A Global Leader in Gene Therapy - Corporate Presentation January 2020 - uniQure
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A Global Leader in Gene Therapy Corporate Presentation January 2020
Forward-looking Statements This presentation contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,” "will,” “would” and similar expressions. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this presentation. These forward-looking statements include, but are not limited to, statements regarding the development of our gene therapies, the success of our collaborations, and the risk of cessation, delay or lack of success of any of our ongoing or planned clinical studies and/or development of our product candidates. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, risks associated with collaboration arrangements, our and our collaborators’ clinical development activities, regulatory oversight, development of product candidates, product commercialization and intellectual property claims, as well as the risks, uncertainties and other factors described under the heading "Risk Factors" in uniQure’s Quarterly Report on Form 10-Q filed on October 28, 2019. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the future.
Strategy to bring gene therapies to patients
Focus on liver-directed
Retain valuable & CNS disorders
commercial rights
Commercialization
Commercialization
Pipeline
Pipeline
Maintain leadership
in commercial-scale
manufacturing of
Intellectual
Intellectual
Manufacturing AAV gene therapies
Property Manufacturing
Expand & maintain Property
our leading IP portfolio
Enabling
Enabling
Technologies
Technologies
Invest in next-generation
technologies
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 3
Key near-term catalysts
• Topline data from HOPE-B pivotal study in late 2020
Hemophilia B
• BLA submission in 2021
• Initiate dosing in Phase I/II study in early 2020
Huntington’s
• Early efficacy data on initial patients in 2021
• Submit IND for AMT-180 in 2020
Hemophilia A
• Begin clinical development in 2021
Spinocerebellar • Initiate IND-enabling study for SCA3 in 2020
Ataxia Type 3 (SCA3) • Submit IND application in 2021
• Continue to increase manufacturing scale and capacity
Manufacturing
• Conduct manufacturing process validation for EtranaDez (AMT-061) in 2020
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 4
Our proprietary pipeline
*Collaboration with Bristol-Myers Squibb
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 5
Global leadership in AAV manufacturing Large-scale AAV Manufacturing • Based in Lexington, MA, expanded to 80,000 ft2 • Proprietary 3rd generation insect cell, baculovirus • Demonstrated 500L stirred-tank production • Scalable up to 2 x 2,000L • Strong intellectual property position Potential Benefits • Control and flexibility • Consistent process from small-scale to large-scale • Highly scalable, cost-effective • High-volume capacity • Consistent, stable, high-quality product A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 6
Leveraging AAV5: a potentially best-in-class vector
AAV5 – Clinically demonstrated tolerability and clinical effects
observed to date
AAV5 Vector
• Long-term follow-up data demonstrating safety and tolerability
• 25 patients have received AAV5 across 4 clinical studies1
• Observed clinical effects in the liver and brain
• Low avidity of pre-existing neutralizing antibodies (NAbs)
• Favorable immunogenicity profile for systemic, intravenous delivery
• No confirmed T-cell-mediated immune responses to capsid
1 uniQure clinical trials in Hemophilia B, Sanfilippo B and Acute Intermittent Porphyria
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 7
Hemophilia B Etranacogene dezaparvovec (AMT-061)
Hemophilia B: significant financial burden and
unmet medical needs
Disease prevalence: ~6,000 patients in the United States1 and ~14,000 patients in Europe2
Clinical burden Patient burden Economic burden Societal burden
Lifelong bleeding Cumbersome ~$610,000 annual >$20 million lifetime
risk with current treatment with cost of factor IX cost per severe
standard of care and adherence issues, replacement therapy patient in the US5
accrual of joint quality of life and for severe patients in
damage3 pain3 the US4
1. US CDC/ATHN Hemophilia community count, March 2019. 2. Estimated based on population in Europe and prevalence reported in Iorio et al. Ann Intern Med. 2019. doi: 10.7326/M19-1208.
3. VandenDriessche T and Chuah MK. Hum Gene Ther. 2017;28(11):1013-1023. 4. Noone et al. American Society of Hematology annual meeting 2019, Poster 2118. 5. uniQure internal data, cost including
factor therapy and medical costs
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 9
Etranacogene dezaparvovec (AMT-061) Key Treatment Features • Demonstrated ability to increase FIX activity to therapeutic levels • No bleeding events post-treatment • No replacement therapy for bleeds outside surgery • No requirement of immunosuppression • No exclusion of patients with pre-existing NAbs Key Safety Features • Well-tolerated with no serious adverse events related to treatment • No inhibitor development A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 10
AMT-060: sustained dose-dependent increases
in FIX activity
Cohort 1 Cohort 2
Mean FIX activity (95% CI): Mean FIX activity (95% CI):
5.1 (1.6 – 8.6) 7.5 (4.2 – 10.7)
20 20
1 (7.1) 2 (5.3) 3* (1.3) 4* (8.2) 5* (3.5) 6 (11.1) 7 (7.1) 8 (8.5) 9 (3.9) 10 (6.7)
FIX activity (IU/dL)
FIX activity (IU/dL)
10 10
0 0
0 20 40 60 80 100 120 140 160 180 200 220 0 20 40 60 80 100 120 140 160 180 200 220
Weeks following AMT-060 treatment
Values in parentheses represent mean FIX activity over time. Only values at least 10 days after last FIX concentrate administration are included. FIX prophylaxis was continued
after AMT-060 and tapered between Weeks 6 and 12. *Patients 3, 4 and 5 retrospectively tested positive for AAV5 neutralizing antibodies using the luciferase-based assay.
Dashed line indicates sample collection occurred after the data cut (09Oct2019). Values after the data cut (Patient 4, year 3.5; Patient 10, year 4) are not included in calculations
of mean
A G LFIX
O Bactivity.
AL LEA FIX,
D Efactor
R I N IX;
G ECI,
N Econfidence
T H E R A Pinterval;
Y IU, international units J A N U A R Y 2 0 2 0 | 11Etranacogene dezaparvovec: Phase 2b sustained FIX
activity in the functionally curative range
Mean FIX activity at 1 year: 41% of normal
FIX activity measured by a one stage clotting assay conducted in a central lab. aPTT, activated partial thromboplastin time
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 12Etranacogene dezaparvovec (EtranaDez):
HOPE-B Phase III pivotal study
• Approximately 60 patients enrolled - severe and moderately-severe Hemophilia B
• More than half of eligible patients treated
• Open label, single-dose, multi-center, multi-national trial
• Patients with AAV5 neutralizing antibodies not excluded
• Patients serve as their own control; 6-month lead-in to establish baseline
• Study objectives:
• Increase FIX activity
• Reduce frequency of bleeding episodes
• Decrease use of FIX replacement therapy
• Assess efficacy and safety
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 13Huntington’s Disease AMT-130
Huntington’s disease: prevalence and overview
• Patient population1: • Autosomal dominant neurodegenerative
• ~25,000 patients in United States disorder
• ~25,000 patients in Europe • Expansion of CAG trinucleotide huntingtin
(HTT) exon1
• Underreported due to lack of treatment
options • No disease-modifying therapies available
• Disease stage prevalence2:
• 30.5% Early stage
• 35.5% Middle stage
• 34.0% Late stage
1 Neuroepidemiology 2016;46:144–153
2 Journal of Medical Economics. 2013 Aug;16(8):1043-50
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 15AMT-130: major gene therapy opportunity
• One-time administration of disease-modifying
therapy
Huntington’s • Proprietary miQURETM silencing platform
AMT-130
• Strong mutant HTT knockdown in deep structures
and cortex
• Only program to target full-length HTT protein
• No treatments available
aggregates and highly toxic HTT exon1 protein
• Strong preclinical data fragments
• Near-term goal: Begin • Potential to be first gene therapy to market
dosing of Phase I/II trial
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 16AMT-130: extensive preclinical validation
Model Efficacy Safety Distribution
Cultured human
neurons
Rodents
(HD rat4)
(4 types HD mouse3)
NHP
(Non-human primate1)
Pig
(tgHD Minipig2)
Recent publications
1. Samaranch L, et al. Gene Ther 2017;24:253-261; 5. Evers MM et al. Mol Ther. 2018;26(9):2163-2177
2. Evers M, et al. Mol Ther 2017;5(Suppl. 1):247; 6. Spronck EA et al. Mol Ther Methods Clin Dev. 2019 Mar 16;13:334-343
3. Spronck EA, et al. Hum Gene Ther 2017;28:A78; 7. Keskin S et al. Mol Ther Methods Clin Dev. 2019 Oct 4;15:275-284
4. Miniarikova J, et al. Gene Therapy 2017;24:630-639 8. Caron NS et al. Nucleic Acids Res. 2019 Nov 20. pii: gkz976. doi: 10.1093/nar/gkz976
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 17Huntington’s disease:
expected progression of brain pathology
Somatomotor
• The striatum is the primary site of pathology cortex
Frontal Somatosensory
lobe cortex
2 Parietal
• Premanifest stage: atrophy spreads and 3
3
lobe
cortical thinning occurs
• Motor symptoms manifest as atrophy 1 Occipital
increases lobe
The shading and arrows
indicate the progression of
pathology. Darker shading
represents earlier onset.
1. McColgan P, Tabrizi SJ. Eur J Neurol. 2018;25(1):24-34; 2.Tabrizi SJ, et al. Lancet Neurol 2009;8(9):791-801;
3. Nopoulos PC, et al. Neurobiol Dis 2010;40(3):544-54 Figure adapted from Brundin P, et al. Nat Rev Mol Cell Biol 2010;11:301-7.
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 18AMT-130: well-tolerated and widespread distribution
in the non-human primate (NHP) brain
NHP MRI-guided frontal Distribution throughout NHP brain
convection-enhanced delivery
Caudate
nucleus
Thalamus
Putamen
Globus
pallidus
Hippocampus
No procedure-related neurological symptoms Putaminal delivery AAV5-GFP
following infusion into the striatum
uniQure, data on file. MRI, magnetic-resonance imaging Samaranch L. et al, Gene Ther. 2017 Apr;24(4):253-261. Figure 3
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 19AMT-130: strong reduction of mutant HTT in the
minipig brain
Libechov transgenic (tgHD) minipigs: Comparable mutant huntingtin protein
• Lifespan: 12-20 years knockdown at 6 and 12 months
• Body weight: 50-140 kg
• Brain weight: 90-100 g
• Highly developed immune system Cortex Striatum
125 6 months
MRI-guided 12 months
mutant HTT protein
100
(% from naive)
Convection-enhanced delivery
75
30%
50 50%
caudate 70%
25
putamen
0
Pu te
us
ns
m
l
Th ala
l
en
M
ra
ta
S/
da
lu
am
Po
on
m
po
d
el
o-
yg
au
ta
r
m
al
eb
at
ef
m
C
Te
m
Pr
er
A
So
C
Bars represent average ± SEM of n=3-4 animals/group
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 20AMT-130: neuropathology in diseased mouse model
N-Acetyl Aspartate (tNAA) Myo-Inositol (MI)
Neuronal integrity marker Gliosis marker
6.0 Q175FDN 7 Q175FDN
*** *
Mean concentration
Mean concentration
5.5 6
tNAA (mM)
mI (mM)
5.0 5
4.5 4
4.0 3
9
9
11
11
r
r
l
l
ro
ro
ffe
ffe
0
10
0
0
X1
nt
nt
X1
X1
2X
bu
bu
2
co
co
3
3
5.
5.
n
n
1.
1.
T
T
io
io
W
W
at
at
ul
ul
gc AMT-130 gc AMT-130
rm
rm
Fo
Fo
Leavitt BR, Vallès. et al., Manuscript in preparation
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 21AMT-130: full-length and exon1 HTT lowering in
striatum and cortex in diseased mouse model
Full-length HTT mRNA
Full Full lenght
length HTTHTTin
inStriatum
Striatum Full length HTT
Full-length HTT in
in Cortex
Cortex
1.5
Relative expression to Formulation Buffer
Relative expression to Formulation Buffer
1.5
(CAG)n
5’UTR E1 E2 E6 (AAAA)n 1.0
1.0
7
0.5 0.5
0.0 0.0
5UTR Exon 1-2 Exon 64 5UTR Exon 1-2 Exon 64
Exon1
Exon1 HTT
HTT ininStriatum
Striatum Exon1
Exon HTT ininCortex
Relative expression to Formulation Buffer
Relative expression to Formulation Buffer
1.5 1.5
1 HTT Cortex
Exon-1 HTT mRNA
1.0 1.0
(CAG)n
5’UTR E1 Intron 1 (AAAA)n 0.5 0.5
0.0 0.0
Early intron 1 Intron 1 Early intron 1 Intron 1
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 22AMT-130: significant differentiating features
Silences mutant Huntington Silences mutant Huntington No direct miRNA toxicity and no
protein species at the site of the protein as well as the more toxic off-target effects
pathology small fragments
Significant, long-term and Uniquely silences exon1 toxicity miHTT expression is well-regulated
therapeutic knock-down in the and the technology does not
striatum and sensorimotor cortex generate a passenger strand
miQURE technology spreads No long-term neurofilament-light
throughout the target CNS region increase in HD pig study (18
via extracellular vesicles months follow-up)
Long-term silencing after a single Reversal of pathology in a relevant No immune-related toxicity
administration HD animal model
No need for repeated intrathecal Reversal of neuronal integrity and No cytotoxic T cells recognizing
injections partial reversal of gliosis AAV5 epitopes
(inflammation) in Q175FDN mice
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 23AMT-130: goal of clinical treatment
Motor
diagnosis
Premanifest Manifest
100
AMT-130
← Function (%)
Slow or halt
disease
progression
I II III IV V
0
Presymptomatic Prodromal Early Moderate Advanced
Adapted from Ross CA, et al. Nat Rev Neurol 2014;10:204-16
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 24AMT-130: Phase I/II clinical trial Study Overview • Objectives: assess safety, tolerability and efficacy • Multicenter, randomized, double-blinded study • Controlled with imitation surgery • Two dose cohorts with a total of 26 patients • Early manifest patients • 18-month follow-up (5 years for treated patients) A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 25
AMT-130: Phase I/II efficacy endpoints
Biomarkers Clinical Parameters*
• NF-L (neurofilament light) • Total motor score
• mHTT in CSF • Total functional capacity
• Other exploratory markers
Imaging (MRI and MRS) Quantitative Motor Function
• Measures of neural function • Finger, hand and foot tapping
• Striatal volume (atrophy) • Grasping and lifting (chorea)
*Unified Huntington’s Disease Rating Scale
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 26AMT-130: Phase I/II clinical trial design
Cohort 1: 10 patients (6 dosed, 4 control) Cohort 2: 16 patients (10 dosed, 6 control)
Subject 1&2 Subject 3&4 Subject 5-10 Subject 11&12 Subject 13&14 Subject 15-26
1:1 1:1 2:1 1:1 1:1 2:1
randomization randomization randomization randomization randomization randomization
1 dosed 1 dosed 4 dosed 1 dosed 1 dosed 8 dosed
1 control 1 control 2 control 1 control 1 control 4 control
3-month 3-month 1-month 1-month 1-month
enrollment enrollment enrollment enrollment enrollment
stagger stagger stagger stagger stagger
followed by followed by followed by followed by followed by
DSMB Review DSMB Review DSMB Review DSMB Review DSMB Review
#1 #2 #3 #4 #5
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 27Research Pipeline
AMT-180: a novel approach to Hemophilia A
Novel Approach
• Product Construct – AAV5 including C7 Promoter and FIX-Super9™
• Super9™ is a proprietary modified FIX that, when activated through normal
mechanisms, activates FX independently of FVIII
Long-term and Effective in all Compatible with Comparable with
stable expression HemA patients bypass agents emicizumab
• Hepatocyte-friendly • Sufficient thrombin • Safe in combination • Comparable efficacy in
• Non-thrombogenic generation to stop with rFVIIa and/or HemA with and without
bleeding episodes FEIBA and emicizumab inhibitors
• Not neutralized by FVIII
inhibitors
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 29AMT-190: a new approach to Fabry disease
Novel Approach
• Product Construct – AAV5 including modified NAGA
• Modified NAGA has therapeutic α-gal activity and gB3 reduction
More effective than Patients with and Non-immunogenic
replacement therapy without inhibitors
• More stable in plasma • Many Fabry patients • No loss of activity due
• More efficient uptake develop inhibitors to α-gal to α-gal inhibitors
• Better end-organ replacement therapy
distribution • NAGA is not neutralized by
α-gal inhibitors
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 30AMT-150: a gene therapy for SCA3
Novel Approach
• AAV5, SCA3 miRNA administered by intrathecal or cisterna magna injection
• Leverages HD platform and experience, including miQURE™ gene silencing technology
• Potential to be first to market
Cause Damage Symptoms Unmet Need
• CAG repeat expansion • Brain degeneration • Ataxia • No medication that
in ATXN3 gene cerebellum and • Dystonia/rigidity slows the progressive
brainstem • course of the lethal
• Ataxin-3 protein Muscular atrophy
disease
acquires toxic properties • More widespread in • Paralysis
later stages
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 31Key near-term catalysts
• Topline data from HOPE-B pivotal study in late 2020
Hemophilia B
• BLA submission in 2021
• Initiate dosing in Phase I/II study in early 2020
Huntington’s
• Early efficacy data on initial patients in 2021
• Submit IND for AMT-180 in 2020
Hemophilia A
• Begin clinical development in 2021
Spinocerebellar • Initiate IND-enabling study for SCA3 in 2020
Ataxia Type 3 (SCA3) • Submit IND application in 2021
• Continue to increase manufacturing scale and capacity
Manufacturing
• Conduct manufacturing process validation for EtranaDez (AMT-061) in 2020
A GLOBAL LEADER IN GENE THERAPY JANUARY 2020 | 32You can also read
