Corporate Presentation MAY 2019 - uniQure › Corporate Presentation May 2019_v2.pdf · date of...

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 M A Y 2 0 1 9 | 1

Corporate Presentation

MAY 2019


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 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.


Our mission

To deliver curative,

one-time therapies

that transform the lives

of patients.


Our strategic imperatives

Develop a proprietary pipeline of gene therapy candidates focused on

liver-directed and CNS disordersPipeline

Maintain leadership in commercial-scale manufacturing of AAV gene

therapiesManufacturing

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 portfolioIntellectual

Property

Retain valuable commercial rights Commercialization


Expanding our proprietary pipeline


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


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


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


Hemophilia B

AMT-061


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


Increases in FIX Activity up to 57%

Mean FIX activity at 26 weeks of 47.1%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 at 26 weeks post-treatment


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


miQURE™ Gene Silencing Technology


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.


Defect

geneDeliver correct

gene

Correct gene

function

Gene

replacement

Toxic

geneDegrade toxic

gene

No toxicity

miQURE™

treatment

miQURE™

technology

miQURE™ vs. gene replacement


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


• 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


miQURE™: scaffold advantage - no off-target

effects

LETM

1

RFFL

ALD

H18

A1

PGPEP1

ODF2

ADGRA2

ZNF59

6

KIF

C1_

1

GRFA

1

RUBCN

APOL6

SH3T

C2

NRP2

KIA

A20

22

CACNA1C

CSRNP3

NEGR1

SYNCRIP

HM

BS

ACTB

0

50

100

150

200R

ela

tive e

xp

ressio

n (

%)

Rela

tive to form

ula

tion b

uffer

BLAST siSPOTR

iPS-derived neurons

iPS-derived astrocytes

Processing fidelity superior to conventional miRNA


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

23

miQURE™

Gene

Degradation

miQURE™ spread of efficacy


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 therapymiQURE™ gene therapy

miQURE™: high commercial & clinical attractiveness


Huntington’s Disease

AMT-130


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


Executing in Huntington’s Disease


• The striatum is the primary site of

pathology

• Premanifest stage: atrophy

spreads and cortical thinning

occurs

• 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

33

Somatosensory

cortex



neurotoxicity is caused by 2 pathways


Toxic Pathway 2: 2013 Sathasivam,

2015 Bates, 2017 Neueder, 2018

Neueder, 2018 Romo.


neurotoxicity is caused by 2 pathways


AMT-130

AMT-130 AMT-130 targets all toxic

HTT species

• Targets HTT exon1

• miQURE™ active in nucleus

and cytoplasm

AMT-130: blocks all toxic pathways


RG6042

All competitors only

target toxic Pathway 1

• RG6042: HTT exon 36

• WVE-1201..: SNP in HTT

exon 50+67

• VY-HTT01: not HTT

exon1

Other investigative industry programs are not believed

to bind exon1 and only block toxic Pathway 1


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


AMT-130: widespread distribution in brain

1 Lower Limit of Detection

Vector DNA distribution

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

0

5 0

1 0 0

1 5 0

mu

ta

nt H

TT

pr

ote

in

(%

)

(r

ela

tiv

e to

P

BS

+

5

% s

uc

ro

se

)

P B S + 5 % S u c r o s e

1 x 1 01 3

g c A A V 5 - m iH T T

3 x 1 01 3


* * * * * *

P B S + 5 % S u c r o s e

1 x 1 01 3


3 x 1 01 3


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 03

1 04

1 05

1 06

1 07

1 08

Ve

ct

or

ge

no

me

co

pie

s

pe

r

g D

NA

L L O D

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

Penetration throughout NHP brain


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

Pre

fronta

l

Som

ato-S

/M

Tempora

l

Cau

date

Puta

men

Am

ygdal

a

Thalam

us

Pons

Cer

ebel

lum

0

25

50

75

100

125

mu

tan

t H

TT

pro

tein

(% f

rom

na

ive

)

6 months

12 months

Cortex Striatum

30%

50%

70%

putamen

caudate


AMT-130: goal of clinical treatment

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

Premanifest

Motor

diagnosisManifest

Presymptomatic Prodromal Early Moderate Advanced

I II III IV V

100

0

← Function (%)

Slow or halt

disease

progression

AMT-130


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 EndpointsIND 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)


Research Pipeline Expansion


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


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 0 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 - i n j e c t io n

hF

IX p

ro

te

in (

%)

v e h ic le

A A V 5 - L P 1 - F I A V

A A V 5 - P - I D A V

A A V 5 - P - F I A V


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


Tajima Y et al. Am J Human Genetics 2009

Wild type

Fabry

Modified NAGA

Fabrazyme

Replagal


• 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



SCA3 mouse model

• N = 3 per group

• In-life 6 weeks

Cisterna agna

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_C0

25

50

75

100

SCA3 mouse brainstem

Mu

tan

t a

tax

in-3

pro

tein

(%

)R

ela

tiv

e t

o c

on

tro

l

* *

Up to 65% ataxin-3 lowering

in SCA3 mice


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

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