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

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. 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 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.

The therapeutic application of RNAi has been around for more than 18 years. Youthful duo snags a swift Nobel for Andrew Fire and Craig Mello RNA control of genes Alison Abbott Nature 443 , 488 (2006) Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 3

Mechanism of HTT degradation by miQURE TM AAV-miQURE TM : Lowering of toxic protein Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 4

What is AMT-130 and how do we deliver it? One-time intracranial administration of AMT-130 into striatum (caudate nucleus and putamen) AMT-130 is an AAV vector AAV5 capsid Expression cassette ITR ITR miRNA CAG promoter polyA 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; Catheter positioning under high resolution MRI CED, convection-enhanced delivery; MRI, magnetic resonance imaging Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 5

AMT-130: non-allele-selective mi HTT for clinical development Preclinical Safety Preclinical Efficacy Pharmacology Immunogenicity Non-allele specific Lowering of HTT Serum NAbs do not Long lasting HTT mi HTT shows efficacy protein in the striatum limit the initial intra- lowering in striatum in large and small and cortex with AMT- parenchymal brain and cortex after a transgenic animals. translates in administration. single AMT-130 More effective than improvement of administration without the allele selective neuropathology, HD- signs of toxic or approach. like behavior in animal adverse events in models. large animal models. Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 6

AMT-130: goal of treatment Motor diagnosis Premanifest Manifest 100 AMT-130 ← Function (%) Slow or halt disease progression I II III IV V 0 Presymptomatic Prodromal Early Moderate Advanced Adapted from Ross CA, et al. Nat Rev Neurol 2014;10:204-16 Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 7

Proof-of-Concept of AMT-130 gene therapy: From patient cells to large animals HD Rat 4 Non-human primate 1 4 types HD Mouse 3 tgHD Minipig 2 HD human neurons Diseased HD rodent NHP HD pigs models Efficacy Efficacy Distribution Safety Safety Efficacy Safety 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 Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 8

High and widespread vector DNA levels in the tgHD minipig brain 6-12 months after CED of AAV5-miHTT High and sustained vector DNA levels at 6 Libechov tgHD minipig: • Life-span: 12-20 years and 12 months post AMT-130 administration • Body weight: 50-140 kg Cortex Striatum 6 months • Brain weight: 90-100 g 10 8 • Per treatment group, interim sacrifices: 12 months 10 7 VG copies / µg DNA • 6 months (n=3/group) JAN18 • 12 months (n=4/group) SEP18 10 6 TBD [in-life] • >24 months (n=8/group) 10 5 10 4 LLoQ caudate 10 3 putamen 10 2 Prefrontal Somato-S/M Temporal Caudate Putamen Amygdala Thalamus Pons Cerebellum White matter MRI-guided CED Evers MM., et al. , Molecular Therapy (2018); Vallès A. et al., poster 15 Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 9

Strong reduction of human mutant HTT protein in tgHD minipig brain 12 months after CED of AAV5-miHTT mHTT protein lowering up to 75% Widespread brain mHTT lowering 6 months 12 months Cortex Striatum 125 100 (% from naive) mutant HTT 75 30% 50 50% 70% 25 0 M s m l l e n a s r a a e t e l u n / a t r a u t n S m o o m t d d l a o - P l p g o u a a e m r m a t y l b f t u a e a m e C e e h r m P r T t P A T e i o h C S W Evers MM., et al. , Molecular Therapy (2018); Vallès A. et al., poster 15 Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 10

Intracranial frontal MRI-guided CED injection of AMT-130 in large animal striatum is well tolerated • Frontal approach trajectory of infusion Non-human primate MRI-guided frontal CED • Striatum (putamen/caudate nucleus) • Multiple studies performed in a total of 80 animals (non-human primates and HD minipigs) No procedure-related neurological symptoms following infusion into the striatum Image reproduced from: https://www.neuroscientificallychallenged.com/blog/know-your-brain-striatum UniQure, data on file. CED, convection enhanced delivery; MRI, magnetic-resonance imaging Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 11

AMT-130: GLP toxicology studies in non-human primates MRI and pathology: mainly related to the neurosurgical procedure and not to AMT-130 administration • MRIs • Unremarkable in most NHPs (60%) at 6-months. • Pathology • Granulomatous inflammation at the injection sites and adjacent areas in all groups, including controls. Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 12

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 PD Disease modification Clinical outcome Pharmacokinetics Pharmacodynamics Understanding of biological mechanism Drug exposure What the drug Effects on key Therapeutic levels does to the body aspects of disease clinical benefit Slowing of symptoms miHTT levels HTT protein lowering and health improvement Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 13

Translatable biomarkers under development Membrane protein miHTT • Brain volumetry P h o s p h o l i p i d b i l a y e r • MRS neuronal dysfunction • mHTT in CSF • miRNA in CSF CSF collection and EV isolation Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 14

AMT-130: projected biomarker change Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 15

Estimation of brain volumes in early manifest HD patients Striatal volumes in healthy adults, adults with early manifest HD, and NHPs Potential anterior catheter trajectories Gill S. et al ., Poster 97 Changing treatment paradigms For scientific exchange purposes only – do not duplicate, disseminate, or distribute February 2019 | 16