Pharmaceutical aspects of the development of anti-infectives

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 • Enterobacteriaceae • ESBLs, notably in Klebsiella • chromosomal b -lactamases • Enterobacter, Citrobacter etc • Salmonella typhi • Shigella dysenteriae • Pseudomonas aeruginosa • Burkholderia cepacia • Stenotrophomonas maltophilia • multi-resistant staphylococci • penicillin-resistant pneumococci • macrolide-resistant group-A streptococci • VAN-R enterococci • Corynebacterium jeikeium • Mycobacterium tuberculosis

8. Limited choice of therapy • penicillin- and macrolide-resistant pneumococci • macrolide-resistant Group A streptococci • ESBL bearing Enterobacteriaceae • Enterobacteriaceae over-expressing chromosomal b-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 • Commercial activities • Market research • Quantifying opportunities • Preparing for launch • Launching / selling • Life cycle • Development Depts. • Large scale synthesis • Formulation • Manufacture • Safety evaluation • Clinical evaluation • Regulatory • Intellectual Property

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

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. b-lactam antibiotics

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

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

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

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

25. Carbapenems

26. Structures of meropenem and imipenem + cilastatin CH3 OH CH3 H CON H CH3 CH3 S NH N O COOH Meropenem N H 2 OH S H H C OOH + CH3 CH NH NH S N O N H O COOH COOH Imipenem 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 b-lactams !!

28. Quinolones

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

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