Examples of Traditional vs. Precision Therapies 1) James Kennedy, Centre for Addiction and Mental Health 2) Niya Chari, CBCN 3) Michael Duong, Roche 4) Linsay Davis, AveXis 5) Josh Silvertown, Bayer Canada

1. Development and Application of
Pharmacogenetic Testing
James L. Kennedy MD, FRCPC, FRSC.
Director, Molecular Brain Science Dept,
Centre for Addiction and Mental Health;
Professor & Co-Head, Division of Brain & Therapeutics
Dept of Psychiatry, University of Toronto.
Fellow of the Royal Society of Canada.
& DJ Mueller, C Zai, A Tiwari, G Zai, Vanessa Goncalves.
CORD Conference Panel, Nov 18, 2019
Univ of Toronto
Disclosures: CAMH is 15% co-
owner of Myriad Canada Ltd;
JLK is Myriad USA SAB
member (unpaid); author on
patents

2. The CAMH Pharmacogenetics Study
(`IMPACT`)
■ Assessment of six liver enzyme genes and two
serotonin system genes
■ Testing feasibility and acceptance by psychiatrists
and by primary care physicians
■ In-hospital genetic panel assay
■ Interpretation of results is given to physician
■ Patient follow-up & Physician survey
www.IM-PACT.ca
www.pharmacogenetics.ca

3. Response & side effects
Additional
factors
CYP450 Dopamine
Serotonin
etc.
PharmacodynamicsPharmacokinetics
Smoking
Ethnicity
NutritionGender
Fitness
Compliance
Age

5. 0
1
2
3
4
5
6
7
8
9
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
2012 2013 2014 2015 2016 2017
Participants (Thousands)
Participants
IMPACT Pharmacogenetics: Publications, Physicians & Patients
11,400
patients
3,200
doctors
178
publications First patient enrolled
through Pharmacists
Personalized Medicine
Experts (PRIME) study
Launch of online
registration
process
IMPACT gene
test becomes
available for
family physicians
First patient
consents
Mobile lab collects
first samples from
rural communities

6. 25.7%
34.7%
19.2%
5.4%
0.6%
3.6%
10.8%
Very Helpful Helpful Neutral Not Helpful Very
Unhelpful
Not
Applicable
Missing
To what extent has the genetic information
been helpful in your further treatment
decisions?
(N=200)

7. ž Caucasian female of Ashkenazi Jewish descent
¡ Anorexia, severe OCD, depression
¡ Previous meds failed (quetiapine -900mg, & citalopram 20
mg
¡ fluoxetine – 80mg per day x 3 mo – no response
1) genetic test resultsà ultra-rapid CYP2D6 metabolizer
2) Incr fluoxetine to 120mg/d - some response, no side
effects
3) Prozac 160 mg per day!!
§ all her OCD, anxiety and mood symptoms improved
§ She returned to college full time; family very happy

8. Footnote [5]: “Use of this drug may increase weight gain”

9. 67% more
remission

10. Amer J Med Genetics. 2019;180B:46–54
Enrichment of pathogenic variants in genes associated with
inborn errors of metabolism in psychiatric populations
V Sriretnakumar 1, R Harripaul1, JB. Vincent1,4, JL Kennedy1,4, J So1,5.
1. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health; 2.
Department of Psychiatry, University of Toronto; 3 The Fred A. Litwin Family Centre in Genetic Medicine,
University Health Network and Mount Sinai Hospital; Toronto, Ontario, Canada.
Abstract: Many genetic conditions can mimic mental health disorders, with psychiatric symptoms
that are difficult to treat with standard psychotropic medications. We tested the hypothesis that
psychiatric populations are enriched for pathogenic variants associated with inborn errors of
metabolism (IEMs). Using next-gen sequencing, 2046 psychiatric patients were screened for
pathogenic variants in genes associated with: Niemann-Pick disease type C (NPC), Wilson disease
(WD), homocystinuria (HOM), and acute intermittent porphyria (AIP). Among the 2046 cases, carrier
rates of 0.83, 0.98, and 0.20%, for NPC, WD and HOM, and affected rates of 0.10 and 0.24% for
NPC and AIP were seen, respectively. An enrichment of NPC and AIP pathogenic variants was
found in the psychiatric cohort, especially in schizophrenia patients. Thus we find pathogenic
variants in genes associated with IEMs are over-represented in psychiatric populations. Underlying
undiagnosed IEMs could account for the psychiatric symptomatology in a subset of psychiatric
patients. Carriers for IEMs may have an increased risk for psychiatric disorders, particularly in the
context of poor treatment response.

11. Sriretnakumar et al (con’t):
Niemann-Pick C & Porphyria variants are 100x
more frequent in psychiatric populations
Two patients (0.10%) with schizophrenia were found to
have homozygous N931I likely pathogenic variant for
Niemann-Pick C, thus a predicted significant increase vs
0.001% in the general population (p = 2.4×10-4).
Five patients had pathogenic variants in the HMBS gene,
thus a predicted significantly increased rate of Acute
Intermittent Porphyria in the psychiatric cohort (0.24%) vs
0.003 in general population (p = 1.031×10-10).

12. What Has Pharmacogenetics Taught Us
Thus Far Re: Drug Development?
1. Every patient is genetically unique.
2. A blockbuster drug for all pts with a
given condition is unlikely
3. Measure the heterogeneity !!
4. Drugs with rare serious adverse
events should be rescue-able
5. Genes found to predict response
are potential new targets for
discovery
drug ‘A’ drug ‘B’ drug ‘C’

13. Benefits to Patients and Society
Matching the right drug at the right dosage may
mean that we stand to increase our ability to:
■ Treat patients right the first time
■ Minimize the risk of dangerous side effects
■ Reduce the risk of suicide
■ Give family doctors tools they can use - increasing
their ability to manage patients in the community
■ Save 100s of millions of dollars in prescriptions
that are ineffective or harmful
■ Evidence-based biomedical test reduces stigma
against people with mental illness

14. CAMH Neurogenetics Group
Larry and Judy
Tanenbaum

15. Forest plot of random-effects meta-analyses of five prospective, randomized
controlled trials of Pharmacogenetic guided therapy on remission in major
depressive disorder.
Meta-Analysis of 5 Pharmacogenetic Guided
Therapy for Depression RCTs Bousman et al, (Dec, 2018)

16. Examples of Traditional vs Precision Therapies: The
Patient Perspective
Niya Chari, Canadian Breast Cancer Network
November 18th-CORD Access to Innovation Conference

17. The Canadian Breast Cancer Network
CBCN connects with tens of thousands of women and families across Canada
each year.
MISSION
The Canadian Breast Cancer Network is a national,
patient/survivor directed organization committed to
ensuring the best quality of care for all Canadians affected
by breast cancer.
The best quality of life for all Canadians affected by breast
cancer
VISION

18. Defining Precision Medicine
• Traditional approaches to treating cancer
have included combination of surgery,
radiation and chemotherapy
• Advent of targeted therapies has moved
treatment into a new era of “precision
oncology”
• Critical to ensure that terminology is well-
defined to promote patient understanding
• Precision therapy-identifying treatment
based on a specific molecular abnormality
thought to be a driver of a person’s cancer
and delivering treatment against that target

19. Clinical Development in a Personalized World
Michael Duong, Ph.D.
Head of Personalized Healthcare
Hoffmann-La Roche Ltd.

20. Source: 1) Health Policy Brief: The Relative Contribution of Multiple Determinants of Health Outcomes, Health Affairs,
August 21, 2014, http://www.healthaffairs.org/healthpolicybriefs/
2) Nature 539, 467-468 (24 November 2016)
Exogenous determinants
(behaviour, socio-economic,
environment, etc.)60%
1,100 terabytesgenerated per lifetime of a person
6 terabytesGenetic
determinants30% generated per lifetime of a patient
Medical/clinical
determinants10% 0.4 terabytes
generated per lifetime of a patient
Determinants of Health Outcomes
Realizing the true potential of personalized healthcare

21. THE PERSONALIZED HEALTHCARE PARADIGM
TREAT THE DISEASE
TREAT THE PATIENT
TREAT THE PERSON
10%
40%
100%
Medical and clinical determinants of health
only allow us to understand the biology of
the disease. Treatment decisions based on
disease information can only capture up to
10% of health outcomes.
Genomic information and multi-omic
information in combination with disease
information has the potential to capture up
to 40% of health outcomes for patients.
Only when we understand the person,
including all their exogenous factors can we
capture up to 100% of health outcomes. To
achieve this, we must collect data on the social
determinants of health – data which are only
available in the real world.
PHC shifts the paradigm from treating the disease to treating the
person. This means that we not only need to understand the
complexities of the disease but also the complexities of the person
and the environment from which they come.

22. • Outcome measures that are more
meaningful to patients and that are
actually measured in the real world
• Study participants should be more
reflective of real world population
MAKE CLINICAL TRIALS MORE REAL
More relevant patient population
Patient-centered/real world outcomes
• Adaptive trial designs can ensure
study results are more reflective of
real world setting
Innovative study designs

23. DEFINITIONS
Real World Data
Real world data (RWD) are the data relating to patient health status and/
or the delivery of health care routinely collected from a variety of sources:
• Electronic health records (EHRs)
• Claims and billing activities
• Product and disease registries
• Patient-generated data including in home-use settings
• Data gathered from other sources that can inform on health status, such as
mobile devices
Real World Evidence
Real world evidence is the clinical evidence regarding the usage and
potential benefits or risks of a medical product derived from analysis of
RWD.
da·ta
/ˈdadə,ˈdādə/
ev·i·dence
/ˈevədəns/

24. Doing now what patients need next

25. Precision Diagnosis
Information-based diagnosis can assist not only in
identifying tumor type and stage, but also in revealing
important genetic mutations that drive cancer.
A number of tests are being explored and utilized to
identify specific biomarkers to aid in treatment
decision-making
• Immunohistochemical assays
• Multi-gene assays
• Next generation DNA sequencing
• Liquid biopsies

26. a v ex is. com
UNDERSTANDING GENE
REPLACEMENT THERAPY
US-UNB-18-0126 09/18

27. AVEXIS.COM • 2
The AveXis Commitment
We Are: A clinical-stage gene therapy company
relentlessly focused on bringing gene therapies out of
the lab and into the clinical setting for patients and
families who desperately need them.
Our Mission: We are dedicated to harnessing the
potential of gene replacement therapy as an effective
treatment for rare and life-threatening genetic diseases
that affect the nervous system.

28. a v e xi s.c o m
3
CONFIDENTIAL
DISCOVER THEGENETIC EVOLUTION
Although the l ogic be h i nd GRT is simple, the s c i e nc e be h i nd it h a s remained elusive for years. 1
The field of genetics h a s a d v a n c e d significantly from Mendel’s early discoveries. With e m e r g i ng g e n e
therapy approvals a n d others currently b e i n g developed, a new era of ge ne t i c s c i e nc e h a s emerged. 1 - 4
1860s
1953
1984
-
2000
1999
-
2002
2018
Gregor Mendel’ s p e a plant studies help
to establish the rules of
g enetic inheritance. 5
The structure of D N A is
characterized. 2 , 6
Scientists successfully
s e q u e n c e the h u m a n g en ome. 7
A number of individual g e n e therapy c as es result
in complications . A d e ath in a clinical trial sets b a c
k research. 4
C h i n a approves
2003 the first g e n e
therapy in the world.8
2017
FDA approves the
first g e n e therapy
for use in the US.9
es
With numerous
promising c a n d i d a t
in the pipeline, a
Science publication
declares “ G e n e
Therapy C o m e s
of Age.”1
References: 1. Dunbar CE, et al. Science. 2018;359(6372):eaan4672. 2. Gayon J. C RBiol. 2016;339(7-8):225-230. 3. Boudes PF. Eur J Intern Med. 2014;25(1):31-36. 4. Keeler
AM,et al. Clin Transl Sci. 2017;10(4):242-248. 5. Gregor Mendel: the father of modern genetics. May 22, 2013. https://history.nih.gov/exhibits/nirenberg/HS1_mendel.htm. 6. The
Nobel Prize in physiology or medicine 1962. https://www.nobelprize.org/nobel_prizes/medicine/laureates/1962. 7. Hood L & Rowen L. Genome Med. 2013;5(9):79. 8. Zhang WW,
et al. Hum Gen Ther. 2018;29(2):160-179. 9. FDAapproval brings first gene therapy tothe United States. August 30, 2017. https://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/ucm574058.htm.

29. AVEXIS.COM • 4
Understanding Gene Replacement Therapy

30. GENE
REPLACEMENT
THERAPY
GENE
THERAPY
REPLACEMENT
Gene replacement therapy is being
studied as a treatment option for
genetic disease, and we want to
help you understand the science
behind it.

31. Genes are small sections of DNA.
DNA is inherited from your parents
and carries instructions that tell
the body how to function properly.
Specific genes tell the body how
to make specific proteins.
GENE

32. Proteins play important roles
in the body, like helping your
cells to function properly or
acting as the building blocks
of your body.
PROTEIN

33. If a gene has an error, and the
body can’t make a specific
protein, it can be damaging to a
person’s health.
ERROR

34. GENETIC DISEASE
A genetic disease or disorder is the result of an errorin
one or more of a person’s genes.
The disease a person has depends on which gene inhis
or her DNA has the error. Depending on the disease or
disorder, the gene can be inherited from one or both
parents.
Or, sometimes it’s a change that just happens randomly.
A genetic disease caused by a single gene that isfaulty
or missing is called a monogenic disease.
GENETIC DISEASE

35. a v e xi s.c o m
1
1
CONFIDENTIAL
NEWPOSSIBILITIESFOR MONOGENIC DISEASES
M o n o g e n i c diseases are ideal targets for GRT b e c a u s e they c a n result from the loss or malfunction of a single g e n
e . Examples include 1 - 5 :
• Cystic fibrosis ( C F )
• D u c h e n n e muscular dystrophy ( D MD )
• Hemophilia
• Spinal muscular atrophy ( S MA)
• Rett syndrome
• S o m e forms of amyotrophic lateral sclerosis ( ALS)
• S o m e forms of Parkinson’s d i s e a se
References: 1. Saraiva J, et al. J Control Release. 2016;241:94-109. 2. Boudes PF. Eur J Intern Med. 2014;25(1):31-36. 3. Lisowski L, et al. Curr Opin Pharmacol.
2015; 24:59-67. 4. Prakash V,et al. Mol Ther. 2016;24(3);465-474. 5. Klein C & Westenberger A. Cold Spring Harb Perspect Med. 2012;2(1):a008888. 6. Wang CH, et
al.
J Child Neurol. 2007;22(8):1027-1049. 7. Lin CW, et al. Pediatr Neurol. 2015;53(4):293-300.

36. HEALTHY
GENES
A CLOSER LOOK AT MONOGENIC DISEASESA CLOSER LOOK AT MONOGENIC DISEASES

37. INDIVIDUALS
WITH
MONOGENIC
DISEASES
A CLOSER LOOK AT MONOGENIC DISEASESA CLOSER LOOK AT MONOGENIC DISEASES

38. GOAL OF GENE REPLACEMENT THERAPY
Gene replacement
therapy attempts to
give the body a new,
working copy of the
missing or faulty
gene that can make
a particular protein
the body needs.
GOAL OF GENE REPLACEMENT THERAPY

39. HOW GENE
THERAPY WORKS
In the lab, a new, working
copy of a specific gene
is made.
Then the new gene is placed
inside a vector. A vectoracts
like an envelope or a delivery
vehicle. It carries the new
gene to cells throughout the
body.

40. Gene Replacement Therapy Delivery Routes
Collins M & Thrasher A. Proc Biol Sci 2015;282(1821).
FOR MEDICAL EDUCATION ONLY

41. When the
vector reaches
the nucleus of
the cell, it
releases the
working copy
of the gene.

42. The gene
starts working
to make
protein, and it
doesn’t stop.

43. CONSIDERATIONS OF
GENE REPLACEMENT THERAPY
Supportive therapies will continue to be important for patients treated
with gene replacement therapy.
Gene replacement therapy may not be right for all patients.
The safety and efficacy of all gene replacement therapies being studied
are specific to the vector and the disease targeted.
Especially in gene therapy models with gene placement into the cell’s
DNA, risks of undesired effects may occur and are being studied.
Data continues to emerge about the lasting effects of gene replacement
therapy.
Gene replacement therapy may halt progression of disease but does not
reverse the damage that happened before treatment.
CONSIDERATIONS OF
GENE REPLACEMENT THERAPY

44. AVEXIS.COM • 21
QUESTIONS

45. ///////////
Clinical Development
Considerations in
Precision Oncology
Example in TRK
Fusion Cancer
CORD, Access to Innovation
Conference,
Nov 6, 2019
Josh Silvertown, PhD, MBA
Senior Manager and
Medical Affairs Strategist
MA-LAR-CA-0090-2

46. I am an employee of Bayer Inc.
Bayer has provided an unrestricted sponsorship to support the CORD meeting.
This presentation may contain information regarding indications and/or instructions which differ from the
approved use of products available in Canada.
For complete information on Bayer products, please refer to the respective product monograph:
https://www.bayer.ca/omr/online/vitrakvi-pm-en.pdf
Disclaimers
Presentation to CORD; Nov 18, 2019
Page 2

47. From traditional to precision oncology
Precision Medicine: Innovation in Oncology Clinical Development
Positive predictive
biomarkers
Molecular
profiling
“Conventional
treatment” (eg, systemic
chemotherapy)
Molecular-
driven
therapy
Markers predictive
of resistance or
adverse events
3

48. TRK fusion cancer:
Identified in >24 histologies and counting
Cancers enriched
For TRK fusions
Frequency >75%
Cancers harbouring TRK
Fusions at lower frequencies
5% to 25%
<5%
Adapted from Cocco et al. NTRK fusion-positive cancers and TRK
inhibitor therapy. Nat Rev Clin Oncol. 2018 (ePub ahead of print)
4

49. Larotrectinib’s clinical development program overcame
traditional hurdles in drug development
1. Hyman DM, et al. J Clin Oncol. 2017;35:LBA2501.
2. Drilon A, et al. N Engl J Med. 2018;378:731-739.
3. https://www.bayer.ca/en/media/news/?dt=TlRRPQ==&st=1
First drug to be simultaneously investigated in adult and
pediatric populations1,2.
First drug to be approved by Health Canada with a tumour
agnostic indication.
Presentation to CORD; Nov 18, 2019

50. New ways of treating rare cancer requires new trial
designs
Need for
modification
of clinical
trial design
Increase in
number of
potentially
actionable
mutation targets
Limited number
to recruit into
rare cancer
clinical studies
Existing
evidence for
rare cancer
treatments is
poor
Pediatric
population is
underserved
6
Presentation to CORD; Nov 18, 2019

51. 7
Basket Design –
Biomarker Specific, Histology-Agnostic Cohorts
Tao, Jessica J., Alison M. Schram, and David M. Hyman. "Basket studies: Redefining clinical
trials in the era of genome-driven oncology." Annual review of medicine 69 (2018): 319-331.
Melanoma Thyroid cancer Colorectal cancer Lung cancer
Increase access to
therapy
Small cohorts lead to
faster results
Establishment of standard
of care in rare diseases
Drug activity can depend
on tumour histology
Patient heterogeneity can
impact validity
Challenging to define
controls
Comparison issues due to
excessive testing of
subgroups
Presentation to CORD; Nov 18, 2019

52. 8
Pooling Biomarker-Positive Patients for a Rare
Disease
Hyman et al, 2019. Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. Presented at ESMO 2019. Barcelona, Spain. (445PD)

53. 9
Hyman et al, 2019. Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. Presented at ESMO 2019. Barcelona, Spain. (445PD)
Balancing the challenge (and expectations) of
heterogeneity among rare diseases

54. 10
What is a pragmatic approach to measure efficacy
in basket trials?
Hyman et al, 2019. Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer. Presented at ESMO 2019. Barcelona, Spain. (445PD)
Presentation to CORD; Nov 18, 2019

55. 11
Take-home messages
Unique challenges exist in oncology
drug development for tumor agnostic
drugs but can be addressed with
appropriate and innovative trial designs.
Basket trial designs are effective and
feasible in studying treatments for a rare
disease (i.e. pediatric cancers, TRK
fusion cancer).