Changing treatment paradigms with AMT-130, a gene therapy for HD - - PowerPoint PPT Presentation

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Changing treatment paradigms with AMT-130, a gene therapy for HD - - PowerPoint PPT Presentation

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Changing treatment paradigms with AMT-130, a gene therapy for HD Pavlina Konstantinova, PhD Sr. Director Discovery, uniQure 26 February 2019 Design by: Forward-looking Statements This presentation contains forward-looking statements.

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Pavlina Konstantinova, PhD

  • Sr. Director Discovery, uniQure

26 February 2019

Design ¡by: ¡

Changing treatment paradigms with AMT-130, a gene therapy for HD

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Forward-looking Statements

This presentation contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “should,” "will,” “would” and similar expressions. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this 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

  • ngoing 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 Quarterly Report on Form 10-Q filed on November 1, 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.

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The therapeutic application of RNAi has been around for more than 18 years.

Youthful duo snags a swift Nobel for RNA control of genes Alison Abbott Nature 443, 488 (2006) Andrew Fire and Craig Mello

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AAV-miQURETM:

Lowering of toxic protein

Mechanism of HTT degradation by miQURETM

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One-time intracranial administration of AMT-130 into striatum (caudate nucleus and putamen)

What is AMT-130 and how do we deliver it?

  • 1. Samaranch L, et al. Gene Ther 2017;24:253-261;
  • 2. Evers M, et al. Mol Ther 2017;5(Suppl. 1);247. AAV5, adeno-associated viral vector serotype;

CED, convection-enhanced delivery; MRI, magnetic resonance imaging

AAV5 capsid Expression cassette

miRNA

CAG promoter ITR polyA ITR

AMT-130 is an AAV vector Catheter positioning under high resolution MRI

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AMT-130: non-allele-selective miHTT for clinical development

Preclinical Safety Preclinical Efficacy Pharmacology Immunogenicity Long lasting HTT lowering in striatum and cortex after a single AMT-130 administration without signs of toxic or adverse events in large animal models. Lowering of HTT protein in the striatum and cortex with AMT- translates in improvement of neuropathology, HD- like behavior in animal models. Non-allele specific miHTT shows efficacy in large and small transgenic animals. More effective than the allele selective approach. Serum NAbs do not limit the initial intra- parenchymal brain administration.

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AMT-130: goal of treatment

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

Premanifest Motor diagnosis Manifest Presymptomatic Prodromal Early Moderate Advanced I II III IV V 100 ← Function (%)

Slow or halt disease progression

AMT-130

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Proof-of-Concept of AMT-130 gene therapy: From patient cells to large animals

NHP HD pigs

HD human neurons Diseased HD rodent models

Safety Efficacy Safety Efficacy Safety Efficacy Distribution

4 types HD Mouse3 tgHD Minipig2 HD Rat4

  • 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

Non-human primate1

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High and widespread vector DNA levels in the tgHD minipig brain 6-12 months after CED of AAV5-miHTT

Evers MM.,et al., Molecular Therapy (2018); Vallès A. et al., poster 15

Libechov tgHD minipig:

  • Life-span:

12-20 years

  • Body weight:

50-140 kg

  • Brain weight:

90-100 g

  • Per treatment group, interim sacrifices:
  • 6 months (n=3/group)

JAN18

  • 12 months (n=4/group)

SEP18

  • >24 months (n=8/group)

TBD [in-life]

putamen caudate MRI-guided CED

High and sustained vector DNA levels at 6 and 12 months post AMT-130 administration

Prefrontal Somato-S/M Temporal Caudate Putamen Amygdala Thalamus Pons Cerebellum White matter

102 103 104 105 106 107 108 VG copies / µg DNA

12 months 6 months

Cortex Striatum

LLoQ

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Strong reduction of human mutant HTT protein in tgHD minipig brain 12 months after CED of AAV5-miHTT

Evers MM.,et al., Molecular Therapy (2018); Vallès A. et al., poster 15

mHTT protein lowering up to 75% Widespread brain mHTT lowering

P r e f r

  • n

t a l S

  • m

a t

  • S

/ M T e m p

  • r

a l C a u d a t e P u t a m e n A m y g d a l a T h a l a m u s P

  • n

s C e r e b e l l u m W h i t e m a t t e r

25 50 75 100 125 mutant HTT (% from naive)

6 months 12 months

Cortex Striatum

30% 50% 70%

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  • Frontal approach trajectory of infusion
  • Striatum (putamen/caudate nucleus)
  • Multiple studies performed in a total
  • f 80 animals (non-human primates

and HD minipigs)

Intracranial frontal MRI-guided CED injection of AMT-130 in large animal striatum is well tolerated

UniQure, data on file. CED, convection enhanced delivery; MRI, magnetic-resonance imaging

Non-human primate MRI-guided frontal CED

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

No procedure-related neurological symptoms following infusion into the striatum

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AMT-130: GLP toxicology studies in non-human primates

  • MRIs
  • Unremarkable in most NHPs

(60%) at 6-months.

  • Pathology
  • Granulomatous inflammation at

the injection sites and adjacent areas in all groups, including controls.

MRI and pathology: mainly related to the neurosurgical procedure and not to AMT-130 administration

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The selection of translatable biomarkers for AMT-130

  • Adequate translational PK/PD biomarker (efficacy) measures are crucial to

support moving forward into clinical development

PK Pharmacokinetics PD Pharmacodynamics Disease modification Clinical outcome

Understanding of biological mechanism

Drug exposure levels What the drug does to the body Effects on key aspects of disease Therapeutic clinical benefit miHTT levels Slowing of symptoms and health improvement HTT protein lowering

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Translatable biomarkers under development

  • Brain volumetry
  • MRS neuronal dysfunction
  • mHTT in CSF
  • miRNA in CSF

CSF collection and EV isolation

miHTT

Membrane protein P h
  • s
p h
  • l
i p i d b i l a y e r
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AMT-130: projected biomarker change

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Striatal volumes in healthy adults, adults with early manifest HD, and NHPs

Estimation of brain volumes in early manifest HD patients

Gill S. et al., Poster 97

Potential anterior catheter trajectories

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MRS neuronal dysfunction is restored by AMT-130 treatment in Q175FDN mice

Mean concentration tNAA (mM)

WT control Formulation buffer 5.2X10

9

1.3X10

1 1

4.0 4.5 5.0 5.5 6.0

***

gc AMT-130 Q175FDN HTT protein

(pg/ug total protein)

F B 5 . 2 X 1

9

1 . 3 X 1

1 1

50 100 150

gc AMT-130 Striatum

HTT protein lowering in striatum tNAA MRS levels in Q175FDN mice

Leavitt B. et al., Poster 42

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15% brain transduction (striatum, cortex) causes mutant HTT protein lowering in HD pig cerebrospinal fluid

p r e d o s e 3 m o n t h s 6 m o n t h s 5 0 1 0 0 1 5 0

T i m e p o s t - i n j e c t i o n C S F m t H T T p r o t e i n ( % p r e d o s e )

3 0 % 5 0 % 7 0 %

5y old HD minipigs, at 6 mo after treatment

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AMT-130: miHTT is present up to 6 months in CSF of NHPs

  • miQURE in the CSF is a promising translatable PK biomarker

predose week 4/5 week 12/13 week 18/19 week 24/25 1×101 1×102 1×103 1×104 1×105 1×106 CSF miHTT-24nt

(molecules /mL) Group 3 (7E12 gc/brain) Group 2 (2E12 gc/brain) Group 4 (2E13 gc/brain)

Stable therapeutic expression in CSF up to 6 months post-injection

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Therapeutic spread: Transfer of therapeutic miRNAs within secreted extracellular vesicles

Sogorb-Gonzalez M. et al., Poster 7

, 1 x . 5 x 1 x 2 x 5 x , 1 x . 5 x 1 x 2 x 5 x , 1 x . 5 x 1 x 2 x 5 x 200 400 600 800 1000

miHTT detection after EV transfer

miHTT molecules/recipient cells EV-miHTT 106 MOI EV-miHTT 107 MOI EV-PBS

105 106 107 105 106 107 101 102 103 104 105 106 107

MOI AAV5-miHTT

miHTT molecules

Day 5 Day 12

miHTT secreted within EVs

LLOD
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  • AMT-130 has received orphan drug status from the

US Food and Drug Administration (FDA) and from the European Medicines Agency (EMA)

  • Investigational New Drug (IND) application cleared

from the US Food and Drug Administration (FDA) and clinical development for AMT-130 initiated

AMT-130: IND cleared

www.uniqure.com. Accessed 21 Feb 2018

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Acknowledgements

Immunology: Lukas Schwarz Sumiati Baatje Valerie Sier-Ferreira Non-clinical/Development: Erich Ehlert Jaap Twisk Jacek Lubelski Lisa Spronck Martin de Haan Scott McMillan Clinical/Medical Affairs: Daniel Leonard Eileen Sawyer Joseph J. Higgins Project Management: Gabriela Szmyd Nathalie Pech-Zwahlen Sander van Deventer

New Therapeutic Target Discovery Group

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BACK-UP slides

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Improvement of motor symptoms and extended survival Reduced clasping

High AAV5-miHTT Vehicle

v e h i c l e L o w M i d H i g h 5 1 0 1 5 2 0

C l a s p i n g t e s t

( 1 2 w e e k s o f a g e ) T i m e t o t o u c h h i n d l e g s ( s ) A A V 5 - m i H T T

Extended survival

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miQURETM: High processing precision, no saturation of RNAi mechanism and no off-target activity

miR-26a let-7a miR-21 miR-125b miR-92a miR-21 let-7f miR-199 miR-9 miR-199 let-7g miR-9 let-7i miR-103a miR-27b miHTT miR-9 miR-92b let-7c miR-125a miR-30c miR-181a miR-335 miR-23b miR-25 miR-9 miR-221 miR-30d miR-143 miR-9 miR-99a miR-26b miR-99b miR-125a miR-93 miR-199 miR-21 miR-199a miR-30a miR-100 let-7e let-7d miR-23b miR-335 miR-23a miR-214 miR-10b miR-99a miR-143 Total small RNA count 104 105 106 107 108 mature miRNA counts 1.58%

conventional miRNA

Guide strand (active) Passenger strand (off-targets) Drosha Dicer

miQURETM

Guide strand (active) No passenger Drosha

L E T M 1 R F F L A L D H 1 8 A 1 P G P E P 1 O D F 2 A D G R A 2 Z N F 5 9 6 K I F C 1 _ 1 G R F A 1 R U B C N A P O L 6 S H 3 T C 2 N R P 2 K I A A 2 2 2 C A C N A 1 C C S R N P 3 N E G R 1 S Y N C R I P S T 8 S I A 1 C A L C R L L I X 1 D D I T 4 L R E R G A D G R F 5 C O M T D 1 R G P D 4 C L D N 5 D A C H 1 Z F P M 1 H M B S A C T B 50 100 150 200

mRNA expression (%)

(Relative to formulation buffer) 107 MOI AAV5-miHTT 107 MOI AAV5-GFP BLAST siSPOTR IPA HKG

Evers MM. et al., Manuscript in preparation

no saturation RNAi mechanism no off-target activity