HSG 2016's Innovators Forum included presenters from Wave Life Sciences, uniQure, and Ionis Pharmaceuticals.

1. HD Innovators Forum
Thursday, November 3
4:45-4:45pm
Moderators:
Blair Leavitt and Christopher Ross
HSG Scientific Advisory Committee Chairs

2. Presenters
HSG 2016: DISCOVERING OUR FUTURE
Mike Panzara, MD, MPH
WAVE Life Sciences
Pavlina Konstantnova, PhD
uniQure
Anne Smith, PhD
Ionis Pharmaceuticals

3. Use of optimized stereochemistry to target the Huntington’s
Disease allele mRNA by antisense oligonucleotide treatment
Michael A. Panzara, MD, MPH
Head of Neurology Franchise, WAVE Life Sciences
November 3, 2016

4. Founded
• Ontorii
(USA)• Chemistry &
Pharmacology
• Chiralgen (Japan)
• Manufacturing
2009 2013
Merger
• WAVE Life
Sciences
2015
Financings
• 2 private
rounds
• ~$196MCash
License
• Tuschl ssRNAi • IPO
(WVE)
2016
• Two IND filings expected for Huntington’s disease lead programs (WVE-120101, WVE-120102) YE
2016
• Clinical Trials expected to commence 2017 for 2 lead Huntington’s disease programs 2017
• IND filing and initiation of clinical trial for lead program in Duchenne Muscular Dystrophy in 2017
• Targeting 6 IND filings by end of 2018
• 20+ programs in early
discovery and pre-clinical
development
• Strategic partnerships complement
internal neurology focus areas (ex. Pfizer May 2016)
• Cash runway into 2019
2018+
Pipeline Growth
• GalNAc POC
• 2 INDs expected YE
2016
6 IND
Submissions
by 2018
Manufacturing Capabilities Expanded
Foundation of Intellectual Property
• Collaboratio
n• Metabolic disease
• Hepatic targeting technology
2017:Clinical
Platform Expansion & Pipeline Development
WAVE Life Sciences
A Genetic Medicines Company
Developing targeted therapies for patients impacted by rare diseases
Clinical Development
• Initiate 3 clinical trials 2017
• 2 additional INDs YE 2017

5. BACKGROUND
3
 Phosphorothioate (PS) backbone modification introduced into nucleic acid based
therapies:
 Provides good stability and bio-availability
 Adopts random three-dimensional arrangements during synthesis
 Results in exponentially diverse drug mixtures with 2N stereoisomers (N = number of
PS)
 Drug mixtures may suffer from efficacy, safety and distribution issues
19 phosphorothioate (PS) linkers
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
Each PS linker
= OR = 219
Mipomersen
(219 = 524,288)
Stereo-random Rp-stereoisomer Sp-stereoisomer Drug mixture
Phosphodiester Phosphorothioate
Sp
Rp

6. • WAVE proprietary platform precisely
controls oligonucleotide
stereochemistry
• Enables control of pharmacology and
rational drug design with potential to
improve stability, activity, stability,
immunogenicity and specificity
• Scalable synthesis
• Applicable to any nucleic acid based
therapy and targeting moieties
• Unique ability to optimize
pharmacology across the therapeutic
class
PLATFORM
4
Mixture
s
Rp Sp Nucleotide Linker
WAVE Chemical Control
WAVE Optimized Isomers
Stability Activity Immune Specificity
WAVE Design
Antisense RNAi Exon skipping
Optimized isomers

7. WAVE Pipeline
Key
: Est 2017
Clinical Trial
I: Anticipated
IND filings
C: Candidate
Nomination
Estimated
inflection point for
candidate
selection efforts
This chart contains forward-looking statements.
Core
Neurolog
y
Portfolio
(2)

8. Two lead programs in HD, IND filings expected in2016
The Disease
• Autosomal dominant disorder, involving the
HTT gene, characterized by chorea,
psychiatric illness and cognitive decline
• Approximately 30,000 individuals
have symptomatic HD in the United
States
• No approved disease-modifying
therapies available
WAVE Approach
• Selective reduction of mutant HTT while
leaving wild-type HTT intact could be
disease modifying
• Targeting single nucleotide
polymorphisms (SNPs) associated with
causative mutations provides an
approach to allele-specific gene silencing
• Over two-thirds of patients are eligible to use
WAVE’s first two programs due to prevalence
of SNPs associated with the mutant alleles
Huntington (HTT)
Wild-type (healthy) allele
Mutant allele SNP
CAG repeat
Disease causing
mutations
SNP associated with CAG repeat
Enables targets for allele-specific
silencing
100%
75%
25%
0
%
Number of SNPs
targeted
HDPatients
covered
Cumulative HD Patient Coverage
50%
Huntington’s Disease (HD)
~77% ~80%
~71%
~55%
1 2 3 4

9. WVE-120101 Selectively Cleaves mHTT RNA
No Complement Immune System Response

10. WVE-120101 Selectively Reduces
mHTT mRNA and Protein

11. Distribution of WVE-120101 in Cynomolgus
NHP Brain
Animal # 42, Slice
8
Red dots are WVE-120101. Arrow
points to nuclear and perinuclear
distribution of WVE-120101 in
cingulate cortex
In Situ Hybridization ViewRNA stained
tissue
WVE-120101 detectable in deep gray matter structures following
intrathecal administration

12. Distribution of WVE-120101 in Cynomolgus
NHP Brain
WVE-120101 detectable in deep gray matter structures following
intrathecal administration
Animal # 42, slice
8
D
Red dots are WVE-120101. Arrow
points to nuclear and perinuclear
distribution of WVE-120101 in caudate
nucleus

13. • Two concurrent global Phase 1b/2a placebo-controlled studies targeting
SNP1 and SNP2
• Primary Objective: Assess safety and tolerability of single ascending and
multiple intrathecal doses in early manifest HD patients
– Exploratory pharmacokinetic, pharmacodynamic, clinical and MRI endpoints
– SNP determination at initial screening visit
– Key inclusion criteria
• Age ≥25 to ≤65
• Stage I or Stage II Huntington’s disease
• INDs expected to file by YE 2016
WVE-120101 and WVE-120102 Clinical
Development

14. Patient Selection for WVE-120101/2
Clinical Studies
Patients with the targeted SNP on the same allele as the pathogenic CAG
expansion will be eligible

15. • Control of oligonucleotide stereochemistry enables rational drug design and
control of pharmacology of nucleic acid therapeutics
– Potential to improve stability, activity, stability, immunogenicity and specificity
– Scalable synthesis
– Application to any nucleic acid based therapy and targeting moieties
• In HD, WVE-120101 selectively decreased mHTT mRNA and protein levels
compared with wtHTT in multiple cell lines with SNP1 allele with good brain
distribution
– Targeting SNP1 and SNP2 may provide the possibility of treating over two-thirds of
the total HD patient population
• The ability to selectively reduce mHTT protein, while retaining healthy HTT
protein, might provide disease-modifying effects in HD
Conclusions

16. Refining experimental gene therapies for Huntington’s
and other diseases
Pavlina Konstantinova
Director Emerging Technologies
24th of February 2016, CHDI meeting
Development of HTT lowering gene
therapy using AAV vectors
Pavlina Konstantinova, PhD
Director Emerging Technologies

17. THIS PRESENTATION CONTAINS FORWARD-LOOKING STATEMENTS THAT INVOLVE SUBSTANTIAL RISKS AND
UNCERTAINTIES. ALL STATEMENTS, OTHER THAN STATEMENTS OF HISTORICAL FACTS, CONTAINED IN THIS
PRESENTATION, INCLUDING STATEMENTS REGARDING OUR STRATEGY, FUTURE OPERATIONS, FUTURE
FINANCIAL POSITION, FUTURE REVENUES, PROJECTED COSTS, PROSPECTS, PLANS AND OBJECTIVES OF
MANAGEMENT, ARE FORWARD-LOOKING STATEMENTS. THE WORDS “ANTICIPATE,” “BELIEVE,” “ESTIMATE,”
“EXPECT,” “INTEND,” “MAY,” “PLAN,” “PREDICT,” “PROJECT,” “TARGET,” “POTENTIAL,” “WILL,” “WOULD,”
“COULD,” “SHOULD,” “CONTINUE,” AND SIMILAR EXPRESSIONS ARE INTENDED TO IDENTIFY FORWARD-
LOOKING STATEMENTS, ALTHOUGH NOT ALL FORWARD-LOOKING STATEMENTS CONTAIN THESE IDENTIFYING
WORDS.
WE MAY NOT ACTUALLY ACHIEVE THE PLANS, INTENTIONS OR EXPECTATIONS DISCLOSED IN OUR FORWARD-
LOOKING STATEMENTS, AND YOU SHOULD NOT PLACE UNDUE RELIANCE ON OUR FORWARD-LOOKING
STATEMENTS. ACTUAL RESULTS OR EVENTS COULD DIFFER MATERIALLY FROM THE PLANS, INTENTIONS AND
EXPECTATIONS DISCLOSED IN THE FORWARD-LOOKING STATEMENTS WE MAKE. THE FORWARD-LOOKING
STATEMENTS CONTAINED IN THIS PRESENTATION REFLECT UNIQURE’S CURRENT VIEWS WITH RESPECT TO
FUTURE EVENTS, AND UNIQURE ASSUMES NO OBLIGATION TO UPDATE ANY FORWARD-LOOKING
STATEMENTS EXCEPT AS REQUIRED BY APPLICABLE LAW.
FORWARD-LOOKING STATEMENTS

18. Idea of Gene Therapy is Simple
18
Replace in a one-time administration a gene that does not function with a functioning gene to
“fix” what is causing disease
Gene
Therapeutic
correction
Vector
Delivery
vehicle
Manufacturing
Gene / vector
copies
Administration
Target tissue

19. 19 Confidential
natural AAV DIRECTED EVOLUTION optimized AAV
Natural AAV Variants and Target Tissue Tailored Vectors
TROPISM
AAV1
Exclusivity for LPLD
AAV2
AAV5
Exclusivity for
LIVER and CNS
AAV6
AAV8
AAV9
Synthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic
AAV MutantsSynthetic AAV
Super Mutants
4D Therapeutics

20. AAV5 uniQure’s Proprietary and Proven Vector
• Validated delivery technology
• 20 patients successfully treated
• Lowest prevalence of pre-existing
antibodies amongst natural AAV serotypes
• Successful delivery in liver and brain
tissues
• Potential for a wide variety of indications
across multiple therapeutic areas
• Initial efficacy established in Hemophilia B
and Sanfilippo B
• Proven safety in three clinical trials
20
AAV5

21. 21
1Pringsheim et al. Mov. Disord. (2012)
• Worldwide prevalence
of 2.71 in 100,0001;
• EU/US 5.70 in 100,0001
• No treatment available
• Published proof of concept of
therapeutically relevant knock-
down in humanized mouse/rate
models
• Lead selection completed
• Non-clinical safety
toxicology studies
ongoing
• Initiate first-in-man study
Market
Status
Data to Date
Next Steps
Huntington's Disease Program Overview
Target indication - Reduction of mutant aggregating huntingtin to decrease toxic burden

22. 22
Product development for AAV5 HD gene therapy
Age/years
Symptomseverity
10 20 30 40 50 60 70 80
Disease onset
and diagnosis
Single treatment
AAV5-miRNA gene
therapy
• Slow down disease progression
• Treatment after disease onset
Slow down of
disease progression
Pre-symptomatic phase Symptomatic phase

23. 23
Companies developing HTT lowering therapies
(both alleles are targeted)
 IONIS PHARMACEUTICALS STARTED PHASE I/IIA TRIAL IN JULY
2015 WITH ASO TARGETING HTT
 VOYAGER/GENZYME DEVELOP AAV1-MIRNA TARGETING HTT (TO
BE IN GLP-TOX IN 2017)
 SPARK IS PROCEEDING WITH AAV1-MIRNA TARGETING HTT (TO BE
IN GLP-TOX IN 2016)

24. 24
AAV5-miHTT gene therapy for HD
Therapeutic RNA interference
binding to cell surface
heparan sulphate proteoglycan
internalization vesicle escape and
transport to nucleus
Uncoating and
miRNA expression
AAV vector
cytoplasm
nucleus
AAA
Target cell
(neurons)
Huntingtin mRNA
binding
Huntingtin
degradation

25. AAV5-miHTT targeting HTT exon 1
Wild type HTT gene
Mutant HTT gene
CAG tract
Expanded CAG tract
 Silencing of both wild-type (wt) and mutant (mt) HTT alleles
 In HD rodent models 75% knock-down of HTT is therapeutic (Drouet et al.
2009, Boudreau et al. 2009, Stiles et al. 2012)
 In NHPs 50% knock-down of HTT is well tolerated (Kordasiewicz et al. 2012,
McBride et al. 2012)

26. The miHTT therapeutic lead selection process
Therapeutic candidate selection
• In vitro selection
• miRNA scaffold optimization – incorporate best miHTT in different cellular scaffolds
• In vivo efficacy in HD mice – transduction, HTT silencing, phenotype improvement
• Safety – ongoing
Miniarikova et al. MolTher NA, 2016
CAG promoter polyAmiHTT-451
~2.8 kb
5’ITR 3’ITR
CAG, chicken beta actin promoter; ITR, inverted terminal repeats

27. Broad brain distribution of AAV5-GFP-miHTT – in mice
Amber Southwell,
UBC 27
Forebrain, striatum, cortex, and hippocampus

28. AAV5-miHTT
AAV5-miScr
miScr miHTT
AAV5-miHTT
AAV5-miScr
miScr miHTT
AAV5-miHTT induces strong HTT silencing in humanized HD mouse
28
Target specificity and miHTT efficacy
Miniarikova et al, MolTher NA,2016
Amber Southwell, UBC
75%
50%
Humanized HD mouse
miHTT
128QhHtt -
hHtt -

29. AAV5-miHTT treatment prevents neurodegeneration in HD rat model
29
Phenotype improvement
Miniarikova et al. submitted
AAV5-miHTTAAV5-miSCR
DARPP-32 lesions

30. 30
AAV5 delivery studies in NHP and HD minipigs
MRI-guided CED delivery to NHP

31. PutameninfusionThalamusinfusion
Snapshot from the end of the infusion
127µL
207µL
MRI-guided CED
13 consecutive acquisitions with 5min delay (total time: min)
FirstcannulaplacementSecondcannulaplacement
Left Right
Thalamus + Putamen infusion

32. Broad distribution of AAV5-GFP - in NHP
32
Transduction efficiency NHP after MRI-CED
8 weeks post bilateral infusion
α-GFPAAV5-CAG-GFP
127µL by CED
AAV5-CAG-GFP
207µL by CED
Valley Biosystems

33. AAV5-miHTT gene therapy demonstrates efficacy in TgHD
minipig study
12 wild-type minipigs
12 TgHD minipigs
2-3 years of age
-2 0 2 3 4 6 8 12-1 1 5 7 9 1110
CSF
serum
CSF
serum
CSF
serum
plasma
CSF
serum
plasma
CSF
serum
plasma
CSF
serum
plasma
CSF
serum
plasma
CSF
serum
plasma
N=3 formulation buffer
N=3 1E+13 GC/pig AAV5-GFP
N=3 1E+13 GC/pig AAV5-miHTT
N=3 3E+13 GC/pig AAV5-miHTT
Immunohistochemistry: - GFP
- HTT
- Iba1
- GFAP
DNA isolation: - AAV5 distribution
RNA isolation: - miHTT expression
- mtHTT reduction
Protein isolation: - mtHTT quantitation
Weeks:
Sampling:
Bilateral CED infusion
putamen and thalamus

34. Broad distribution after thalamic injection – in pigs
34
AAV5-GFP transduction efficiency mini pig
Jan Motlík, Liběchov
(Evers et al, in preparation)
α-GFP

35. Broad AAV5-miHTT vector distribution correlates with
transgene expression and HTT lowering in HD minipig
> STRONG CORRELATION BETWEEN VECTOR GENOME COPIES AND MIHTT EXPRESSION
35
0 . 1 1 1 0 1 0 0
1 0
2
1 0
3
1 0
4
1 0
5
1 0
6
1 0
7
1 0
8
m a t u r e m i H T T m o l e c u l e s p e r c e l l
AAV5-miHTTgenomecopies
pergDNA
R
2
= 0 . 8 7 4 4
P = 1 . 1 1 2 e - 0 1 3
Evers et al, in preparation

36. AAV5-miHTT treatment results in strong mutant HTT mRNA
reduction in TgHD minipig brain
Evers et al, in preparation
C a u d a t e n u c l e u s
mtHTTmRNAexpression(%)
(normalizedbyGAPDH,relativetoSaline)
S
a
lin
e
1
E
+
1
3
A
A
V
5
- G
F
P
1
E
+
1
3
A
A
V
5
- m
iH
T
T
3
E
+
1
3
A
A
V
5
- m
iH
T
T
0
5 0
1 0 0
1 5 0
T h a l a m u s
mtHTTmRNAexpression(%)
(normalizedbyGAPDH,relativetoSaline)
S
a
lin
e
1
E
+
1
3
A
A
V
5
-G
F
P
1
E
+
1
3
A
A
V
5
-m
iH
T
T
3
E
+
1
3
A
A
V
5
-m
iH
T
T
0
5 0
1 0 0
1 5 0
C o r t e x
mtHTTmRNAexpression(%)
(normalizedbyGAPDH,relativetoSaline)
S
a
lin
e
1
E
+
1
3
A
A
V
5
-G
F
P
1
E
+
1
3
A
A
V
5
-m
iH
T
T
3
E
+
1
3
A
A
V
5
-m
iH
T
T
0
5 0
1 0 0
1 5 0

37. GLP-TOX studies path
> GLP-TOX STUDIES PLANNED IN TWO RELEVANT LARGE BRAIN SPECIES
> Cynomolgus monkeys - full GLP-TOX study to mimic the clinical trial design
> Targeting striatum and/or thalamus
> MRI guided CED infusion filling 80% of structure
> Vector distribution
> Safety
> HTT lowering and biomarkers
> Minimum 6 months in-life
> HD minipig – long term safety, up to 5 years
> Mimic clinical trial design
> Demonstrate long term vector persistence
> Evaluate long-term consequences of HTT lowering
> Generate long-term safety data prior product approval
37
Gene Therapy is a new technology, so long-term safety is crucial

38. uniQure’s HD clinical trial concept
> GENE TRANSFER WILL BE A THERAPEUTIC
TREATMENT
> MAIN GOAL: DELAY OR STOP DISEASE
PROGRESSION
> BASED ON THE MOA AND CHANGES IN BRAIN
VOLUMES AND MORPHOLOGY WE PROPOSE:
> THERAPEUTIC INTERVENTIONS IN PATIENTS IN
EARLY HD STAGES
> THE CONCEPT OF EARLY INTERVENTION IS IN
DISCUSSION WITH PHYSICIANS AND REGULATORY
AGENCIES.
38
Treat patients in early stage of disease progression
J-P Vonsattel, 1985
Atrophy of the striatum
(caudate and putamen)
Cortical thinning
Ventricular enlargement
Neuropathology of HD
Normal Grade 2 Grade 3 Grade 4
caudate and putamen

39. 39
Acknowledgements and collaborators
uniQure
Jana Miniarikova Juliana Bronzova Sebastian Kugler
Melvin Evers Jean-Marc Burgunder
Cynthia Brouwers Bernhard Landwermeyer
Jolanda Snapper
Bas Blits
Raygene Martier
Tom van der Zon
Sander van Deventer Nicole Deglon
Charles Richard Virginie Zimmer
Harald Petry
Amber Southwell
Ilaria Zanella Michael Hayden
Angelina Huseinovic
Annemart Koornneef
Piotr Maczuga
Richard van Longestein
Huining Li
Florie Borel
Evelyn Hanenmaijer
GHI, Munster
Ralf Reilmann
IAPG, Libechov
Jan Motlik
Stefan Juhas
Zdenka Eledorova
Taneli Heikkinen
Outi KontkanenUCSF/Valley
Ignacio Munoz-Sanjuan
Douglas Macdonald
David Howland

40. 40
Thank You!
From the uniQure Team

41. IONIS-HTTRx: An Antisense Oligonucleotide
in Development for the Treatment of
Huntington’s Disease
03 November 2016
Anne Smith, PhD
Ionis Pharmaceuticals

42.  Founded: 1989
 Location:
Carlsbad, CA
 ~400 employees
 Focus:
 Drug discovery
 Early clinical
development
 Manufacturing
Ionis Pharmaceuticals, Inc.
42

43. The number of new drugs approved by the US FDA per billion dollars
(inflation adjusted) spent on research and development from 1950 to 2010.
Drug Discovery Productivity is Declining
Scannell et al. 2012. Nature Rev Drug Discov.
100
10
1
#drugs/billion$spent
0.1
1950 1960 1970 1980 1990 2000 2010
FDA tightens regulation
post-thalidomide
First wave of biotechnology-
derived therapies
FDA clears backlog
following PDUFA
regulations plus small
bolus of HIV drugs
43

44. Drug Discovery Platforms
Small Molecules Proteins
Lipitor
Nucleic Acids
antisense
oligonucleotides
(ASOs)
Gene Therapy
antibody
insulin
44

45. DMPKRx
RNase H
Removes toxic RNA
Antisense Oligonucleotide (ASO) Mechanisms
RNase H1
Antisense
mRNA for disease-causing
protein
Reduces production of
a toxic protein
Increases production of
a therapeutic protein
Example: IONIS-HTTRx Example: nusinersen Example: IONIS-DMPKRx
45

46. Broad Clinical ASO Activity in Multiple Tissues
46
Ionis Clinical
Experience:
>6000 subjects dosed
>100 clinical studies

47. Antisense Technology Uniquely Addresses
Challenging Neurological Diseases

48. ASOs are Poised to Capitalize on Advances in
Biology and Molecular Medicine
 Advances in biology  dramatic shift in neurology
 From empiric diagnoses (treat the symptoms)
 To diagnoses based on understanding of the underlying
disease pathophysiology (treat the root cause)
 Sound translational science to create ASO drugs to
genetically-identified targets
 Basic science – validate target mechanism of the ASO
 Animal models –
 test ASO potency, delivery and distribution to the target
 develop PK/PD models to guide dose selection
 Clinical studies – early assessment of target engagement and
effects on disease pathology
48

49.  Ideal target for an ASO
 HD neuropathology appears to be due to gain-of-toxic
function of the mutant huntingtin protein (muHtt)
 Decreasing muHtt synthesis is expected to target the primary
disease mechanism
 Patients can be identified with certainty via genetic test
 IONIS-HTTRx
 An ASO that targets mRNA transcribed from the human
huntingtin gene
 Not allele-specific; targets both mutant and wild-type
huntingtin mRNA
ASO Development for Huntington’s Disease
49

50. IONIS-HTTRx Activity via RNase H1 Mechanism
50
1

51. IONIS-HTTRx: A “Generation 2+” ASO
A G T C T G A T T C
MOEDNA
G C A T C G A A C C
gap
MOE
5’-wing 3’-wing
O
O
B
HO
O
O
B
P
O
S
O
O
O
OCH3
OCH3
O
O
B
O
O
HO
B
P
O
S
O
O
O
OCH3
OCH3
O
O
B
O
O
O
B
P
O
S
O
Miller et al. Archives of Neurology, 2008
“Gapmer” design
 20 bases
 DNA in middle (to
activate RNase H1)
 MOE modification
at ends
51
Gen 2+ ASOs
 Diffusible
 Stable
 Dose-dependent
 Reversible

52. IONIS-HTTRx History
Year Event
2003 Initiated first neuro program
2005 Initiated Huntington program
Screened for ASOs and tested in mice for tolerability and
mRNA knockdown
First huntingtin-targeting ASOs introduced into HD mouse
models
2011 First medical advisory board meeting to shape IONIS-HTTRx
clinical program
2013 Isis/Roche partnership
2015 IONIS-HTTRx entered clinical testing in a multi-site Phase 1/2a
study
52

53. IONIS-HTTRx: Preclinical Pharmacology and
Toxicology Summary
 ASOs targeting HTT mRNA have pharmacologic
activity in mouse models of HD
 improve motor function, hypoactivity and stress response in
BACHD mice
 improve motor function and protect against gene expression
changes in YAC128 mice
 preserve striatal volume and increase survival in R6/2 mice
 Identified several ASOs targeting HTT mRNA that are
well tolerated in mice (up to 1 year of dosing)
 ASOs targeting HTT mRNA distribute widely in the
non-human primate CNS; huntingtin suppression is
well-tolerated
53
Kordasiewicz et al. 2012, Stanek et al. 2013

54.  Safety/tolerability study in 36 patients
 Placebo-controlled
 Each patient receives 4 doses of study drug by IT
injection, spaced 28 days apart
 After 4th dose, patients participate in a 4-month post-
treatment period
 NCT02519036
IONIS-HTTRx First Clinical Study
54

55. IONIS-HTTRx First Clinical Study: Study
Progression
Post-Treatment
Period
Post-Treatment
Period
Post-Treatment
Period
Post-Treatment
Period
Cohort B
(N=8)
Cohort C
(N=8)
Cohort D
(N=16)
each represents one dose followed by a 28-day observation period
Cohort A
(N=4)
55

56.  Primary Objective
 To evaluate the safety and tolerability of IONIS-HTTRx in
patients with early Huntington’s disease
 Secondary Objective
 To characterize the CSF PK of IONIS-HTTRx
 Exploratory Objectives
 To assess plasma PK properties of IONIS-HTTRx
 To explore effects of IONIS-HTTRx on PD markers and on
clinical endpoints relevant to HD
IONIS-HTTRx First Clinical Study: Objectives
56

57.  Safety assessments include:
 Laboratory tests
 Neurological exams
 Assessments of cognitive, motor and neuropsychiatric function
 Vital signs
 ECG
 Potential markers of target engagement and
pharmacodynamic effect include:
 Neuroimaging
 Clinical, cognitive and functional scales
 CSF huntingtin protein and CSF markers of brain health
IONIS-HTTRx First Clinical Study: Assessments
57

58.  First dose in Sept 2015
 Recently completed enrollment of 3rd dose level and
obtained Data Safety Monitoring Board agreement to
initiate 4th dose level
 Study completion expected late 2017
IONIS-HTTRx Status of First Clinical Study
58

59. Acknowledgements
►Thank you to the patients and families who give their time to HD studies◄
IONIS-HTTRx FIH Clinical Study PIs and KOLs
Sarah Tabrizi – global lead PI
Roger Barker, David Craufurd, Bernhard Landwehrmeyer, Blair Leavitt, Carsten
Saft, Ed Wild
Roche
Christian Czech, Irene Gerlach, Hansruedi Loetscher, Scott Schobel
UCSD
Don Cleveland
CHDI Foundation
Robi Blumenstein, Doug Macdonald, Cristina Sampaio
Ionis Pharmaceuticals
Frank Bennett
Holly Kordasiewicz
Kristin Balogh, Tiffany Baumann, Bethany Fitzsimmons, Sue Freier, Marc
Gleichmann, Sarah Greenlee, John Grundy, Scott Henry, Gene Hung, Roger Lane,
John Matson, Curt Mazur, Dan Norris, Michael Oestergaard, Erika Paz, Noah Post,
Frank Rigo, Punit Seth, Eric Swayze, Ed Wanciewicz, Andy Watt, Tom Zanardi