Rob June 22, 2021 1

RE S E A RCH A ND DE V E LOP ME NT DA Y 2021 | 1JUNE 22 , 2021

Rob Clinical trial patient

for etranacogene dezaparvovecJune 22, 2021


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 the COVID-19 pandemic, 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 March 1, 2021 and Quarterly Report on Form 10-

Q filed May 10, 2021. 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.

Forward-looking Statements


Agenda for today

Welcome Maria Cantor 8:30 a.m.

Leadership in Gene Therapy Matt Kapusta 8:32 a.m.

R&D Vision and Strategy Ricardo Dolmetsch, Ph.D. 8:45 a.m.

Huntington’s Disease Program Update David Cooper, M.D. 8:55 a.m.

Q&A Session 9:15 a.m.

Coffee Break (10 minutes) 9:30 a.m.

Expanding Research Pipeline Research Team 9:40 a.m.


Hemophilia B Program Update David Cooper, M.D. 10:55 a.m.


Closing Remarks Matt Kapusta 11:25 a.m.


Leadership inGene Therapy

Matt KapustaCHIEF EXECUTIVE OFFICER

RE S E A RCH A ND DE V E LOP ME NT DA Y 2021 | 5JUNE 22 , 2021RE S E A RCH A ND DE V E LOP ME NT DA Y 2021 | 5JUNE 22 , 2021

Our mission is to deliver

curative, one-time

administered genomic

medicines that transform

the lives of patients.

InGENEuity through

ImagGENEation…


AAV Engine: Leveraging our leading technology platform to develop and

commercialize products targeting the CNS, liver and heart/muscle

uniQure: our focus

AAV Technology EngineManufacturing & Enabling Tools



uniQure: A gene therapy pioneer with a >20-year history and deeply engrained

culture of innovation across an increasingly validated platform

InGENEuity: our history of innovation

First FirstFirstFirst


uniQure: A gene therapy pioneer with a >20-year history and deeply engrained

culture of innovation across an increasingly validated platform

InGENEuity: our history of innovation

15 years LeadingWorld-class100+ patients

InGENEuity: a case study in delivering value through innovation


2008Licensed wtFIX gene cassette used by St. Jude in watershed first-in-human study

2017Announced transition to AMT-061 with AAV5/FIX-Padua transgene

2015Initiated Phase 1/2 study of AMT-060 with wtFIX transgene

2018Initiated Ph 2b dose-confirmation study and Phase 3 pivotal study

2020Completed dosing of 54 patients in Ph 3 pivotal study

2020Announced $2 billion CSL license and collaboration agreement

2021Announced 1 year follow-up data on all patients

Leapfrogging hemophilia B with a first and best-in-class gene therapy


InGENEuity: breaking ground in Huntington’s disease

2021

2022

2023

N=2

Control

N=2

Treated

N=10

TreatedN=6

Control

N=10

Control

N=31

Treated

4 pts w/ 1 year offollow-up

16 pts w/1 to 2 years of follow-up

41 pts w/up to 3 years of follow-up

Robust, controlled U.S. protocol

has potential to “actually speed

drug development”, per FDA…

Significant cash runway to transform our pipeline

Re-imaGENEing the R&D pipeline

Runway to 2H 2024

Extends runway through 2025

Extends runway into 2026 and beyond

~$700M of cash on hand

+$1.3B in potential other milestones + royalties

+$300M in nearer-term milestones



Doubling the pipeline by 2026


5-year

Pipeline

Goals:

3-4 Phase 3

commercial

programs

5-8 Phase 1/2

programs

7-12

preclinical

programs


Larger market opportunities built on validated targets and technologies


Key criteria:

● Best and/or first in class

● Human validation

● Leverage proven technologies

● Larger indications



Leveraging a broad, enabling technology platform to build an optimized and

differentiated pipeline

Re-imaGENEing our enabling technology

Re-imagining

where/how

we deliver…

Next-gen tools developed:

● Novel AAV capsids

● Next-gen promoters

● Optimized administration techniques

● Improved formulations

What we aim to accomplish:

● Potent expression

● Targeted delivery

● Uniform transduction

● Redosing


Leveraging a broad, enabling technology platform to build an optimized and

differentiated pipeline

Re-imaGENEing our enabling technology

Re-imagining

what we

deliver…

Next-gen tools:

miQURE® (gene silencing)

goQURE™ (gene silence/replace)

AbQURE™ (vectorized antibodies)

What we aim to accomplish:

● Insertion of genes

● Suppression of genes/proteins

● Substitution of genes


Consistency & Comparability from Discovery to Commercialization

2L STR 50L STR 500L STR 1,000-10,000 STR

Currently Deployed Currently Deployed Currently Deployed Being Developed

Early research Large animal studies cGMP cGMP

Status

Usage

Manufacturing for the future: Establishing larger scale and highly cost-effective

capabilities to address more prevalent disorders

Re-imaGENEing our in-house manufacturing

COGS


Initiated construction of a second cGMP manufacturing facility in Amsterdam

that will complement commercial manufacturing in Lexington, Massachusetts.

Re-imaGENEing our capabilities

Lexington, MAIncreasing to 100,000 sq ft (~200 FTEs)

Amsterdam, NL111,000 sq ft (~200 FTEs)

Research

Process Development

Analytical Development

Quality

Coming in 2021

cGMP Manufacturing

Coming in 2022

Process Development

Analytical Development

Quality

cGMP Manufacturing

Pilot Plant coming in 2021

Research

Coming in 2022



Preparing Etranacogene dezaparvovec for commercialization in hemophilia B

• 52-week follow-up data on all patients demonstrate sustained and durable responses

• FDA confirms 52-week follow-up period to support durability beginning at steady-state

Advancing the clinical development of AMT-130 for Huntington’s Disease

• Initiated dosing in 2nd, higher dose cohort of U.S. Phase 1/2 study

• CTA approval in the UK for EU Phase 1/2 study; Germany and Poland expected in Q3 2021

Expanding the research pipeline & enabling tool platforms

• New enabling technology platforms, including goQURE and AbQURE

• Unveiling of 4 new product candidates

• Updates on Fabry and SCA3 programs

Building-out the future of our manufacturing capabilities

• Construction of new cGMP manufacturing capabilities in Amst, NL and pilot plant in Lex, MA

What’s new in today’s meeting


Today’s featured speakers

Dr. Ricardo DolmetchPresident, R&D

Dr. David Cooper

Vice President,

Clinical Development

Dr. Melvin Evers

Vice President,

Research

Dr. Astrid

Valles-Sanchez

Assoc. Director,

Adult Neurology

Dr. Ying-Poi Liu

Assoc. Director,

Adult Neurology

Dr. Paula Miranda

Sr. Scientist, Liver


R&D Visionand Strategy

Ricardo Dolmetsch, Ph.D.PRESIDENT, RESEARCH & DEVELOPMENT

Jesse

Huntington’s Disease

patient advocate


Our areas of focus

AAV Technology Engine

CNS Liver Heart and Muscle


Challenges in AAV Gene Therapy

Delivery Cargo Manufacturing

• Biodistribution

• Dosing and Redosing

• Pre-existing Antibodies

• Route of Administration

• Effective gene knock-down

• Efficient delivery of genes

• Gene replacement and editing

• Effective delivery of biologics

• Robustness and reliability

• Cost of goods

• Speed from idea to clinic

• Regulatory acceptability


Delivery platforms

Delivery QUREDose™ - Dosing through neutralizing antibodies and

re-dosing technology

Smart AAV - Antibody-mediated delivery of AAV to specific

tissues

QURE-HDL™ - High density lipoprotein-mediated delivery of

AAV to the liver


QUREDose allows precision dosing of transgenes, re-treatment of patients with partial responses,

treatment of children with growing tissues, and improved biodistribution.

QUREDose – efficient titration and redosing of AAV5

Human studies to be initiated in 2022

Dose with AAV5 Plasmapheresis Re-dose with AAV5


Smart AAV – A new generation of capsids for the CNS

Smart AAV capsids combine the advantages of AAV5 with antibody-directed delivery to get

cargo across the blood brain barrier (BBB) and to improve transduction of cells in the

CNS

Llama

AntibodySCFv introduced

into AAV CAP

(BBB) Receptor-mediated transcytosis

Cell-type specific delivery

Blood CSF


QURE-HDL – A capsid that dramatically improves liver transduction

QURE-HDL increases liver transduction fifteen-fold; extending our platform to diseases in

which we need to transduce the entire liver.

lcat_k249pon_p1

pon_p2

lcat_s108

epi2_c1477

ABCA1_ep2

ep2-c1477

ep2_s15060

5

10

15

Primary human hepatocytes (PHH)

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ld c

han

ge v

s w

tAA

V5

MOI 1E4 MOI 1E5 MOI 1E6

444 579

AAV Variant QL1 QL2 QL3 QL4 QL5 QL6 QL7 QL8

HDL

HDL-binding domain


Cargo platforms

Cargo

LinQURE™ - Multiple miRNAs delivered in a single AAV

AbQURE™ - AAV delivery of Antibodies systemically and in

the CNS

GoQURE™ - Gene replacement platform

MiQURE® - Safe and effective miRNAs delivery platform


LinQURE – Delivering multiple micro-RNAs in a single AAV

LinQURE can deliver multiple micro-RNAs in a single AAV allowing potent silencing of single

genes and silencing of multiple genes in a pathway.

PolyA signalPromoter

miRNA2

LinQURE

miRNA1

miRNA3

SNCA1

SNCA2

SNCA1

SNCA2

SNCA1

SNCA2

SNCA1

SNCA2

0.0

0.5

1.0

1.5

SNCA mRNA lowering in striatum

Primer set

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ha

ng

e

[1 =

co

ntr

ala

t.]

AAV5 - miSCR

AAV5 - miSNCA15

AAV5- miSNCA5

AAV5-miSNCA5+15

***

miRNA-A

miRNA-B

miRNA-A + B

A B A B A B A B


GoQURE – replacing a defective gene

GoQURE can simultaneously silence a disease gene and replace it with a healthy gene

Promoter

miQURETransgene PolyA

Go Stop

Transgene miQURE


AbQURE – single administration delivery of antibodies

AbQURE uses the power of AAV5 to deliver therapeutic antibodies systemically from the

liver or into the central nervous system from cells in the brain.

Ab1

Ab2

High affinity binding Efficient antibody secretionin HEK293T cells

An

tib

od

y (

µg

/ m

L)

15

10

5

0

Ab1 SP1

Ab1 SP2


Our technology platform enables our pipeline

Hemophilia B

Fabry Disease

Huntington’s Disease

Spinocerebellar Ataxia 3

Parkinson’s Disease

ALS

Alzheimer’s Disease

Liver

CNS

QUREDose Smart AAV QURE-HDL miQURE LinQURE GoQURE AbQURE

✓

✓

✓ ✓

✓

✓

✓✓

✓✓

✓ ✓

✓

✓


How do we select our targets?

We have a best-in class portfolio that maximizes opportunities and balances risk

Unmet Need

Human Validation

Addressable Population

Safety

Technical Tractability

Clinical Tractability

Differentiation

We do well

by doing

good


We are extending gene therapy to large CNS indications

Huntington’s

Disease

~100,000 patients

in US and EU

Alzheimer’s Disease

~3 million patients

with AD in US have an

APOE4 allele

Parkinson’s

Disease

~2 million patients

the US and EU

ALS (c9ORF72)

~5000 patients

the US and EU


David L. Cooper, MD MBAVP CLINICAL DEVELOPMENT

HD PROGRAM LEAD


• Autosomal dominant inherited disorder

(50% risk if your parent has HD)

• Affects ~25,000 patients each in U.S./EU

• Initially described based upon

characteristic chorea

• Dystonia, incoordination, ataxia, and later

rigidity and bradykinesia contribute to

functional impairment

• Cognitive and behavioral symptoms may

occur early

• Progressive course from onset ~age 45

to death over 10-15 years

Huntington’s disease (HD): an overview


≥ 40 CAG repeat HTT

DNA

Prolonged CAG repeat exon 1 HTT

mRNA

Expanded polyglutamine tract in protein

Protein aggregation

Neuronal degeneration

Huntington’s disease: how does neurodegeneration occur?

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.

Occipitallobe

Frontal lobe

Somatomotor cortex

Parietal lobe

1

2

33

Somatosensory cortex


AAV5-miHTT (AMT-130)

• Replication-deficient adeno-associated viral vector

serotype 5 (AAV5)

• Codes for microRNA (miRNA) that targets the HTT

mRNA at exon 1

• Blocks expression of HTT protein

AMT-130: a gene therapy approach for early manifest HD

Model Efficacy Safety Distribution

Cultured human neurons ✓ ✓

Rodents(HD rat4) (4 types HD mouse3)

✓ ✓

NHP(Non-human primate1)

✓ ✓ ✓

Pig(tgHD Minipig2)

✓ ✓ ✓

Extensive preclinical validation

One-time intracranial injection of AMT-130

into striatum (caudate nucleus and putamen)

Image reproduced from: https://www.neuroscientificallychallenged.com/blog/know-your-brain-striatum

Caudate

nucleus

Putamen

1) Samaranch L, et al. Gene Ther 2017;24:253-261; 2) Evers M, et al. Mol Ther 2017;5(Suppl. 1):247; 3) Spronck EA, et al. Hum Gene Ther 2017;28:A78; 4) Miniarikova J, et al. Gene

Therapy 2017;24:630-639; 5) Evers MM et al. Mol Ther. 2018;26(9):2163-2177; 6) Spronck EA et al. Mol Ther Methods Clin Dev. 2019 Mar 16;13:334-343; 7) Keskin S et al. Mol Ther

Methods Clin Dev. 2019 Oct 4;15:275-284; 8) Caron NS et al. Nucleic Acids Res. 2019 Nov 20. pii: gkz976. doi: 10.1093/nar/gkz976


• AMT-130 uniquely targets

full length and exon1 HTT

mRNAs

• Novel HD rodent studies

demonstrate effective

lowering of total and exon1

HTT mRNA and protein

species

Sogorb-Gonzalez et al (in preparation)

AMT-130: dose-dependent lowering of HTT exon1 in HD mice

aberrant

splicing


• Stable miHTT expression, mHTT protein lowering, and long-term baseline NFL levels

• Trend confirmed up to 36 months (topline data)

Vallès, Evers et al (Sci Transl Med, 2021)

AMT-130: longitudinal data in transgenic minipigs

pre-d

ose14d28

d3m 6m 9m12

m15

m18

m21

m24

m

0

20000

40000

60000

80000

CS

F N

F-L

(p

g/m

L) rAAV5-miHTT

Control (naive)

pre-d

ose 3m 6m 9m12m

15m

18m

21m

24m

101

102

103

104

105

106

CS

F m

iHT

T

(mo

lecu

les/m

L C

SF

)

CSF

miHTT

CSF

NF-L

brain

mHTT protein


Our approach optimizes benefit/risk tradeoff

• Focused neurosurgical delivery to most

relevant brain regions

• Not targeting 100% knock-down or entire CNS

• 50-75% maximal knock-down in striatum where

benefit/risk of knockdown is clear

• 25-50% cortical knock-down via

anterograde/retrograde transport from site of

caudate/putamen infusion

AMT-130: maximizing potential for clinical impact

Striatum

50-75% HTT

Knockdown

Cortex

25-50% HTT

Knockdown

Figure adapted from Brundin P, et al. Nat Rev Mol Cell Biol 2010;11:301-7.


• wtHTT inactivation during adulthood does not

result in any phenotype1,2

• wtHTT + mHTT results in HD

• Partial reduction of mHTT or both wtHTT/mHTT

in adulthood slows disease progression and

delay onset of HD symptoms3-8

1. Wang G, et al. Proc Natl Acad Sci U S A. 2016;113(12):3359-3364. 2. Pla P, et al. PLoS One. 2013;8(9):e73902. 3. Kordasiewicz HB, et al. Neuron. 2012;74(6):1031-1044. 4. Southwell AL, et al. Sci

Transl Med. 2018;10(461):eaar3959. 5. Boudreau RL, et al. Mol Ther. 2009;17(6):1053-1063. 6. Drouet V, et al. Ann Neurol. 2009;65(3):276-285. 7. Stanek LM, et al. Hum Gene Ther. 2014;25(5):461-

474. 8. Leavitt BR, Kordasiewicz HB, Schobel SA. Huntingtin-Lowering Therapies for Huntington Disease: A Review of the Evidence of Potential Benefits and Risks. JAMA Neurol. 2020;77(6):764–772.

AMT-130: knocking down wildtype (wtHTT) and mutant HTT (mHTT) safe and effective in adult animals

Development Adulthood

XX

or

HD

Slower

progression

to HD7-11

Unaffected5,6

wtHTT mHTT

Adapted from Leavitt et al. 2020

The partial reduction of wtHTT in normal adult rodents

and NHPs was generally safe and well tolerated12


These findings indicate that variant HTT functions normally during development and

that the polyglutamine expansion is a toxic gain-of-function variation.9

Heterozygous loss of function of HTT is well tolerated in humans

• Women with 1 normal, 1 disrupted HTT allele had no detectable abnormal phenotype at age 46; her child

with same abnormality remains asymptomatic1

Mutant HTT expansion is toxic but still functional

• Children with compound heterozygous HTT variations and likely significantly decreased HTT function show

early neurodevelopmental disorders with features of Rett-like syndrome, but not an HD phenotype. 2,3

• Adults with homozygous CAG expansion variations (2 variant alleles) have normal development until onset

of HD; age at onset and pre-onset symptoms were no similar to those with heterozygous HD (1 wtHTT, 1

variant allele); 4-7 in most cases disease course and progression were not different from heterozygous HD.8

1. Ambrose CM, et al. Somat Cell Mol Genet. 1994;20(1):27-38. 2. Lopes F, et al. J Med Genet. 2016;53(3):190-199. 3. Rodan LH, et al. Eur J Hum Genet. 2016;24(12):1826-1827 4. Wexler

NS, et al. Nature. 1987;326(6109):194-197. 5. Kremer B, et al. N Engl J Med. 1994;330 (20):1401-1406. 6. Durr A, et al. J Med Genet. 1999;36(2):172-173. 7. Squitieri F, et al. Clin Genet.

2003;64(6): 524-525. 8. Cubo E, et al; Neurology. 2019;92(18):e2101-e2108. 9. Leavitt BR, et al. JAMA Neurol. 2020;77(6):764–772.

AMT-130: is there human evidence to support safety of wtHTT lowering in adults with HD?


• Double-blind, randomized, imitation-surgery

(sham) controlled study

• 2 dose levels of AMT-130

• Cohort 1: 50%/25% striatal/cortical knockdown

• Cohort 2: 75%/50% striatal/cortical knockdown

• One-time bilateral stereotaxic neurosurgical

administration of AMT-130

• MRI-guided convection enhanced delivery

• 5-year follow-up (blinded first 12 months)

• Conducted at ~12 HD centers in the U.S.

including 3 sites performing surgery

MRI, magnetic resonance imaging

AMT-130: phase 1-2 study design

Screening visit

Baseline visit

Surgery

Periodic visits

(AMT-130 treated patients)

≤12 weeks Randomization

Day 1

Periodic visits

Do

ub

le b

linde

d

Op

en

labe

l

Post-treatment

follow-up:

12 months

Long-term

follow-up:

4 years

5 Y

ea

rs


Key inclusion criteria

• 25 to 65 years of age

• Early manifest HD

• Total functional capacity (TFC) 9-13

(stage 1 or early stage 2)

• Diagnostic Classification Level (DCL)

DCL=4 (motor manifest) or

DCL=3 (multidimensional)

• ≥40 CAG

• Putamen volume of ≥2.5 cm3 (per side) and

caudate volume of ≥2.0 cm3 (per side)

• Stable concomitant prior to screening

HD medications for ≥3 months

Key exclusion criteria

• Presence of an implanted deep brain

stimulator devices

• Relevant brain/spinal pathology

• Medical contradictions to anesthesia

• Previous gene therapy or RNA-/DNA-

targeted HD investigational agents

AMT-130: phase 1-2 initial inclusion/exclusion criteria


AMT-130: phase 1-2 proof-of-concept endpoints

*Unified Huntington’s Disease Rating Scale

Clinical Parameters*

● Total motor score

● Total functional capacity

Imaging (MRI and MRS)

● Measures of neural function

● Striatal volume (atrophy)

Biomarkers

● NF-L (neurofilament light)

● mHTT in CSF

● Other exploratory markers

Quantitative Motor Function

● Finger, hand and foot tapping

● Grasping and lifting (chorea)


• First gene therapy infusion in HD patients

• First GT with 6 infusions (3 sets of bilateral infusions)

• First convection-enhanced infusion into caudate

AMT-130: observations from surgical procedure

Neurosurgical committee representing all dosing

sites reviews all trajectory plans pre-op



Bilateral SmartFrame

Placement/Alignment

Bilateral Catheter

Placement

Convection Enhanced

MRI-guided Infusions


Real-time MRI imaging of AMT-130 allows visualization of intra-striatal delivery


R Putamen Post L Putamen PostL Caudate Head


AMT-130: a year of exceptional progress in clinical development

05 April 2021

Completion of Enrollment in First

Cohort of Phase 1-2 Clinical Trial

1 June 2021

DSMB Recommendation

on Initiating US Cohort 2

16 June 2021

First Two Cohort 2

Procedures

2020 2021

Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May June

19 June 2020

First 2 Patients in

Phase 1-2 Clinical Trial

13 October 2020

Enrollment of Next 2 Patients

in Phase 1-2 Clinical Trial

25 September 2020

DSMB Recommendation to Continue

Cohort 1 Enrollment in Phase 1-2 Study 8 February 2021

DSMB Recommendation to Continue

Cohort 1 Enrollment in Phase 1-2 Study


AMT-130: EU open-label study will augment phase 1-2 signal-detection capacity

Low-dose

AMT-130 (6 patients)

High-dose


Sham surgery(10 patients)

26 patients expected

to enroll

Crossover after DSMB/FDA

review of initial data

Low-dose


High-dose


15 patients expected

to enroll

CT-AMT-130-01 (Phase 1a/2) double-blind sham-controlled

CT-AMT-130-02 (Phase 1b/2) open-label


• Primary focus of the phase 1-2 clinical

program is demonstration of safety of

AMT-130 administration

• Patients in U.S. study will be unblinded by

groups after 12-month visits

• Efficacy/biomarker data will be analyzed

after each cohort/study is completed

• Developing natural history dataset to map

expectations for progression

• We believe that the phase 1-2 studies will

demonstrate disease modification to

inform a phase 3 program

Reilman et al Movt Dis 2014, based on Ross et al Nature Reviews Neurol 2014

AMT-130: expectations for complete phase 1-2 data

Trial Population

Early Manifest HD


• Safety and tolerability

• Chemistry biomarkers from CSF and blood serum

• NfL – compared to baseline and control

• mHTT in CSF – compared to baseline and control

• Markers for inflammation and immunogenicity

• Volumetric MRI Imaging

• Volume compared to baseline, control and natural history

• Functional MRS Imaging

• Measurement of neuronal function compared to baseline and control

AMT-130: preliminary data on first 4 randomized patients

Subject 1&2

1:1

randomization

1 dosed

1 control

Subject 3&4

1:1

randomization

1 dosed

1 control


Questionand AnswerSession


Timefor a coffee break


Expanding the Research Pipeline


SpinocerebellarAtaxia 3(ataxin-3)

Melvin Evers, Ph.D.VICE PRESIDENT, RESEARCH


Autosomal dominant disorder

• Spinocerebellar ataxia type 3 (SCA3) is the

most common SCA

• Prevalence is 1-2:100,000 total population;

~7000 patients in the US and Europe

• Average onset 37 years

Symptoms

• Ataxia

• Dystonia/Rigidity

• Muscular atrophy

• Paralysis

• Median survival 20 years after diagnosisStop MJD Inc.

Spinocerebellar Ataxia Type 3 (SCA3)


SCA3: mutant ataxin-3 protein forms toxic aggregates leading to neurodegeneration

Eichler L et al. Am J Neuroradiol (2011)

CAG repeat

polyQ repeat

ATXN3 mRNA

Mutant

ataxin-3 protein

Toxic ataxin-3

protein aggregation

Neurodegeneration

Spinal cord

Cerebellum

Brainstem

Brain stem

Cerebellum

SCA3 Healthy control


AMT-150: AAV5-microRNA against ATXN3 to lower toxic ataxin-3 protein

CAG repeat

miQURE®

ITR

polyA

ITR

Pol II promoter

miQURE®

miQURE®

polyQ repeat

Reduction of toxic ataxin-3 protein

ATXN3 mRNA

Degradation of ATXN3 mRNA


AMT-150: prevention of neuropathology in LV-SCA3 mouse brain

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AMT-150

AMT-150

AMT-150 AMT-150 AMT-150


• Transgenic SCA3 mice with highest brainstem

transduction show partial SCA3 phenotype

improvement

Martier R., et al., Mol Ther Methods Clin Dev. 2019 Oct 28;15:343-358. University of Michigan Health System Department of Neurology

AMT-150: functional improvement in transgenic SCA3 mice after high dose cisterna magna delivery

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tro

l

65%

Contr

ol

AAV5-

miA

TXN3

0

25

50

75

100

Cerebellum

Mu

tan

t a

tax

in-3

pro

tein

(%

)R

ela

tiv

e t

o c

on

tro

l

53%

7 10 15 20 25 30 35

0

1000

2000

3000

4000

weeks

To

tal L

oco

mo

tor

Acti

vit

y

8wk Injection (Cisterna Magna)

Veh WT

Veh Q84/Q84

AMT-150

AMT-150


Fronta

l lobe

Tempora

l lobe

Parie

tal l

obe

Occ

ipita

l lobe

Stria

tum

Hip

pocam

pus

Pons dors

al 1

Pons dors

al 2

Pons ve

ntral

DCN

Cer

ebel

lar co

rtex

Cer

vica

l SC

Thoraci

c SC

Lumbar

SC

100

101

102

103

104

105

106

107

AM

T-1

50 v

DN

A

(gc

/µg

DN

A)

Low

HighCortex Midbrain Brainstem Cerebellum

LLOD

Spinal Cord

AMT-150: cerebrospinal fluid delivery results in dose-dependent transduction non-human primate brain

AMT-150

CerebellumBrainstem

Spinal cord


• AMT-150 lowers ataxin-3 mRNA and protein in SCA3 patient-derived neurons

• AMT-150 reduces neuropathology in LV-SCA3 mouse brain and causes

functional improvement in SCA3 mice after cisterna magna administration

• Cerebrospinal fluid delivery of AMT-150 results in transduction of the brain

stem, spinal cord, and cerebellum in non-human primates

• IND-enabling studies in non-human primates are ongoing

AMT-150: summary


Next key

program

milestones

in SCA-3:

GLP TOX

study ongoing

in non-human

primates

IND filing

and start

of clinical

development

AMT-150: next key program milestones

Pre-IND

meeting


Fabry Disease(α-galactosidase A)

Paula Miranda, Ph.D.SENIOR SCIENTIST, RESEARCH


X-linked genetic disorder

• Deficiency of α-galactosidase A (GLA)

• Prevalence: 1:3,700 – 80,000 live births*

• Population: ~15,000 in US and Europe

Symptoms

• Fatigue and hearing loss

• Neuropathic pain

• Angiokeratomas

• Corneal opacity

• Cardiac disease

• Renal failure

• Stroke risk

* Spada, et al, Am. J. Hum. Gent. 2006:79, 31-40

Fabry disease: a lysosomal storage disease (LSD)


α-galactosidase A (GLA) degrades

• Globotriaosylceramide (Gb3)

• Lyso-Gb3

Systemic accumulation of substrate in lysosomes

of endothelial cells in the kidney and heart

Standard of care is bi-weekly enzyme

replacement therapy

• Limited tissue penetration and biodistribution

• Poor cross-correction hampers substrate clearance

• Disease progresses despite current treatment

Desnick and Schuchman Annu. Rev. Genomics Hum. Gent. 2012; 13:307-35

Fabry disease: progresses even under enzyme replacement therapy

Gb3 accumulation and inclusion

bodies in Fabry mouse kidney

Control (Glawt/Y) Fabry (Glako/Y)


AMT-191: delivers highly efficient one-time treatment

AAV

capsid

Expression

cassette

GLA

ITR

polyA

ITR

Promoter

AAV5-GLAAAV5 encoding an

α-galactosidase A (GLA) transgene

Decreased Gb3 accumulation in treated

Fabry mouse kidney

WT+

vehicle

Fabry +

vehicle

Fabry +

AAV5-GLA

cortical Gb3 medullary Gb3


• Dose-dependent and sustained GLA protein

and activity levels in plasma and in liver

• GLA activity >3000-fold increase baseline

plasma levels

• Good correlation of GLA protein and activity

in plasma

AMT-191: delivers highly efficient treatment in Fabry mice

KO Low Mid High1

10

100

1000

10000

100000

GLA activity in Fabry mouse plasma(12 weeks post-treatment)

GL

A a

cti

vit

y (

nm

ol/h

/mL

)

Vehicle AAV5-GLA

>3000-fold

Vehicle AAV5-GLA

GLA-protein in Liver

KO Low Mid High102

103

104

105

106

107

108

Vector DNA level

in Fabry mouse liver

ge

no

me

co

pie

s/μ

g D

NA

LLOQ

: below LLoQ

Vehicle AAV5-GLA

10 100 1000 10000 10000010

100

1000

10000

Log10 GLA activity

in plasma (nmol/h/mL)

Lo

g10

GL

A p

rote

in

lev

els

in

pla

sm

a (

ng

/mL

)

WT KO Low Mid High

10

100

1000

10000

100000

1000000

GLA-activity in Liver tissue

GL

A-a

cti

vit

y (

nm

ol/

h/m

g)

Vehicle AAV5-GLA

>3000-fold


Cross correction in kidney and heart:

• Higher GLA-activity levels

• Gb3 and LysoGb3 substrate reduction

• Phenotypical correction: improvement

of pain perception

AMT-191: results in kidney and heart cross-correction and phenotypical correction in Fabry mice

WT KO Mid60

80

100

120

Nociception (hot-plate)

Tim

e t

o r

eacti

on

(sec)

**

Vehicle AAV5-GLA

**

WT KO Low Mid High

0

2

4

8

10

12

14

LysoGb3 levels in Kidney

Lys

o-G

b3 (

pm

ol/m

g p

rote

in)

Vehicle AAV5-GLA

WT KO Low Mid High

0

5000

10000

15000

Gb3 levels in Kidney

Gb

3 (

pm

ol/m

g p

rote

in)

Vehicle AAV5-GLA

WT KO Low Mid High

0

250

500

1500

2000

2500

3000

Gb3 levels in Heart

Gb

3 (

pm

ol/m

g p

rote

in)

Vehicle AAV5-GLA

WT KO Low Mid High

0

2

4

6LysoGb3 levels in Heart

Gb

3 (

pm

ol/m

g p

rote

in)

Vehicle AAV5-GLA


• High and sustained plasma GLA

activity levels without anti-GLA IgG

development

• Increased GLA activity in liver and

heart cross-correction

AMT-191: highly efficient increase of GLA in non-human primates

Ctrl 1 Ctrl 2 NHP1 NHP20

100

200

300

400

500

600

Liver

GL

A-a

cti

vit

y

(nm

ol/

h/m

g p

rote

in)

AAV5-GLAControls

Ctrl 1 Ctrl 2 NHP1 NHP20

50

100

150

Heart

GL

A-a

cti

vit

y

(nm

ol/

h/m

g p

rote

in)

AAV5-GLAControls

Wk-3Wk-1 D1 D4 D8 Wk2 Wk4 Wk80

200

400

600

800

1000

GLA activity plasma

NHP GLA-treated

time

GL

A a

cti

vit

y n

mo

l/h

/mL

-20 20 40 60

0

2000

4000

6000

50000

100000

150000

Anti-GLA IgG

Days post treatment

EC

L S

ign

al

Inj

LLOD

-20 20 40 60

0

200

400

600

800

1000

anti-NAGA IgG

Days post treatment

EC

L S

ign

al

Inj

LLOD

FD5 - C7.GLA

FD6 - C7.GLA

FD7 - EF1a.GLA

FD8 - EF1a.GLA

NHP1 NHP2102

103

104

105

106

107

108

Liver DNA

DN

A liv

er

(co

pie

s/μ

g)

AAV5-GLA

14 Days

56 Days


Frequency

and accessibility

GLA activity

in plasma

Cross correction

Tolerance

Target organ

Vector

Immunogenicity profile

ERT *

Bi-weekly

Cumbersome

Fluctuating levels

Low tissue penetration

and biodistribution

Patients at risk

develop anti-GLA

Systemic

not applicable

Single-treatment

Re-dosing

High and steady

levels (>3000 fold)

Cross-correction

(Heart & Kidney)

Liver-driven

expression may

lead to tolerization

Liver

Low

Single-treatment

+

+

Liver-driven

expression may


Liver

Medium/High

Single-treatment

+/-

+/-

Potential risk

Heart

unknown

Cumbersome

+

+/-

Potential risk

-

not applicable

Promoter not applicableStrong liver-promoter

(proprietary) Liver-promoter

Ubiquitous

(variable expression)-

Enzyme

Replacement

Therapy

AAV5-GLAAAV8-mediated

Liver-directed

AAV-mediated

cardiac tropismPatient derived stem

cells (lentiviral)

Single-treatment

+

+

Liver-driven

expression may


Liver

High

(immunosuppression in NHP)

Liver-promoter

AAV2/6-mediated

Liver-directed

AMT-191: therapeutic landscape in Fabry Disease


• AMT-191 shows high and sustained GLA protein and activity levels

in the plasma of small and large animal models

• AMT-191 results in phenotypic correction in Fabry mouse models

• Expression of AMT-191 in the liver results in GLA activity in

kidney and heart in mice and non-human primates

AMT-191: summary


AMT-191: key program milestones

Next key

program

milestones

in Fabry

disease:

Begin GLP

toxicology study

ongoing in non-

human primates

in 2022

IND filing

in 2023


Parkinson’s Disease (Alpha-Synuclein)

Astrid Vallès-Sánchez, Ph.D.ASSOCIATE DIRECTOR, ADULT NEUROLOGY


Polygenic neurodegenerative disorder

• Second most common after Alzheimer’s disease

• 0.5-1% (65–69 years), rising to 1-3% (>80 years of age)

Symptoms

• Bradykinesia accompanied with resting tremor or rigidity

• Next to motor deficits, very debilitating non-motor

symptoms

• rogressive deterioration and severe impact on patient’s

and caregiver’s quality of life

No disease-modifying therapies

Familial PD (5-20%): mutations in PARK-family genes

• PARK1: SNCA gene (encoding α-synuclein)

• Mutations (SNPs), duplications or triplications of SNCA

lead to early disease onset

• a-synuclein pathology: familial and sporadic PD

Kouli et al, I : arkinson’s Disease: athogenesis and Clinical Aspects (20 ) | Agamanolis, Neuropathology (2011) | Goedert et al, Nat Rev Neurol (2013)

Parkinson’s disease (PD)

tremor

rigidity

bradykinesia

postural disturbance

loss of smell

autonomic dysfunction

pain

fatigue

sleep disturbances

cognitive disturbances

psychiatric disturbances

speech


α-synuclein

• Localized in presynaptic terminals

• Axonal transport and neurotransmitter release

α-synuclein pathology

• Misfolded and aggregated α-synuclein leads to toxicity

• Aggregated α-synuclein is the main component of

Lewy bodies

• Hallmark of PD and of other α-synucleopathies

(multiple system atrophy, Lewy body dementia)

• Prion-like spreading of α-synuclein aggregates

Increased extent of neuropathology with disease

progression

• Neurodegeneration affects dopaminergic circuits and

other neurotransmitter systems

• Lewy body pathology: Brainstem > Midbrain > Cortex

Kouli et al, I : arkinson’s Disease: athogenesis and Clinical Aspects (20 ) | Agamanolis, Neuropathology (2011) | Goedert et al, Nat Rev Neurol (2013)

α-synuclein aggregation as a hallmark of neurodegeneration


AMT-210:our proposed approaches to reduce a-synuclein toxicity

Complementary

Approaches

1.SNCA miQURE® and

LinQURE to reduce

production of mRNA/protein

2.AbQURE to reduce

extracellular α-synuclein

3.Combination using

GoQURE

miQURE® AbQURE


Main design criteria:

• Goal: safety and general applicability to

broad PD population

• Target all four SNCA transcripts

• No targeting of SNCB or SNCG

• Avoidance of common SNPs

Criteria in vitro lead candidate selection:

• Correct processing and no saturation of

RNAi machinery

• Endogenous mRNA and protein lowering

• Lack of off-target effects

AMT-210: miQURE lead candidate selection


• Processing: major miSNCA isoforms determined for top candidates

• Expression levels well within endogenous miRNA levels

• Efficient mRNA and protein lowering

AMT-210: miSNCA processing and expression leads to efficient SNCA mRNA and α-synuclein protein lowering

0 10 20 30 40

24bp

23bp

25bp

miSNCA A

Perc

en

t to

to

tal m

iSN

CA

A (

%)

Control A B C

0.0

0.5

1.0

1.5SNCA mRNA

SN

CA

exp

ressio

n

miSNCA candidates

Control A B C

0

100

200

300

400Total -synuclein

HT

RF

ra

tio

/ug

to

tal p

rote

in

miSNCA candidates

AAV-miSNCA dose AAV-miSNCA dose


• Demonstrated target engagement in A53T SNCA KI rats

• Combining candidates show synergistic effect, supporting LinQURE approach

• Rescue of motor phenotype in C. elegans α-synuclein model

AMT-210: initial experiments support in vivo target engagement and phenotypic rescue

SNCA1

SNCA2

SNCA1

SNCA2

SNCA1

SNCA2

SNCA1

SNCA2

0.0

0.5

1.0

1.5

Primer set

Fo

ld c

ha

ng

e

[1 =

co

ntr

ala

t.] Control miQURE

AAV-miSNCA B

AAV-miSNCA A

AAV-miSNCA A+B

Motor phenotype rescue in C. elegans

D1 D4 D8

0

100

200

300

400

Days of adulthood

Sp

ee

d (

μm

/s)

dsSNCA

miSNCA A

miSNCA B*** ***

******

*** *** ****** ***

Empty-control

SNCA mRNA lowering in A53T KI rats


Ab1

Ab2

High affinity

α-synuclein binding Efficient antibody secretionin HEK293T cells

Antib

ody (

µg /

mL)

15

10

5

0

Ab1 SP1

Ab1 SP2

• Good α-synuclein binding of selected

antibodies

• Efficient secretion in vitro

AMT-210: reduction of α-synuclein pathological spreading via vectorized anti-α-synuclein human antibodies

AbQURE


• We propose two complementary approaches to reduce pathological

α-synuclein expression and spread in arkinson’s disease

• miQURE and LinQURE lead candidates are correctly processed

and expressed in vitro and lead to dose-dependent α-synuclein

mRNA and protein lowering

• in vitro testing of AbQURE candidates show high α-synuclein

binding and efficient secretion

• Studies in in vivo PD models show target engagement and

phenotypic correction

AMT-210: summary



Begin GLP

toxicology

study in

non-human

primates

Proof-of-

concept studies

in Parkinson’s

disease rodent

models

IND filingNext key

program

milestones in

Parkinson’s

disease:


AmytrophicLateral Sclerosis(C9ORF72)

Ying Poi Liu, Ph.D.ASSOCIATE DIRECTOR, ADULT NEUROLOGY


Autosomal dominant disorder

• Age of onset 40 – 60

• Median survival from diagnosis 20 - 48 months

• 5000 new ALS patients/year in US and Europe;

incidence is 2 per 100,000 people

• Familial ALS cases ~10%, with C9orf72 mutation ~1/3

Symptoms

• Muscle weakness, atrophy and spasms

• Language dysfunction

• Swallowing problems

• Neuropathic pain

• Paralysis

• Respiratory failure

Arora and Khan, 2020 - Treasure Island (FL): Motor Neuron Disease. StatPearls Publishing, Chio et al., 2009 -

Amyotroph Lateral Scler. Oct-Dec;10(5-6):310-23, Yun and Ha, 2020 - Int J Mol Sci. Jun; 21(11): 3801

Amyotrophic lateral sclerosis (ALS)


• G4C2 repeat expansion in C9orf72 gene:

• RNA toxic gain-of-function

• Production of toxic dipeptides

• Degeneration of upper and

lower motor neurons

• Target brain regions: spinal cord,

brainstem and motor cortex

Amyotrophic lateral sclerosis: dual mechanisms of C9orf72 pathology

Exon 1a 1b

ATG

GGGGCC(n)

C9orf72 gene

MUTATION

RNA toxicity

sense RNA

antisense RNA

Dipeptide protein toxicity

sense mRNA

antisense mRNA

dipeptide proteins

ER stress

RNA foci


AMT-161: AAV5-miQURE targets RNA toxicity in C9orf72 pathology

AAV

capsid

Expression

cassette

miRNA

ITR

polyA

ITR

Promoter

miQURE technology

AAV encoding an artificial miRNA

to silence C9orf72 mRNA

sense RNA

antisense RNAsense mRNA

antisense mRNA

dipeptide proteins

miRNA expression

Degradation only of RNA from mutant allele

Reduction of RNA foci

and dipeptide proteins

dipeptide proteinsRNA foci


C

T

L

# 1# 2

AMT-161: cerebrospinal fluid delivery results in widespread cortical and spinal distribution in non-human primates

Vector DNA distribution miRNA expression Correlation miRNA vs vector DNA

# 1# 2

r=0.9277

p≤0.01


Cortex Striatum0

50

100

150

RN

A le

vels

(%

to

GF

P)

Intronic C9orf72 mRNA

*****

** AAV5-GFP

AAV5-miC32AAV5-miC46

Cortex Striatum10 -1

100

101

102

103

104

105

miC

levels

(to

GF

P)

miQURE expressionAAV5-GFP

AAV5-miC32

AAV5-miC46

GFP miC32 miC460

10

20

30

RNA foci (cortex)

To

tal %

of

cells (

>5 f

oci)

**

**

AMT-161: C9orf72 mRNA and RNA foci lowering in transgenic mice injected with AAV5-miQURE


100

101

102

103

104

105

miC

levels

(to

GF

P)

miQURE expression

AAV5-GFP

AAV5-miC32

AAV5-miC46


100

101

102

103

104

105

miC

levels

(to

GF

P)

miQURE expression

AAV5-GFP

AAV5-miC32

AAV5-miC46


• AMT-161 targets the mutant allele of C9orf72

• Cerebrospinal fluid delivery of AMT-161 results in widespread

cortical and spinal distribution in non-human primates

• Administration of AMT-161 results in lowering of C9orf72 mRNA

and reduction in RNA foci in a transgenic mouse model

AMT-161: summary



Begin GLP

toxicology

study in

non-human

primates

Proof-of-

concept studies

in disease

models in 2022

IND filingNext key

program

milestones

in ALS:


Autosomal Dominant Alzheimer’s Disease (ApoE)

Ricardo Dolmetsch, Ph.D.PRESIDENT, RESEARCH & DEVELOPMENT


Polygenic neurodegenerative disorder

• 5-6 million patients; >10 million patients within ten years

• APOE4 highest genetic risk for late-onset AD

• 40% of patients with AD have the ε4 allele,

• ~25% of these patients (10% of all AD) are homozygous

for ε4

• ~1.1 trillion-dollar cost in 2050

Symptoms

• Gradual loss of memory, judgement, and ability to function

Current treatment

• Aducanumab reduces amyloid burden and is associated

with a small change in the rate of decline in some patients

• Symptomatic therapies like AchE inhibitors are modestly

useful

Alzheimer’s disease

Auguste Deter

The first person diagnosed with

Alzheimer’s disease (1901)

Healthy Alzheimer’s

Pathological hallmarks

• Accumulation of amyloid plaques and neurofibrillary

tangles (NFT)

• Brain atrophy starting with hippocampus associated

with both synaptic and neuronal lossModified from National Institutes of Health Public domain, unknown author


Human Apolipoprotein E (APOE)

• Key regulator of cholesterol transport and metabolism in the

liver and the brain

• Binds to cell surface receptors (LDLR, VLDLR, LRP1, HSPG)

• APOE genotype impacts protein structure, lipid binding and

receptor interaction

APOE variants affect Alzheimer’s disease differently

• ε4 → increases probability of AD

• ε2 → protective variant

• ε3* variants are protective and prevents formation of NFT and

cognitive decline despite other disease-causing mutations

Raman et al., 2020

APOE4 accelerates multiple pathways

APOE4 accelerates multiple pathways


Alzheimer’s disease strategy: GoQURE - silence toxic APOE and overexpress a protective APOE variant

GoQURE approach

Expression

cassette

AAV

capsid

Expression

cassette

ITR

polyA

ITR

Promoter miQUREAPOE

Reduce toxic APOE: miQURE®

+

Expression of protective APOE variant


Alzheimer’s disease: key program milestones

Lead

selection

in 2022

Begin GLP

toxicology

study in

non-human

primates

Proof-of-

concept studies

in disease

models in 2022

IND filingNext key

program

milestones in

Alzheimer’s:


Temporal Lobe Epilepsy


acquisition of Corlieve Therapeutics

uniQure acquires Corlieve and advances its gene therapy to treat

Temporal Lobe Epilepsy (TLE), a large indication with high unmet need

• Highly compelling and strategic transaction:

• Expands uniQure’s pipeline of transformational gene therapies

• Strengthen’s uniQure’s global leadership in miRNA silencing technology

• Targets 1.3 million people with TLE, of which up to 800,000 are drug-resistant

• Targets kainate receptors which play a critical role in TLE

• Preclinical proof-of-concept demonstrating clear suppression of epileptic seizures

• Clear development path with a rapid proof of concept

• Diversifies our platform to include HEK293 mammalian cell manufacturing

• Upfront cash payment of €46.3 million:

• €43.7 million of development milestones through hase /2

• € 0 million of milestones associated with hase 3 development and regulatory approvals


refractory temporal lobe epilepsy (TLE)

• TLE is the most common type of focal epilepsy

• TLE is associated with damage to the temporal

lobe and hyperexcitability of the hippocampus

• It’s often caused by brain injury, tumors or a

prolonged febrile seizure

• TLE affects approximately 1.3 million people in the

U.S. and Europe; ~400,000 patients are

inadequately treated

• Refractory TLE patients have a poor quality of life

and a reduced lifespan

• The standard of care is lobectomy or laser tissue

ablation but only 1-2% of eligible patients

undergo surgery


kainate receptors are implicated in TLE

• Kainate receptors are excitatory glutamate

receptors that are epileptogenic and

believed to be aberrantly expressed in

the hippocampus of refractory TLE

patients

• They drive seizures through recurrent

excitation

• Kainate receptor knock-out mice are

resistant to epilepsy in a pilocarpine TLE

model

Epileptic Condition

CA3

Dentate gyrus

Mossy fibersCA1

Schaffercollaterals

Perforantpathway

rMF

+ectopic KAreceptors

Seizures

AMPAreceptors

0

15

10

*

5

KainateR KOWT

Peret et al 2014


• AMT-260 is an AAV gene therapy that

delivers an engineered miRNA

targeting kainate receptors

• AMT-260 & AMT-261* dramatically

reduce seizures in a pilocarpine

seizure rodent model

• AMT-260 reduces seizures in human

brain slices from patients with

refractory TLE

AMT-260 reduces seizures in preclinical models of TLE

0

10

20

30

40

# S

eiz

ure

/ d

ay

Control AMT260 AMT261

* *

332690 332700 332710 332720 332730 332740 332750 332760 332770 332780 332790 332800 332810 332820 332830 332840 332850 332860 332870 332880 332890 332900 332910

-120

-100

-80

-60

-40

-20

0

20

40

60

80

100

203800 203810 203820 203830 203840 203850 203860 203870 203880 203890 203900 203910 203920 203930 203940 203950 203960 203970 203980 203990 204000 204010-150

-100

-50

0

50

100

150

20 µV

+ Control vector

+ AMT260

Mouse

TLE model

Resected

human

brain slices

*variant of AMT-260



Next key

program

milestones

in Temporal

Lobe Epilepsy:

GLP TOX

study ongoing

in non-human

primates

IND filing

and start

of clinical

development

Pre-IND

meeting


HOPE-B52-WeekAnalysis

David L. Cooper, M.D., MBAVP CLINICAL DEVELOPMENT

HEMOPHILIA B PROGRAM LEAD


Key inclusion criteria

• ale adults ≥ years

• FI activity ≤2% of normal

• Continuous prophylaxis for ≥2 months

Key exclusion criteria

• Factors that might affect the evaluation of

AMT-061 efficacy or safety

• FIX inhibitors

• Active hepatitis B/C infection

• Uncontrolled HIV infection

Pre-existing anti-AAV5 NAbs were assessed,

but not used as an exclusion criteria

No prophylactic immunosuppression

HIV, human immunodeficiency virus; NAbs, neutralizing antibodies; wks, weeks.

HOPE-B pivotal trial: study design

~ 4 wks

~ 4 wks

Long-term

follow-upEvery 6 months

Post-treatment

follow upMonthly visits

Weekly visits

Dosing visitSingle dose of AMT-061 2×1013

gc/kg

Lead-in phase

(≥ 26 weeks)

Visits every 2 months, phone calls

on alternating months

Week 1

Week 12

Month 12

Screening visit

Month 60

Month 18


FDA recently provided feedback on the statistical analysis plan

• Single primary efficacy endpoint instead of co-primary endpoints

• Annualized bleeding rate (ABR) should be primary measure of efficacy for gene therapies

• ABR should be assessed after all subjects have stable Factor IX (FIX) expression

• Analysis should count all bleeds reported by patient, not investigator adjudicated new and true

bleeding events

Primary endpoint

• 52-week ABR after stable FIX expression has been achieved, compared to ABR in lead-in period

• ABR will be measured from week 26 to week 78 after infusion

Secondary endpoints

• FIX activity at 6, 12 and 18 months after dosing

• Rates of total, spontaneous, traumatic, and FIX treated/untreated bleeds

• FIX consumption compared with lead in period

• Correlation of FIX activity levels with pre-existing anti-AAV5 neutralizing antibody titers

• Safety

HOPE-B study endpoints modified per FDA feedback


54 subjects were dosed and completed 26-weeks of follow-up

aOr equivalent scan (magnetic resonance elastography, shear wave elastography).bFAS, full analysis set includes subjects who enrolled, entered the lead-in phase, were dosed with AMT-0 and provided ≥ efficacy endpoint assessment.cPer-Protocol population (N = 53), which included all subjects from the FAS who adhered to a stable and adequate prophylaxis use during the lead-in phase,

completed assessments through the 6-month visit, and had no major protocol deviations that impacted the interpretation of efficacy

HOPE-B pivotal trial: subject disposition

75 subjects screened

13 subjects discontinued

prior to dosing

54 subjects dosed

(FAS population)b,c

8 screen failures 67 entered lead-in phase


HOPE-B pivotal trial: baseline demographics

Full analysis set

(N = 54)

Age, years

Mean (Standard deviation)

Range (min-max)

41.5 (15.8)

19-75

Severity of hemophilia B at time of diagnosis, n (%)

Severe (FIX <1%)

oderately severe (FI ≥ % and ≤2%)

44 (81.5)

10 (18.5)

Pre-screening FIX treatment (n, %)

Extended half-life

Standard half-life

31 (57.4)

23 (42.6)

Pre-existing anti-AAV Neutralizing Antibodies (NABs, n (%) 23 (42.6)


FIX activity increased to a mean of 39.0%

at month 6

• Change from baseline +37.8%

FIX activity maintained at a mean of 41.5%

at month 12

• Change from baseline +40.3%

aUncontaminated central laboratory data (the visit did not occur within 10 days of exogeneous FIX use). FIX levels beginning with the Week 3 assessment were used

in the analysis. Subjects with 0 uncontaminated central-laboratory post-AMT-061 values had change from baseline assigned to zero for this analysis and had their

post-baseline values set equal to their baseline value. aseline factor I was imputed based on subject’s historical hemophilia severity documented on the case

record form. If the subject had documented severe factor IX deficiency (FIX plasma level < 1%), their baseline factor IX activity level is imputed as 1%. If the subject

had documented moderately severe factor I deficiency (factor I plasma level ≥ % and ≤ 2%), their baseline factor I activity level was imputed as 2%.

SD, standard deviation.

overview of FIX activity Up to 52 weeks (month 12)

3941.5

0

5

10

15

20

25

30

35

40

45

50

55

60

26-week 52-week

FIX Activity

Mild

hemophilia

Non-hemophilia

FIX levels


Analysis of all treated subjects including subject with partial dose and with NAB titer 3212

no clinically significant impact of pre-existing NABs on mean FIX activity between months 6 to 12


Sustained FIX levels were associated with significantly reduced spontaneous bleeding

during the first year of follow-up

Lead-in period includes 33.12 observed years in 54 subjects (mean 32 weeks per subject); Post-treatment period excludes the first 21 days (23 weeks per subject)

spontaneous bleeds were reduced further in the second six months after treatment

All subjects (N=54) Lead-In Months 0-6 Months 7-12

Number of Bleeds

All bleeds 136 29 26

All bleeds treated with FIX 118 15 14

Spontaneous bleeds treated with FIX 44 6 2

Traumatic bleeds treated with FIX 58 7 7

• Per FDA guidance, data shows all reported bleeds, even if adjudicated by the investigator to be non-

bleed or a continuing bleed


During post-treatment period of up to 2 years, 30 subjects (55.6%) had no bleeds,

39 subjects (72.2%) had no bleeds treated with FIX

Lead-in period includes 33.12 observed years in 54 subjects (mean 32 weeks per subject); Post-treatment period excludes the first 21 days (23 weeks per subject)

adjusted annualized bleeding rates (ABR) reduced on treatment compared with lead-in period

Adjusted Mean ABR

All subjects (N=54)

Lead-in

ABR

Year 0-1

ABR

%

ReductionP-value

All bleeds 3.98 1.33 66.6% p<0.0001

All bleeds treated with FIX 3.39 0.68 79.9% p<0.0001

Spontaneous bleeds treated with FIX 1.16 0.18 84.5% p<0.0001

Traumatic bleeds treated with FIX 1.75 0.30 82.9% p<0.0001

Joint bleeds treated with FIX 1.92 0.30 84.4% p<0.0001


At 52 weeks follow-up, compared with the lead-in period

• 96% (52/54) subjects discontinued prophylaxis and remain prophylaxis-free

• 96% reduction in FIX consumption in IU/year (mean reduction of 246,537 IU/year)

• 96% reduction in FIX infusion rate per year (adjusted mean 72.5 to 3.0, p<0.001)

Analyses include two subjects who remain on prophylaxis (1 subject received a partial infusion, 1 subject FIX expression remained <2%).

IU, international unit

substantial reductions in FIX replacement and use of prophylaxis when compared with lead-in


• 53 subjects had 408 AEs

• 39 subjects had 91 treatment related AEs

• 9 subjects received steroid treatment for

transaminase elevations

• All discontinued steroid use prior to Week 26

• FIX activity preserved in the mild range (8%-

39%)

• 7 subjects had infusion related reactions*

• Infusion discontinued in 1 (received ~10% dose)

• Infusion completed successfully in remaining 6

• No inhibitors were reported

• No statistical relationship between safety

and pre-existing NAbs was observed

*Infusion reactions include events reported on the day of dosing as probably or possibly related to treatment

post-treatment adverse events

AE, preferred term

N = 54

n (%)

At least one related incident AEa 39 (72.2)

Alanine aminotransferase (ALT) increased 9 (16.7)

Headache 8 (14.8)

Influenza like illness 7 (13.0)

Aspartate aminotransferase (AST) increased 5 (9.3)

Fatigue 4 (7.4)

Blood creatine phosphokinase (CPK) increased 4 (7.4)

Nausea 4 (7.4)

Dizziness 4 (7.4)

Infusion-related reactions 3 (5.6)

Arthralgia 3 (5.6)

Treatment-related AEs with an

incidence ≥5% post treatment


• Mean FIX activity significantly increased to near-normal levels at 26 weeks post-

etranacogene dezaparvovec, and was maintained at near-normal levels at 52 weeks

• The majority of subjects did not report bleeding after treatment

• Significant reductions in bleeding and improvement in ABR compared to routine

prophylaxis

• 96% of subjects were able to discontinue prophylaxis

• 96% reduction in FIX use and infusions

• Most common safety findings were transaminase elevations requiring steroid treatment

and infusion-related reactions, supporting positive benefit/risk of treatment

• Based upon recent FDA feedback on the statistical analysis plans, final analysis is now

planned at 18 months to support marketing authorization applications

conclusions


Matt KapustaCHIEF EXECUTIVE OFFICER

Rob June 22, 2021 1

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