Antimicrobial Drug Development: a crisis?

Alasdair MacGowan Bristol Centre for Antimicrobial Research & Evaluation University of Bristol/North Bristol NHS Trust 18 th 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

20

th

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

21

st

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 product class BMS Abbott J+J/Basilea Wyeth Cubist Pfizer Arpida Roche Theravance GSK Oscient Peninsula Ranbaxy Iseganan garenoxacin ABT-773 ABT-493 BAL 5788 Tigecycline daptomycin dalbavancin Iclaprim Ro-49/CS-023 telavancin SB-275833 GSKI ramoplanin doripenem vanbezolid peptides 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 injectable antigram positive uncertain topical/non absorbable antigram negative 4 (2005-2007) 8 (2005-2010) 2 2 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% 18% 13% 7% expected growth +6% +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 Bayer Abbott J+J market share 2002 2011 21.1 18.1 12.8 11.6 7.9 9.4 17.8 11.8 11.3 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

30%

Worldwide Pharmaceutical Sales

30%

Last Year (2002 –2003) Last Four Years (1999 –2003)

20% 20% Total Pharma Market = 10% Total Pharma Market = 10% 10% 10% 0% 0% Source: IMS MIDAS, PADDS

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

•

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 Market saturation LIMITED INVESTMENT Increasing resistance

•

Increasing level of generic competition

•

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

•

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

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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 agent penicillin streptomycin tetracycline vancomycin methicillin nalidixic acid gentamicin cefotaxime ciprofloxacin linezolid daptomycin year approved year 1943 1947 1952 1952 1960 1964 1967 1981 1988 2000 2003 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 MRCoNS 95% 84% 30% 23% 10% 2% 83% 75% 73% 61% 35% 31% ciprofloxacin resistant erythromycin resistant trimethoprim resistant clindamycin resistant gentamicin resistant tetracycline resistant trimethoprim resistant gentamicin resistant erythromycin resistant tetracycline resistant teicoplanin resistant clindamycin resistant

Streptococci and Enterococci (www.bsacsurv.org) S.pneumoniae

E.faecalis

E.faecium

17% 8% 2% 43% 86% 32% 20% 15% erythromycin resistant penicillin non-susceptible clindamycin resistant high level gentamicin resistant ampicillin resistant HL gentamicin resistant vancomycin resistant teicoplanin resistant

Gram-negative rods (www.bsacsurv.org) E.coli

Serratia spp 59% 24% 11% 10% 7% 3% 3% 97% 96% 92% 90% 21% 20% 14% 4% ampicillin resistant co-amoxiclav resistant gentamicin resistant cefuroxime resistant ciprofloxacin resistant ceftazidime resistant pip/tazobactam resistant 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 withdrawal from antibacterial R&D medical/political concern policies/strategies changed sustainable antibacterials R&D threat to antibacterial utility & health outcomes ensure future availability of antibacterials, maintains/improves health outcomes Modified - A White

Resistance and NPV

90 80 70 60 50 40 30 20 10 0 Turnover antibiotic A Resistance to antibiotic A Turnover antibiotic B Resistance to antibiotic B 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 20 10 2013 0 90 80 70 60 50 40 30

Antibacterial need 1920-40 past 1960-80 Antibacterial productivity ?

now 1990-2010 Policies & Regulation future A White

Are there new targets?

indication genes Gram + pathogens Gram – pathogens RTI pathogens complete broad spectrum 680 530 200-300 130 essential single genes 200-300 150-300 150-300 100 essential gene complexes 120 70 70 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

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genomics has revolutionised antibacterial discovery it provides targets, not drugs now unprecedented number of novel antibacterial strategies

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optimisation of clinical candidates is very challenging lack of pipeline compounds belief genomes, high throughput screening and combinational chemistry have not delivered

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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 success rate 60% screen Strategic Project development candidates lead compound 20% 50% time 2-3 years

From target to drug 2) Development Phase pre clinical Ph1 MICology pharmacokinetics pharmacodynamics mechanism of activity mechanism of resistance Ph2 exposure in 200-300 patients (no dose ranging) Ph3 RCT vs comparitors for each indication (2 studies required) 2000-4000 patient exposures Duration 5-6 years cost $800-950 million

Success rate first human dose to market

100 90 80 70 60 50 40 30 20 10 0 33 6 6 1 First human dose to market 47 9 8 2 First patient dose to market 75 43 32 14 First pivotal dose to market 80 75 80 75 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

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Proposed actions to address present situation

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governmental support for basic science research in chemotherapy and orphan drugs (i.e. NIH cancer programme) combined academic/industry programmes legislative change

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streamline approvals dose escalation, single RCT, delta issue

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responsibilities of Generics Houses

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economic incentives

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rapid price setting

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price comparability, USA, Canada, EU

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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