybe moxifloxacin 1999 no gatifloxacin 1999 no linezolid 2000 yes cefditoren 2001 no ertapenem 2001 no gemifloxacin 2003 no daptomycin 2003 yes telithromycin tigecycline doripenem

2004 2005 2005

x x

maybe maybe

no

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)

Present/futureDrugs in development

large pharma

smaller pharma

biotechnology sector

largest 15 companies have accounted for 93% of licenced new antibacterials since 1980

PresentNew molecular entities (NME) in publically disclosed R&D by largest 15 companies

therapeutic area numberNME

%share

cancer 67 21inflammation/pain 33 10metabolic/endocrine 34 11pulmonary 32 10infection 31 10neurological 24 7.5vaccines 18 6psychiatric 16 5cardiac 15 5haematology 12 4gastro intestinal 13 4genito urinary 12 4ocular 4 1dermatology 4 1

315

PresentNew molecular entities in infection

area numberNME

anti HIV 12other antiviral 5anti bacterial 5 (1.5% all NME)

anti parasite 5anti fungal 3topical 1

PresentNew molecular entities from 7 largest biotechnology companies

therapeutic area numberNME

inflammation/immunomodulator 24metabolic/endocrine 15cancer 13inherited enzyme deficiencies 9cardiovascular 6haematological 3dermatological 3renal 3neurology 2pulmonary 2antibacterials 1

PresentAntibacterials in development (PI II/III

company product class status BMS garenoxacin FQ Ph3 complete Abbott ABT-773 macro Ph3 complete ABT-493 FQ unknown J+J/Basilea BAL 5788 lactam Ph3 Wyeth Tigecycline tetra at EMEA Cubist daptomycin new at EMEA Pfizer dalbavancin glyco Ph3 Arpida Iclaprim dihydro ?Ph2 Roche Ro-49/CS-023 Blactam Ph2/3 Theravance telavancin glyco Ph2/3 GSK SB-275833 new Ph2/3 GSKI new ?pre clinical Oscient ramoplanin new Ph2/3 Peninsula doripenem Blactam licence in US Ranbaxy vanbezolid oxa PhI Iseganan peptides new 3

Future

community iv/po mainly RTI 4(2005-2007)

injectable antigram positive 8(2005-2010)

uncertain 2topical/non absorbable 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; ROW48%; 22%; 13%; 17%

proportion bysales

expectedgrowth

antibacterials 62% +6%antivirals2:1 HIV : non HIV 18% +22%biologicals 13% +14%antifungals 7% +10%

Market for antibacterial drugs USD (billion) in 2002

drug class totalsales

nosocomialinfection

cephalosporins 4.44 0.43fluoroquinolones 3.62 0.17macrolides 2.96 -other lactams 2.17 -penicillins 1.03 0.14carbapenems 0.45 0.22aminoglycosides 0.32 0.04glycopeptides 0.28 0.25oxazolidinones 0.15 0.05streptogramins 0.03 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 market share comment 2002 2011 GSK 21.1 9.4 loss of augmentin Pfizer 18.1 17.8 loss of azithromycin retain linezolid Bayer 12.8 11.8 loss of ciprofloxacin retain moxifloxacin Abbott 11.6 11.3 loss of clarithromycin ?gain ABT-773; ABT-492 J+J 7.9 2.9 loss of levofloxacin

?gain ceftobiprole

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Worldwide Pharmaceutical Sales

Last Year(2002–2003)

Last Four Years(1999–2003)

Total Pharma Market = 10%

Total Pharma Market = 10%

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Source: IMS MIDAS, PADDS

CA

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Anti-infectives have grown significantly less than all othersegments, mainly due to lack of launches, genericisation, and

pricing pressure

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

• Highly saturated with many similar products

• Novel product success reliant on significant innovation and/or differentiation

• Community physicians tend to stick with 2–3 products with which they are very familiar

Acute nature of disease

• 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 generics

Increasing resistance

LIMITED INVESTMENT

Market saturation

• Resistance means hospital physicians are reluctant to prescribe new drugs

• Instead, only use them when alternative treatments have been exhausted

• Increasing level of generic competition

• Makes it difficult for new branded drugs to compete in terms of price

Death of the blockbuster: antibacterial marketdynamics do not promote investment

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

• 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

Net present value (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

Antibiotics and 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

What impacts NPV?

Antibiotic Resistance

Emergence of resistance to newly introduced antibacterials

agent yearapproved

year

resistancefirst reported

penicillin 1943 1940streptomycin 1947 1947tetracycline 1952 1956vancomycin 1952 1987methicillin 1960 1961nalidixic acid 1964 1966gentamicin 1967 1969cefotaxime 1981 1981 (Ampc)

1983 (ESBL)ciprofloxacin 1988 1987linezolid 2000 1999daptomycin 2003 -

Present resistance in the UK(www.bsacsurv.org : bacteraemia)

Staphylococci

MRSA 95% ciprofloxacin resistant84% erythromycin resistant30% trimethoprim resistant23% clindamycin resistant10% gentamicin resistant2% tetracycline resistant

MRCoNS 83% trimethoprim resistant75% gentamicin resistant73% erythromycin resistant61% tetracycline resistant35% teicoplanin resistant31% clindamycin resistant

Streptococci and Enterococci(www.bsacsurv.org)

S.pneumoniae 17% erythromycin resistant8% penicillin non-susceptible2% clindamycin resistant

E.faecalis 43% high level gentamicin resistant

E.faecium 86% ampicillin resistant32% HL gentamicin resistant20% vancomycin resistant15% teicoplanin resistant

Gram-negative rods(www.bsacsurv.org)

E.coli 59% ampicillin resistant24% co-amoxiclav resistant11% gentamicin resistant10% cefuroxime resistant

7% ciprofloxacin resistant3% ceftazidime resistant3% pip/tazobactam resistant

Serratia spp 97% cefotaxime resistant96% cefuroxime resistant92% ampicillin resistant90% co-amoxiclav resistant21% pip/tazobactam resistant20% ciprofloxacin resistant14% gentamicin resistant

4% ceftazidime resistant

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 R&D

sustainable antibacterials R&D

threat to antibacterial utility & health outcomes

ensure future availability of antibacterials, maintains/improves health

outcomes

Modified - A White

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Turnover antibiotic AResistance to antibiotic ATurnover antibiotic BResistance to antibiotic B

NPV = 198.9

NPV = 163.1

Year

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2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

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Resistan

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Turnover antibiotic AResistance to antibiotic ATurnover antibiotic BResistance to antibiotic B

NPV = 198.9

NPV = 163.1

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2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

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Turnover antibiotic AResistance to antibiotic ATurnover antibiotic BResistance to antibiotic B

NPV = 198.9

NPV = 163.1

Year

Resistance and NPV

Antibacterial need

Antibacterial productivity

Policies & Regulation

1920-40 1960-80 1990-2010 futurepast now

?

A White

Are there new targets?

indication genes essentialsinglegenes

essentialgene

complexesGram +pathogens

680 200-300 120

Gram –pathogens

530 150-300 70

RTI pathogens 200-300 150-300 70

complete broadspectrum

130 100 80

from Labischinski

target area number of knownessential genes

number of marketantibacterials

targetingDNA replication 19 3division 5 0transcription 6 1translation 54 7fatty acid synthesis 7 1cell wall synthesis 11 2nucleotid synthesis 8 0co-enzyme synthesis 4 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

• immunologydefensinsantibodiesvaccines

From target to drug

1) Research Phase

Exploratory Research Strategic Project

molecular target

screen development candidates

lead compound

success rate

60% 20% 50%

time 2-3 years

From target to drug

2) Development Phase

pre clinical Ph1 Ph2 Ph3

MICologypharmacokineticspharmacodynamics

RCT vs comparitorsfor each indication(2 studies required)

mechanism of activitymechanism of resistance

exposurein 200-300

patients(nodose

ranging)2000-4000

patient exposures

Duration 5-6 years cost $800-950 million

33

6 61

47

9 82

75

43

32

14

80 75 8075

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Su

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%)

First human dose tomarket

First patient dose tomarket

First pivotal dose tomarket

Submission to market

Anti-infective Cardiovascular Anticancer Nervous system

Attractiveness: in A-I early POP and high likelihood of technical success

Source: CMR International 2003

Success rate first human dose to market

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

rapid price setting

price comparability, USA, Canada, EU

wild card exclusivity

extended patient lives

• economic incentives

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 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