Investor and Analyst Breakfast - uniQure IR Breakfast Presentatio… · This presentation contains...

Investor and Analyst Breakfast

American Society for Gene & Cell Therapy

Annual Meeting

Washington, D.C.

May 12, 2017

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 press

release. 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, product commercialization

and intellectual property claims, as well as the risks, uncertainties and other factors described under the

heading “Risk Factors” in uniQure’s 2016 Annual Report on Form 10-K filed with the Securities and

Exchange Commission on March 15, 2017. 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.

M A Y 1 2 , 2 0 1 7 | 4

• Welcome Matt KapustaChief Executive Officer

• Scientific Overview Harald Petry, Ph.D.Chief Scientific Officer

• AAV5-miHTT gene therapy for Huntington’s

Disease

Pavlina Konstantinova, Ph.D.Director, New Therapeutic Target Discovery

• Neutralizing antibodies on efficacy of AAV

delivery

Harald Petry, Ph.D.Chief Scientific Officer

• Repeated gene delivery in NHP with AAV5

through immune adsorption

Valerie Sier-Ferreira, Ph.D.Head of Immunology

• Detection of AAV vector DNA and transgene

RNA in liver tissue by FISH

Valerie Sier-Ferreira, Ph.D.Head of Immunology

• Questions and Discussion Group

M A Y 1 2 , 2 0 1 7 | 5

• Circulating Anti-AAV5 Neutralizing Antibody Titers up to 1:1031 Do Not Affect Liver

Transduction Efficacy of AAV5 Vectors in Non-Human Primates (Poster 198).

• Successful Repeated Hepatic Gene Delivery in Non-Human Primates Achieved with

AAV5 by Use of Immune Adsorption (Poster 395).

• AAV5-miHTT Gene Therapy Demonstrates Broad Vector Distribution and Strong

Mutant Huntingtin Lowering in a Huntington’s Disease Minipig Model. (oral

presentation)

• Detection of AAV Vector DNA and Transgene RNA in Liver Tissue by Fluorescent In

Situ Hybridization (Poster 567).

• Novel AAV Vector Reservoirs: peripheral Blood Cells and Hematopoietic Progenitors.

(collaborator presentation)

AAV5-miHTT gene therapy for

Huntington’s Disease

Pavlina Konstantinova, Ph.D.

Director, New Therapeutic Target Discovery

M A Y 1 2 , 2 0 1 7 | 7

≥ 40 CAG repeat HTT DNA

Prolonged CAG repeat exon 1 HTT mRNA

Expanded polyglutamine (polyQ) tract

Protein aggregation

Neuronal degeneration

• Neurodegenerative disorder

• Autosomal dominantly inherited

• Prevalence: 1:10,000-30,000

• Age of onset around midlife

• Symptoms:

• Motor problems/chorea

• Cognitive decline

• Psychiatric disturbances

• Genetic testing available

• Only palliative treatment

TRACK-HD

Sagittal MRI

co

ntr

ol

Ea

rly H

D

M A Y 1 2 , 2 0 1 7 | 8

≥ 40 CAG repeat HTT DNA

Prolonged CAG repeat exon 1 HTT mRNA

Expanded polyglutamine (polyQ) tract

Protein aggregation

Neuronal degeneration

• Neurodegenerative disorder

• Autosomal dominantly inherited

• Prevalence: 1:10,000-30,000

• Age of onset around midlife

• Symptoms:

• Motor problems/chorea

• Cognitive decline

• Psychiatric disturbances

• Genetic testing available

• Only palliative treatment

TRACK-HD

Sagittal MRI

co

ntr

ol

Ea

rly H

D

M A Y 1 2 , 2 0 1 7 | 9Adapted from Ross et al., Nat. Rev. Neurol. 10, 204-2016 (2014)

fu

nction (

%)

Age

presymptomatic prodromal early moderate advanced

1 2 3 4 5

Motor diagnosis

PremanifestAMT-130

slowdown

disease

progression

Manifest

45

100

0

6525

M A Y 1 2 , 2 0 1 7 | 10

ITR

polyACAG promotor

miHTT-451

ITR

AAV5-miHTT (AMT-130):

• Replication deficient

• Adeno-associated virus, serotype 5

• Designed to deliver engineered miHTT

• Reduction of huntingtin expression

• Low potential off-target effects

M A Y 1 2 , 2 0 1 7 | 11Miniarikova et al., Molecular Therapy NA 2016, Samaranch et al., Gene Therapy 2017

mu

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Control AAV5-GFP injection

Striatum

gc/mouse

AAV5-miHTT

Cortex

gc/mouse

AAV5-miHTT

AAV5-miHTT

M A Y 1 2 , 2 0 1 7 | 12

HT

T a

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te

s

P B S +

5 % s u c r o s e

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1 02

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AAV5-miHTTPBS+ 5%sucrose

Prevention of neuronal dysfunction Suppression of mutant huntingtin aggregation

Miniarikova et al., Gene Therapy, accepted

M A Y 1 2 , 2 0 1 7 | 13Evers MM, ASGCT 2017 presentation 536

striatum

thalamus

1. PBS + 5%sucrose

2. 1x1013 gc AAV5-miHTT

3. 3x1013 gc AAV5-miHTT

striatum thalamus

GFP GFP

*

*

*

**

**

*

* *

4. 1x1013 gc AAV5-GFP:

M A Y 1 2 , 2 0 1 7 | 14

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

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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

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tu

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vector DNA microRNA

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

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M A Y 1 2 , 2 0 1 7 | 15


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M A Y 1 2 , 2 0 1 7 | 16

• Dose-dependent reduction of HTT in HD rodent and tgHD minipig models translates

in therapeutic benefit.

• Widespread vector distribution upon (MRI-guided) CED delivery in NHP and tgHD

minipigs supported selection of striatum as the target brain structure.

• Long-term expression, tolerability and efficacy supports further clinical

development of HTT-lowering gene therapy for HD with AMT-130.

M A Y 1 2 , 2 0 1 7 | 17

Effective liver-directed gene delivery,

despite the presence of neutralizing

antibodies in non-human primates

Harald Petry, Ph.D.

Chief Scientific Officer

M A Y 1 2 , 2 0 1 7 | 18

Approach:

• NAB impact on AAV5 transduction was tested in 14 NHP

• Sera of those 14 NHP all had pre-existing anti-AAV5 NAB titers ranging from 1:57 to 1:1031

• Those 14 NHP were injected intravenously with increasing doses of AAV5-hFIX:

• 5e11 gc/kg (n=3)

• 5e12 gc/kg (n=5)

• 2.5e13 gc/kg (n=3)

• 9.3e13 gc/kg (n=3)

• Transduction efficiency was assessed by measuring:

• Circulating FIX protein levels in plasma 7 days after vector infusion.

• Vector DNA in the liver 6 months after vector infusion (post mortem).

Impact of neutralizing antibodies (NAB) directed against AAV5 on

efficacy of liver directed gene delivery in non-human primates (NHP)

M A Y 1 2 , 2 0 1 7 | 19

M A Y 1 2 , 2 0 1 7 | 20

M A Y 1 2 , 2 0 1 7 | 21

• Demonstration that successful AAV5-based liver-directed gene delivery can be

achieved in NHP, despite the presence anti-AAV NAB titers up to at least 1:1031.

• Poses question whether patients with pre-existing anti-AAV5 antibodies could benefit

from AAV5-based gene therapy.

M A Y 1 2 , 2 0 1 7 | 22

Successful repeated hepatic gene delivery

in non-human primates achieved with AAV5

by use of immune adsorption

Valerie Sier-Ferreira, Ph.D.

Head of Immunology

M A Y 1 2 , 2 0 1 7 | 23

Background:

• Presence of circulating neutralizing antibodies (NABs)

against AAV vector capsids impair transduction of the

target cells and therapeutic efficacy.

Goal:

• To overcome anti-AAV pre-existing antibodies due to

exposure to wild type AAV

o To increase the number of patients eligible for the therapy

• To overcome anti-AAV antibodies raised after exposure to

AAV therapy

o To facilitate re-administration of AAV gene therapy

Approach:

• Immuno-adsorption procedure

M A Y 1 2 , 2 0 1 7 | 24

• Experimental set-up proof of concept in NHPs

• Mean Reduction levels NABs by immuno-adsorption: 11 times

M A Y 1 2 , 2 0 1 7 | 25

• SEAP and hFIX transgenes expression

o Proteins levels

o mRNAs levels

M A Y 1 2 , 2 0 1 7 | 26

• Data demonstrate that the use of an immune adsorption procedure enables

successful re-administration of an AAV5-based gene transfer in NHPs.

M A Y 1 2 , 2 0 1 7 | 27

Fluorescent in situ hybridization (FISH):A powerful method to determine DNA/RNA

distribution following AAV-based gene delivery

M A Y 1 2 , 2 0 1 7 | 28

“haat-GFP” vector DNA/RNA is visualized in green (FISH), Albumin RNA in purple (FISH), GS protein in blue (IHC)

Why FISH and IHC?

• To determine distribution

• To determine the cell specificity

• To quantify on the level of “a cell”

Following liver targeted AAV gene delivery

M A Y 1 2 , 2 0 1 7 | 29

FISH

IHC

Image analysis

(confocal microscopy,

HALO program)

M A Y 1 2 , 2 0 1 7 | 30

M A Y 1 2 , 2 0 1 7 | 31

• The combination of FISH and IHC permit to assess the physiological transduction

profile of AAV in the liver which is a valuable tool to further optimize AAV-targeting.

• To develop AAV-based gene therapies with increased efficiency and selectivity.

M A Y 1 2 , 2 0 1 7 | 32

Closing Remarks

and

Discussion

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