Rare Disease Day 2015 Conference Day 1: Daniel Gaudet MD PhD Dept of Medicine, Université de Montreal

1. ROC POP
Working with Rare Diseases as
Extreme Expressions of Common
Diseases:
Lessons from Orphan Lipid Disorders
Daniel Gaudet MD PhDDaniel Gaudet MD PhD
Dept of Medicine, Université de MontrealDept of Medicine, Université de Montreal

2. SummarySummary
 Introduction
 ROC POP approaches of Lipid disorders
 Emerging therapies for orphan lipid disorders: lessons,
opportunities and challenges
 FH Canada and SMASH
 Future challenges

3. Typical Characteristics of Orphan Lipid DisordersTypical Characteristics of Orphan Lipid Disorders
 Lack of sufficient scientific and medical knowledge;
→ misdiagnosis or delay in diagnosis
 Clinical guidelines for the management of lipid disorders do not apply
to extreme forms (most often mendelian or oligogenic orphan
diseases);
 No curative treatment available; Several emerging therapies in
development;
 Lack of relevant information (patients and health professionals) ;
 Important clinical, social, emotional and economical impact (severe
health consequences, assurability, employability, cost of disease,
QALYs, etc..)

4. ROC POP APPROACHES OF
LIPID DISORDERS

5. « ROC POP »: What’s in a Name?
from Rare and Orphan disorders to Common diseases and
Population health;
 ROC POP: a sequential approach of personalized medicine;
 Lessons learned from extreme phenotypes are helpful to those
affected by less severe, more common forms
Several orphan lipid disorders are the extreme expression of
common phenotypes:
 very low HDL-C (Tangier, Fish-eye disease, etc)
 very high Lp(a)
 very high IDL-C (dysbetalipoproteinemia, apoE resistance)
 very high LDL-C (HoFH, severe HeFH)
 Very high triglycerides (LPLD, multifactorial chylomicronemia)
 HeFH and severe statin intolerance (myositis or rhabdomyolysis)

6. Adapted from Nature 461, 747-753 (2009)
Lipid Disease-Causing Variants
Low-med
frequency
variants with
variable
effect
Low-med
frequency
variants with
variable
effect
Rare variants
of small effect
usually hard
to identify by
genetic
means
Rare variants
of small effect
usually hard
to identify by
genetic
means
high-effect
common
variants
influencing
common
disease
(eg: apoE)
high-effect
common
variants
influencing
common
disease
(eg: apoE)
Allele frequency
50.0
3.0
1.5
1.1
0.001 0.005 0.05
Effect size
LDLR
LPL

7. ROC POP Applied to Drug Development for Lipid
Disorders
 The « ROC POP » sequential strategy for drug
development:
 Evaluate the efficacy and safety of emerging therapies in
extreme forms of dyslipidemias;
 If the treatment is not developed for orphan designation
only, then assess the treatment in less severe forms;
 Make sure that the patients benefit from the effort.

8. EXTREME
HYPERCHOLESTEROLEMIA
AND
EXTREME
HYPERTRIGLYCERIDEMIA

9. FH Geographical DistributionFH Geographical Distribution
• Known prevalence is higher in some populations:
• South Africa
• French-Canadians
• Finland
• Mediterranean countries
• Lebanese Christians
• Asia: Malaysia, Japanese clusters
Heterozygous FHHeterozygous FH
• One mutant allele in FH causing
genes
• Null vs defective alleles
• Incidence: (more than 1: 350)
Homozygous FHHomozygous FH
• Two mutated alleles in LDLR, APOB,
PCSK9, LDLRAP1, LIPA, APOE genes
• True Homozygote if two identical
mutations inherited
• Compound//multiple Heterozygotes
• Null vs defective alleles
• Incidence: (1 : 1,000,000)

10. Discovery of Cholesterol biosynthesis pathway (Bolch)
And LDL receptor (Brown & Goldstein)
HoFH and HeFHHoFH and HeFH
In HoFH loss-of-function mutations in both LDLR alleles
(HoFH or compound HeFH)
Resulting in loss of LDL receptor activity
Leading to decreased clearance of LDLs from the plasma
High LDL-C and Premature cardiovascular disease

11. F r e d r ic k so n ’s n e a r e st p h e n o ty p e
(e tio lo g y )
T y p e I
(fa m ilia l c h y lo m ic r o n e m ia )
T y p e I I I
(a p o E r e sis ta n c e )
T y p e I V
(se c o n d a r y c a u se s d o m in a t e )
T y p e V
(o lig o g e n ic )
C o -m o r b id it ie s a O R
[9 5 % C I ]
p -v a lu e b O R
[ 9 5 % C I ]
p - v a l u e
O R
[ 9 5 % C I ]
p - v a l u e
O R
[ 9 5 % C I ]
p - v a l u e
O b e s i ty ( B M I ≥ 3 0 k g / m 2
)
0 .5 8
[ 0 .1 3 - 2 .5 8 ]
0 .4 7 2
4 .0 1
[ 2 .1 2 - 7 .5 7 ]
< 0 .0 0 1
3 .4 1
[2 .1 3 - 5 .4 7 ]
< 0 .0 0 1
4 .6 8
[2 .7 1 - 8 . 0 9 ]
< 0 .0 0 1
C o r o n a r y A r te r y D is e a s e
0 .6 5
[ 0 .1 4 - 3 .1 2 ]
0 .5 8 9
1 .4 6
[ 0 .6 7 - 3 .1 5 ]
0 .3 3 8
1 .7 0
[0 .9 9 - 2 . 9 2 ]
0 . 0 5 6
1 .9 4
[1 .0 3 - 3 . 6 6 ]
0 .0 4 1
P e r ip h e r a l A r t e r y D i s e a s e N A N A
1 9 .4 2
[ 2 .0 6 - 1 8 2 .8 6 ]
0 .0 1 0
1 .5 6
[ 0 .1 0 - 2 5 .4 6 ]
0 .7 5 3 N A N A
A r te r ia l H y p e r te n s i o n
1 . 1 0
[ 0 .3 9 - 3 .0 6 ]
0 .8 6 3
0 .7 2
[ 0 .3 6 - 1 .4 3 ]
0 .3 5 1
1 .2 1
[0 .7 7 - 1 .9 2 ]
0 .4 0 8
1 .9 6
[1 .1 3 - 3 . 4 0 ]
0 .0 1 7
D ia b e t e s
3 .1 9
[ 0 .9 3 - 1 0 .9 7 ]
0 .0 6 6
1 .8 4
[ 0 .8 0 - 4 .2 5 ]
0 .1 5 4
3 .5 8
[2 .0 5 - 6 .2 5 ]
< 0 .0 0 1
6 .5 0
[ 3 .4 7 - 1 2 .1 5 ]
< 0 .0 0 1
G lu c o s e I n to le r a n c e N A N A
3 .6 3
[ 1 .2 6 - 1 0 .4 7 ]
0 .0 1 7
3 .1 0
[1 .0 4 - 9 .2 0 ]
0 .0 4 2
6 .7 8
[ 2 .1 9 - 2 1 .0 1 ]
0 .0 0 1
P a n c r e a ti t i s
3 6 1 .4 0
[ 4 1 .0 6 - 3 1 8 1 .2 0 ]
< 0 .0 0 1
2 2 .6 3
[ 2 .2 3 - 2 2 2 .1 8 ]
0 .0 0 8
3 8 .2 8
[ 4 .8 7 - 3 0 0 .7 0 ]
0 .0 0 1
5 4 .4 3
[ 6 .8 2 - 4 3 4 .4 7 ]
< 0 .0 0 1
Risk Associated with Chylomicronemia (TG >10 mmol/L)Risk Associated with Chylomicronemia (TG >10 mmol/L)
Familial Multifactorial

12. F r e d r ic k so n ’s n e a r e st p h e n o ty p e
(e tio lo g y )
T y p e I
(fa m ilia l c h y lo m ic r o n e m ia )
T y p e I I I
(a p o E r e sis ta n c e )
T y p e I V
(se c o n d a r y c a u se s d o m in a t e )
T y p e V
(o lig o g e n ic )
C o -m o r b id it ie s a O R
[9 5 % C I ]
p -v a lu e b O R
[ 9 5 % C I ]
p - v a l u e
O R
[ 9 5 % C I ]
p - v a l u e
O R
[ 9 5 % C I ]
p - v a l u e
O b e s i ty ( B M I ≥ 3 0 k g / m 2
)
0 .5 8
[ 0 .1 3 - 2 .5 8 ]
0 .4 7 2
4 .0 1
[ 2 .1 2 - 7 .5 7 ]
< 0 .0 0 1
3 .4 1
[2 .1 3 - 5 .4 7 ]
< 0 .0 0 1
4 .6 8
[2 .7 1 - 8 . 0 9 ]
< 0 .0 0 1
C o r o n a r y A r te r y D is e a s e
0 .6 5
[ 0 .1 4 - 3 .1 2 ]
0 .5 8 9
1 .4 6
[ 0 .6 7 - 3 .1 5 ]
0 .3 3 8
1 .7 0
[0 .9 9 - 2 . 9 2 ]
0 . 0 5 6
1 .9 4
[1 .0 3 - 3 . 6 6 ]
0 .0 4 1
P e r ip h e r a l A r t e r y D i s e a s e N A N A
1 9 .4 2
[ 2 .0 6 - 1 8 2 .8 6 ]
0 .0 1 0
1 .5 6
[ 0 .1 0 - 2 5 .4 6 ]
0 .7 5 3 N A N A
A r te r ia l H y p e r te n s i o n
1 . 1 0
[ 0 .3 9 - 3 .0 6 ]
0 .8 6 3
0 .7 2
[ 0 .3 6 - 1 .4 3 ]
0 .3 5 1
1 .2 1
[0 .7 7 - 1 .9 2 ]
0 .4 0 8
1 .9 6
[1 .1 3 - 3 . 4 0 ]
0 .0 1 7
D ia b e t e s
3 .1 9
[ 0 .9 3 - 1 0 .9 7 ]
0 .0 6 6
1 .8 4
[ 0 .8 0 - 4 .2 5 ]
0 .1 5 4
3 .5 8
[2 .0 5 - 6 .2 5 ]
< 0 .0 0 1
6 .5 0
[ 3 .4 7 - 1 2 .1 5 ]
< 0 .0 0 1
G lu c o s e I n to le r a n c e N A N A
3 .6 3
[ 1 .2 6 - 1 0 .4 7 ]
0 .0 1 7
3 .1 0
[1 .0 4 - 9 .2 0 ]
0 .0 4 2
6 .7 8
[ 2 .1 9 - 2 1 .0 1 ]
0 .0 0 1
P a n c r e a ti t i s
3 6 1 .4 0
[ 4 1 .0 6 - 3 1 8 1 .2 0 ]
< 0 .0 0 1
2 2 .6 3
[ 2 .2 3 - 2 2 2 .1 8 ]
0 .0 0 8
3 8 .2 8
[ 4 .8 7 - 3 0 0 .7 0 ]
0 .0 0 1
5 4 .4 3
[ 6 .8 2 - 4 3 4 .4 7 ]
< 0 .0 0 1
Risk Associated with Chylomicronemia (TG >10 mmol/L)Risk Associated with Chylomicronemia (TG >10 mmol/L)
Familial Multifactorial

13. Establish the Cause of Extreme HyperTGEstablish the Cause of Extreme HyperTG
Rule-out FCS
(rule-in CAD and
cardiometabolic risk)
Rule-in FCS
(pancreatitis risk)
Recessive disease:
LPL
APOC2
GPIHPB1
LMF1
Biomarkers Value
Multifactorial
Chylomicronemia
FCS
Plasma TG Value
(mg/dl)
95th
percentile
99th
percentile
Plasma TG Distribution
in the population
900150
99.8th
percentile

14. EMERGING THERAPIES FOR
ORPHAN LIPID DISORDERS :
Opportunities and challenges

15. Some Economic and Social Challenges of OrphanSome Economic and Social Challenges of Orphan
Drug Development in Clinical LipidologyDrug Development in Clinical Lipidology
 Orphan drugs are expensive. Ability to pay is limited; The
prevalence of extreme lipid disorders is often too low to
provide an adequate return to R&D expenditure;
 Access to the drug often requires companion genetic
testing (which increases the cost);
 Treatment of less severe forms with the same drug, when
feasible, may compensate for the R&D expenditure;
 Lessons learned from drug development for extreme lipid
disorders generate new knowledge from which a larger
proportion of the population or other orphan diseases
might benefit.

16. Current Challenges of Emerging Therapies for HoFH
and Orphan Hypercholesterolemia
 Drugs are developped for HoFH only (Eg: Mipomersen,
Lomitapide and others: HDL-peptide mimetics, ANGPTL3
inhibitors, PPPAR delta inhibitors);
 Very severe HeFH, FH with statin intolerance, etc.: PCSK9-
inhibitors;
 PCSK-9 inhibitors not effective in null HoFH. Some efficacy
in defective HoFH;
 who will have access to the drug? Genotyping required?
 Who will reimburse? On which criteria?

17. Omics Sciences and Emerging TG-Lowering TherapiesOmics Sciences and Emerging TG-Lowering Therapies
Potential targets for gene replacement therapy:
LPL, apoC2, ApoA-5, GPIHBP1
Targets for ASO and anti-sense therapy:
apoB, apoC-III, DGAT1 or 2, PCSK9, ANGPTL3
MicroRNAs
Aptamers
Cell Pathways:
Peptide linker technologies
metabolic pathways:
DGAT-1inh, MTPI, PCSK9 inh
Peptide-based mimetics:
HDL, apoE, etc

18. AAV1-Capsid
Containing the AAV2-LPL s447x
cassette
In vivo intramuscular injection
Glybera Gene Replacement Therapy for LPL Deficiency
• First Gene replacement therapy being
authorized in the occidental world (in
Europe).
• All pivotal clinical studies were conducted in
Canada (Qc). The drug was initially
designed in Canada (BC).
• Designed for patients with FCS due to loss-
of-function LPL gene mutations.
• Not for multifactorila chylomicronemia or
FCS caused by apoA-5, apoC-2, GPIHPB1,
LMF-1 gene mutations.
• Requires genotyping (genetic test)

19. Orphan Drug Development may reveal Important BiologicalOrphan Drug Development may reveal Important Biological
Pathways:Pathways: Lessons from LPL Gene Replacement therapyLessons from LPL Gene Replacement therapy
33
H-Chylomicron Kinetics atH-Chylomicron Kinetics at 14 Weeks and 52 Weeks14 Weeks and 52 Weeks
N=5
N=3
Time after test meal (hrs)
POST (wk 14)
POST (wk 52)
N=5
PRE
[3H]activityinCMs*(%ID/100ml)
*measured by
scintillation counting
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0 5 10 15 20 25
CM=Chylomicrons
EMA/882900/2011-Assessment Report, 19 July 2012.

20. APOCIIIRx Anti-Sense Therapy
•Structure: 20-nucleotide (20-mer) antisense oligonucleotide (ASO)
•Complementary, specific ASO sequence that crosses the hepatocyte cell
membrane and binds in coding region of mRNA for ApoC-III

21. APOCIIIAPOCIIIRxRx Efficacy in LPLD…UnexpectedEfficacy in LPLD…Unexpected
21
Gaudet D et al. N Engl J Med 2014;371:2200-2206

22. Orphan Drug Development may reveal Important BiologicalOrphan Drug Development may reveal Important Biological
Pathways:Pathways:
22
Gaudet D et al. N Engl J Med 2014;371:2200-2206

23. FH CANADA and SMASH

24. HO
FH
CANADA
FH Canada
WWW.fhcanada.net

25. SMASHSMASH
 SMASH: Systems and Molecular Approaches of Severe
Hyperlipidemias
 SMASH: Signature Moléculaire et Approche
Systémique des Hyperlipidémies Sévères

26. SMASHSMASH
 SMASH: Systems and Molecular Approaches of Severe
Hyperlipidemias
 SMASH: Signature Moléculaire et Approche
Systémique des Hyperlipidémies Sévères
 SMASH: Significato Molecolare e Approccio
Sistematico all‘(H)iperlipidemia Severa
 SMASH: Systematischen und Molekulare
Annä herungen für Schwerem Hyperlipidä mie

27. Systems Approaches of Orphan Lipid Disorders
Gene replacement therapy
Genome Editing
(CRISPR, TALen)
Pre mRNA AON
siRNA
miRNA
piRNA
Aptamers
•Cell pathway pharmacology
•Peptide mimetics,
• linker technology
•New Rx, biodrugs
and targets
EMERGING TREATMENTSEMERGING TREATMENTS
•.nutritional support
•Nutrigenetic treatments
•Life habits
• Family-sensitive approaches
•Personalized
community medicine
• Public Health
TARGE
TDOMAINDOMAIN
Proteome/metabolome/interactome
Transcriptome
Genome
Lipoproteins phenome/
human phenomes
Sociome
•Functional meals
•Disease adapted meals
•Life habits
•Epigenetic therapy
(diet, epi-drugs)
Epigenome
Population/communi
ty systems
Genes/mutations/epimutations
mRNA transcripts
Proteins/networks
Phenotypes/individuals

28. SMASH ComponentsSMASH Components
1. SMASH-Registry
2. SMASH-Biobank
3. SMASH-platforms
4. e-SMASH
5. SMASH-Clinics
6. SMASH-Projects
7. SMASH-Innovations
8. SMASH-P4

29. WP9 Data
Management
WP9 Data
Management
WP2partnership,capacitybuilding,fundingWP2partnership,capacitybuilding,funding
WP7TranslationalaccessWP7Translationalaccess
WP4
Registry,
Database
WP4
Registry,
Database
WP5
Clinical
Research
/trials
WP5
Clinical
Research
/trials
WP6
Innovations
WP6
Innovations
WP8 GELSWP8 GELSWP 10
Biorepository of
Orphan lipid
disorders tissues
WP 10
Biorepository of
Orphan lipid
disorders tissues
Capacity building
Funding proposal
Support to clinical trials,
multinational access
Scientific content /
Clinical protocols
Regulatory and ethical,
ISO, SOPs, GCP/GLP
training
Regulatory, ethical, SOPs,
expertise
Training tools,
Repository,
Communication tools
SMASH WP1 Management, Governance and CoordinationSMASH WP1 Management, Governance and Coordination
WP3 Education, Health services and P4 medicine,
communication, guidelines, e-tools
WP3 Education, Health services and P4 medicine,
communication, guidelines, e-tools

30. SMASH
WP5
Biobank
registry
PARTNERS Patients
Advisory
Boards
Companion
tests
Clinical
innovations
WP5E
WP5D
WP5C
WP5B
WP5A
WP5F
Translational
AT-OMICS
Unit
Clinical platforms,
SOPs
GCP/omics training
of HQP and
expertise
Core labs (ISO) Clinical trials
Conception and/or
execution
OMiCS Contract
Research
Organization
SMB
Network of
Investigational
Sites (National,
international)
Orphan, extreme
lipid disorders
National:
FH Canada,
CORD
International
Provinclal

31. CONCLUSION

32. Some Economic and Social Challenges of OrphanSome Economic and Social Challenges of Orphan
Drug Development in Clinical LipidologyDrug Development in Clinical Lipidology
 Development of a promising drug is in the public interest;
 Equity: people with rare diseases are entitled to same
quality of treatment than those suffering from common
diseases;
 Patients tell the story…and generate the evidence;
 The development of specialized resources including a
network of platforms and well-trained clinical sites with
expertise in orphan diseases and complex early phase
clinical trials is essential;

33. ACKNOWLEDGEMENTSACKNOWLEDGEMENTS
 All patients affected by rare, extreme, orphan, lipid disorders
and their families;
 All patients affected by a genetic lipid disease (rare or not);
 All patients with common lipid disorders;
 Patients suffering from any orphan disease and their
families;
 FH Canada, particularly: Jacques Genest, Rob Hegele, and
all others
 CORD
 All SMASH partners