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Pharmaceutical aspects of the development of anti-infectives
Dr Jeffrey R Edwards
Infection Therapy Area
AstraZeneca
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.
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.
RESISTANCE
• 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 .........
• resistance varies between countries
• within hospitals, ITUs have the problems
• resistance is seen in the community.
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
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
Untreatable bacteria
• multi-resistant staphylococci
• vancomycin-resistant enterococci
•Corynebacterium jeikeium
•Mycobacterium tuberculosis
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 !
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.
The infrastructureTherapy areas
• GI
• Cancer
• CNS
• CVS
• Pain
• Respiratory
• Infection
The infrastructureTherapy areas
• GI
• Cancer
• CNS
• CVS
• Pain
• Respiratory
• Infection
Commercial activities
• Market research
• Quantifying opportunities
• Preparing for launch
• Launching/ selling
• Life cycle
The infrastructureTherapy 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
The infrastructureTherapy 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
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.
A compound too far .............. ??
-lactam antibiotics
Nucleus
COOH
penem
N
S
O
H H
COOH
carbapenem
NO
H H
SNH
penicillin
NO
COOH
CH3
CH3
COOH
carbacephem
N
NH
OCOOH
cephalosporin
N
NH S
O
Outer membrane
-Lactamase
Cytoplasmic membrane
Periplasmic space
Peptidoglycan
Penicillins
benzylpenicillin / methicillin or oxacillin ampicillin / amoxycillin amoxycillin + clavulanate piperacillin piperacillin + tazobactam
Continuing problem of instability to -lactamases
Cephalosporins
cefotaxime ceftriaxone ceftazidime cefepime / cefpirome
Problems of emergence of resistance, commonly -lactamases
Carbapenems
Structures of meropenem and imipenem + cilastatin
HOH
CH3
N
CONCH3
CH3
CH3
S
COOHO
H
NH
Meropenem
NH
Imipenem
NHCH
HOH
CH3
NS
COOHO
H
NH
SCOOH
NH2
OCOOH
Cilastatin
+
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 !!
Quinolones
Quinolones
• what has been ‘added’ since ciprofloxacin?• what will be added in the future?
• toxicity seen in
• temafloxacin• trovafloxacin• grepafloxacin• moxifloxacin• clinafloxicin• others struggling?
Really new ...........
genome-based target discovery
Model GenomesE. coli or S. cerevisiae
essential for viability
selectivity
spectrum
technical feasibility
TARGETS
Filters
literature reviewknowledge/experience
literature reviewknowledge/experience
literature reviewknowledge/experience
Antibacterial Antifungal
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.
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.
World market for anti-infectives is ~$US 37 billion
• World market for anti-infectives is ~$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.
The cost of developing a multi-indication anti-bacterial is
~ $US 400 - 600 million
No company can do everything, so .......
Focus research in
• selected areas
• against drug-profiles which are based on
• medical need and
• commercial attractiveness.
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.
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 therewill be no precedent upon which to make judgements.
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.
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.
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.
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.
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.