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Pioneering Personalized Medicine

through Partnering

Jörg Teubner

Marketing Manager Personalized Healthcare, QIAGEN

November 19, 2011

Personalized MedicineDefinition

Definition of Personalized Medicine:

Personalized Medicine is the use of information about a

person's genes, proteins and environment to prevent and

treat disease.

Molecular assays measuring levels of proteins, genes or

specific mutations deliver the neccessary results to provide a

specific therapy for an individual's condition by stratifying

disease status, selecting the proper medication and

tailoring drug dosages to a particular patient's specific

condition and needs.

The challenge: Selection of the suitable drug

Valuable drugs go to unsusceptible patients

Source: Brian B. Spear, Margo Heath-Chiozzi, Jeffrey Huff, “Clinical Trends in Molecular Medicine, Volume 7, Issue 5, 1 May 2001, Pages 201-204

Anti-Depressants

Asthma

Diabetes

Arthritis

Alzheimer

Cancer

62%

60%

57%

50%

30%

25%

Drug Efficacy

= Drug does not work

.A specific drug works in some

patients, in some not.

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IPASS (IRESSA Pan-ASia Study): randomised, parallel-group study to assess the efficacy, safety and tolerability

of gefitinib (novel drug) versus carboplatin/paclitaxel (standard therapy) as first line treatment in a clinically

selected patient population from Asia.

IPASS Study

Sample & Assay Technologies

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma.

TS. Mok, Y-L. Wu, S. Thongprasert, C-H. Yang, D-T. Chu, N, Saijo, et al., NEJM, Sep 2009; 361: 947-957.

Example: Non-small cell lung carcinoma (NSCLC)

Drug efficacy correlates with EGFR mutation status

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"Routine use of KRAS mutational testing in colorectal cancer patients could save the

health care system more than $600 million in drug costs alone."

Example: metastatic Colorectal carcinoma (mCRC)

Drug efficacy correlates with KRAS mutation status

KRAS mutation negativeKRAS mutation positive

Panitumumab+BSC

Best Supportive Care

(BSC)

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer.

R.G. Amado, M. Wolf, M. Peeters, et al., Journal of Clinical Oncology, Vol 26, (10), 2008: pp. 1626-1634

Clinical trial demonstrating that patients with a wild type KRAS gene in DNA from colorectal cancer cells,

showed significant benefit to treatment with Panitumumab (“Vectibix”). Patients whose tumor contained

mutated KRAS gene had no drug response.

Panitumumab+BSC

Best Supportive Care

(BSC)

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Pathology today and tomorrow

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Pioneering Personalized Medicine through Partnering

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Complex

sample

Sample and Assay Technologies

1Sample

Technologies2

Pure

Analyte3

Assay

Technologies4

Target Detected

Golgi apparatus, Glycoproteins, Microtubules, Mitochondria, Mitochondrial

nucleic acids, Vacuoles, Talin, Nucleolus, Polymerases, Ceramides,

Chromosomes, Chromatin, mRNA, Cytoplasm, Leucocytes, Sugars, Lipids,

Salts, Urea, Carbonic acids, Cofactors, Precursors, Hemoglobins,

Erythrocytes, Monocytes, Smooth endoplasmatic reticulum, Macrophages,

Thrombocytes, Platelets, Lymphocytes, Basophils, Eosinophils, Neutrophils,

Megacaryocytes, Plasma, Clotting factors, Actin, Microfilaments, Serum,

Fibrin, Lysosomes, Ezrin, DNA, Hemaglobins, Heptaglobins, Transferrin,

Fibrinogen, Serum albumin, tRNA, Salts, Polymerases, Centrioles,

Immunoglobulins, DNA,, Cytokines, Angiotensins, Chemokines, Bradykines,

Plasma membranes, Ribosomes, Actin, Vesicles, Complement components,

Nuclei, Rough endoplasmatic reticulum, Nucleoli, Golgi apparatus,

Glycoproteins, Microtubules, Mitochondria, Mitochondrial nucleic acids,

Vacuoles, Talin, Nucleolus, Polymerases, Ceramides, Chromosomes,

Chromatin, mRNA, Cytoplasm, Leucocytes, Sugars, Lipids, Salts, Urea,

Carbonic acids, Cofactors, Precursors, Hemoglobins, Erythrocytes,

Monocytes, Smooth endoplasmatic reticulum, Macrophages, Thrombocytes,

Platelets, Lymphocytes, Basophils, Eosinophils, Neutrophils,

Megacaryocytes, Plasma, Clotting factors, Actin, Microfilaments, Serum,

Fibrin, Lysosomes, Ezrin, Hemaglobins, Heptaglobins, Transferrin,

Fibrinogen, Serum albumin, tRNA, Carrier proteins

Golgi apparatus, Glycoproteins, Microtubules, Mitochondria, Mitochondrial

nucleic acids, Vacuoles, Talin, Nucleolus, Polymerases, Ceramides,

Chromosomes, Chromatin, mRNA, Cytoplasm, Leucocytes, Sugars, Lipids,

Salts, Urea, Carbonic acids, Cofactors, Precursors, Hemoglobins,

Erythrocytes, Monocytes, Smooth endoplasmatic reticulum, Macrophages,

Thrombocytes, Platelets, Lymphocytes, Basophils, Eosinophils, Neutrophils,

Megacaryocytes, Plasma, Clotting factors, Actin, Microfilaments, Serum,

Fibrin, Lysosomes, Ezrin, DNA, Hemaglobins, Heptaglobins, Transferrin,

Fibrinogen, Serum albumin, tRNA, Salts, Polymerases, Centrioles,

Immunoglobulins, DNA,, Cytokines, Angiotensins, Chemokines, Bradykines,

Plasma membranes, Ribosomes, Actin, Vesicles, Complement components,

Nuclei, Rough endoplasmatic reticulum, Nucleoli, Golgi apparatus,

Glycoproteins, Microtubules, Mitochondria, Mitochondrial nucleic acids,

Vacuoles, Talin, Nucleolus, Polymerases, Ceramides, Chromosomes,

Chromatin, mRNA, Cytoplasm, Leucocytes, Sugars, Lipids, Salts, Urea,

Carbonic acids, Cofactors, Precursors, Hemoglobins, Erythrocytes,

Monocytes, Smooth endoplasmatic reticulum, Macrophages, Thrombocytes,

Platelets, Lymphocytes, Basophils, Eosinophils, Neutrophils,

Megacaryocytes, Plasma, Clotting factors, Actin, Microfilaments, Serum,

Fibrin, Lysosomes, Ezrin, Hemaglobins, Heptaglobins, Transferrin,

Fibrinogen, Serum albumin, tRNA, Carrier proteins

DNA Information

ASSAY

Technologies

SAMPLE

Technologies

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therascreenFully validated workflows

Diagnostic ResultsPatient

sampleSample technologies Assay technologies

Sample

PAXgene

Tissue

“Classical”

FFPE TissueAutomated: QS-RGQ

Manual: QIAamp (eg. DNA FFPE)

RotorGene-Q

PyroMark Q24

Comprehensive&

Complex Tasks

Selective &

Sensitive Tasks

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therascreen

Reliability

Regulatory status (CE-IVD)

Workflow solutions

Short Turn around time

ARMS Scorpions qPCR

Highest Sensitivity on the

market

Selective mutation detection

Ease of use

One-step procedure

Pyrosequencing

Comprehensive results in

real-time

Complex mutation testing

with simple data interpretation

Small amount of starting material

therascreen

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therascreen RGQ PCR workflow

~ 140main ~ 15 min~ 2,5 h

DNA purificationDNA

Assessment

Result

Interpretation

Mutation

Testing

therascreen (RGQ)

PCR Kits

Rotor-Gene Q Analysis Software

The PCR procedure takes less than 3h.

QIAamp DNA FFPE

Tissue Kit (56404)

“optional”

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Features of the therascreen PCR portfolio

QIAGEN Bidirectional DNA

Sequencing

Lower Limit of Detection <1% 25-30%

Analytical Sensitivity 100% 70-75%

Amplicon Size ~100bp 200bp

Procedure time (ex DNA extn) <3h 11h

Complexity Low High

Result Output Objective Subjective

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Pyrosequencing workflow

~ 2h ~ 10-60 min~ 15 min

DNA purification PCR PyrosequencingSample prep

therascreen Pyro

Kits

PyroMark Q24

Vacuum Prep Workstation

PyroMark Q24

PyroMark Q96ID

PyroMark Q96MD

Pyrosequencing provides quantitative results in a sequence context

in as little as 1 hour after PCR

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Features of the therascreen Pyro portfolio

therascreen Pyro KitsBidirectional

DNA Sequencing

TAT ~ 3h 11h

Regulatory Status CE-IVD marked assays n.a.

Information output Sequencing data Sequencing data

Starting materialHighly fragmented DNA in small

amounts (<10ng per reaction)

DNA shouldn’t

be too bad in

quality

Workflow SolutionWorkflow validation – from

Sample to Result– – –

Robustness +++ +

Result interpretation“one-click” result – easy

interpretation

Quite complex

and time

consuming

Sensitivity ~ 5% ~ 25% and more

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therascreen Pyro Kits

Specification Assay Design Mutations

KRAS Prescription of Erbitux & Vectibix in mCRC

patients, only when KRAS wt is present in the

cells

2 PCR + 2

Sequencing rxn

Plug-in

G12A G12D G12S G12V G12R

G12C G13D

Q61H Q61E Q61L

EGFR Detection of mutations & deletions in E18 –

E21. Important for Iressa and Tarceva in

mNSCLC first line therapy

4 PCR + 5

Sequencing rxn

Plug-in

G719S G719A G719C S768I

T790M L858R L861Q L861R

Deletions (20 most common ones)

BRAF Mutations in the BRAF occur mainly in

Melanoma (Zelboraf (Vemurafinib)

2 PCR + 2

Sequencing rxn

Reverse assay

V600E G464V G469A

V600M G464E G469V

V600A G466V G469E

V600G G466E

NRAS Mutations in NRAS codon 12, 13 & 61

metastatic colorectal cancer (mCRC) &

melanoma tumors

2 PCR + 2

Sequencing rxn

G12D G12S G12C G12V G12A

G12R G13D G13R G13V G13C

G13A G13S Q61L

Q61P Q61E Q61R Q61K Q61H

MGMT

“MBA”

Involved in repairing alkylated DNA.

Inactivation of the MGMT-gene leads to tumor

formation

1 PCR + 1

Sequencing rxn

48 rxn Kit !

4 CpG sites

UGT1A1

“MBA”

Only commercial assay on the market that can

detect var *6 & var *28 in the UGT1A1 gene

2 PCR + 2

Sequencing rxn

*6 = Gly Arg

*28 = 6 7 TA repeats

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Pioneering Personalized Medicine through Partnering

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Patient flowBased on NSCLC/EGFR testing

Origination

Primary Care

Evaluation

Specialist

Evaluation

Diagnosis

1st Line

Treatment

Fulfilment,

Adherence,

Re-evaluation

Maintenacne

Treatment

2nd Line Tx

3rd Line Tx

Patient

classification

Pathologist

Pathologist

Oncologist

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Conferences and educational events

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Pioneering Personalized Medicine through Partnering

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The CDx roadmap - stages in the life of a CDx

Used by pharma on

clinical trial patients

Development and

Regulatory Expertise

Used by diagnostic

labs on samples of

„real“ patients

Platform and product

distribution and marketing

Identify BiomarkersDevelop

Approved CDxSell CDxBiomarker

Discovery

Tools for Biomarker

Selection

Used by pharma on

preclinical and clinical

samples

Used by pharma on

model systems (cell-

lines)

Tools for Biomarker

Discovery

Drug development

Phase I and II

Drug development

Phase II and III Sell Drugs

Drug discovery

Pharma R&D

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TOMTOVOK™

Zelboraf

BKM120

QIAGEN partners:

and many more ...

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Your benefit: kits detecting clinical relevant mutations

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Pioneering Personalized Medicine through Partnering

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mCRC patients

11.250

new patients / year

~ 44.000€

per patient

KRAS testing for all patients

300€/patient

= 3,4M€Panitumumabtreatment incl. testing

35.6%

of all patients carry

KRAS mutations

Panitumumab for wtKRAS

368,3M€

Total costs

493M€

Total savings

121,3M€

each year

Total costs

371,7M€

Panitumumabtreatment w/o testing

Cost-EffectivenessCost saving-example for KRAS testing in mCRC (Turkey)

Source: based on GICS 2009: Huge cost savings from KRAS testing in Metastatic Colorectal Cancer, http://globocan.iarc.fr/ and Gelbe Liste 2011

+

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Pioneering Personalized Medicine through Partnering

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Pioneering Personalized Medicine through Partnering

Thanky you very much for your attention