Why Precision Medicine and Personalized Healthcare and Why Now? Links to Canada’s Rare Disease Strategy The Future is Now 1) Marc LePage, Genome Canada 2) Michael Duong, Roche 3) Danica Stanimirovic, National Research Council 4) Daniel Gaudet, University of Montreal 5) Christine Dalgleish, Patient Perspective 6) Jamie Bruce, Khure Health

1. ABOUT GENOME CANADA
• A non-profit created by the Canadian
scientific community – Canada was not
part of the Human Genome Project
• Launched in 2000 to:
• Invest in large-scale research and
leading-edge technologies
• Translate discoveries into
applications across multiple
sectors
• Connect ideas and people to find
new uses for genomics
• Facilitate the responsible uptake
of genomics into society
• Develop a next-generation,
high-performance bioeconomy
2

2. Genome Canada`s
Precision Health Strategy
CORD - Access to Innovation Conference
Toronto, Nov 18., 2019
Marc LePage, President & CEO
Genome Canada
1

3. 1
2
5
4
3
6
7
8
9 10
GENOME
CANADA: Our
network
Federal
Government
Industry
Provincial
Governments
Universities
Non Profit
Organization
3

4. Genomics and Precision Health
4

5. Precision Health: Our Approach
Phase 1 – Laying the Foundation:
Precision Health Large-Scale
Applied Research Projects
Phase 2 – Into the Clinic:
Rare Disease Clinical
Implementation
Phase 3 – Beyond Rare Disease:
Clinical Implementation of Other
Disease Indications
Phase 4 – This is Canada:
Building a National Database
through a Large Population Cohort
5

6. Genome Canada Funding Competitions Fundin
g
2004 – Applied Human Health $130 M
2010 – Advancing Technology Innovation through
Discovery
$4M
2012 – Genomics and Personalized Health $147 M
2017 – Genomics and Precision Health $162 M
2012-2017 – Technology Development and
Bioinformatics
$64 M
TOTAL $507 M
Phase 1 – Laying the Foundation
Precision Health Large-Scale Applied
Research Projects
6

7. Silent genomes
GenCOUNSEL
Care4Rare-Solve
Identifying novel genes and breaking
the ‘Newfoundland Curse’
Precision Health
LSARPS

8. Precision Health
LSARPS
Reducing the burden of infectious disease
Pace’Omics
Genomics in Society
Unlocking autism’s code

9. Phase 2 – Into the Clinic
Recommendation #1
Develop a national vision for the
implementation of genomics into the
health-care system. Start with a
demonstration project in a targeted
area to raise the profile of precision
health in Canada and provide a
framework to leverage synergies from
existing work
9

10. Rare Disease Clinical Implementation
Goal – establishment of a pan-Canadian program to implement
genomics in the clinic, with an initial focus on rare disease.
3-5
Specialists
(>11 for 10%)
3-6
Years for a
diagnosis
40%
Received >3
misdiagnoses
$15,000
($8,000-$23,000)
Cost per patient
Unmet Clinical
Need in Canada
10

11. Building on our strengths
• 200 clinicians
• 21 sites
• 100 scientists
• 32 countries
• >1300 rare diseases studied
• >5000 families recruited
• 50% of families diagnosed
11

12. Building on our strengths
• RDMM Network, funded in partnership
with CIHR, connects clinicians
discovering new genes with scientists
who study them in model organisms
• This work will lead to improved
understanding of how specific gene
mutations cause rare diseases, which
will ultimately generate therapeutic leads
12

13. 30/yr
5,016,322
4,330,206
1,165,903
1,356,836 8,421,698
525,073
964,693
772,238
154,750
40,333
44,445 38,650
800/yr
0/yr
50/yr200/yr 100/yr
30/yr
50/yr14,411,424
Statistics Canada estimates Q4 2018
Canada: 37,242,571
Access to clinical exome sequencing
13

14. Requesting clinical sequencing
14

15. Phase 3 – Beyond Rare Disease:
Clinical Implementation of Other DiseaseIndications
• The rare disease program will be a vehicle for supporting a learning
health-care system and advancing next generation health-care
delivery
• It will lay the foundation
for the next phase with
a focus on advancing
precision health for
other disease
indications
15

16. Phase 4 – This is Canada:
Building a National Population Cohort
• The health of a nation, as well
as its wealth and innovation are
increasingly based on
management of large national
data assets.
• These large data sets are
essential for the delivery of
precision health; providing the
reference set – the baseline –
AND can serve as powerful
engines for innovation
and economic development
• Canada should build a large
national population cohort—
100,000 Canadians
• It will be representative across
disease, demographic,
ancestry and region and
capture the uniquely Canadian
population, including
Indigenous and founder
populations
16

17. QUESTIONS??
Marc LePage, President &CEO, Genome Canada

18. Transforming Healthcare:
Roche Perspective
Michael Duong
Head of Personalized Healthcare
Hoffmann-La Roche Ltd.
Confidential and proprietary - Not for distribution or promotion.

19. Healthcare
Transformation?
Why
Confidential and proprietary - Not for distribution or promotion.

20. Transforming Healthcare into a
personalized one
Imagine a world in which we can harness the advance in
scientific knowledge, data analytics and digital technology to
give each individual patient the treatment she/he needs.
Advances in science, data, analytics and digital technology
promise a shift in the way we do healthcare. A shift that
brings into focus the individual profile of each patient in
health and disease.
Confidential and proprietary - Not for distribution or promotion.

21. A transformational moment for healthcare
The challenge: increased complexity in all facets of healthcare
Knowledge acceleration Information management
Medical knowledge doubled
every 50 years in 1950.
Today, it doubles every 72
days
Disease complexity
There are 200 tumor types,
which can have up to 1.2
million mutations.
Diagnostic complexity
Only 2% of US cancer
patients are exposed to
comprehensive diagnostics.
90% of patients exposed to
comprehensive diagnostics
have a treatment option.
Processing patient
information from disparate
sources in multi-disciplinary
teams is highly complex.
Confidential and proprietary - Not for distribution or promotion.

22. Increased understanding
of disease biology
More educated and
empowered patients
Novel technologies in research,
clinic and personal use
Evolving regulatory
environment
Partnerships between
non-traditional players
Demand for value-based,
outcome-driven healthcare
A transformational moment for healthcare
The opportunity: the right treatment for the right patient at the right time
A transformational moment for healthcare
The opportunity: the right treatment for the right patient at the right
time
Confidential and proprietary - Not for distribution or promotion.

23. can we leverage medical knowledge, data and
technology to improve patient outcomes?
How
Confidential and proprietary - Not for distribution or promotion.

24. Digital Health
EMR / RWD/ PRO
Advanced imaging
Digital pathology
Genomics
Deep and
broad data from
multiple sources
Confidential and proprietary - Not for distribution or promotion.

25. High resolution
view of each
patient and their
disease
and precise care
that is right for
this particular
patient

26. A virtuous circle of knowledge and impact
Transforming research, development and patient care
X-Ray
Step Count
Blood Test
Genetic Test
Digital Tools
Omics
Clinical Data
Imaging
Generated Data
New Treatment Options
Comparative Studies
Empirical Conclusions
Roche personalised health care (PHC) programme © 2019Confidential and proprietary - Not for distribution or promotion.

27. Past patient
journey
Diagnosis
(often at
advanced
stages)
In-person
management
Treatment
(usually by
location)
Challenging
access
We have an opportunity to
transform the patient
journey from…
Confidential and proprietary - Not for distribution or promotion.

28. A future patient journey that is fully personalized –
yielding better outcomes and faster access to care
Early & accurate diagnosis
(initial and recurrence)
Continuous &
remote outcome
capture, patient
management
Personalized
care plans
Full access to
optimal care
Data &
insights
Confidential and proprietary - Not for distribution or promotion.

29. Envisioning a world of personalised healthcare solutions for
patients
What’s next
Confidential and proprietary - Not for distribution or promotion.

30. Opportunities to address together the evolving healthcare needs
The challenge: overcoming those hurdles together
Healthcare professionals:
• Lack of understanding about the potential of the
personalisation of healthcare
• Resistance to use of digital technologies
• Lack of data sharing between researchers
Healthcare system:
• Lack of public and policy maker awareness
• Lack of access to high quality genomic/
biomarker testing
• Lack of access to targeted therapies
• Outdated regulations governing different
aspects of personalisation of healthcare
Patient communities:
• data privacy and ownership
• Lack of understanding of PHC
• Discrimination against people with specific
genetic risks
• Lack of patient involvement in the co-
creation
Confidential and proprietary - Not for distribution or promotion.

31. Doing now what patients need
next

32. NRC’s Challenge Program in Disruptive
Technologies for Cell and Gene Therapy
‘Glybera re-invented’ project
Danica Stanimirovic, MD, PhD
Director, Translational Bioscience, Human Health Therapeutics
CORD Workshop
November 18-19th, 2019

33. 2
The NRC’s Human Health Therapeutics Research Centre aims to
transform human health outcomes for the benefit of society, in
collaboration with public and private sector organizations.
MISSION
We accelerate the discovery and development of innovative medicines in
Canada, including:
• Advanced biologics, e.g. vaccines, antibody-based therapies, etc.
• Biomanufacturing, including capacity building
• Cell and gene therapy, including disruptive technology solutions.
National Research Council of Canada:
The Government of Canada’s largest science and research organization

34. 3
Addressing Unmet Needs
Brain
Cancer
Infectious
diseases
Rare Diseases

35. Protected B | Business Confidential
Addressing Rare Diseases at HHT
4
Models and screens for
metabolic modifiers
Gene therapies and
genome editing
Enzyme(protein)
replacement therapies
CHEO
• Dravet syndrome (Ideation)
• Glut-1 deficiency syndrome
iPSC neuro/CRISPR
iPSC BBB models (CRISPR)
CHEO’s drug library
CGT Program
• LPLD – Glybera re-invented
• Other rare diseases
AAV design and production
Genome editing (long-term)
Industry and academia
• Lysosomal storage diseases
(Hunter, Gaucher, Tay Sachs,
Neuronal Ceroid Lipofuscinosis)
• Fragile X
Brain delivery (BBB carriers)
Protein/enzyme engineering and
improvements
Therapeutic
Modalities
DiseasesCapacities

36. Challenge Program:
Disruptive Technologies for Cell and Gene Therapy
5
• Disruptive Technology Tools and Platforms to accelerate development
and address some barriers and cost drivers for CAGT
• Collaborative partnerships with the Canadian ecosystem to coordinate
non-commercial development model and delivery of CAGTs
• Capacity building activities for clinical translation and development of
novel therapies
• Mandate aimed at benefit to Canada and the innovation ecosystem
Develop made-in-Canada solutions to improve accessibility and
affordability of engineered cell and gene therapies of the future

37. 6
Promise of Gene Therapies
Finding rare..
>7000 rare diseases
25-30 mill Americans live with rare diseases
Curing rare…
Emerging treatment modalities
Ø Gene therapy
Ø Genome editing

38. 7
Challenges
$1.1 million $500K per eye$2.1 million

39. 88
Canadian ‘Readiness’ for GTs
• No commercial scale GT manufacturing capacity
• No clinical scale GMP AAV manufacturing capacity

40. 9
Glybera-reinvented:
A driver project to build capacity and new models of delivery
Therapy already developed and tested clinically but is NOT available/accessible
Demonstration of collaborative partnership models to build Canadian value chain and
enable clinical deployment of accessible and affordable Canada-made gene therapies
Disruptive technologies that will reduce cost of biomanufacturing and enable new
generation of safe, accessible and affordable gene therapies
Glybera reinvented
Treat Canadian patients with gene
therapies priced at least 5-fold less
compared to commercially
available alternatives.
Viral vectors scale-up and engineering Follow-on gene therapies

41. 10
Glybera history
Ø Lipoprotein lipase deficiency (LPLD) is rare genetic disease that disproportionately affects
Canadian population in Saguenay region
Ø Genetic mutation causing the disease and the treatment for the disease – a gene therapy –
were discovered in Canada at UBC (Dr. Michael Hayden and Dr. Colin Ross)
Ø UniQure acquired rights to develop and biomanufacture the therapy - Glybera
Ø Pivotal clinical trials conducted in Canada (Quebec) (Dr. Daniel Gaudet)
Ø The gene therapy was approved in EU and priced at $1mill euros
Ø There was no uptake of treatment and company abandoned commercial rights in 2017
Ø Long-term monitoring of patients demonstrated drug efficacy and lower burden of disease
Ø Glybera was never approved in Canada

42. 1111
The primary goal is to design an improved version of
Glybera, manufacture it in Canada and offer the
treatment to the LPLD-affected Canadians through
clinical trials in the first instance, and eventually as an
affordable and accessible treatment option.
The project will forgE innovative collaborative models
(public-public and public-private partnerships) to build a
full value chain for gene therapy development in
Canada that will become foundational for development of,
and patient access to, future gene therapies in Canada.
Glybera re-invented

43. 12
Improved drug substance (composition of
matter and proof of improvement)
Lead construct selection, safety & efficacy
Process optimization, scale-up, formulation
& stability
Canadian viral vector GMP facility
(clinical trial material)
Clinical trials (approval & funding)
PROJECT PLAN
DESIGN & SELECTION
PRECLINICAL EVALUATIONS
BIOPROCESS DEVELOPMENT & SCALE-UP
BIOPROCESS TRANSFER TO CMO
CTA & CLINICAL TRIAL
DeliverablesModules
G
&
C
NRC
Collaborators

44. 1313
Canadian value chain
from design to clinic
Creating lasting footprint for
future gene therapies in Canada
Establishing viable clinical-
scale biomaufacturing
capacity for GTs in Canada
Engaging federal and provincial
governments and Heath
Canada to innovate in clinical
trial design and delivery
Engaging all of you to
advocate for new models
and access to treatments
Building on past experience
with the first (Canadian)
approved gene therapy
Foundations

45. Protected B | Business Confidential
14

46. 15
Glybera re-invented

47. Protected B | Business Confidential
16
Lipoprotein Lipase Deficiency
Clinical Features
• Presents in childhood, failure to thrive
• Chronic abdominal pain (nausea, vomiting)
• Painful skin lesions (cutaneous xanthomas)
• Hepatosplenomegaly, pancreatitis, death
• LPL normally breaks down
triglycerides
• Blood triglyceride levels:
50-1000x normal
Prevalence
• 2 per 1,000.000
• In Quebec (Saguenay): 1 in 6000

48. Protected B | Business Confidential
17
Genetic Disease Discovery
Patient presented at Vancouver’s Children’s Hospital with extreme hypertriglyceridemia1987
PatientNormal
Hayden, Langlois, Kastelein, &
Brunzell identify the first mutation
in the LPL gene
Linked the LPL gene to Type 1
Hyperlipidemia
1989

49. Protected B | Business Confidential
18
10 IM injections/cat
AAV1-LPLS447X
Proof of Principle in Mice
1x1011 gc/kg
control
0 0.5 2 4 6 81Week
AAV1-LPLS447X
Proof of Principle in Cats

50. Protected B | Business Confidential
19
Glybera® (alipogene tiparvovec) Received
European Regulatory Approval Nov. 2, 2012
“Glybera is indicated for adult patients diagnosed with familial lipoprotein lipase deficiency (LPLD)
and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions. The
diagnosis of LPLD has to be confirmed by genetic testing. The indication is restricted to patients
with detectable levels of LPL protein”
Pivotal clinical trials (UniQure): Quebec (Dr. Daniel Gaudet)

51. Protected B | Business Confidential
20
6-year follow-up:
• Prevented all serious pancreatitis
• Significant reduction in use of healthcare resources
2016
Long-term benefit to patients

52. Protected B | Business Confidential
The million-dollar drug
21
April 2017

53. How Do Systems Need to Change
to Promote Access to Novel Therapies
for Rare Diseases:
Lessons from Lipoprotein Lipase Deficiency
Daniel Gaudet MD PhD
ECOGENE-21 and
Clinical Lipidology and Rare Genetic Lipid Disorders Unit
Community Gene Medicine Center
Département of Médecine, Université de Montréal

54. Severe Hypertriglyceridemia
Multifactortial Chylomicronemia
Familial chylomicronemia syndrome
LPLD

55. recurrent acute
pancreatitis (RAP)
NAFLD / NASH
Post-prandial
dysmetabolism
-lipid
-glucose
-liver and peripheral
tissues
Diabetes:
-type 2
-type 1 like
(pancreatic insufficiency)
Effect on vigilance
fatigue
anxiety, emotional
impact
Apo A-1, ABC1,
LCAT deficiency
hypobetalipoproteinemia
anemia, hemolysis
recurrent
thrombocytosis
Thrombotic events
recurrent (asx)
thrombocytopenia
hepatomegaly
splenomegaly
Low (< 18) BMI
sub-type:
-lipoatrophy
-CKD
-heart failure
arthralgia
Consequences

56. FCS from Patients’ Shoes
Davidson M, et al. . The burden of familial chylomicronemia syndrome: Results from the global IN-FOCUS study. J Clin Lipidol. 2018 12(4):898-907
Gaudet D. Et al , submitted 2019

57. Balancing Risks and Benefits by Integrating Novel
Therapies in a Systems Approach is Challenging
mRNA transcripts
APPROACHESTARGET
mutations/epimutations
Proteins/networks
Phenotypes/individuals
Population
DOMAIN
Proteome/interactome
Transcriptome
Genome
TG-rich Lipoproteins
Human phenome
Sociome
Epigenome
-Gene replacement
therapy
-Genome editing
-ASO -siRNA
-miRNA -piRNA
-Peptide mimetics
-Linker technology
-Enzyme replacement
-Targeted agents
-Companion tests
Combination therapies
-Precision medicine
approches
- Cascade screening
-Public health genetics
-Epigenetics modifiers
-miRNAs
-Methylation agents
-Nutrigenetics
-Functional foods
-Gut microbiota Rx
-Life habits
-cultural factors
Adapted from Gaudet D, J Clin Lipidol, 2016

58. AAV1-Capsid
Containing the AAV2-LPL s447x cassette
In vivo intramuscular injection
Lessons from Glybera Gene Replacement Therapy for LPLD
• First Gene replacement therapy being
authorized in the occidental world
• Nineteen Canadians treated 10 years
ago
• Signs of efficacy decrease over years

59. AAV2-LPLS447X Cassette
ITR CMV LPLS447X WPRE pA ITR
AAV1-capsid
TODAY, GLYBERA WOULD BE DESIGNED DIFFERENTLY

60. Lessons from Glybera
n Glybera did not cure LPLD;
n Limited and unpredictable long term efficacy;
n Very expensive (above $1 million);
n No effective combination therapies available at the time that
clinical studies were conducted ;
n Industry-driven patients’ registry (maintained at regulators
request) is painful;
.

61. Challenges for the Next Generation of Gene
Replacement Therapy
n Access means decreasing the cost (pricing);
n Dealing with all factors affecting the cost requires partnership,
communication and creativity;
n Assessing the long term F-U safety and efficacy is
challenging;
n Approval and reimbursement issues.
n Connecting the stakeholders;
n Dealing with alternative treatments or combination therapies;

62. An Example of Alternative Treatment for LPLD:
Volanesorsen Apo-C III ASO (V 2.5)
MOEMOE
↑ affinity
↑ stability
↑ tolerability
↑ affinity
↑ stability
↑ tolerability
RNase H
Substrate
DNA
Chimeric RNase H ASO Design
n Specific sequence not repeated throughout
genome, reducing potential for off-target
binding
10
RNase H Terminating Mechanism

63. LPLD
Gaudet D et al. N Engl J Med 2014;371:2200-2206
Volanesorsen Effect on TG concentration in LPLD reveals
non-LPL Dependent Pathways for Disease Management

64. APOC3 Gene As a Target for LPLD Patients
n Possible synergy between LPL gene replacement therapy and
apoC-III inhibition;
n Several patients being currently treated with volanesorsen
(special access program) received Glybera 10 years ago;
n Volanesorsen enconters approval (registration) problems in
North America;
n Next generation APOC3-ASO are developed and APOC3-
siRNA are emerging;
n ApoC3 CRISPR-cas (genome editing) is in development

65. Conclusion

67. Healtcare providers
Industry/ biotechs - Health decision makers
- Payers
- Public agencies
- Research centers

68. « connecting the dots »
Access to
Health services

69. ACKNOWLEDGEMENTS
1. Patients and their families;
2. The ECOGENE-21 Clinical and Translational Research Unit team;
3. The Clinical Lipidology and Rare Lipid Disorders Unit, CMGC, Dept of
Medicine, Université de Montréal;
Centre de médecine génique communautaire
Unité de lipidologie clinique et dyslipidémies rares

70. CORD 2019
Access to Innovation Conference

71. Our family

72. Abby’s diagnostic journey begins
Global
Developmental
Delay
6 clinics
20+ visits
Genetics

73. Abby’s MRI | March 2014
¨ Mild atrophy of
cerebellar hemispheres
and vermis
MRI Results

75. Care4Rare

76. Exome sequencing

77. Rare disease by the numbers

78. RDMM

79. Life goes on

80. Abby’s MRI | November 2018
¨ Significant progressive
increase in degree of
diffuse atrophy of
cerebellar hemispheres
and vermis
MRI Results

81. Abby’s MRI | Comparison
MRI 2014 MRI 2018

82. Team Dalgleish

83. Rare disease diagnostic journey
Current approach

84. Rare disease diagnostic journey
Current approach Precision health

85. Change

87. BRINGING LIFE
TO PERSONALIZED MEDICINE
Personalized Rare and
Specialty Disease Solutions

88. $0
$250
$500
$750
2016 2020 2024
North American Rx Market
Traditional Specialty
Our Relationship with Medicine is
Being Redefined
THE SHIFT TO PERSONALIZATION
Wave of new therapies for Rare and
Specialty disease
Specialty Rx will account for over 50%
of the market by 2024
Highly personalized therapies will
change how physicians work
Matching patients with personalized
therapies will be the new norm