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Antimicrobial Drug Development: a crisis? Alasdair MacGowan Bristol Centre for Antimicrobial Research & Evaluation University of Bristol/North Bristol.

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Presentation on theme: "Antimicrobial Drug Development: a crisis? Alasdair MacGowan Bristol Centre for Antimicrobial Research & Evaluation University of Bristol/North Bristol."— Presentation transcript:

1 Antimicrobial Drug Development: a crisis? Alasdair MacGowan Bristol Centre for Antimicrobial Research & Evaluation University of Bristol/North Bristol NHS Trust 18 th October, 2005

2 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

3 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 20 th Century

4 Prospects of a post-antibiotic era? Evolving resistance with antibiotic use Emergence of superbugs Unmet needs of the hospital treatment market 21 st Century

5 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?

6 Past FDA approved antibacterial agents 1983-2002

7 Past New drugs approved since 1998 - USA & EU

8 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)

9 Present/future Drugs in development  large pharma  smaller pharma  biotechnology sector largest 15 companies have accounted for 93% of licenced new antibacterials since 1980

10 Present New molecular entities (NME) in publically disclosed R&D by largest 15 companies

11 Present New molecular entities in infection

12 Present New molecular entities from 7 largest biotechnology companies

13 Present Antibacterials in development (PI II/III

14 Future

15 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

16 The worldwide anti infective market - 2002 total value$26 billion split:USA; EU; Japan; ROW 48%; 22%; 13%; 17%

17 Market for antibacterial drugs USD (billion) in 2002 Data from the seven major pharmaceutical markets (USA, France, Germany, Italy, Spain, UK, Japan)

18 Expected changes in antibacterial market ( Global market 2002$26 billion (+1.8% growth until 2011)

19 Worldwide Pharmaceutical Sales Last Year (2002–2003) Last Four Years (1999–2003) Total Pharma Market = 10% Annual Growth Rate Source: IMS MIDAS, PADDS CAGR Anti-infectives have grown significantly less than all other segments, mainly due to lack of launches, genericisation, and pricing pressure

20 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

21 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 market dynamics do not promote investment

22 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

23 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)

24 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: Antibiotics and NPV

25 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?

26 Antibiotic Resistance Emergence of resistance to newly introduced antibacterials

27 Present resistance in the UK ( : bacteraemia) Staphylococci

28 Streptococci and Enterococci (

29 Gram-negative rods (

30 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 sustainable antibacterials R&D threat to antibacterial utility & health outcomes ensure future availability of antibacterials, maintains/improves health outcomes Modified - A White

31 Resistance and NPV

32 Antibacterial need Antibacterial productivity Policies & Regulation 1920-401960-801990-2010 future pastnow ? A White

33 Are there new targets? from Labischinski

34 Labischinski  large number of targets known; many not exploited

35 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

36 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

37 Academic based research almost exclusively focused on alternative strategies phage therapy pathogenicity/virulence immunology defensins antibodies vaccines

38 From target to drug 1)Research Phase Exploratory ResearchStrategic Project molecular target screendevelopment candidates lead compound success rate 60%20%50% time 2-3 years

39 From target to drug 2)Development Phase Duration 5-6 yearscost $800-950 million

40 Attractiveness: in A-I early POP and high likelihood of technical success Source: CMR International 2003 Success rate first human dose to market

41 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  rapid price setting  price comparability, USA, Canada, EU  wild card exclusivity  extended patient lives economic incentives

42 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

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