1. Pharmaceutical aspects of the development of anti-infectives Dr Jeffrey R Edwards Infection Therapy Area AstraZeneca

2.  Why develop a new anti-infective agent?  The infrastructure required, competition for resources  Really ‘new’, another variant or ‘a compound too far’?  Discovery and development.

3.  Why develop a new anti-infective agent?  The infrastructure required, competition for resources  Really ‘new’, another variant or ‘a compound too far’?  Discovery and development.

4. RESISTANCE

5. Bacterial resistance is now a high-profile issue for Governments, International bodies and the press But....... there always has been and there always will be bacterial resistance to anti-microbials we probably don’t really know how to select a dosing regimen and use agents optimally we don’t help by being imprecise with terminology: we fail to distinguish between ‘mechanisms of resistance’ and therapeutic failure we rarely identify unusual events or show diminished susceptibility: breakpoints have a lot to answer for! Some observations.........

6. resistance varies between countries within hospitals, ITUs have the problems resistance is seen in the community.

7. Some highly publicised resistance problems multi-resistant staphylococci penicillin-resistant pneumococci macrolide-resistant group-A streptococci VAN-R enterococci Corynebacterium jeikeium Mycobacterium tuberculosis Enterobacteriaceae ESBLs, notably in Klebsiella chromosomal  -lactamases Enterobacter, Citrobacter etc Salmonella typhi Shigella dysenteriae Pseudomonas aeruginosa Burkholderia cepacia Stenotrophomonas maltophilia

8. Limited choice of therapy penicillin- and macrolide-resistant pneumococci macrolide-resistant Group A streptococci ESBL bearing Enterobacteriaceae Enterobacteriaceae over-expressing chromosomal  lactamases Pseudomonas aeruginosa Pseudomonas spp. Acinetobacter spp. Burkholderia cepacia Stenotrophomonas maltophilia

10. Untreatable bacteria multi-resistant staphylococci vancomycin-resistant enterococci Corynebacterium jeikeium Mycobacterium tuberculosis

12. Summary There are a relatively small number of untreatable bacteria There is a reduction in the choice of agents to use There is an unquantified issue relating to undetected diminished susceptibility Therefore, new agents are needed !

13.  Why develop a new anti-infective agent?  The infrastructure required, competition for resources  Really ‘new’, another variant or ‘a compound too far’?  Discovery and development.

14. The infrastructure Therapy areas GI Cancer CNS CVS Pain Respiratory Infection

15. The infrastructure Therapy areas GI Cancer CNS CVS Pain Respiratory Infection Commercial activities Market research Quantifying opportunities Preparing for launch Launching/ selling Life cycle

16. The infrastructure Therapy areas GI Cancer CNS CVS Pain Respiratory Infection Development Depts. Large scale synthesis Formulation Manufacture Safety evaluation Clinical evaluation Regulatory Intellectual Property Commercial activities Market research Quantifying opportunities Preparing for launch Launching / selling Life cycle

17. The infrastructure Therapy areas Infection Development Depts Large scale synthesis Formulation Manufacture Safety evaluation Clinical evaluation Regulatory Intellectual property Commercial activities Market research Quantifying opportunities Preparing for launch Launching and selling Life cycle

18.  Why develop a new anti-infective agent?  The infrastructure required, competition for resources  Really ‘new’, another variant or ‘a compound too far’?  Discovery and development.

19. A compound too far.............. ??

20.  -lactam antibiotics

21. Nucleus COOH penem N S O HH COOH carbapenem N O HH SNH penicillin N O COOH CH 3 3 COOH carbacephem N NH O COOH cephalosporin N NH S O

22. Outer membrane  -Lactamase Cytoplasmic membrane Periplasmic space Peptidoglycan

23. Penicillins  benzylpenicillin / methicillin or oxacillin  ampicillin / amoxycillin  amoxycillin + clavulanate  piperacillin  piperacillin + tazobactam Continuing problem of instability to  -lactamases

24. Cephalosporins  cefotaxime  ceftriaxone  ceftazidime  cefepime / cefpirome Problems of emergence of resistance, commonly  -lactamases

25. Carbapenems

26. Structures of meropenem and imipenem + cilastatin H OH CH 3 N CON CH 3 S COOH O H NH Meropenem NH Imipenem NHCH H OH CH 3 N S COOH O H NH S COOH NH 2 O COOH Cilastatin +

27. Gaps in the spectrum of carbapenems methicillin-resistant staphylococci some enterococci some pseudomonads ? B. cepacia S. maltophilia Newer molecules have exhibited toxicities not normally associated with  lactams !!

28. Quinolones

29. what has been ‘added’ since ciprofloxacin? what will be added in the future? toxicity seen in temafloxacin trovafloxacin grepafloxacin moxifloxacin clinafloxicin others struggling?

30. Really new........... genome-based target discovery

31. Model Genomes E. coli or S. cerevisiae essential for viability selectivity spectrum technical feasibility TARGETS Filters literature review knowledge/experience literature review knowledge/experience literature review knowledge/experience Antibacterial Antifungal

32. Genome-based target discovery new targets do not guarantee new drugs new targets have no ‘history’ how will they be viewed by Regulatory agencies ? how will you, the user, feel about a series of agents about which you know nothing ? will you reserve them as drugs to use last ? diversity in the compound-collection is very important when screening.

33.  Why develop a new anti-infective agent?  The infrastructure required, competition for resources  Really ‘new’, another variant or ‘a compound too far’?  Discovery and development.

34. World market for anti-infectives is ~$US 37 billion

35. anti-bacterials is ~$ 24 bn hospital anti-bacterials is $ 8.5 bn serious hospital anti-bacterials is $ 2.5 bn s/h respiratory is $ 0.7 - 1 bn.

36. The cost of developing a multi-indication anti-bacterial is ~ $US 400 - 600 million

37. No company can do everything, so....... Focus research in selected areas against drug-profiles which are based on medical need and commercial attractiveness.

38. New agents will come from genome-based programmes The process Select and validate a target design a 500,000 HTS identify hits and ‘sanitise’ progress chemistry select lead series optimise leads select candidate(s) for development. With attrition at every stage, you’r lucky to do this in 5 years.

39. Evaluating candidates for development (assume you have in vitro and in vivo activity) perform extensive laboratory studies on short-list pre-screen for toxicity assess pK in animals and model for human kinetics can it be manufactured? select candidate After these several years, is it still competitive? If this is a new target and a new chemical series there will be no precedent upon which to make judgements.

40. Developing a new agent (1) be sure of toxicological support for the compound a secure route of manufacture patent protection of the molecule and its route of synthesis secure resources for the pre-clinical phase the ‘proof of concept testing’ the complete clinical package to support both Regulatory and launch requirements.

41. Developing a new agent (2) decide upon which indications to trial, globally narrow-spectrum does not mean narrow indications select and access suitable clinical trial centers many are not acceptable to major Agencies co-ordinate microbiology, kinetics, clinical programme and all other components of a regulatory dossier plan launches in anticipation of acceptable licenses file your dossier(s) and be prepared to interact with and respond rapidly to questions hopefully, launch in first territories and prepare for others.

42. BUT................................. you can be well through the process when things change! IDSA guidelines new problems with an established class may result in changes in Regulatory requirements ESBLs had not been documented when cefepime was discovered.

43.  Why develop a new anti-infective agent?  The infrastructure required, competition for resources  Really ‘new’, another variant or ‘a compound too far’?  Discovery and development.

44. Summary the process is increasingly complex and expensive we all agree that new anti-infective agents are required conversely, the difficulty in discovering and developing new molecules in not appreciated fully some of the ‘problems’ and ‘needs’ require precise definition new agents will emerge only with the co-operation of providers, users and Regulators.