25 Feb. 2015

Biomarker assay development based on drug R&D strategy

Nobuhiro Kobayashi

DaiichiSankyo

The views expressed here are the speaker’s personal perspectives and

do not reflect official policy of DaiichiSankyo Co., Ltd.

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Fit-for-purpose clinical biomarker

assay development based on the

drug R&D strategy

What is biomarker?

What is drug R&D?

What is fit-for-purpose?

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What is biomarker ? Definition and Classification of Biomarker (FDA)

Definition:

A characteristic that is objectively measured and evaluated as an

indicator of normal biologic processes, pathogenic processes, or

biological responses to a therapeutic intervention. Source: DDT Glossary, FDA

Classification:

•Prognostic biomarker: Indicates future clinical course of the patient with respect to

some specified clinical outcome, in the absence of a Tx intervention

•Predictive biomarker: Measured prior to an intervention / Identifies patients who are

relatively susceptible to a particular beneficial or harmful drug effect versus less

susceptible patients

•Pharmacodynamic biomarker: Response-indicator biomarker / Post Tx measurement

•Efficacy-response biomarker: Efficacy-surrogate biomarker, Surrogate endpoint /

Subset of general pharmacodynamic biomarkers

Source: Marc K Walton, FDA @ MRD in Acute Lymphoblastic Leukemia Workshop (April 2011)

Presentation Name | CONFIDENTIAL

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My definition and goal of biomarker 1/2

• Pharmacodynamic (PD) biomarker: direct (or indirect)

effector of drug target downstream

• Proof of Mechanism (POM) : verify/validate the evidence based on

the biology in patients/healthy volunteer.

• Efficacy biomarker: efficacy-surrogate biomarker for each

target indication.

• Safety biomarker: target-related or drug related toxic

signs to achieve safe clinical trial for patients.

Evaluate value of drug candidate

compounds appropriately

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• Pharmacodynamic (PD) biomarker: direct (or indirect)

effector of drug target downstream

• PK/PD : confirm the effective drug exposure in patients.

• Predictive biomarker: contributor of disease phenotype

which has strong link to the drug target to choose right

patients for right drug.

Maximize value of drug candidate

compounds

Realize personalized medicine

My definition and goal of biomarker 2/2

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What is drug Research & Development ?

医薬品・医療機器・医療技術の研究開発(R&D)は、そもそも個人の関心・興味に駆動される、自由な研究ではない。市販に向けて、国際的に法律に基づいて当局からの承認取得を前提として、科学と技術を結集して行なう事業（商品開発）かつ法的プロセスである。

強力なマネージメントが必須 福島 雅典ら、臨床評価 42巻2号P251, 2014より抜粋

Research and development (R&D) for innovative drugs, medical

devices, medical technologies is NOT free research driven by

personal interests. It is business (product development) and a

legal procedure to be challenged calling upon science and

technology, in preparation for launching a new product on the

premise of marketing authorization based on international

specifications .

Need intensive management Adapted from M. Fukushima, et. al. Clinical Eval 42 (2) 251, 2014

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Typical flow of BM strategy/plan for each project

• Tangible examples : POC plan, Indication selection, Differentiation, etc.

Overall strategy

• How to achieve the goal of overall strategy using BM

• Tangible examples : Stratification of patient, MoA, PK/PD, efficiency, Safety, etc.

BM strategy

• To design over all BM analysis plan in Ph1/2 studies, which facilitate BM implementation

Overall BM analysis plan

• To optimize BM assay and data analysis in each clinical study protocol according to overall BM plan

Each clinical study design based on BM plan

• To implement appropriate BM data analysis to enable decision making

BM data analysis based on BM strategy

Pre

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This is a primary theme in my today’s presentation.

Presentation Name | CONFIDENTIAL

What is fit-for-purpose for biomarker assay?

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Case I : Safety marker

Agewall S et al. Eur Heart J 2011;32:404-411

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author

2010. For permissions please email: journals.permissions@oup.com.

Troponin

Troponin has become a major criterion for myocardial infarction

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Relation between troponin level and possible causes.

Agewall S et al. Eur Heart J 2011;32:404-411

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author

2010. For permissions please email: journals.permissions@oup.com.

99th percentile of normal subject Criteria for MI

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Joint ESC/ACCC Consensus document J. Am. Coll. Cardiol. 36 958-69 (2000)

Time course of troponin level in human

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High sensitive troponin-I assay system

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Human troponin-I assay Comparison

Presentation Name | CONFIDENTIAL

Method Rapid diagnostic

test (PATHFAST TnI)

Electrochemilum

inescence (ECL)

Single molecule

counting (SMC)

Single molecule

arrays (SIMOA)

Cal. range

(pg/mL) 20 - 50000 10 – 50000? 0.4 - 600 0.079 - 300

Detection limit

(pg/mL) 8 1.1-1.9 0.09 0.01

99th percentile

(pg/mL) 28 19.3 10.1 NA

Sample vol.

(minimum) 50 uL/test 150 uL/test?

100 uL/test (50 uL/test)

42 uL/test

Approval US/EU(?)/JA EU/JA None None

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Case II : PD marker

Peptide X : The PD marker has been validated in preclinical

study using mouse plasma.

A project team wants to confirm response of the marker at SAD/MAD studies.

However, peptide X is unstable in human plasma, and need a cumbersome pre-treatment for assay development.

What will you do then?

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Case III : PD marker

TRAP-5b : Isozyme of tartrate-resistant acid

phosphatate (TRAP)

TRAP-5b is considered as the most important marker of bone resorption

rate in renal failure patients. Bone metabolism markers like CTX, NTX,

BAP and osteocalcin accumulate in blood because the markers are not

cleared by the dysfunctional kidney. This can lead to elevated marker

levels in renal osteodystrophy, a bone disease affecting the majority of

renal failure patients, causing misinterpretation of bone marker results.

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10. キット

研究用キットを使用する場合には，施設ごとに分析法バリデーションを実施する必要がある．ただし，LC及びLBAガイドラインの内容に従えない場合もあるため，その場合には対応可能な範囲でガイドラインに準じてバリデーションを実施し，その妥当性を確認する必要がある．なお，キットの製造元が確認したキットの有効（使用）期限に関する情報は参照しても良い．

キットのロット変更の際には，ロット間において同一試料中の分析対象物質の定量値に差がないことを確認することが望ましい．

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Summary and Message

Summary : Fit-for-purpose biomarker assay

development should be considered not only

biological characterization of analyte (endogenous

substance), but also objectives based on BM strategy

to implement fit-for-purpose biomarker assay

development.

Massage : Analytical experts (person in charge of BM

assay development) should also join the discussion

on BM strategy/plan, and commit to creation of more

realistic BM plan.

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Acknowledgement

DaiichiSankyo, TMCP

Kazumi Ito

Ryo Atsumi

Taro Tokui

DaiichiSankyo, DMPRL

Tsuyoshi Karibe

JBF Task force of the draft concept paper

Kosuke Iijima, Kyowa Hakko Kirin Co., Ltd.

Chikashi Eguchi, LSI Medience Corp.

Masaaki Kakehi, Takeda Pharmaceutical Co., Ltd.

Yoshitaka Taniguchi, Toray Research Center, Inc.

Noriyuki Danno, JCL Bioassay Corp.

Takahiro Nakamura, Shin Nippon Biomedical Laboratories, Ltd.

Takehisa Matsumaru, Otsuka Pharmaceutical Co., Ltd.

Takashi Miyayama, Chugai Pharmaceutical Co., Ltd.

Itadaki Yamaguchi, Sumika Chemical Analysis Service, Ltd.