A Global Leader in Gene Therapy Corporate Presentation January - - PowerPoint PPT Presentation

A Global Leader in Gene Therapy

Corporate Presentation January 2020

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,

• ur 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.

For Forward-look

• oking S

ng Statem ements ents

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 3 J A N U A R Y 2 0 2 0

Strat ategy t to

• brin

ing g gene t ene ther herapies es t to

• pat

atients

Pipeline Manufacturing Enabling Technologies Intellectual Property Commercialization

Focus on liver-directed & CNS disorders Expand & maintain

• ur leading IP portfolio

Maintain leadership in commercial-scale manufacturing of AAV gene therapies Invest in next-generation technologies Retain valuable commercial rights Commercialization Pipeline Manufacturing Enabling Technologies Intellectual Property

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 4 J A N U A R Y 2 0 2 0

Key ey near near-ter term c catal alysts ts

• Topline data from HOPE-B pivotal study in late 2020
• BLA submission in 2021

Hemophilia B

• Initiate dosing in Phase I/II study in early 2020
• Early efficacy data on initial patients in 2021

Huntington’s

• Submit IND for AMT-180 in 2020
• Begin clinical development in 2021

Hemophilia A

• Initiate IND-enabling study for SCA3 in 2020
• Submit IND application in 2021

Spinocerebellar Ataxia Type 3 (SCA3)

• Continue to increase manufacturing scale and capacity
• Conduct manufacturing process validation for EtranaDez (AMT-061) in 2020

Manufacturing

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 5 J A N U A R Y 2 0 2 0

Our ur prop

• prietary p

pip ipel eline

*Collaboration with Bristol-Myers Squibb

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 6 J A N U A R Y 2 0 2 0

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

Global al l lead ader ershi hip i p in AAV manufactur facturing ng

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 7 J A N U A R Y 2 0 2 0

AAV5 – Clinically demonstrated tolerability and clinical effects

• bserved to date
• 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

Lev Lever eraging A AAV5: 5: a a pot

• ten

entially b bes est-in in-cl clas ass v vector

• r

AAV5 Vector

Hemophilia B

Etranacogene dezaparvovec (AMT-061)

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• 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

Hem emop

• philia B

B: sig igni nifican ant f fin inan ancial b bur urden en and and unm unmet et m med edica ical need needs

Clinical burden Patient burden Economic burden Societal burden Lifelong bleeding risk with current standard of care and accrual of joint damage3 Cumbersome treatment with adherence issues, quality of life and pain3 ~$610,000 annual cost of factor IX replacement therapy for severe patients in the US4 >$20 million lifetime cost per severe patient in the US5

Disease prevalence: ~6,000 patients in the United States1 and ~14,000 patients in Europe2

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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

Etranacog nacogene d ene dezapar arvov

• vec (

ec (AMT-06 061) 1)

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10 20 20 40 60 80 100 120 140 160 180 200 220 FIX activity (IU/dL)

6 (11.1) 7 (7.1) 8 (8.5) 9 (3.9) 10 (6.7)

Cohort 2

Mean FIX activity (95% CI): 7.5 (4.2 – 10.7)

AMT MT-060 060: s sus ustained d dos

• se-dep

dependen endent i t incr creas eases es in in FI FIX act activity

10 20 20 40 60 80 100 120 140 160 180 200 220 FIX activity (IU/dL)

1 (7.1) 2 (5.3) 3* (1.3) 4* (8.2) 5* (3.5)

Cohort 1

Mean FIX activity (95% CI): 5.1 (1.6 – 8.6)

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

• f mean FIX activity. FIX, factor IX; CI, confidence interval; IU, international units

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 12 J A N U A R Y 2 0 2 0 FIX activity measured by a one stage clotting assay conducted in a central lab. aPTT, activated partial thromboplastin time

Etran anacogene d dez ezap aparvovec: P Phas hase 2b e 2b sus ustai ained FI FIX act activity in in the f he func unctionally cur curat ative r rang ange

Mean FIX activity at 1 year: 41% of normal

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• 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

Etranacog nacogene d ene dezapar arvov

• vec (

ec (EtranaD naDez ez): : HOP OPE-B P Phas hase I e III p piv ivot

• tal s

stud udy

Huntington’s Disease

AMT-130

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• Patient population1:
• ~25,000 patients in United States
• ~25,000 patients in Europe
• Underreported due to lack of treatment
• ptions
• Disease stage prevalence2:
• 30.5% Early stage
• 35.5% Middle stage
• 34.0% Late stage
• Autosomal dominant neurodegenerative

disorder

• Expansion of CAG trinucleotide huntingtin

(HTT) exon1

• No disease-modifying therapies available

Hunti ting ngton’ ton’s d diseas ase: p e: preval alence a nce and overview ew

1 Neuroepidemiology 2016;46:144–153 2 Journal of Medical Economics. 2013 Aug;16(8):1043-50

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Huntington’s

AMT-130

• No treatments available
• Strong preclinical data
• Near-term goal: Begin

dosing of Phase I/II trial

• One-time administration of disease-modifying

therapy

• Proprietary miQURETM silencing platform
• Strong mutant HTT knockdown in deep structures

and cortex

• Only program to target full-length HTT protein

aggregates and highly toxic HTT exon1 protein fragments

• Potential to be first gene therapy to market

AMT MT-130 130: m major ajor g gene t ene ther herapy op

• ppor
• rtunity

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AMT MT-130: e 0: extens nsive p e preclini nical cal v validati dation

• n
• 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 Gene Ther 2017;28:A78;
• 4. Miniarikova J, et al. Gene Therapy 2017;24:630-639

Recent publications

Model Efficacy Safety Distribution Cultured human neurons   Rodents

(HD rat4) (4 types HD mouse3)

  NHP

(Non-human primate1)

   Pig

(tgHD Minipig2)

  

• 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

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 18 J A N U A R Y 2 0 2 0

• The striatum is the primary site of pathology
• Premanifest stage: atrophy spreads and

cortical thinning occurs

• Motor symptoms manifest as atrophy

increases

• 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

Hunti ting ngton’ ton’s d diseas ase: e: ex expec ected ed p prog

• gression of
• f brai

ain p pat atho hology

Figure adapted from Brundin P, et al. Nat Rev Mol Cell Biol 2010;11:301-7.

The shading and arrows indicate the progression of

• pathology. Darker shading

represents earlier onset.

Occipital lobe Frontal lobe Somatomotor cortex Parietal lobe

1 2 3 3

Somatosensory cortex

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AMT MT-130 130: w well ell-tol toler erate ated a d and wides espr pread ead d distr tributi bution

• n

in in the non he non-hum human p an primate ( te (NHP) b brain

NHP MRI-guided frontal convection-enhanced delivery

No procedure-related neurological symptoms following infusion into the striatum

Distribution throughout NHP brain

Putaminal delivery AAV5-GFP Caudate nucleus Putamen Globus pallidus Thalamus Hippocampus uniQure, data on file. MRI, magnetic-resonance imaging Samaranch L. et al, Gene Ther. 2017 Apr;24(4):253-261. Figure 3

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 20 J A N U A R Y 2 0 2 0

AMT MT-130 130: s stron

• ng r

red educ uction of

• f mut

utan ant H HTT in TT in the he mini inipig b brain ain

Libechov transgenic (tgHD) minipigs:

• Lifespan:

12-20 years

• Body weight: 50-140 kg
• Brain weight: 90-100 g
• Highly developed immune system

MRI-guided Convection-enhanced delivery Comparable mutant huntingtin protein knockdown at 6 and 12 months

Bars represent average ± SEM of n=3-4 animals/group Prefrontal Somato-S/M Temporal Caudate Putamen Amygdala Thalamus Pons Cerebellum

25 50 75 100 125 mutant HTT protein (% from naive)

6 months 12 months

Cortex Striatum 30% 50% 70%

putamen caudate

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 21 J A N U A R Y 2 0 2 0

AMT MT-130 130: neur neuropathology in in disea eased m mous

• use

e mod

• del

el

Leavitt BR, Vallès. et al., Manuscript in preparation

Mean concentration tNAA (mM)

W T c

• n

t r

• l

F

• r

m u l a t i

• n

b u f f e r 5 . 2 X 1 09 1 . 3 X 1 011 4.0 4.5 5.0 5.5 6.0

***

gc AMT-130 Q175FDN

Mean concentration mI (mM)

W T c

• n

t r

• l

F

• r

m u l a t i

• n

b u f f e r 5 . 2 X 1

9

1 . 3 X 1

1 1

3 4 5 6 7

*

gc AMT-130 Q175FDN

Myo-Inositol (MI) Gliosis marker N-Acetyl Aspartate (tNAA) Neuronal integrity marker

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 22 J A N U A R Y 2 0 2 0

AMT MT-130 130: f ful ull-leng ngth and and ex exon1

• n1 H

HTT low TT lower ering i in n stria iatum and and cor cortex in in dis isea eased m mous

• use m

e mod

• del

el

5UTR Exon 1-2 Exon 64 0.0 0.5 1.0 1.5

Full lenght HTT in Striatum

5UTR Exon 1-2 Exon 64 0.0 0.5 1.0 1.5

Full-length HTT in Cortex

Relative expression to Formulation Buffer

Early intron 1 Intron 1 0.0 0.5 1.0 1.5

Relative expression to Formulation Buffer

Exon1 HTT in Striatum

Early intron 1 Intron 1 0.0 0.5 1.0 1.5

Relative expression to Formulation Buffer

Exon 1 HTT in Cortex

(AAAA)n (CAG)n 5’UTR E1 E2 E6 7 Intron 1 (CAG)n 5’UTR (AAAA)n E1

Full-length HTT mRNA Exon-1 HTT mRNA

Full length HTT in Striatum Full length HTT in Cortex Exon1 HTT in Striatum Exon1 HTT in Cortex

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 23 J A N U A R Y 2 0 2 0

AMT MT-130: s 0: signi nifi ficant d cant differ erenti entiati ating f ng featur ures es

No immune-related toxicity

• No cytotoxic T cells recognizing

AAV5 epitopes Reversal of pathology in a relevant HD animal model

• Reversal of neuronal integrity and

partial reversal of gliosis (inflammation) in Q175FDN mice Long-term silencing after a single administration

• No need for repeated intrathecal

injections No direct miRNA toxicity and no

• ff-target effects
• miHTT expression is well-regulated

and the technology does not generate a passenger strand

• No long-term neurofilament-light

increase in HD pig study (18 months follow-up) Silences mutant Huntington protein as well as the more toxic small fragments

• Uniquely silences exon1 toxicity

Silences mutant Huntington protein species at the site of the pathology

• Significant, long-term and

therapeutic knock-down in the striatum and sensorimotor cortex

• miQURE technology spreads

throughout the target CNS region via extracellular vesicles

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 24 J A N U A R Y 2 0 2 0 Adapted from Ross CA, et al. Nat Rev Neurol 2014;10:204-16

AMT MT-130 130: g goal

• al of
• f clin

clinica cal t treat eatment

Premanifest Motor diagnosis Manifest Presymptomatic Prodromal Early Moderate Advanced I II III IV V 100 ← Function (%)

Slow or halt disease progression

AMT-130

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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)

AMT MT-130: P 0: Phase I e I/II c clini nical cal t trial al

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 26 J A N U A R Y 2 0 2 0 *Unified Huntington’s Disease Rating Scale

AMT MT-130 130: P Phas hase I I/II ef efficac acy end endpoints

Clinical Parameters*

• Total motor score
• Total functional capacity

Imaging (MRI and MRS)

• Measures of neural function
• Striatal volume (atrophy)

Biomarkers

• NF-L (neurofilament light)
• mHTT in CSF
• Other exploratory markers

Quantitative Motor Function

• Finger, hand and foot tapping
• Grasping and lifting (chorea)

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 27 J A N U A R Y 2 0 2 0

AMT MT-130 130: P Phas hase I I/II cli clinical t tria ial d des esign

Cohort 1: 10 patients (6 dosed, 4 control) Cohort 2: 16 patients (10 dosed, 6 control)

3-month enrollment stagger followed by DSMB Review #1 3-month enrollment stagger followed by DSMB Review #2 1-month enrollment stagger followed by DSMB Review #3 1-month enrollment stagger followed by DSMB Review #4 Subject 1&2 1:1 randomization 1 dosed 1 control Subject 3&4 1:1 randomization 1 dosed 1 control Subject 5-10 2:1 randomization 4 dosed 2 control Subject 13&14 1:1 randomization 1 dosed 1 control Subject 11&12 1:1 randomization 1 dosed 1 control Subject 15-26 2:1 randomization 8 dosed 4 control 1-month enrollment stagger followed by DSMB Review #5

Research Pipeline

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 29 J A N U A R Y 2 0 2 0

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

AMT MT-180 180: a a nov novel el ap approach t h to

• Hem

emop

• philia A

A

Long-term and stable expression Effective in all HemA patients Compatible with bypass agents Comparable with emicizumab

• Hepatocyte-friendly
• Non-thrombogenic
• Sufficient thrombin

generation to stop bleeding episodes

• Not neutralized by FVIII

inhibitors

• Safe in combination

with rFVIIa and/or FEIBA and emicizumab

• Comparable efficacy in

HemA with and without inhibitors

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 30 J A N U A R Y 2 0 2 0

More effective than replacement therapy Patients with and without inhibitors Non-immunogenic

• More stable in plasma
• More efficient uptake
• Better end-organ

distribution

• Many Fabry patients

develop inhibitors to α-gal replacement therapy

• NAGA is not neutralized by

α-gal inhibitors

• No loss of activity due

to α-gal inhibitors

Novel Approach

• Product Construct – AAV5 including modified NAGA
• Modified NAGA has therapeutic α-gal activity and gB3 reduction

AMT MT-190 190: a a new new ap approach t to

• Fab

Fabry dise sease se

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 31 J A N U A R Y 2 0 2 0

• CAG repeat expansion

in ATXN3 gene

• Ataxin-3 protein

acquires toxic properties

• Brain degeneration

cerebellum and brainstem

• More widespread in

later stages

• Ataxia
• Dystonia/rigidity
• Muscular atrophy
• Paralysis
• No medication that

slows the progressive course of the lethal disease

AMT MT-150 150: a a gene t ene ther herapy f for

• r S

SCA3

Cause Damage Symptoms Unmet Need

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

A G L O B A L L E A D E R I N G E N E T H E R A P Y | 32 J A N U A R Y 2 0 2 0

Key ey near near-ter term c catal alysts ts

• Topline data from HOPE-B pivotal study in late 2020
• BLA submission in 2021

Hemophilia B

• Initiate dosing in Phase I/II study in early 2020
• Early efficacy data on initial patients in 2021

Huntington’s

• Submit IND for AMT-180 in 2020
• Begin clinical development in 2021

Hemophilia A

• Initiate IND-enabling study for SCA3 in 2020
• Submit IND application in 2021

Spinocerebellar Ataxia Type 3 (SCA3)

• Continue to increase manufacturing scale and capacity
• Conduct manufacturing process validation for EtranaDez (AMT-061) in 2020

Manufacturing