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

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.

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 !

The infrastructureTherapy areas

• GI

• Cancer

• CNS

• CVS

• Pain

• Respiratory

• Infection


• GI

• Cancer

• CNS

• CVS

• Pain

• Respiratory

• Infection

Commercial activities

• Market research

• Quantifying opportunities

• Preparing for launch

• Launching/ selling

• Life cycle


• GI

• Cancer

• CNS

• CVS

• Pain

• Respiratory

• Infection

Development Depts.

• Large scale synthesis

• Formulation

• Manufacture

• Safety evaluation

• Clinical evaluation

• Regulatory

• Intellectual Property


• Market research



• Launching / selling

• Life cycle


Infection

Development Depts

• Large scale synthesis

• Formulation

• Manufacture

• Safety evaluation

• Clinical evaluation

• Regulatory

• Intellectual property


• Market research



• Launching and selling

• Life cycle

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



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.

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.

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.

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

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