antti haapalinna 10th december 08 oulu1

Orion Corporation Orion Pharma 10.12.2008 1Antti Haapalinna Nonclinical R&D

Towards better risk management and theranostics with biomarker applications in

drug discovery & development

Antti Haapalinna, Ph.D. (Adjunct Professor)Director, Nonclinical R&D

Orion Corporation R&D, ORION PHARMA

BIO MEETS NANO AND IT 2008 9th-11th of December 2008. Oulu - Finland


Typical description of Pharmaceutical R&D

PreclinicalPharmacology

Preclinical Safety

Screening of millions ofcompounds

Idea MedicineOver 15 years

1 - 2 Products

Exploratory Development Full Development

Phase I Phase II Phase III

0 155 10

Clinical Pharmacology

Years: 5-8

DISCOVERY

• Drug discovery and development is a long and expensive process

• Average total investment is > 500 to 800 M€/ approved product

“for every 5000 new compounds identified, only 250 enter preclinical trials and only one in ten of these drugs are approved.”

Presenter

Presentation Notes

27) High attrition To turn out just one to two products requires about a hundred discovery projects or approaches, involving upwards of 7 million compound tests in early screening assays. This level of screening produces about a thousand compounds with some of the criteria we are looking for. Follow-up molecular design and sophisticated biological testing narrows the number of development candidates. Once safety is confirmed in animal studies, compounds are advanced into human clinical trials where efficacy, safety and toleration are confirmed.


Approximated costs /discovery phases

0

1 000 000

2 000 000

3 000 000

4 000 000

5 000 000

6 000 000

1 2 3 4

Euro

Target protein identificatio/ early validation

Proof of idea, Hit finding/ Lead generation

Lead optimization/ candidate selection

Development for phase I & IND/CTA application

2000 - 10 000molecules studied

200 - 600targeted synthesisand multiple test on variousproperties

One moleculeto phase I


Approximated costs / phases

0

50 000 000

100 000 000

150 000 000

200 000 000

250 000 000

TP POI LO&CS Pre to PhI Ph II Ph III

Discovery & development phases

Euro

Probability of successwhen entering phase 10% 18 %

66%

Number on molecules under evaluation /phase required to achieve one product on market 8 5

1,5

(Compiled and modified from CRM international 2007 Pharmaceutical Factbook & from Pharma 2020 The vision. Which path will you take ? by PriceWaterhouseCoopers)


Clinical efficacy 25%

Clinical safety 13%

Portfolio considerations 9%Low commercial value/

opportinity 5%

Toxicology 30%

Other 15%

Source: CMR International

OTHER:- preclinical efficacy 3%- differential clinical safety 3%- differential clinical efficacy 3%- clinical PK /BA 1 %- preclinical PK/ BA 1%- various 3%

Reasons for discontinuation of development

(26% in phase I)

(47% in phase II and55% in Phase III)


Nature

Analytical ChemistrySynthetic Chemistry

Combinatory chemistryHigh Throughput Screening

GenomicProteomic

1900 1960 1980 1990 2000

Qualitative acitivity-structure relationship

Development of drug discovery technologies

Computer-Aided molecular modelling

“Human genome”


General new technology ”HYPE” cycle

Time

Posi

tion /

inve

stm

ent

Heavy investments

Disappointment

Right applicationand benefits


PharmacologyToxicology

Biotransformation

What the drug does to the body

What the body does to the drug- duration of action

The main issues to be predicted, tested and documented

- active metabolites?- toxic metabolites

Effects of and/or onthe pathologicalprocess ?

MetabolomicsGenomicsProteomics


Systems Approach to Drug Discovery and Development

Pertubated conditionNormal condition

Healthy Diseased state

PhenotypemRNA ProteinDNA Metabolites

TRANSCRIPTOMICS METABOLOMICSPROTEOMICS

PROCESSING EXECUTION

TISSUES, CELLS, BLOOD, URINE

Analysis of molecular level changes

Improved understanding of human biology and molecular mechanisms involved in diseases and adverse effects; biomarkers


What is a biomarker ?

• Biological marker (Biomarker)A characteristic that is objectively measured and evaluated as an indicator of:

– Normal biological processes– Pathogenic processes– Pharmacologic responses to a therapeutic intervention.

Biomarkers definitions working group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharmacol Ther 2001;69(3):89-95.

Biomarkers may be genetic markers (sequence polymorphism); mRNA expression patterns; or protein markers, metabolites (clinical chemistry)… provided the biological relevance in relation to drug and disease (or toxic phenotype) are understood.


Expanding the concept of biomarkers

• Conventional clinical chemistry

• ECG• EEG• Neuropsychological tests

(non-diagnostic)• Sleep patterns• Depression -> stress

– hypothalamus -> ->hypophysis -> ->adrenal -> cortisol

• Nuclear receptors– CAR

• CYP isoenzymes

• Event related potential (ERP)– prepulse inhibition

• PET • SPECT• Functional MRI• MRI spectroscopy

– size of organs– spectroscopy from inside

of organs– spectroscopy of urine

(predicting liver damage; metabonomics)


Types of biomarkers• Translation Biomarker

a biomarker that can be applied in both a preclinical and clinical setting

• Disease Biomarkera biomarker that relates to a clinical outcome or measure of disease

• Efficacy Biomarkera biomarker that reflects beneficial effect of a given treatment

• Staging Biomarkera biomarker that distinguishes between different stages of a chronic disorder

• Surrogate Biomarkera biomarker that is regarded as a valid substitute for a clinical outcomes measure

• Toxicity Biomarkera biomarker that reports a toxicological effect of a drug on an in vitro or in vivo system

• Mechanism Biomarkera biomarker that reports a downstream effect of a drug

• Target Biomarkera biomarker that reports interaction of the drug with its target


Supporting the selection of the best targets

Better understanding of molecular mechanisms, proof-of-idea

Supporting safety / efficacy assessment in animal models,proof-of-concept

Predictive (exploratory)clinical efficacy and safety biomarkersProof-of-mechanism & Concept

Better understanding of the role of interindividual variability of genes in drug response

TARGET ID & CHARACTERISATION

NC RESEARCH & DEVELOPMENT

HIT IDENTIFICATION

LEAD GENERATION AND OPTIMISATION

CLINICAL R&D

Supporting the selection of the best drug candidates

Supporting the prediction of patient population who will benefit

Benefits of the Systems Approach to Drug Discovery and Development

Impact of innovative tools

Better understanding of target’s role in disease process and the biological systems that will be targeted

Potential impact of biomarkers


Nephrotoxicity BiomarkersExample


Supporting the selection of the best targets

Better understanding of molecular mechanisms, proof-of-idea

Supporting safety / efficacy assessment in animal models,proof-of-concept

Predictive (exploratory)clinical efficacy and safety biomarkersProof-of-mechanism & Concept

Better understanding of the role of interindividual variability of genes in drug response

TARGET ID & CHARACTERISATION

NC RESEARCH & DEVELOPMENT

HIT IDENTIFICATION

LEAD GENERATION AND OPTIMISATION

CLINICAL R&D

Supporting the selection of the best drug candidates

Supporting the prediction of patient population who will benefit

Benefits of the Systems Approach to Drug Discovery and Development

Impact of innovative tools

Better understanding of target’s role in disease process and the biological systems that will be targeted

Potential impact of biomarkers


0

10

20

30

40

50

60

70

80

90

Worsened No change Improved

WorsenedNo changeImproved

0

10

20

30

40

50

60

70

80

90

Worsened No change Improved

WorsenedNo changeImproved

Manage risk

Stop development

Examining the genetic polymorphism of target patient population in Phase II -> implications to planning of phase III as well as business implications

– identification of SNP cluster patterns that may predict efficacy

– identification of SNP patterns that may predict appearance of adverse events

(From McLeod and Evans, Ann Rev of Pharmacol and Toxicol, 2001: 41,101-121)

Need of


Pharmacogenomics: to identify variants enabling prediction of drug response including the occurrence of adverse reactions by systemic genomic analysis in

populations of treated subjects

Pharmacogenomics Applied to Drug Development

Drug Therapy Drug Selection Drug Discovery

Individual dose Patient subpopulation Target proteins

Cause of Disease ?Differential Diagnosis ?

Clinical Pharmacology & Therapeutics (2008); 84, 3, 306–309 doi:10.1038/clpt.2008.114 Individual Genomes Instead of Race for Personalized Medicine PC Ng1, Q Zhao1, S Levy1, RL Strausberg1 and JC Venter11J. Craig Venter Institute, Rockville, Maryland, USA

(establishedapplication)

(established…)


Examples - PharmacogenomicsHERCEPTIN Trastuzumab (Genetech)Finding patients who will benefit from

treatment• a humanized monoclonal antibody

against the ERBB2 receptor that is approved for the treatment of breast cancer.

• To receive therapy diagnosed overexpression of ERBB2 receptor has to be shown

• New laboratory test: SPOT-Light® HER2 CISH™ Kit, FDA approval, Jul 1 2008

WARFARINFinding optimal dosing strategy• CYP2C9 (PK), vitamin K epoxide

reductase gene (VKORC1) (PD)• Account for 30-35% of the variability.

BUCINDOLOLFinding patients who will benefit from

treatment• ARCA Biopharma, NDA Busindolol to

heart failure (Sept 2008):• Researchers announced that the heart drug

bucindolol was able to reduce the risk of deathfor any cause among 38 percent of patients sharing a genetic variation in beta 1-adrenergic receptor, when compared to a placebo arm.


+ application for theranostics

• Laboratory Corporation of America of Burlington and ARCA Discovery of Denver have entered into an exclusive collaboration to develop a commercial genetic test to aid in prescribing bucindolol (BT Catalyst, March-April, 2007)

– “…a genetically targeted heart failure drug in development by ARCA.”

Company Information (from web site)Laboratory Corporation of America® Holdings (LabCorp®) is much more than a routine clinical laboratory. As a pioneer in genomic testing and the commercialization of new diagnostic technologies, LabCorp is one of the world's largest clinical laboratories, with annual revenues of $4.1 billion in 2007. Headquartered in Burlington, North Carolina, LabCorp has approximately 26,000 employees and offers a broad range of genomic/esoteric tests. Listed under the ticker symbol LH on the New York Stock Exchange (NYSE), LabCorp tests more than 370,000 specimens daily for over 220,000 clients nationwide

http://findarticles.com/p/articles/mi_m0UFV

http://findarticles.com/p/articles/mi_m0UFV/is_1_21


DETECT DISEASE

STAGE DISEASE

PREDICT RESPONSE

TO TREATMENT

DETERMINE TREATMENT

EFFICACY

MONITOR TREATMENT COMPLIANCE

MONITOR PROGRESSION /RECURRENCE

BIOMARKERS

Challenges ?


SAMPLE PREPARATION

DATA ANALYSIS

ANALYTICAL PLATFORM

FROM DATA TO KNOWLEDGE !!! To make sense of huge amount of data

INTERPRETATION OF RESULTS IN BIOLOGICAL CONTEXT

COMMERCIAL BIOBANKS

Flow chart for systems pharmacology

PROPRIETARY BIOBANK

IN VITRO & IN VIVO STUDIES

Plan & study ! Clinical & nonclinical


GENE PROTEIN METABOLITE GENOTYPING

DATA MANAGEMENT

DATA INTEGRATION

DATA ANALYSIS

Database

Softwares

Integration tools

Data files Data files Data files

Data filesData files

Data files

Data files

Data filesData files

Data mining: Data integration & exploitation

FROM DATA TO KNOWLEDGE - To make sense of huge amount of data

Public databasesINTERPRETATION OF RESULTS IN BIOLOGICAL CONTEXT

Data files


Approximated costs / phases

0

50 000 000

100 000 000

150 000 000

200 000 000

250 000 000

TP POI LO&CS Pre to PhI Ph II Ph III

Discovery & development phases

Euro

Probability of successwhen entering phase 10% 18 %

66%

Number on molecules under evaluation /phase required to achieve one product on market 8 5

1,5

(Compiled and modified from CRM international 2007 Pharmaceutical Factbook & from Pharma 2020 The vision. Which path will you take ? by PriceWaterhouseCoopers)

Translational research, help for risk management ?


Institute Y

University XPatient phenotype clustering

Molecular genetic analyses of phenotype clusters

Verification of mechanism of drug actionPrediction of patient population to benefit of drug

Imagingcompany

Technologycompany

Diagnosticcompany

BioInform.comp

Disease ModelsCROs

Pharma-companies

Multiple stakeholders are needed to achieve world class breakthroughs

YES, but

Hospital Z

Increase understanding of biological mechanismsBetter prediction of drug pharmacokinetics and pharmacodynamics in vivo in humanImprove efficacy of the drug

Adjust dosing based on a biomarkerIdentify genetic markers for drug responseUse genetic tests to select responders for Phase III studies

Improve SafetyShorten development time and reduce development costs

Test for valid and probable valid biomarkersSupport claims in the application for a new drug

Benefits:


Drug discovery and development goal

• To provide a safe and effective therapy with meaningful clinical benefit

New scientific advances and use of new modern methods and approaches will help us to reach this important goal!

– Enabling to predict efficacy and safety at earlier phases of development (”fail early - fail cheap”)

– Enabling to identify who benefits (does not benefit) from a treatment– Enabling to identify who is at risk (not at risk) for adverse events

SYNERGIST OPPORTUNITY; DISCOVERY OF NEW DIAGNOSTICS TOOLS- Early detection of diseases- Prediction of treatment responsiveness

antti haapalinna 10th december 08 oulu1

Health & Medicine