Drug analytics on Embase

Smart data for drug development,

repurposing and safety based on triple

indexing

Ivan Krstic, PhD

Senior Product Development Manager Embase

July 27th 2016

2

Agenda

Data analytics based on manually extracted semantic relationships

between:

– Drug – Disease

• Adverse Reaction

• Therapy

– Drug – Drug

• Interactions

• Combination

• Comparison

very valuable for:

• Drug repurposing

• Drug development

• Drug safety

3

Fatigue

564

Everolimus

Drug

interaction

Drug

comparison

Drug

therapy

Adverse

drug

reaction

Drug

combination

Tumor

neuroendocrine

320

Paclitaxel

221

Exemestane

259

Bevacizumab

270

Erythromycin

26

Rifampicin

28

Ketoconazole

28

Azathioprine

65

Paclitaxel

172

Rapamycin

192

Breast

cancer

633

Kidney

carcinoma

993

Diarrhea

570

Stomatitis

616

Manually

extracted

semantic

relationships

4

Indexing for Embase is a manual process

performed by trained indexers with a biomedical

background, with the exception of articles designated

for automatic indexing.

Indexers read and analyze the full text of articles in

order to identify relevant concepts, and index them with

the most specific Emtree terms.

Index terms are controlled by the Emtree thesaurus

resulting in consistent coverage of concepts that

may be expressed in many different ways in the

literature.

Indexing principles

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Indexing: subheadings

Subheadings are Emtree terms that are also used as concept

qualifiers for drugs, diseases and devices to refine their meaning,

providing a very precise idea of what an article covers.

Important

Definition

Drug subheadings

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Indexing: key subheadings

Concept Key Subheading

drug adverse drug reaction

drug drug combination

drug drug comparison

drug drug interaction

drug drug therapy

device adverse device effect

device device comparison

disease drug therapy

disease side effect

Nine subheadings are denoted key subheadings.

Important

Definition

7

Indexing: triple-linking

Triple-indexing is a three level indexing of the full text of an article,

and it consists of:

‒ Concept (drug or device or disease)

‒ Key subheading (relationship)

‒ Linked concept (e.g. stomatitis, hypertension, nausea, etc.)

Triple indexing has started in Q1 of 2007 for the drug triples (drug

therapy from Q2 of 2009). Devices began in Q2 of 2014.

Important

Definition

Everolimus Adverse

drug

reaction

Stomatitis

Manually Extracted Semantic Relationships

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How can the Manually Extracted Semantic Relationships

be searched

Filter options

For each drug, device and

disease manually

extracted semantic

relationships can be

identified and filtered

(simple search a drug and

use drug filter)

Search query language

'everolimus'/'drug therapy'/'breast cancer'

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How are the Manually Extracted Semantic Relationships

displayed?

In individual results

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How are the manually extracted semantic relationships

displayed?

In filters

Drug repositioning

12

Drug repositioning to treat (rare) diseases

Compounds targeted for repositioning have already gone through extensive

preclinical testing and have shown safety in their original indication.

The key benefits are:

Shorter development time

Lower development costs - safety profiles of the products will have

already been established

Higher success rates

13

Manually extracted drug-disease relationships for drug

repositioning

Drug therapy = Used as a drug subheading to identify a drug used to treat

disease / indication (including curative, palliative, symptomatic or prophylactic

treatment)

Everolimus

Drug

therapy

Tumor

neuroendocrine

320

Breast

cancer

633

Kidney

carcinoma

993 Important

Definition

Everolimus (Afinitor®)

15

Everolimus (Afinitor®)

http://clincancerres.aacrjournals.org/content/16/5/1368

mTOR Signalling in cancer:

• Positively regulates cell growth

and proliferation

• Positively regulates cellular

metabolism & adenosine

triphosphate (ATP) production

• Promotes angiogenesis

• Promotes cell growth by

negatively regulating

degradative processes in cells

Mechanism of Action: mTOR inhibitor (inhibits the mammalian target of

rapamycin)

mTOR inhibitors can be used to block the multiple biologic effects caused by

the aberrant activation of mTOR found in several cancer types.

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Everolimus is approved for various conditions

• Advanced kidney cancer (US FDA approved in March 2009)

• Prevention of organ rejection after renal transplant (April 2010)

• Subependymal giant cell astrocytoma (SEGA) associated with tuberous

sclerosis (TS) (October 2010)

• Progressive or metastatic pancreatic neuroendocrine tumors not surgically

removable (May 2011)

• Breast cancer in post-menopausal women with advanced hormone-receptor

positive, in conjunction with exemestane (July 2012)

• Prevention of organ rejection after liver transplant (Feb 2013

• Progressive, well-differentiated non-functional, neuroendocrine tumors

(NET) of gastrointestinal (GI) or lung origin (February 2016).

Launch Date March 2009

First Full-Year Sales (2010) $243 million

Sales in 2015 $1.6 billion

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Semantic relationship between Everolimus and treated indications

Everolimus – list of all on-label and off-label use indexed on Embase

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Relation between approval year and records reporting

direct relationship between drug and indication

Pub. year Kidney cancer

Pancreatic neuroendocrine

tumor

Breast cancer

Neuroendocrine tumor

Tuberous sclerosis

2016 66 17 43 20 10

2015 84 45 82 39 26

2014 102 29 104 29 15

2013 142 74 139 36 26

2012 170 71 124 81 10

2011 190 12 63 69 11

2010 144 2 60 32 3

2009 114 34 21 2

2008 9 2 2

# of published articles for Everolimus per year

Is Tuberous Sclerosis next use to be approved for Everolimus ?

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Relation between approval year and records reporting

direct relationship between drug and indication

Pub. year Kidney cancer

Pancreatic neuroendocrine

tumor

Breast cancer

Neuroendocrine tumor

Tuberous sclerosis

2016 66 17 43 20 10

2015 84 45 82 39 26

2014 102 29 104 29 15

2013 142 74 139 36 26

2012 170 71 124 81 10

2011 190 12 63 69 11

2010 144 2 60 32 3

2009 114 34 21 2

2008 9 2 2

# of published articles for Everolimus per year

Take-home message: Semantic relationship between drugs and indications

can be used to guide drug repositioning strategies.

Nivolumab

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Nivolumab

Indications (approved):

• Hodgkin's disease

• malignant melanoma

• non-small cell lung cancer

• renal cell cancer

Off-label use:

• colorectal cancer

• lung cancer

• ovary cancer

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Nivolumab for Colorectal cancer in Clinical trials

Embase search:

'nivolumab'/'drug therapy'/'colorectal cancer' AND 'nivolumab'/'clinical trial'

Kadcyla (ado-trastuzumab

emtansine)

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Kadcyla (ado-trastuzumab emtansine)

In a clinical trial of women with advanced HER2 positive breast cancer who

were already resistant to trastuzumab alone

Kadcyla improved median overall survival by 5.8 months (30.9 months vs. 25.1

months) compared to the combination of lapatinib and capecitabine.

25

Potential new use for Kadcyla

Is there an evidence for a new use?

New drug combinations for

combination drugs

27

What is a Drug combination on Embase?

Drug combination = Used as a drug subheading for drugs given in

combination or concomitantly

Everolimus Drug

combination

Paclitaxel

221

Exemestane

259

Bevacizumab

270

Important

Definition

28

Drug combinations for new combinations

Everolimus is approved for breast cancer in post-menopausal women with

advanced hormone-receptor positive, HER2-negative type cancer, in

conjunction with exemestane (FDA July 2012)

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New combinations for Everolimus

PUBYEAR everolimus-

drug combination- exemestane

everolimus- drug combination-

bevacizumab

2016 14 1 2015 46 17 2014 56 19 2013 73 34 2012 53 54 2011 11 47 2010 2 42 2009 3 36 2008 16 2007 4

Is the combination

with bevacizumab

next to be approved

for the treatment of

kidney cancer or

colorectal cancer?

30

New combinations for Kadcyla

New formulation looks promising – combination of trastuzumab emtansine

(Kadcyla), paclitaxel, and pertuzumab in clinical trials.

Potential new

combination

with

Pertuzumab

Drug-drug interactions

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What is a drug-drug interaction on Embase?

Drug interaction = alteration of the effects of a drug by reaction with another drug

or drugs, with foods or beverages, or with a preexisting medical condition. Used

as a drug subheading.

Everolimus

Drug

interaction

Erythromycin

26

Rifampicin

28

Ketoconazole

28

Important

Definition

33

Drug-drug interactions

Long list of drug with

reported interactions

with everolimus – to

be listed in the label.

Drug-drug comparison

35

What is a drug-drug comparison on Embase?

Drug comparison = Used as a drug subheading when two or more drugs are

compared within the same study.

Everolimus Drug

comparison

Azathioprine

65

Paclitaxel

172

Rapamycin

192

Important

Definition

36

Seamless access to drug comparison data

Analytical capability provides access to information on drug-drug comparison

in literature.

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Drug comparison – smooth access to records with clinical

efficacy and safety data

Drug safety

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What is an Adverse drug reaction on Embase?

Adverse drug reaction = Used as a drug subheading to identify a drug for

which an undesired side effect is reported (when used at therapeutic dose

ranges in humans)

Fatigue

564

Everolimus

Adverse

drug

reaction

Diarrhea

570

Stomatitis

616

Important

Definition

40

Seamless access to safety signals

41

Manually extracted semantic relationships for drug

safety

Safe and rational use of drug

Better risk management

Assess

causalities

42

Everolimus - safety signals per year

Smart data available in Embase helps to improve Risk

Management (Causality assessment and Signal confirmation)

43

Summary

Manually extracted semantic relationships can be used to:

guide drug repositioning strategies

investigate potential for development of combination drugs

identify drug-drug interactions

collect drug-drug comparison information

improve risk management (Causality assessment and Signal

confirmation)

Thank you!

Any questions?

Ivan Krstic, PhD

Senior Product Development Manager Embase

i.krstic@elsevier.com