Corporate Presentation APRIL 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 A P R I L 2 0 1 9 | 1

Corporate Presentation APRIL 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 A P R I L 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 Annual Report on Form 10-K filed on February 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.

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 A P R I L 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 A P R I L 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 A P R I L 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 A P R I L 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 A P R I L 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 A P R I L 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

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Hemophilia B

AMT-061

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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

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Increases in FIX Activity up to 51% Mean FIX activity at 12 weeks of 38%

Main Efficacy Findings:

 Sustained increases in FIX activity  No bleeding events post-infusion  No infusions of replacement therapy  No requirement of immunosuppression

Main Safety Findings:

 Well-tolerated  No serious adverse events  No inhibitor development

AMT-061: FIX activity up to 16 weeks post-treatment

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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

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Huntington’s Disease

AMT-130

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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

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AMT-130: widespread distribution in brain

1 Lower Limit of Detection

Vector DNA distribution

1

Vector genome copies

per g DNA

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

Penetration throughout NHP brain

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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

P r e f r

• n

t a l S

• m

a t

• S

/ M T e m p

• r

a l C a u d a t e P u t a m e n A m y g d a l a T h a l a m u s P

• n

s C e r e b e l l u m

mutant HTT protein (% from naive)

putamen caudate

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AMT-130: Phase I/II dose escalation study

Clinical Parameters (e.g. UHDRS) Quantitative Motor Function Volumetric MRI and MRS Patient-reported outcomes Biomarkers (e.g. mHTT in CSF)

Efficacy Endpoints

IND Cleared – Phase I/II Study Overview

• Objectives: assess safety, tolerability and efficacy
• Multicenter, randomized, double-blinded study
• Controlled with imitation surgery
• Two dose cohorts with a total of 25 patients
• Early manifest patients with ≥ 44 CAG repeats
• 18-month follow-up (5 years for treated patients)

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Research Pipeline Expansion

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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
• Stable long-term

expression

• Non-immunogenic
• 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 A P R I L 2 0 1 9 | 20

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 50 100 150 200 250

hFIX protein (%) in NHPs

weeks post-injection

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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 A P R I L 2 0 1 9 | 22 Tajima Y et al. Am J Human Genetics 2009

Wild type Fabry Modified NAGA Fabrazyme Replagal

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• 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

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SCA3 mouse model

• N = 3 per group
• In-life 6 weeks

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 A P R I L 2 0 1 9 | 25

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