DEVELOPING DRUGS IN THE NEW ERA OF PERSONALIZED …€¦ · Base: Oncology=38, CNS/Neurology=17, Immunology=17 Q. Considering the therapeutic area(s) your company works in, which

C © 2017 PAREXEL INTERNATIONAL CORP.

DEVELOPING DRUGS

IN THE NEW ERA OF

PERSONALIZED

MEDICINES Anita Nelsen - Head of Genomic Medicine, Sr. Director,

PAREXEL International

Dr. Sy Pretorius - Sr. Vice President, Chief Scientific Officer,

PAREXEL International

© 2017 PAREXEL INTERNATIONAL CORP. / 2

PROPOSED AGENDA

WELCOME

• What is precision medicine?

• The rise & impact of precision medicine

• Impact on drug development

• Impact on clinical development

• Impact on clinical trials

• The role of genomics in development

• Case studies

• Emerging trends

• Summary and conclusion

• Q&A


WHAT ARE PRECISION OR PERSONALIZED MEDICINES

Leverage biomarkers,

often genetic, to

determine who is most

likely to benefit from

a treatment, who is at

higher risk of a side

effect, or who needs

a different dose

Source: Adapted from Bayer Healthcare, “Personalized Medicine.” https://pharma.bayer.com/en/research-and-

development/research-focus/oncology/personalized-medicine/index.php (accessed May 2105).

With

personalized medicine Each patient receives the right medicine for them

Benefit No benefit Adverse effects

Patients

Therapy Therapy Therapy

Biomarker diagnostics

Each patient benefits from individualized treatment

Without

personalized medicine Some benefit, some do not

Benefit No benefit Adverse effects

Therapy

Patients


RISE AND IMPACT OF PRECISION MEDICINES

Nearly 1 in 4 of the

new drugs approved

by the U.S. Food and

Drug Administration

between 2014-16

were

precision medicines.

¼

Currently the FDA lists

almost 200 approved

medicines with

pharmacogenomic

biomarker information

in their labeling.

200

132 of these are

considered precision

medicines leveraging

a biomarker to direct

treatment decisions.

132

Over the next five

years, the proportion

of personalized

medicines in clinical

development is

expected to increase

to nearly 70%.

70%

http://www.personalizebdmedicinecoalition.org/Res

ources/Personalized_Medicine_at_FDA. Accessed

04 May 2017

Tufts Center for the Study of Drug Development Impact

Report, Volume 17, No 3, May/June 2015


IMPACT ON DRUG DEVELOPMENT

• Precision medicines are impacting across a wide range of therapeutic areas including Psychiatry, Infectious

and Cardiovascular Diseases

• In the three therapeutic areas having a more robust base for analysis, Oncology followed by Immunology and

Neurology showed the greatest penetration in the three areas accounting for a majority of the Genomic

budget – Bioinformatics, Target Validation and Pharmacogenomics.

*Percentages reported for Pharmacogenomics and Data Analytics represent the mean of means for individual activities within these service areas. Detailed information for individual capabilities available in appendix.

Base: Oncology=38, CNS/Neurology=17, Immunology=17

Q. Considering the therapeutic area(s) your company works in, which of the following genomic medicine activities do you typically utilize for each? Please select all that apply for each therapeutic area.

79% 76%

64%

35% 29%

53% 59%

41%

24%

41%

71%

65%

51%

39%

29%

BIOINFORMATICS TARGET VALIDATION PHARMACOGENOMICS DATA ANALYTICS DRUG REPOSITIONING

Oncology CNS/Neurology Immunology


When asked to report on the proportion of studies including some aspect of

Genomic Medicine, utilization was found to be greatest in the earlier phases

of development and then declines in later phases, as expected.

N=55

PHASE II

N=45

PHASE III

57%

N=33

PHASE IV

IMPACT ON CLINICAL DEVELOPMENT

Q. Considering the following stages of clinical development, approximately what proportion of

studies your company does in each stage includes some aspect of genomic medicine?

N=50

PHASE I

Genomic Medicine Use by Study Phase

63% 57% 49% 30%


• Basket trials

• Umbrella trials

• Master trials

• Co-development of test

• Sub-populations/disease

sub-types

• Ethnic variation

• Safety/adverse events

• Targeted selection or

stratification using genetic/

biomarker

• Dose selection

• Smaller numbers of patients

IMPACT ON CLINICAL TRIALS

TRIAL

DESIGNS

EXPLAIN VARIABLE

RESPONSE TO

TREATMENT

PATIENT

SELECTION


Application of genomics in developing

precision medicines


THE RIGHT

PATIENT

THE RIGHT DRUG

THE RIGHT TIME

THE RIGHT DOSE

THE “RIGHT” REASONS TO INCLUDE GENOMICS IN DRUG DEVELOPMENT…

• Companion diagnostics

• Patient enrichment

• Novel clinical trial design

• PK Variability/ADME

• Genetic risk factors

• Drug combinations

• Drug target of specificity

• Targeted pathway

• Drug repurposing

• Drug resistance

• Disease progression

• Non-invasive biomarker


APPLICATION OF CUTTING-EDGE

METHODOLOGIES THAT

INTEGRATE GENOMICS DATA CAN

REVEAL NEW SCIENTIFIC INSIGHTS

• The human immune response system is

highly complex with cross-talk between multiple

immune-mediated pathways.

• Many currently available medicines that target the

immune system affect multiple pathways – some

desired, others not.

• Using cutting-edge methodologies (e.g., causal

reasoning, advanced network analysis) to integrate,

analyze, and interpret multi-omics experimental data

led to discovery of novel drug targets that may have

selectivity for IL23 pathways.

-300 -200 -100 0 100 200 300

Comp.1 [25.66%]

-200

-150

-100

-50

0

50

100

150

200

Co

mp

.2 [

12

.25

%]

J Immunol (2014) 192: 2527-8

EBI Immunogenomics Conference 2015

Transcriptomics: IL23 vs IL12 Proteomics: IL23 vs. IL12

Integrated Multi-omics Network

Causal Reasoning & Inference

Novel Target Candidates


WHAT IS PHARMOCOGENOMICS?

• Pharmacogenomics is the study of DNA and RNA characteristics as they relate to drug response1

• Provides insights into drug exposure, efficacy, and safety

1 http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-for-genomic-biomarkers-pharmacogenomics-

pharmacogenetics-genomic-data-and-sample-cod.html accessed 02Sep16

Pharmacogenomics helps us understand why

people who receive the same drug respond differently

http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-sample-cod.html
























PHARMACOGENETICS EXPLAINS EXPOSURE DIFFERENCES

• In a Phase I drug-drug interaction study,

a subset of healthy volunteers had elevated

levels of Drug X when administered with

the client’s medicine.

• Drug X is primarily metabolized by a CYP450

enzyme. Genetic variation in the CYP450

gene was evaluated to determine if genetic

variants that lead to reduced enzyme activity

might explain increased exposure of Drug X.

• The poor metabolizer CYP450 genotype was

associated with elevated exposure of Drug X.

• The client’s medicine likely did not impact

Drug X exposure.

IM intermediate metabolizer

PM poor metabolizer

WT wild-type metabolizer

Drug X plasma concentrations over time by CYP450 genotype

Co

nce

ntr

ati

on

PM

PM

PM

IM

WT

Time (hrs)


Atopic Dermatitis Psoriasis Acne

Drug

Discovery

Today

(2014) 19

(9): 1364-71

DRUG REPURPOSING CAN ACCELERATE MEDICINE DEVELOPMENT

A comprehensive clinical transcriptomics analysis across multiple dermatologic conditions identified additional

dermatology indications for this medicine, discovered mechanistic connections between skin diseases and

generated new hypotheses to accelerate medicine development.


PRECISION MEDICINES

Big Data Analytics New ‘OMES

e.g. microbiome

Electronic Health

Records

Co-Development

Partners

Patient Partnerships New Technology

(cfDNA, CTC)

Data Sharing Smart

Phones/Wearables

EMERGING TRENDS IMPACTING PRECISION MEDICINES


A JOURNEY WITH GREAT PROMISE…. AND CHALLENGES TOO

• Complex trial designs including co-development

of companion test

• Regulatory requirements are emerging in

global markets

• Reimbursement considerations for drug and test

• Ethics and local laws pose challenges for sampling

and testing

• Storage and computational resources for big data

• Ensuring accuracy of results from evolving

technologies such as NGS

• Integrating and analyzing multi-omics data

• Making big data accessible and understandable to

drug development scientists

• Creating and communicating reproducible workflows

for complex analyses

Clinical trials for Precision

Medicines may look very different

from traditional drug trials

Hard to have breadth of expertise

needed to capitalize on turning

GENES > TARGETS > PRECISION MEDICINES


THANK YOU


Documents

DEVELOPING DRUGS IN THE NEW ERA OF PERSONALIZED …€¦ · Base: Oncology=38, CNS/Neurology=17, Immunology=17 Q. Considering the therapeutic area(s) your company works in, which