Leadership in Gene Therapy - Corporate Presentation September 2021 - uniQure
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Leadership in
Gene Therapy
Corporate Presentation
September 2021
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 the COVID-19 pandemic, 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 Annual Report on Form 10-K filed on March 1, 2021 and Quarterly Report on Form 10-Q filed July 26, 2021. 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. LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 2
uniQure: our focus
AAV Engine: Leveraging our leading technology platform to develop and
commercialize products targeting the CNS, liver and heart/muscle
AAV Technology Engine
Manufacturing & Enabling Tools
L EAD
LEA ERS H
DERS HII PP I N
INGEN E THTHERA
GENE ERAP YPY S EP TEMBER
SEPT 2021
EMB E R 2021 | 3
inGENEuity: our history of innovation uniQure: A gene therapy pioneer with a >20-year history and deeply engrained culture of innovation across an increasingly validated platform First First First First LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 4
inGENEuity: our history of innovation uniQure: A gene therapy pioneer with a >20-year history and deeply engrained culture of innovation across an increasingly validated platform 15 years 100+ patients World-class Leading LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 5
Re-imaGENEing the R&D pipeline
Doubling the pipeline by 2026
5-year
Pipeline 3-4 Phase 3
commercial
5-8 Phase 1/ 2
programs
7-12
preclinical
Goals: programs programs
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 6
Re-imaGENEing the R&D pipeline
Larger market opportunities built on validated targets and technologies
● Best and/or first in class
● Human validation
Key criteria:
● Leverage proven technologies
● Larger indications
L EAD
LEA ERS H
DERS HII PP I N
INGEN E THTHERA
GENE ERAP YPY S EP TEMBER
SEPT 2021
EMB E R 2021 | 7
Re-imaGENEing our enabling technolgy
Leveraging a broad, enabling technology platform to build an optimized and
differentiated pipeline
Re-imagining Next-gen tools developed: What we aim to accomplish:
where/how ● Novel AAV capsids ● Potent expression
we deliver… ● Next-gen promoters ● Targeted delivery
● Optimized administration techniques ● Uniform transduction
● Improved formulations ● Redosing
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 8
Re-imaGENEing our enabling technolgy
Leveraging a broad, enabling technology platform to build an optimized and
differentiated pipeline
Re-imagining Next-gen tools: What we aim to accomplish:
what we miQURE® (gene silencing) ● Insertion of genes
deliver… goQURE (gene silence/replace) ● Suppression of genes/proteins
● Substitution of genes
AbQURE (vectorized antibodies)
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 9
Re-imaGENEing our in-house manufacturing Manufacturing for the future: Establishing larger scale and highly cost- effective capabilities to address more prevalent disorders LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 10
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 11
Recent company progress & upcoming events
• Closed commercialization and licensing agreement with CSL
• Presented 52-week data from HOPE-B pivotal trial
Hemophilia B
• On track to announce 78-week top-line data and prepare
regulatory submissions for marketing approval
• Began patient enrollment in second dose cohort of Phase 1-2 U.S. clinical trial
Huntington’s • On track to begin patient enrollment in Phase 1b-2 European clinical trial
• Preliminary imaging/biomarker data on first four patients by year-end 2021
Spinocerebellar • Initiating IND-enabling studies
Ataxia Type 3 (SCA3) • Anticipate submitting IND application by year-end 2022
• Hosted Research & Development Day
Manufacturing and
• Continue to increase manufacturing scale and capacity
Technology Platform
• Conduct manufacturing process validation to support Hem B regulatory filings
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 12HOPE-B 52-Week Analysis Hemophilia B Etranacogene dezaparvovec (AMT-061) Etranacogene dezaparvovec (AMT-161) A GL O BAL L EAD ER I N GEN E TH ERAP Y MAY 2021 13
HOPE-B pivotal trial: study design
• Key inclusion criteria
• Male adults ≥18 years
• FIX activity ≤2% of normal
• Continuous prophylaxis for ≥2 months
• Key exclusion criteria
• Factors that might affect the evaluation of
AMT-061 efficacy or safety
• FIX inhibitors
• Active hepatitis B/C infection
• Uncontrolled HIV infection
• Pre-existing anti-AAV5 NAbs were assessed,
but not used as an exclusion criteria
• No prophylactic immunosuppression
HIV, human immunodeficiency virus; NAbs, neutralizing antibodies; wks, weeks.
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 14Etranacogene dezaparvovec (EtranaDez):
HOPE-B Phase III pivotal study
• 54 patients treated as of March 2020
• Severe and moderately-severe Hemophilia B patients
• Open label, single-dose, multi-center, multi-national trial
• Patients with AAV5 neutralizing antibodies not excluded
• Patients served 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
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 15Etranacogene dezaparvovec (EtranaDez):
HOPE-B Phase III pivotal study
Primary endpoint
• 52-week ABR after stable FIX expression has been achieved, compared to ABR in lead-in period
• ABR will be measured from week 26 to week 78 after infusion
Secondary endpoints
• FIX activity at 6, 12 and 18 months after dosing
• Rates of total, spontaneous, traumatic, and FIX treated/untreated bleeds
• FIX consumption compared with lead in period
• Correlation of FIX activity levels with pre-existing anti-AAV5 neutralizing antibody titers
• Safety
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 16Overview of FIX activity up to 52 weeks (month 12)
• FIX activity increased to a mean of 39.0%
at month 6
• Change from baseline +37.8%
• FIX activity maintained at a mean of
41.5% at month 12
• Change from baseline +40.3%
aUncontaminated central laboratory data (the visit did not occur within 10 days of exogeneous FIX use). FIX levels beginning with the Week 3 assessment were used in the analysis. Subjects with 0
uncontaminated central-laboratory post-AMT-061 values had change from baseline assigned to zero for this analysis and had their post-baseline values set equal to their baseline value. Baseline factor IX
was imputed based on subject’s historical hemophilia B severity documented on the case record form. If the subject had documented severe factor IX deficiency (FIX plasma level < 1%), their baseline
factor IX activity level is imputed as 1%. If the subject had documented moderately severe factor IX deficiency (factor IX plasma level ≥1% and ≤ 2%), their baseline factor IX activity level was imputed as
2%. SD, standard deviation.
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 17HOPE-B: Endogenous FIX activity to 52 weeks 1
Stable and durable FIX activity
post-etranacogene
dezaparvovec treatment
Following treatment, FIX activity
increased rapidly to a mean of
39.0 (SD; min, max) IU/dL
(±18.7; 8.2, 97.1) at Week 26
and 41.5 IU/dL (±21.7; 5.9,
113.0) at Week 52.
No clinically meaningful
relationship was seen between
pre-existing anti-AAV5 NABs and
individual subject mean FIX
between month 6 and 12.
1Uncontaminated central laboratory data (the visit did not occur within 5X half life). FIX levels beginning with the Week 3 assessment were used in the analysis. Subjects with 0 uncontaminated central -
laboratory post-AMT-061 values had change from baseline assigned to zero for this analysis and had their post -baseline values set equal to their baseline value.
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 18No clinically significant impact of pre-existing NABs on
mean FIX activity between months 6 to 12
Analysis of all treated subjects including subject with patrial dose and with NAB titer 3212
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 19Spontaneous bleeds were reduced further in the second
six months after treatment
Sustained FIX levels were associated with significantly reduced spontaneous bleeding
during the first year of follow-up
Per FDA guidance, data shows all reported bleeds, even if adjudicated by the investigator
to be non-bleed or a continuing bleed
Lead-in period includes 33.12 observed years in 54 subjects (mean 32 weeks per subject); Post -treatment period excludes the first 21 days (23 weeks per subject)
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 20Adjusted annualized bleeding rates (ABR) reduced on
treatment compared with lead-in period
During post-treatment period of up to 2 years, 30 subjects (55.6%) had no bleeds, 39 subjects (72.2%)
had no bleeds treated with FIX
Lead-in period includes 33.12 observed years in 54 subjects (mean 32 weeks per subject); Post -treatment period excludes the first 21 days (23 weeks per subject)
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 21Substantial reductions in FIX replacement and use of
prophylaxis when compared with lead-in
At 52 weeks follow-up, compared with the lead-in period
• 96% (52/54) subjects discontinued prophylaxis and remain prophylaxis-free
• 96% reduction in FIX consumption in IU/year (mean reduction of 246,537 IU/year)
• 96% reduction in FIX infusion rate per year (adjusted mean 72.5 to 3.0, pPost-treatment adverse events
• 53 subjects had 408 AEs
• 39 subjects had 91 treatment related AEs
• 9 subjects received steroid treatment for transaminase
elevations
• All discontinued steroid use prior to Week 26
• FIX activity preserved in the mild range (8%-39%)
• 7 subjects had infusion related reactions*
• Infusion discontinued in 1 (received ~10% dose)
• Infusion completed successfully in remaining 6
• No inhibitors were reported
• No statistical relationship between safety and pre-
existing NAbs was observed
*Infusion reactions include events reported on the day of dosing as probably or possibly related to treatment
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 23A global licensing deal with CSL Behring in hemophilia B
Transaction is a historic collaboration in gene therapy and hemophilia, with uniQure eligible to
receive more than $2B in total economics
• $450M upfront payment received in 2Q 2021
• $1.6B in regulatory and commercial milestones
• Double-digit royalty payments up to low-twenties percentage of net product sales
• Full reimbursement of uniQure’s clinical and regulatory costs
Collaboration enables uniQure to leverage CSL Behring’s world-class global hemophilia
commercial infrastructure
• Hemophilia is a well-established, specialized and highly competitive global market
• CSL Behring has been a leader in bleeding disorders for more than 30 years
• Deep, long-standing relationships with hemophilia communities worldwide
• One of the broadest product portfolios in hematology and thrombosis
• $1B+ in hemophilia sales in 2019 with commercial sales in more than 100 countries
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 24AMT-130 LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 25
Huntington’s disease (HD): an overview
• Autosomal dominant inherited disorder
(50% risk if your parent has HD)
• Affects ~25,000 patients each in U.S./EU
• Initially described based upon
characteristic chorea
• Dystonia, incoordination, ataxia, and later
rigidity and bradykinesia contribute to
functional impairment
• Cognitive and behavioral symptoms may
occur early
• Progressive course from onset ~age 45
to death over 10-15 years
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 26AMT-130: a gene therapy approach for early manifest HD
• AAV5-miHTT (AMT-130)
• Replication-deficient adeno-associated viral
vector serotype 5 (AAV5)
• Codes for microRNA (miRNA) that targets the
HTT mRNA at exon 1
• Blocks expression of HTT protein
Extensive preclinical validation
Model Efficacy Safety Distribution
Cultured human neurons ✓ ✓
Rodents
(HD rat4) ✓ ✓
(4 types HD mouse3)
NHP
(Non-human primate1) ✓ ✓ ✓
Pig
(tgHD Minipig 2) ✓ ✓ ✓
1) Samaranch L, et al. Gene Ther 2017;24:253-261; 2) Evers M, et al. Mol Ther 2017;5(Suppl. 1):247; 3) Spronck EA, et al. Hum Ge ne Ther 2017;28:A78; 4) Miniarikova J, et al. Gene Therapy
2017;24:630-639; 5) Evers MM et al. Mol Ther. 2018;26(9):2163-2177; 6) Spronck EA et al. Mol Ther Methods Clin Dev. 2019 Mar 16;13:334-343; 7) Keskin S et al. Mol Ther Methods Clin Dev. 2019 Oct
4;15:275-284; 8) Caron NS et al. Nucleic Acids Res. 2019 Nov 20. pii: gkz976. doi: 10.1093/nar/gkz976
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 27AMT-130: longitudinal data in transgenic pigs
brain CSF
mHTT protein NF-L
80000
Control (naive)
rAAV5-miHTT
CSF NF-L (pg/mL)
60000
40000
20000
0
e d d m m m m m m m m
os 14 28 3 6 9 12 15 18 21 24
-d
p re
• Stable miHTT expression, mHTT protein lowering, and long-term baseline NFL levels
• Trend confirmed up to 36 months (topline data)
Vallès, Evers et al (Sci Transl Med, 2021)
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 28AMT-130: maximizing potential for clinical impact
Our approach optimizes benefit/risk tradeoff
• Focused neurosurgical delivery to most relevant
brain regions
• Not targeting 100% knock-down or entire CNS
• 50-75% maximal knock-down in striatum
where benefit/risk of knockdown is clear
• 25-50% cortical knock-down via
anterograde/retrograde transport from site
of caudate/putamen infusion
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 29AMT-130: knocking down wildtype (wtHTT) and mutant HTT
(mHTT) safe and effective in adult animals
• wtHTT inactivation during adulthood does not
result in any phenotype 1,2
• wtHTT + mHTT results in HD
• Partial reduction of mHTT or both wtHTT/mHTT in
adulthood slows disease progression and delay
onset of HD symptoms 3-8
The partial reduction of wtHTT in normal adult rodents
and NHPs was generally safe and well tolerated 12
1. WangG, et al. Proc Natl Acad Sci U S A. 2016;113(12):3359-3364. 2. Pla P, et al. PLoS One. 2013;8(9):e73902. 3. Kordasiewicz HB, et al. Neuron. 2012;74(6):1031-1044. 4. Southwell AL, et al. Sci Transl
Med. 2018;10(461):eaar3959. 5. Boudreau RL, et al. Mol Ther. 2009;17(6):1053-1063. 6. Drouet V, et al. Ann Neurol. 2009;65(3):276-285. 7. Stanek LM, et al. Hum Gene Ther. 2014;25(5):461-474. 8. Leavitt
BR, Kordasiewicz HB, Schobel SA. Huntingtin-Lowering Therapies for Huntington Disease: A Review of the Evidence of Potential Benefits and Risks. JAMA Neurol . 2020;77(6):764–772.
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 30AMT-130: phase 1-2 study design
• Double-blind, randomized, imitation-surgery • MRI, magnetic resonance imaging
(sham) controlled study
• 2 dose levels of AMT-130
• Cohort 1: 50%/25% striatal/cortical
knockdown
• Cohort 2: 75%/50% striatal/cortical
knockdown
• One-time bilateral stereotaxic neurosurgical
administration of AMT-130
• MRI-guided convection enhanced delivery
• 5-year follow-up (blinded first 12 months)
• Conducted at ~12 HD centers in the U.S.
including 3 sites performing surgery
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 31AMT-130: phase 1-2 initial inclusion/exclusion criteria
Key inclusion criteria Key exclusion criteria
• 25 to 65 years of age • Presence of an implanted deep brain
stimulator devices
• Early manifest HD
• Total functional capacity (TFC) 9-13 • Relevant brain/spinal pathology
(stage 1 or early stage 2) • Medical contradictions to anesthesia
• Diagnostic Classification Level (DCL)
DCL=4 (motor manifest) or • Previous gene therapy or RNA-/DNA-targeted
DCL=3 (multidimensional) HD investigational agents
• ≥40 CAG
• Putamen volume of ≥2.5 cm3 (per side) and
caudate volume of ≥2.0 cm3 (per side)
• Stable concomitant prior to screening
HD medications for ≥3 months
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 32AMT-130: phase 1-2 proof-of-concept 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
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 33AMT-130: a year of exceptional progress in clinical
development
16 June 2021
First Two Cohort 2
Procedures
13 October 2020
19 June 2020 Enrollment of Next 2 Patients 05 April 2021 30 August 2021
First 2 Patients in in Phase 1-2 Clinical Trial Completion of Enrollment in First Third and Fourth
Phase 1-2 Clinical Trial Cohort of Phase 1-2 Clinical Trial Cohort 2 Procedures
2020 2021
Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul Aug
25 September 2020 1 June 2021
DSMB Recommendation to Continue DSMB Recommendation
Cohort 1 Enrollment in Phase 1-2 Study 8 February 2021 on Initiating US Cohort 2
DSMB Recommendation to Continue
Cohort 1 Enrollment in Phase 1-2 Study
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 34AMT-130: EU open-label study will augment phase 1-2 signal-
detection capacity
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 35AMT-130: preliminary data on first 4 randomized patients
• Safety and tolerability Subject 1&2
1:1
• Chemistry biomarkers from CSF and blood serum randomization
1 dosed
• NfL – compared to baseline and control 1 control
• mHTT in CSF – compared to baseline and control
• Markers for inflammation and immunogenicity
Subject 3&4
• Volumetric MRI Imaging 1:1
• Volume compared to baseline, control and natural history randomization
1 dosed
• Functional MRS Imaging 1 control
• Measurement of neuronal function compared to baseline and control
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 36Expanding the Research Pipeline A GL O BAL L EAD ER I N GEN E TH ERAP Y MAY 2021 37
Spinocerebellar Ataxia Type 3 (SCA3)
Autosomal dominant disorder
• Spinocerebellar ataxia type 3 (SCA3) is the
most common SCA
• Prevalence is 1-2:100,000 total population;
~7000 patients in the US and Europe
• Average onset 37 years
Symptoms
• Ataxia
• Dystonia/Rigidity
• Muscular atrophy
• Paralysis
• Median survival 20 years after diagnosis
Stop MJD Inc.
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 38SCA3: mutant ataxin-3 protein forms toxic aggregates
leading to neurodegeneration
CAG repeat
ATXN3 mRNA
polyQ repeat Cereb ellum
Mutant Brainstem
ataxin-3 protein Spinal cord
SCA3 Healthy control
Toxic ataxin-3
protein aggregation
Cereb ellum
Neurodegeneration
Eichler L et al. Am J Neuroradiol (2011)
Brain stem
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 39AMT-150: AAV5-microRNA against ATXN3 to lower toxic
ataxin-3 protein
ITR ITR
miQURE®
Pol II promoter polyA
CAG repeat
ATXN3 mRNA
miQURE®
miQURE®
Reduction of toxic ataxin-3 protein
polyQ repeat
Degradation of ATXN3 mRNA
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 40AMT-150: functional improvement in transgenic SCA3 mice
after high dose cisterna magna delivery
AMT-150 • Transgenic SCA3 mice with highest brainstem
transduction show partial SCA3 phenotype
improvement
Veh WT AMT-150
Veh Q84/Q84
Total Locomotor Activity
4000
8wk Injection (Cisterna Magna)
Cerebellum Brainstem
Mutant ataxin-3 protein (%)
Mutant ataxin-3 protein (%)
3000
100 100
Relative to control
Relative to control
75
53% 75
65% 2000
50 50
1000
25 25
0 0
0
7 10 15 20 25 30 35
ol
3
ol
3
N
tr
N
tr
TX
on
TX
on
iA
C
iA
C
-m
weeks
-m
V5
V5
A
A
A
A
Martier R., et al., Mol Ther Methods Clin Dev . 2019 Oct 28;15:343-358. Univ ersity of Michigan Health Sy stem Department of Neurology
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 41Fabry disease: a lysosomal storage disease (LSD) X-linked genetic disorder • Deficiency of α-galactosidase A (GLA) • Prevalence: 1:3,700 – 80,000 live births* • Population: ~15,000 in US and Europe Symptoms • Fatigue and hearing loss • Neuropathic pain • Angiokeratomas • Corneal opacity • Cardiac disease • Renal failure • Stroke risk * Spada, et al, Am. J. Hum. Gent. 2006:79, 31-40 LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 42
AMT-191: delivers highly efficient one-time treatment
AAV5-GLA Decreased Gb3 accumulation in treated
AAV5 encoding an Fabry mouse kidney
α-galactosidase A (GLA) transgene cortical Gb3 medullary Gb3
WT
+
AAV vehicle
capsid
Expression
cassette Fabry
+
vehicle
ITR ITR
Promoter GLA polyA
Fabry
+
AAV5-GLA
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 43AMT-191: delivers highly efficient treatment in Fabry mice
Vector DNA level GLA-activity in Liver tissue
• Dose-dependent and sustained GLA protein
GLA-activity (nmol/h/mg)
in Fabry mouse liver 1000000
genome copies/μg DNA
10 8 100000
>3000-fold
and activity levels in plasma and in liver
10 7
10 6
10000 • GLA activity >3000-fold increase baseline
10 5 1000 plasma levels
10 4
10 3
: below LLoQ
LLOQ
100
• Good correlation of GLA protein and activity
10 2 10
in plasma
KO Low Mid High WT KO Low Mid High
Vehicle AAV5-GLA Vehicle AAV5-GLA
GLA activity in Fabry mouse plasma
levels in plasma (ng/mL)
(12 weeks post-treatment) 10000
GLA-protein in Liver
Log10 GLA protein
GLA activity (nmol/h/mL)
100000 >3000-fold
1000
10000
1000
100
100
10
10
1 10 100 1000 10000 100000
Vehicle AAV5-GLA KO Low Mid High Log10 GLA activity
Vehicle AAV5-GLA in plasma (nmol/h/mL)
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 44AMT-191: results in kidney and heart cross-correction and
phenotypical correction in Fabry mice
Cross correction in kidney and heart:
Lyso-Gb3 (pmol/mg protein)
Gb3 levels in Kidney LysoGb3 levels in Kidney
Gb3 (pmol/mg protein)
• Higher GLA-activity levels
15000 14
12
10000
10
8
• Gb3 and LysoGb3 substrate reduction
5000
4
• Phenotypical correction: improvement
2
of pain perception
0 0
WT KO Low Mid High WT KO Low Mid High
Vehicle AAV5-GLA Vehicle AAV5-GLA
Nociception (hot-plate)
Time to reaction (sec)
Gb3 levels in Heart LysoGb3 levels in Heart **
120 **
Gb3 (pmol/mg protein)
6
Gb3 (pmol/mg protein)
3000
2500
100
2000 4
1500
500 80
2
250
60
0 0 WT KO Mid
WT KO Low Mid High WT KO Low Mid High
Vehicle AAV5-GLA Vehicle AAV5-GLA
Vehicle AAV5-GLA
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 45AMT-191: highly efficient increase of GLA in non-human
primates
GLA activity plasma
Liver DNA
NHP GLA-treated • High and sustained plasma GLA
GLA activity nmol/h/mL
activity levels without anti-GLA IgG
DNA liver (copies/μg)
1000
10 8 14 Days
10 7 56 Days 800 development
10 6
10 5
600
• Increased GLA activity in liver and
10 4
10 3
400
heart cross-correction
200
10 2
NHP1 NHP2
0
AAV5-GLA Wk-3Wk-1 D1 D4 D8 Wk2 Wk4 Wk8
time
Anti-GLA IgG
Heart
Liver 150000 1000
(nmol/h/mg protein)
(nmol/h/mg protein)
600 150 100000
50000 800
500
GLA-activity
GLA-activity
ECL Signal
6000
ECL Signal
400 100 600
300 4000
400
200 50
2000
100 200
0 0 LLOD 0 LLOD
0
Ctrl 1 Ctrl 2 NHP1 NHP2 Ctrl 1 Ctrl 2 NHP1 NHP2 -20 Inj 20 40 60 -20
Days post treatment
Controls AAV5-GLA Controls AAV5-GLA
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 46Acquisition of Corlieve Therapeutics
uniQure acquires Corlieve and advances its gene therapy to treat
Temporal Lobe Epilepsy (TLE), a large indication with high unmet need
• Highly compelling and strategic transaction:
• Expands uniQure’s pipeline of transformational gene therapies
• Strengthen’s uniQure’s global leadership in miRNA silencing technology
• Targets 1.3 million people with TLE, of which up to 800,000 are drug-resistant
• Targets kainate receptors which play a critical role in TLE
• Preclinical proof-of-concept demonstrating clear suppression of epileptic seizures
• Clear development path with a rapid proof of concept
• Diversifies our platform to include HEK293 mammalian cell manufacturing
• Upfront cash payment of €46.3 million:
• €43.7 million of development milestones through Phase 1/2
• €160 million of milestones associated with Phase 3 development and regulatory approvals
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 47Refractory temporal lobe epilepsy (TLE)
• TLE is the most common type of focal epilepsy
• TLE is associated with damage to the temporal
lobe and hyperexcitability of the hippocampus
• It’s often caused by brain injury, tumors or a
prolonged febrile seizure
• TLE affects approximately 1.3 million people in the
U.S. and Europe; ~400,000 patients are
inadequately treated
• Refractory TLE patients have a poor quality of life
and a reduced lifespan
• The standard of care is lobectomy or laser tissue
ablation but only 1-2% of eligible patients
undergo surgery
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 48Kainate receptors are implicated in TLE
Epileptic Condition
CA1
Mossy fibers
• Kainate receptors are excitatory glutamate Schaffer AMPA
collaterals CA3 receptors
receptors that are epileptogenic and Seizures
believed to be aberrantly expressed in rMF
the hippocampus of refractory TLE Dentate gyrus
+ectopic KA Perforant
patients receptors pathway
• They drive seizures through recurrent 15
excitation *
• Kainate receptor knock-out mice are 10
resistant to epilepsy in a pilocarpine TLE
5
model
0
WT KainateR KO
Peret et al 2014
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 49AMT-260 reduces seizures in preclinical models of TLE
40
# Seizure / day
30
• AMT-260 is an AAV gene therapy that Mouse 20
delivers an engineered miRNA TLE model 10
* *
targeting kainate receptors 0
• AMT-260 & AMT-261* dramatically Control AMT260 AMT261
+ Control vector
reduce seizures in a pilocarpine 100
seizure rodent model
80
60
40
20
•
0
AMT-260 reduces seizures in human -2 0
-4 0
-6 0
brain slices from patients with -8 0
-1 0 0
20 µV
Resected -1 2 0
3 3 2 6 9 03 3 2 7 0 03 3 2 7 1 03 3 2 7 2 03 3 2 7 3 03 3 2 7 4 03 3 2 7 5 03 3 2 7 6 03 3 2 7 7 03 3 2 7 8 03 3 2 7 9 03 3 2 8 0 03 3 2 8 1 03 3 2 8 2 03 3 2 8 3 03 3 2 8 4 03 3 2 8 5 03 3 2 8 6 03 3 2 8 7 03 3 2 8 8 03 3 2 8 9 03 3 2 9 0 03 3 2 9 1 0
refractory TLE human + AMT260
150
brain slices 100
50
0
-5 0
-1 0 0
-1 5 0
2 0 3 8 0 02 0 3 8 1 02 0 3 8 2 02 0 3 8 3 02 0 3 8 4 02 0 3 8 5 02 0 3 8 6 02 0 3 8 7 02 0 3 8 8 02 0 3 8 9 02 0 3 9 0 02 0 3 9 1 02 0 3 9 2 02 0 3 9 3 02 0 3 9 4 02 0 3 9 5 02 0 3 9 6 02 0 3 9 7 02 0 3 9 8 02 0 3 9 9 02 0 4 0 0 02 0 4 0 1 0
*variant of AMT-260
LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 50LEA DERS HI P IN GENE THERA PY SEPT EMB E R 2021 | 51
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