Welcome to AstraZeneca

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Welcome to AstraZeneca

• Life Inspiring Ideas

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Key Facts about AstraZeneca

• One of the world's leading pharmaceutical
  companies employing over 58,000 people.
• Spends over 11 million every working day on R
  D (Total RD spend in 2002 3.1 billion)
• Strong RD pipeline, including a number of
  significant innovations.
• Active worldwide with
• Sales in over hundred countries
• Manufacturing in twenty countries.
• Research Centres in five countries.
• Sales in 2002 totalled 17.8 billion, with an
  operating profit of 4.4 billion.

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Global RD Sites in AstraZeneca
Södertälje Mölndal Lund
Wilmington Montreal Boston
Reims
Bangalore
Charnwood Alderly Park
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Key Facts about AstraZeneca RDGlobal Discovery

• AZ employs more than 7,000 people at nine major
  sites in five countries
• In 2002, invested about 3.1 billion in RD
• Key Therapy Areas include
• Oncology/Infection
• Cardiovascular/GI
• CNS/Pain Control
• Respiratory/Inflammation.

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Key Facts about AstraZeneca RDGlobal Development

• AZ employs approximately 4,000 people at six
  major research sites in the US, the UK and Sweden
  but functions as an integrated global structure.
• Employs people with skills in
• Clinical research
• Regulatory affairs
• Pharmaceutical development
• Process chemistry.

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AstraZeneca Entities in India

• AstraZeneca Research Foundation India (AZREFI)
• A non profit organisation fostering biomedical
  research related to Infectious Diseases and Drug
  Discovery
• AstraZeneca Pharma India Limited (AZPIL)
• International Sales and Marketing Office of
  AstraZeneca PLC (ISMO) (formerly called as
  Astra-IDL).
• AstraZeneca India Private Limited (AZIPL)
• Drug Discovery Research Centre and is a wholly
  owned subsidiary of AstraZeneca PLC.

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AZREFI

• Non-profit organization supporting research in
  the anti-infectives area.
• Maintain a scientific library with access to over
  a 100 journals relating to biological and
  chemical sciences. (accessible to the public)
• Organize and conduct international scientific
  symposia/seminars/workshops.

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ASTRAZENECA RD

• 1985-1986
• Astra Research Centre India (ARCI) founded as a
  society.
• Laboratories set-up in Malleswaram.
• 1987-1995
• Astra AB fully funded all research activities in
  India.
• Processes for the production of Molecular Biology
  Tools, building blocks for peptide synthesis,
  production of recombinant proteins were developed
  and transferred to companies
• Initiated drug discovery projects in infectious
  diseases like malaria and tuberculosis
• June 1999
• Global merger of Astra AB and Zeneca PLC
• June 2003
• AstraZeneca moves to the state of the art
  facility to conduct research in TB

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The Opportunity
AZ Wishes to Make a Contribution to Developing
World Medicine
Todays smaller markets, can be tomorrows
blockbuster
Opportunity to work closely with other AZ
infection units
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Drug Discovery Process

• A hit/lead in drug discovery can be identified
  from
• Endogenous substrate of the enzyme
• An existing drug (Fast Follower)
• Genomics
• Proteomics
• High Throughput Screening (HTS)
• Serendipity

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Genome Based Target Discovery

• Truly new drugs and not variants of existing
  drugs
• Imparts Selectivity/Specificity of the targets
• New targets have no history
• New agents are new in the market
• Diversity is important in screening for leads
• New targets do not necessarily guarantee new
  drugs
• Will they be reserved as the last resort?

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High Throughput Screen
discretes combi-chem mixtures natural
products receptors standards
IC50 Elastase 53.67
IC50 Thrombin 78.46
2º SCREENING
MANAGE SAMPLES
2º screening IC50, Dose Response, KI
REVIEW RESULTS
MANAGE PLATES
Library s/w Reg Systems Ext. Suppliers
RUN ASSAY
REVIEW TESTSETS
DEVELOP ASSAYS
In Excel. Template builder.
CREATE TESTSETS
AUTOMATION
TestSet Status AWAITING REVIEW ACCEPTED REJECTED R
EADY
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The HTS Path to New Drugs

• Select and validate a target
• Design and run a HTS
• Identify hits clean up (HI)
• Progress chemistry
• Select lead series (LI)
• Optimise leads (LO)
• Select candidate for development (CD)
• Time 5-10 years
• Cost US 400-600 million

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The Process Leading to Candidate Drugs

• Goals include improvements in
• Potency
• Selectivity
• ADME
• Toxicity

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Drug Discovery Process - New Model
Months 12 6 12
18 6 36 12
102
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Why TB?

• Medical need
• Expertise
• Infrastructure
• Genomics
• Focus

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Tuberculosis Medical Need

• gt 16 million cases
• 1 refractory to present therapy
• 3 million deaths
• 8 million new cases
• No new drug in the last 40 years
• HIV impact

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Tuberculosis Issues

• Disease diagnosis
• Need for sterilisation
• Multiple drug therapy
• Duration of therapy/ Relapse
• Latency
• (Multiple) drug resistance

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Dynamics of TB
Exposure
No Infection 70
Infected 30
Primary TB Disease
Latent TB Infection
Post-Primary TB Disease
HIV
Normal
2 23 per lifetime
5 10 per year
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India - TB Burden

• India has more cases of tuberculosis than any
  other country in the world
• Twice as many cases as China
• Incidence rate of more than 200 per 100000

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TB is a Leading Killer of Adults

• TB kills more adults than any other infectious
  disease
• Because it affects adults, tuberculosis causes
  enormous social and economic disruption
• The burden of TB is enormous but is hidden by
  stigma and poor diagnostic quality

Estimated number of deaths, India 1999
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TB Affects Young Adults Most
New smear-positive TB, RNTCP, 1993-2000
Thousands

• TB may create more orphans than any other disease
• Recent studies suggest that every year in India
  more than 300,000 children leave school on
  account of their parents TB

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Cause of Death in HIV Infection
Tuberculosis
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Current Therapy (DOTS)Directly Observed Therapy
Short Course

• First 2 months (Induction Phase)
• Isoniazid (I) Rifampicin (R) Ethambutol (E)
  Pyrazinamide (P)
• Next 4 months (Continuation Phase)
• Isoniazid Rifampicin (R)

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TB Treatment in Humans-Relapse
gt90
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An ideal new anti-TB compound

• Sterilising activity
• Effective against latent organisms
• Effective therapy in weeks
• Effective as monotherapy
• New mechanism of action
• Not used or inactive against other infections
• Active against M.avium or M.intracellulare

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The Objective

• Discover novel compounds efficacious in the
  treatment of Tuberculosis
• The new compounds should enable a shortening of
  the present duration of therapy to four months.

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Shortening of Therapy

• Target lt 4 months
• Why

Todays treatment - 6 months costs(1000/patien
t) by DOTS 95 success Treatment lt 4
months- consequences
20 patients
DOTS
50 patients
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Main Causes of Antibiotic Failure

• False Failure
• Erroneous diagnosis
• Underlying disease unaffected by antibiotics
• Inactivation of the antibiotic
• Failure related to the patient
• Compliance failure
• Inappropriate administration route
• Immunodepressed hosts
• Pharmacological failures
• Insufficient amount or drug inappropriately
  administered (route and regimen)
• Insufficient attention to Pharmacodynamic
  parameters
• In situ inactivation
• Factors related to the microorganism
• Wrong pathogen
• Resistance acquired during treatment
• Insufficient bactericidal activity, bacterial
  persistence
• Inoculum effect

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THE BANGALORE UNIT

• The Infrastructure - Equipped with state of the
  art instrumentation for full fledged drug hunting
  capability
• In vitro disciplines including throughput
  screening facilities with compound libraries
• In vivo disciplines like ADME, Animal Sciences
• Chemistry including Medicinal and Synthetic
  chemistry

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Working with Mycobacterium Tuberculosis

• M.Tb is an infectious pathogen (Class 3) and
  hence the facility must adhere to highest levels
  of bio-safety
• The current facility has a bio-safety level three
  facility
• M.Tb are very slow growing bacteria
• They divide once every 24 hours (compare to
  e.coli which divides every 20 min)
• susceptibility testing takes about 8 days.
• PK-PD parameters are ill defined necessitating
  the use of lengthy animal models (8-10 weeks)
  very early.

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Animal Model for Tuberculosis

• Species Balb/c mice
• Infection MTB H37Rv
• Route Inhalation
• Infection-Dose Interval 4 wks
• Route Per Oral
• Dosing-Sac Interval 1 day
• Sampling cfu per lung
• Analysis Log10cfu/lung vs PK/PD parameters

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In addition, SCIT division takes care of compound
acquisition, management and dispensing for HTS.
HTS facility being set up in Bangalore.
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Our Goal

• To nominate an anti-TB drug for safety testing by
  2006

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RD, Bangalore - Current Staff Profile

• 2003- 70 research staff 18 in operations
• 2004- 85 research staff 20 in operations
• Expertise relevant to current objective
• Drug hunting
• Working with a class 3 pathogen
• Molecular biology and Protein engineering -
  supporting Astra since 1987
• Chemistry and ADME being strengthened

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Our Pride

• One of the first major pharmaceutical to devote
  an entire research unit to a Developing World
  Disease.
• A corporate commitment permeating throughout the
  global organisation to make this happen.