uniQure N.V. · NASDAQ:QURE
uniQure — Technical Presentation (May 2019)
17 slides from uniQure's technical presentation, May 1, 2019
Slide 1: Sustained mutant huntingtin lowering in Huntington disease minipigs
uniQure Sustained mutant huntingtin. in Huntington disease minip! AAV5-miHTT (AMT-130) gene
Slide 2: 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,” “poten
Slide 3: Huntington's Disease
Somatomotor Huntington’s Disease cortex Frontal Somatosensory • Autosomal dominant neurodegenerative disorder lobe cortex • Expansion of CAG trinucleotide huntingtin (HTT) exon 1 2 Parietal 3 • No disease-modifying therapies available 3 lobe • Prevalence of 60,000 to 70,000 patients in US and EU •
Slide 4: What is AMT-130 and how do we deliver it?
What is AMT-130 and how do we deliver it? AAV5-miHTT (Company name AMT-130) One-time intracranial injection of AMT-130 AAV5 into striatum (caudate nucleus and putamen) capsid Expression cassette Caudate nucleus Putamen ITR ITR miR-451-HTT CAG promoter polyA • Replication deficient AAV5 • Targeting t
Slide 5: Mechanism of Action of AMT-130
Mechanism of Action of AMT-130 miQURE® technology 1. PoI II expression Tissue specificity and regulation 2. Guide strand activity only Lower risk of off-target 3. No saturation of cellular RNAi Increased safety profile 4. Nuclear and cytoplasmic effect Increased efficacy 5. Indication of spread via
Slide 6: Proof-of-Concept of AMT-130 gene therapy
Proof-of-Concept of AMT-130 gene therapy From patient cells to large animals HD Rat4 Non-human primate1 4 types HD Mouse3 tgHD Minipig2 human neurons Diseased rodent models NHP HD pigs Efficacy Efficacy Efficacy Safety Safety Safety Distribution No off-target effects 1. Samaranch L, et al. Gene Ther
Slide 7: Assessment of AMT-130 persistence in a large brain
Assessment of AMT-130 persistence in a large brain Long-term study in tgHD minipigs 124 CAG/CAA repeat Human Truncated human HTT HTT promoter (Exon 1 to 12) Libechov minipig: Study design Life-span: 12-20 years • Treatment groups: Body weight: 50-140 kg Control (untreated) Brain weight: 90-100 g AAV
Slide 8: Assessment of AMT-130 biodistribution and efficacy
Assessment of AMT-130 biodistribution and efficacy Extensive brain dissection and bioanalysis • Brains cut in n=12 (4mm-thick) slices (4mm punches) • One hemisphere used for bioanalysis sagittal view 6 months interim sacrifice → n=54 punches (alternate slices) 12 months interim sacrifice → n=170 pun
Slide 9: VG copies / μg DNA
VG copies / μg DNA 10 2 10 3 10 4 10 5 10 6 10 7 P 10 8 re fro 2 4 10 nt 12 al 24 LLoQ 26 28 M ot 8 C or 14 in 34 36 46 gu la DELIVERING GENE THERAPY TO PATIENTS te 20 48 In 72 S su VG copies / μg DNA om la 38 r 58 78 10 2 10 3 10 4 10 5 10 6 10 7 10 8 at os 98 Pr ef ro 2 6 4 S en 10 nt so 16 al 12
Slide 10: Widespread vector DNA distribution across cortical regions
Widespread vector DNA distribution across cortical regions Cortex 10 7 12 months VG copies / μg DNA 10 6 10 5 10 4 LLoQ 10 3 al vi l ng r so sen ar m l m in te sp or l/r to ry m l ra a te nia ci oto su nt a l so ro ot po at su ul le ro et m ef pr a o m so na hi rir pe DELIVERING GENE THERAPY TO PATI
Slide 11: Vector DNA in subcortical regions
VG copies / μg DNA C 10 2 10 3 10 4 10 5 10 6 10 7 10 8 au da G 40 lo P te 60 ut 62 bu a 80 s m LLoQ A p a e n 42 c c l li 64 u m d u 66 82 Am b s 84 H e ip yg n s 44 p o da 68 c a la 100 Striatum and DELIVERING GENE THERAPY TO PATIENTS Limbic areas m 102 p u 124 s 120 144 VG copies / μg DNA T Th ha
Slide 12: Highly comparable vector DNA brain distribution
Highly comparable vector DNA brain distribution at 6 and 12 months post-administration Cortex Striatum 10 8 6 months 12 months 10 7 VG copies / μg DNA 10 6 10 5 10 4 LLoQ 10 3 10 2 Te S/M o- l us m eb s r al a Pu ate yg n C ral m n ta te Th da l e r on A me hi e llu am po at d P So fro au ta m m at
Slide 13: Expression of therapeutic miHTT
miHTT (molec/cell) P 10 0 10 1 10 2 10 3 10 4 10 5 10 -1 re fro 2 nt 4 10 12 al M 24 26 C ot 28 LLoQ i n or 8 14 gu 34 36 S la 46 t 48 o m In e 20 38 a t s u l 72 S o a r 58 78 om s e 98 6 ns at o 30 o m ry 16 32 54 74 76 ot Cortex V o r 50 52 P R e u a 88 i s e t rir l 110 90 114 116 ro h i s n a 1
Slide 14: Strong long-term lowering of mutant HTT protein in tgHD minipig brain
Strong long-term lowering of mutant HTT protein in the tgHD minipig brain, comparable at 6 and 12 months Control (untreated) AAV5-miHTT (12 months) Striatum and Mesenceph., Brainst., Cortex Limbic areas Thalamus Cerebellum 6 months ** 12 months 80 * mutant HTT (pg/μg total prot.) ** ** Cortex Striat
Slide 15: Mutant HTT protein in CSF is also lowered
Mutant HTT protein in CSF is also lowered, but does not accurately reflect mHTT lowering in brain tissue Brain mHTT lowering Increase in CSF mHTT levels with age 40% 45% → Prefrontal cortex 80% 75% → Caudate 85% 70% → Putamen from control) 400 125 45% 55% → Thalamus 400 100 Control (untreated) CSF m
Slide 16: Conclusions
Conclusions • Strong and sustained target engagement and efficacy of one-time intrastriatal administration of AMT-130 in tgHD minipigs • Significant correlation between vector DNA, miHTT and mHTT protein lowering • Highly comparable between 6 and 12 months post-administration • First time that susta
Slide 17: Acknowledgements
Acknowledgements Institute of Animal Physiology and Genetics (Czech Republic) Jiri Klima | Bozena Bohuslavova | Zdenka Ellederova | Jan Motlik CHDI (USA) Doug Macdonald | David Howland IRBM (Italy) Roberta Pintauro | Valentina Fodale | Alberto Bresciani uniQure (The Netherlands) Anouk Stam | Cynthia