Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

1The screen versions of these slides have full details of copyright and acknowledgements

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Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim, PharmD, PhD, DABCC, FACBDirector-Function Lead, Clinical Biomarkers,

Daiichi-Sankyo, Inc.

ahalim@dsi.com, abdelbasethalim@gmail.com

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Topics

• Why BM in drug development!

• Potential applications of BM in drug discovery

• Challenges & possible mitigations

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Stages of drug development

6-7y

6-7y

1-2y

1

Number of subjects/trial

20-100

100-500

1,000-10,000

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

2The screen versions of these slides have full details of copyright and acknowledgements

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Projects started between 1990 and 2004 in the United States, Europe and Japan

Attrition in drug development

Pammolli et al., The productivity crisis in pharmaceutical R&D Nature Rev Drug Disc, June 2011

The average time of development from patenting to commercialization —has increased from 9.7 years for products launched during the 1990s

to 13.9 years for products launched from 2000 onwards

PreclinicalPIPIIPIIIRegistration

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Increase in drug development cost - Eroom’s law

Scannell et al., Nature Reviews, 2012

6Too high

development cost

Current drug development strategies are unsustainable

Disease-patients

heterogeneity

Poor in-vivo & in-vitrodisease models

Hesitancy to terminate

early inconclusive

data!

Large phase III trials to demonstrate clinical utility

Too many late failures for lack

of efficacy

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

3The screen versions of these slides have full details of copyright and acknowledgements

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Number of hits for biomarkers-related publications in PubMed

122X

16X

1580X

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How Pharaohs detected pregnancy?A woman’s urine

Barley

Wheat grow 1st Barley grow 1st

♀ baby ♂ baby No pregnancyNeither grow

Testing of this pregnancy theory in 1963 showed 70% predictive value

Wheat

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Biomarkers in drug development

Safety PD

Surrogate• Can substitute

for a clinical endpoint

• Can be usedfor registration

• Ex: PT (INR), Glucose, HbA1c, LDL-C, BP, CD4 count and HIV-1 RNA for AIDS

• Predict/correlate with disease outcome without therapy

• ER status in breast cancer

• CTC count

Exploratory• No enough

evidence to link BM to clinical outcome or to substitute a clinical endpoint

• Support internal decision-making

• Hypothesis generation

• Ex: gene expression, proteomics

CDx

Common• Liver FT

• Renal FT

• CBC

Specialized• LDH

• MetHb

Prognostic Predictive• Predict response

to therapyPOM/efficacy

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

4The screen versions of these slides have full details of copyright and acknowledgements

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PG biomarkers in FDA-approved drug labels; April, 2013

119 BM in 108 drugs

• PG info can describe:– Indication, contraindication, dosage, warning,

– Mechanisms of drug action

– Polymorphic drug target and disposition genes

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Personalized medicine:potential value & benefits

• Pharmaceutical companies

– Enhance drug development and demonstrate better efficacy outcome

• Clinicians, patients, and regulatory bodies

– Effective and safe therapeutics

• Diagnostic companies/labs– Use well characterized subjects to submit a diagnostic claim

at low/no cost or even gain

• Payers– Reduced treatment costs

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Vemurafenib (Zelboraf)/BRAF mutation test

EOP1 meeting with FDA, development of CDx for BRAFV600E

mutation was discussed

Chapman et al., NEJM, 2011

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

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How can a biomarker be useful?

• Biologically/clinically meaningful– Differentiate between normal/disease or response/

no-response, qualitatively or quantitatively

• Analytically valid and well-performing assay– Signal can be distinguished from background noise

– Signal is reproducible

• Good quality samples

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Expectations from biomarker results

• Ideal– A patient result from different labs are very close

– A biomarker data can be used to bridge between different relevant developing programs

• Realistic– A patient results from different labs are within reasonable TAE

– A lab result should not misclassify a subject: normal/patient

– A biomarker results from different studies for a developing program can be integrated

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Challenges

• Do we understand the biology?

• Can we get the right sample?

• Do we have the right assay validated?

• Lack of traceability:– Lab-to-lab

– Within-lab: instrument-to-instrument

– Or even, within-lab, within-instrument: reagent lot-to-lot

• Great disconnect between Dx industry and pharma

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

6The screen versions of these slides have full details of copyright and acknowledgements

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LDL-C and HDL-C predict CHD

http://www.iom.edu/~/media/Files/Activity%20Files/Research/BiomarkersChronDisease/2010-JUN-21/Krauss.ashx

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Inadequate understanding of biology• Endothelial lipase gene (LIPG Asn396Ser) that raise plasma

HDL cholesterol do not seem to lower risk of myocardial infarction

• This raises the question whether raising of HDL cholesterol therapeutically would translate into the expected clinical benefit

Voight et al., The Lancet online May 17, 2012

Harrison et al., Comments, The Lancet online May 17, 2012

Plasma HDL-C concentrations in carriers versus non-carriers of the Ser allele at the LIPGAsn396Ser polymorphism;

Error bars = SE; FHS = Framingham Heart Study; CCHS = Copenhagen City Heart Study; MDC = Malmo Diet and Cancer Study; ARIC = Atherosclerosis Risk in Communities Study

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Intra-tumor heterogeneity

• 63 to 69% of all somatic mutations not detectable across every tumor region

• Gene-expression signatures, allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity

• Phylogenetic reconstruction revealed branched evolutionary tumor growth

• Authors suggest better sampling procedure including multiple biopsies

Gerlinger et al., NEJM, 2012

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

7The screen versions of these slides have full details of copyright and acknowledgements

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Can we have the right tissue quantity and quality?

4 CNB: H&E onlyQNS for EGFR/KRAS

H&E onlyQNS for EGFR/KRAS

20Tietz; Clin Chem, 1979

21 Halim, 2012

Blood hemoglobin: example of standardized assays

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

8The screen versions of these slides have full details of copyright and acknowledgements

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Perceived level of confidence in a laboratory test

Assay develop.

Assay valid.

CLIA: Clinical Laboratory Improvement Act?

CAP: College of American Pathologists?

Yes Yes

Yes Yes Yes

Yes Yes Yes Yes

YesYesYesYesYes

Yes Yes Yes Yes Yes Yes

Yes Yes Yes Yes Yes Yes Yes

Standard of care

CLIA CAP Major lab

Level of confidence

Can beYes

Can be Can be

Off-shelf kit

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Regulated molecular Dx!

• 30% of the HER2 tests have the wrong results; As a consequence, some patients are treated wrongly (Medscape: National Comprehensive Cancer Network (NCCN) 16th Ann Conference, Mar 12, 2011)

• Since 1998, herceptin has been used to treat more than 1.2 million people with HER2-positive breast cancer worldwide (Roche, 2012)

• Roughly 20% of breast cancer is HER2+; The average false + rate of HercepTest is 18%; In fact, one study (Perez et al., 2006) showed 25% false positive rates for labs using tests other than HercepTest (DAKO package insert)

http://www.roche.com/media/media_releases/med-cor-2012-06-11.htm http://www.dako.com/28633_04may10_herceptest__brochure-9086.pdf

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3.8X

Lactate dehydrogenase (LDH) on different platformsSafety (hemolysis), prognostic (melanoma)

CLIA TAE: +/-30%

4122 labs

1.5X

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

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Within-lab/within-platform reagent lot-to-lot change: LDH

Apr 29, 30

4/30

15%, 20% ↑ 22%, 30% ↑Jun 1, 2

Leve

l 1Le

vel 2

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Are regulated biomarker assays, used for routine patient management, and have been on the short

list of historically trusted assays better?

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Beckman

RocheOrtho

Toshiba

Dade

~1.5X

>3X

Different platforms: ALP CLIA/CAP TAE: ± 30%

OlympusSiemens

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

10The screen versions of these slides have full details of copyright and acknowledgements

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Currently available statins can lower LDL-C by 18-46%http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/StatinsUpdate-FINAL.pdf

The National Cholesterol Education Program (NCEP)

LDL-C:

LDL-C level (mg/dL) LDL-C category

Less than 100 Optimal

100–129 Near optimal/above optimal

130–159 Borderline high

160–189 High

190 and above Very high

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LDL-C: different methods

4800 labs

Halim, Biomarkers Med 2009

Difference: ↑60%NCEP guidelines

Very high

High

Borderline

Normal

NCEP goal for a total error

is <12%?

LDL-

C (m

g/dl

)

5100 labs

LDL-

C (m

g/dl

)

Difference: ↓60%

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

11The screen versions of these slides have full details of copyright and acknowledgements

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PT (INR) as a surrogate for appropriate anticoagulation

• INRs below 2 lead to more strokes, whereas INRs above 4 lead to excess bleeding

INR range Benefit

of stroke protectionRisk

of intracranial hemorrhage

<2 1.75 – 4.94 ---2 to 3 1.00 (base) 1.00 (base)3 to 4 --- 2.44 to 6 --- 16

>6 --- 27

Lesco, 2007: http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm085563.pdf

http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/UCM085483.pdf

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PT (INR) results from the same sample splits analyzed in different labs

~3X

Off-target

Ther. target:2.0-3.0

Standard practice

for warfarin

Risk to hemorrhage

2.4

16

27>6.0 immediate Vit K

>4.5 over-anticoag.

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Conclusion• Biomarkers can be a very useful tool in drug development

• Understand biology and biomarker’s role as early as possible

• Biomarker assays range from exploratory (fit-for-purpose basis) to rigorously validated assays when a biomarker is used as a surrogate end point, for patient selection, or randomization

• Of equal or even greater importance to assay validation is the monitoring of assay performance during production

• Lack of traceability makes discrepancies due to lab-to-lab, platform-to-platform, and even reagent lot-to-lot imminent threats

• Continuous flow of platforms and merge, or acquisition make the lab quality a moving object

• Discrepant results can pose a threat to development programs by triggering false decisions

Biomarkers in Drug Development: Potential Use and Challenges

Abdel Halim

12The screen versions of these slides have full details of copyright and acknowledgements

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How to mitigate analytical challenges?

• Global standardization/harmonization is not an imminent objective!

• Ideal: one lab/one site/one platform for a drug development program centralization

• For global trials; Same platform, same methodology

• If a lab has to be changed during a program cross validation

• Analyze in as few batches of samples as possible, preferably using same lot of reagents; Lot-to-lot verification is a necessity

• Understand limitations of each technology and associated error

• Understand limitations of compiling data from different studies and careful interpretation of lab results

• Bridging the disconnect between IVD and pharma understandings of lab quality is crucial

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Good luck

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