Antimicrobial Drug Development: a crisis ?

1. Antimicrobial Drug Development: a crisis? Alasdair MacGowanBristol Centre for Antimicrobial Research & EvaluationUniversity of Bristol/North Bristol NHS Trust 18th 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. 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 • >270 antibiotics in clinical use

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

5. 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

6. PastFDA approved antibacterial agents 1983-2002

7. PastNew drugs approved since 1998 - USA & EU

8. 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)

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

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

11. PresentNew molecular entities in infection

12. PresentNew molecular entities from 7 largest biotechnology companies

13. PresentAntibacterials 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(www.datamonitor.com) Global market 2002 $26 billion (+1.8% growth until 2011)

19. 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 (2002–2003) Last Four Years (1999–2003) Total Pharma Market = 10% Total Pharma Market = 10% CAGR Annual Growth Rate Source: IMS MIDAS, PADDS

20. 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

21. 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 • 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

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. 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

24. 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

25. 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

26. Antibiotic Resistance Emergence of resistance to newly introduced antibacterials

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

28. Streptococci and Enterococci(www.bsacsurv.org)

29. Gram-negative rods(www.bsacsurv.org)

30. 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

31. Resistance and NPV

32. Antibacterial need Antibacterial productivity ? Policies & Regulation past now future 1920-40 1960-80 1990-2010 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 PhaseExploratory Research Strategic Project molecular target screen development candidates lead compound success rate 60% 20% 50% time 2-3 years

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

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

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 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

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 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