October 2, 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 - - PowerPoint PPT Presentation

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Cantor Global Healthcare Conference October 2, 2019

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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 July 29, 2019. Given these risks, uncertainties and

• ther 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.

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• Demonstrated clinical proof of concept in Hemophilia B; achievement of patient enrollment in

HOPE-B pivotal study, with potential to be first- and best-in-class

• Proprietary CNS platform with lead program AMT-130 in Huntington’s disease expected to initiate

dosing in Phase I/II study this year

• Strong pipeline of additional product candidates approaching the clinic including in Hemophilia A,

Fabry disease, and SCA3

• Global commercial rights retained for all core programs
• Leadership in large-scale, cGMP manufacturing of AAV gene therapies

Key corporate achievements and capabilities

• Portfolio of enabling technologies and IP, including miQURE™ gene silencing, FIX-Padua variant,

re-administration, manufacturing processes and AAV5 and other novel vectors and promoters

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Our proprietary pipeline

*Collaboration with Bristol-Myers Squibb

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Leading the way 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

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Leveraging AAV5: a potentially best-in-class vector

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

1 uniQure clinical trials in Hemophilia B, Sanfilippo B and Acute Intermittent Porphyria

AAV5 Vector

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Hemophilia B

Etranacogene dezaparvovec (AMT-061)

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

Main Efficacy Findings:

• Sustained increases in FIX activity
• No bleeding events post-treatment
• 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 treatment
• No inhibitor development

Etranacogene dezaparvovec (EtranaDez): FIX activity at 36 weeks post-treatment in Phase 2b study

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

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Etranacogene dezaparvovec (EtranaDez): HOPE-B Phase III pivotal study

• Achieved enrollment of 62 patients with severe and moderately-severe Hemophilia B
• 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

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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

dosing of Phase I/II

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
• 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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• 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

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AMT-130: goal of clinical treatment to slow or halt disease progression from an early stage

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  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

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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

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

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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)

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AMT-130: Phase I/II clinical trial endpoints

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

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Research Pipeline

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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
• 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,

activates FX independently of FVIII

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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

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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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• Topline data from HOPE-B pivotal study in 2020
• BLA submission in 2021
• Initiate dosing in Phase I/II study before end of 2019
• Preliminary biomarker data on initial patients in 2020
• Submit IND for AMT-180 in 2020
• Initiate IND-enabling study for SCA3 in 2019
• Targeting one new IND-submission each year

Hemophilia B Huntington’s Hemophilia A Other Programs

Key corporate goals