December 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 - - 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 D E C E M B E R 2 0 1 9 | 1

Corporate Presentation December 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 D E C E M B E R 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 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 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.

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 D E C E M B E R 2 0 1 9 | 3

Investment highlights

• Full patient enrollment in hemophilia B pivotal study, with potential to be first/best-in-class gene therapy
• First ever gene therapy for Huntington’s disease recently initiated Phase I/II clinical development
• Strong pipeline of other candidates 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
• Robust portfolio of enabling technologies and intellectual property developed over two decades

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 D E C E M B E R 2 0 1 9 | 4

Our proprietary pipeline

*Collaboration with Bristol-Myers Squibb

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 D E C E M B E R 2 0 1 9 | 5

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

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 D E C E M B E R 2 0 1 9 | 6

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

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 D E C E M B E R 2 0 1 9 | 7

Hemophilia B

Etranacogene dezaparvovec (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 D E C E M B E R 2 0 1 9 | 8

Etranacogene dezaparvovec (AMT-061)

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

9

10 20 30 40 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-060: sustained dose-dependent increases in FIX activity

10 20 30 40 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 of mean FIX activity. FIX, factor IX; CI, confidence interval; IU, international units

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 D E C E M B E R 2 0 1 9 | 10

Etranacogene dezaparvovec: phase 2b sustained FIX activity in the functionally curative range

10

FIX activity measured by a one stage clotting assay conducted in a central lab. aPTT, activated partial thromboplastin time

Mean FIX activity at 1 year: 41% of normal

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 D E C E M B E R 2 0 1 9 | 11

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

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 D E C E M B E R 2 0 1 9 | 12

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 D E C E M B E R 2 0 1 9 | 13

Huntington’s

AMT-130

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

dosing of Phase I/II

Target product profile

• One-time administration of disease-modifying therapy
• Proprietary miQURETM silencing platform
• Strong mutant HTT knockdown in 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

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 D E C E M B E R 2 0 1 9 | 14 Adapted from Ross CA, et al. Nat Rev Neurol 2014;10:204-16

AMT-130: goal of clinical treatment

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 D E C E M B E R 2 0 1 9 | 15

Huntington’s disease: patient prevalence

• Patient population1:
• ~25,000 patients in United States
• ~25,000 patients in Europe
• Underreported due to lack of

treatment options

• Disease stage prevalence2:
• 30.5% Early stage
• 35.5% Middle stage
• 34.0% Late stage

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

Age of onset

The Lancet 2007;369(9557)218-228

CAG-repeat length

CAG-repeat length & age of disease onset

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 D E C E M B E R 2 0 1 9 | 16

• 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 D E C E M B E R 2 0 1 9 | 17

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 non-human primate 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 D E C E M B E R 2 0 1 9 | 18

AMT-130: strong reduction of mutant HTT

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 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

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 D E C E M B E R 2 0 1 9 | 19

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 D E C E M B E R 2 0 1 9 | 20

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

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 D E C E M B E R 2 0 1 9 | 21

AMT-130: Phase I/II clinical trial design

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

DSMB Review #1 after 3-month follow-up and enrollment stagger DSMB Review #2 after 3-month follow-up and enrollment stagger DSMB Review #3 after 1-month follow-up on last patient DSMB Review #4 after 1-month follow-up and enrollment stagger 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 DSMB Review #5 after 1-month follow-up and enrollment stagger

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 D E C E M B E R 2 0 1 9 | 22

Research 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 D E C E M B E R 2 0 1 9 | 23

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

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 D E C E M B E R 2 0 1 9 | 24

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 D E C E M B E R 2 0 1 9 | 25

• 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 D E C E M B E R 2 0 1 9 | 26

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

Hemophilia B Huntington’s Hemophilia A Other Programs

Key corporate goals