Corporate Presentation JULY 2019 D E L I V E R I N G G E N E T H - - PowerPoint PPT Presentation

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 1

Corporate Presentation JULY 2019

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 2

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

• r 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

• versight, 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 July 29, 2019. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no

• bligation to update these forward-looking statements, even if new information becomes

available in the future.

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 3

Our mission

To deliver curative,

• ne-time therapies

that transform the lives

• f patients.

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 4

Our strategic imperatives

Develop a proprietary pipeline of gene therapy candidates focused on liver-directed and CNS disorders Pipeline Maintain leadership in commercial-scale manufacturing of AAV gene therapies Manufacturing Invest and leverage next-generation technologies that optimize and expand the applicability of gene therapy to patients Enabling Technologies Expand and maintain our leading IP portfolio Intellectual Property Retain valuable commercial rights Commercialization

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 5

Expanding our proprietary pipeline

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 6

Complete enrollment in HOPE-B Phase III pivotal study of AMT-061 Initiate dosing of Phase I/II study of AMT-130 Submit IND for AMT-180 Initiate IND-enabling toxicology study for one additional program Hemophilia B Huntington’s Hemophilia A Other Programs

Near-term goals

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 7

Leading the way in AAV manufacturing

Large-scale AAV Manufacturing

• Based in Lexington, MA, expanding to 80,000 ft2
• 3rd generation insect cell, baculovirus
• Demonstrated 500L stirred-tank production
• Scalable up to 2 x 2,000L
• Strong intellectual property position

Benefits

• Control and flexibility
• Consistent process from preclinical to

commercial

• Highly scalable, cost-effective
• High-volume capacity
• Consistent, stable, high-quality product

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 8

Leveraging AAV5: a potentially best-in-class vector

AAV5 – Clinically demonstrated tolerability and outcomes

• Long-term follow-up data demonstrating safety and tolerability
• 25 patients have received AAV5 across 4 clinical studies1
• Demonstrated clinical outcomes in the liver and brain
• Low avidity of pre-existing neutralizing antibodies
• Favorable immunogenicity profile for systemic, intravenous delivery
• No confirmed T-cell-mediated immune responses to capsid

1 Clinical trials in Hemophilia B, Sanfilippo B and Acute Intermittent Porphyria

AAV5 Vector

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 9

Hemophilia B

AMT-061

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 10

Executing in Hemophilia B

• 10-15K patients in US/EU
• >$1B market in 20161
• Near-term goal: Complete

enrollment in pivotal study Hemophilia B

AMT-061

1 GlobalData report 2016

Target product profile

• Potential for functionally-curative increases in FIX activity
• Durable and predictable outcomes
• Low risk of immune responses
• Greater patient eligibility due to low levels of NABs
• Strong intellectual property
• Potential to be first to market

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 11

Increases in FIX Activity up to 54% Mean FIX activity at 36 weeks of 45%

Main Efficacy Findings:

• Sustained increases in FIX activity
• No bleeding events post-infusion
• No infusions of replacement therapy for bleeds
• No requirement of immunosuppression
• No exclusion of patients with pre-existing NABs

Main Safety Findings:

• Well-tolerated
• No serious adverse events related to AMT-061
• No inhibitor development

AMT-061: FIX activity at 36 weeks post-treatment

54.1 30.1 50.9 10 20 30 40 50 60 70 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 FIX activity one-stage aPTT (% of normal) Week Participant 1 Participant 2 Participant 3

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 12

AMT-061: HOPE-B Phase III pivotal study

• Patient dosing underway
• Open label, single-dose, multi-center, multi-national trial
• Approximately 50 patients with severe and moderately-severe hemophilia B
• Patients with AAV5 antibodies will not be excluded
• Patients will 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

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 13

miQURE™ Gene Silencing Technology

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 14

miQURETM our unique gene silencing technology

• Degrades toxic genes without toxic effects
• Delivered with AAV and is active long term
• miRNA spreads in extracellular vesicles in the cerebrospinal fluid (CSF) to

transduce the brain

Shah R, et al. NEJM 2018;379:958-966.

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 15

Defect gene Deliver correct gene Correct gene function

Gene replacement

Toxic gene Degrade toxic gene No toxicity

miQURE™ treatment

miQURE™ technology

miQURE™ vs. gene replacement

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 16

miQURE™: important features

• Expression comparable with cellular miRNAs ensures no saturation of the

natural RNAi mechanism

• No direct toxicity

Specificity & Regulation Safety Bio- distribution & Processing

• Expression from pol II promoter for tissue specificity and regulation
• Liver- or brain-specific expression
• Scaffold for high processing precision and no off-target effects
• No passenger strand
• Induces cytoplasmic and nuclear gene lowering
• Also prevents nuclear aggregates
• Spread via CSF and lymph with extracellular vesicles (EV)
• Full protection of affected target organs

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 17

• High miQURE™ processing

precision (Dicer-independent)

• Safer therapeutic. No

miQURE™ off-target effects (no passenger strand)

• Proprietary IP/ FTO 2022

/license CSH

conventional miRNA

Guide strand (active) Passenger strand (off-targets) Drosha Dicer

miQURE™

Guide strand (active) No passenger Drosha

miQURE™ scaffold: high-processing precision with no off-target effects

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 18

miQURE™: scaffold advantage - no off-target effects

LETM1 RFFL ALDH18A1 PGPEP1 ODF2 ADGRA2 ZNF596 KIFC1_1 GRFA1 RUBCN APOL6 SH3TC2 NRP2 KIAA2022 CACNA1C CSRNP3 NEGR1 SYNCRIP HMBS ACTB

50 100 150 200 Relative expression (%)

Relative to formulation buffer

BLAST siSPOTR

iPS-derived neurons iPS-derived astrocytes

Processing fidelity superior to conventional miRNA

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 19

extracellular vesicles

miQURE™: cytoplasmic and nuclear gene lowering

• Conventional miRNA do not

result in nuclear silencing

• miQURE™ causes nuclear

silencing

• Nuclear silencing is critical in

HD and ALS-c9orf72 where toxic mRNA and protein species cause the disease

nucleus cytoplasm

1 2 3 miQURE™ Gene ene Degrad adat ation

• n

miQURE™ spread of efficacy

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 20

• 1. No tissue specificity
• 2. High efficacy but off-targets and toxicity
• 3. Oversaturation of RNAi
• 4. No nuclear silencing
• 5. No spread of effect with EV
• 1. PoI II expression – tissue specificity and

regulation

• 2. Proprietary miQURE™ scaffold processing,

guide strand activity only, and safer therapeutic

• 3. No saturation of cellular RNAi
• 4. Nuclear and cytoplasmic effect (superior to

conventional miRNA)

• 5. Spread of the miQURE™ effect with EV

Conventional AAV-miRNA therapy miQURE™ gene therapy

miQURE™: high commercial & clinical attractiveness

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 21

Huntington’s Disease

AMT-130

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 22

Huntington’s

AMT-130

• 3-7 per 100K people1
• No treatments available
• Strong preclinical data
• Near-term goal: Initiate

clinical study in 2019

1 Rawlins, MD. Neuroepidemiology 2016;46:144-153

Target product profile

• One-time administration of disease-modifying therapy
• Proprietary miQURETM silencing platform
• Strong mHTT knockdown in both deep structures and cortex
• Preclinically shown to be generally safe and well-tolerated
• Targets full length HTT protein aggregates and highly toxic

HTT exon1 protein fragments

• Potential to be first to market

Executing in Huntington’s Disease

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 23

• The striatum is the primary site of

pathology

• Premanifest stage: atrophy

spreads and cortical thinning

• ccurs
• Motor symptoms manifest as

atrophy increases

Huntington’s disease: expected progression of brain pathology

• 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.

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

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 24

AMT-130: targeting of aberrant exon1 HTT increased survival in exon1 mouse model

R6/2 transgenic mice:

• Express exclusively mutant HTT exon1 (125 repeats)
• Most severe HD-like pathology among HD mouse models
• Do not contain Roche RG6042 target sequence

Strong increase median survival in R6/2 HD mice

NOTE: Previously reported data of Ionis/Roche in R6/2 transgenic mice was obtained with HuASOEx1, which is not the clinical candidate RG6042

Extracted from Ionis/Roche webcast March 2018 Adapted from Figure 6G Kordasiewicz et al., 2012; Neuron 74:1031

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 25

AMT-130: widespread distribution in brain

1 Lower Limit of Detection

Vector DNA distribution

1 x 1 0

3 x 1 0

1

P u t a m e n C a u d a t e T h a la m u s C o r t e x

1 0

1 0

1 0

1 0

1 0

1 0

V e c t o r g e n o m e c o p i e s

p e r µ g D N A

L L O D

Samaranch L. et al, Gene Ther. 2017 Apr;24(4):253-261. Figure 3

Penetration throughout NHP brain

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 26

AMT-130: strong reduction of mHTT

Libechov transgenic (tgHD) minipigs:

• Life-span:

12-20 years

• Body weight:

50-140 kg

• Brain weight:

90-100 g

• Highly developed immune system

N=12

MRI-guided CED

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

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 27

AMT-130: goal of clinical treatment

Adapted from Ross CA, et al. Nat Rev Neurol 2014;10:204-16

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

Slow or halt disease progression

AMT-130

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 28

AMT-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 with ≥ 44 CAG repeats
• 18-month follow-up (5 years for treated patients)

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 29

AMT-130: Phase I/II clinical trial

Clinical Parameters*

• Total motor score
• Total functional capacity
• Composite score

Quantitative Motor Function

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

Volumetric MRI and MRS

• Measures neuronal atrophy

and function Biomarkers

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

Patient-reported outcomes

• Neuro-QoL
• HD QLIFE

Efficacy Endpoints

*Unified Huntington’s Disease Rating Scale

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 30

AMT-130: Phase I/II clinical trial

Cohort 1 Cohort 2

DSMB Review #1 at 3 months follow-up DSMB Review #2 at 3 months follow-up DSMB Review #3 at 3 months follow-up DSMB Review #4 at 1 month follow-up DSMB Review #5 at 1 month follow-up Subject 1&2 1:1 randomization 1 AMT-130 1 control Subject 3&4 1:1 randomization 1 AMT-130 1 control Subject 5-10 2:1 randomization 4 AMT-130 2 control Subject 13&14 1:1 randomization 1 AMT-130 1 control Subject 11&12 1:1 randomization 1 AMT-130 1 control Subject 15-26 2:1 randomization 8 AMT-130 4 control

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 31

Research Pipeline Expansion

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 32

AMT-180: a novel approach to hemophilia 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

Novel Approach

• Product Construct – AAV5 including C7 Promoter and FIX-Super9™
• Super9™ is a proprietary modified FIX that, when activated through normal mechanisms, then

activates FX independently of FVIII

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 33

AMT-180: expression levels in NHPs expected to translate to therapeutically relevant FVIII mimetic activity in humans

male Cynomolgus macaque n=2 IV, 9e13 gc/kg adapted delivery 1) AAV5-LP1-Super9™ 2) AAV5-P-IDAV 3) AAV5-P-Super9™ 1 vehicle treated NHP

• Wk 13: FEIBA injection
• Wk 15: FVIIa injection

AAV5-P-Super9™ AAV5-P-IDAV AAV5-LP1-Super9™ vehicle

• 1

1 2 3 4 5 6 7 8 5 0 1 0 0 1 5 0 2 0 0 2 5 0

h F I X p r o t e i n ( % ) i n N H P s

w e e k s p o s t - in je c t io n h F I X p r o t e i n ( % )

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 34

More effective than replacement therapy Patients with and without inhibitors

• 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

AMT-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

Non-immunogenic

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 35 Tajima Y et al. Am J Human Genetics 2009

Wild type Fabry Modified NAGA Fabrazyme Replagal

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 36

• 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-150: a gene therapy for 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

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 37

SCA3 mouse model

• N = 3 per group
• In-life 6 weeks

Cisterna Magna Cerebellum

AMT-150: 65% ataxin-3 lowering in brainstem of SCA- concept3 mice after cisterna magna injection of miQURE™

miQURETM

Control miQURE_A miQURE_B miQURE_C

25 50 75 100 SCA3 mouse brainstem Mutant ataxin-3 protein (%)

Relative to control

* *

Up to 65% ataxin-3 lowering in SCA3 mice

D E L I V E R I N G G E N E T H E R A P Y T O P A T I E N T S J U L Y 2 0 1 9 | 38

Complete enrollment in HOPE-B Phase III pivotal study of AMT-061 Initiate dosing of Phase I/II study of AMT-130 Submit IND for AMT-180 Initiate IND-enabling toxicology study for one additional program Hemophilia B Huntington’s Hemophilia A Other Programs

Near-term goals