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.
• Welcome Matt Kapusta Chief Executive Officer • Scientific Overview Harald Petry, Ph.D. Chief Scientific Officer • AAV5- miHTT gene therapy for Huntington’s Pavlina Konstantinova, Ph.D. Disease Director, New Therapeutic Target Discovery • Neutralizing antibodies on efficacy of AAV Harald Petry, Ph.D. delivery Chief Scientific Officer • Repeated gene delivery in NHP with AAV5 Valerie Sier-Ferreira, Ph.D. through immune adsorption Head of Immunology • Detection of AAV vector DNA and transgene Valerie Sier-Ferreira, Ph.D. Head of Immunology RNA in liver tissue by FISH • Questions and Discussion Group M A Y 1 2 , 2 0 1 7 | 4
• 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) M A Y 1 2 , 2 0 1 7 | 5
AAV5-miHTT gene therapy for Huntington’s Disease Pavlina Konstantinova, Ph.D. Director, New Therapeutic Target Discovery
• Neurodegenerative disorder ≥ 40 CAG repeat HTT DNA • Sagittal MRI Autosomal dominantly inherited • Prevalence: 1:10,000-30,000 Prolonged CAG repeat exon 1 HTT mRNA • Age of onset around midlife control • Symptoms: Expanded polyglutamine (polyQ) tract • Motor problems/chorea • Cognitive decline Protein aggregation • Psychiatric disturbances Early HD • Genetic testing available Neuronal degeneration • Only palliative treatment TRACK-HD M A Y 1 2 , 2 0 1 7 | 7
• Neurodegenerative disorder ≥ 40 CAG repeat HTT DNA • Sagittal MRI Autosomal dominantly inherited • Prevalence: 1:10,000-30,000 Prolonged CAG repeat exon 1 HTT mRNA • Age of onset around midlife control • Symptoms: Expanded polyglutamine (polyQ) tract • Motor problems/chorea • Cognitive decline Protein aggregation • Psychiatric disturbances Early HD • Genetic testing available Neuronal degeneration • Only palliative treatment TRACK-HD M A Y 1 2 , 2 0 1 7 | 8
Motor diagnosis Premanifest Manifest 100 AMT-130 function (%) slowdown disease progression 1 2 3 4 5 0 presymptomatic prodromal early moderate advanced 25 45 65 Age M A Y 1 2 , 2 0 1 7 | 9 Adapted from Ross et al., Nat . Rev. Neurol. 10, 204-2016 (2014)
ITR ITR miHTT-451 CAG promotor polyA 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 | 10
Striatum Cortex AAV5-miHTT gc/mouse gc/mouse AAV5-miHTT AAV5-miHTT S t r i a t u m C o r t e x H T T p r o t e i n l e v e l ( % ) H T T p r o t e i n l e v e l ( % ) P B S + 5 % S u c r o s e 1 0 0 1 0 0 9 5 . 2 x 1 0 g c / m o u s e 1 0 2 . 6 x 1 0 * * A A V 5 - m i H T T 1 1 * 1 . 3 x 1 0 * 5 0 5 0 * * 0 0 m u t a n t w i l d - t y p e m u t a n t w i l d - t y p e m u t a n t w i l d - t y p e m u t a n t w i l d - t y p e t e t e t e t e n n n n p p p p a a a a y y y y t t t t t t t t u u u u - - - - d d d d m m m m l l l l Control AAV5-GFP injection i i i i w w w w H T T a l l e l e H T T a l l e l e M A Y 1 2 , 2 0 1 7 | 11 Miniarikova et al., Molecular Therapy NA 2016, Samaranch et al., Gene Therapy 2017
Suppression of mutant huntingtin aggregation Prevention of neuronal dysfunction AAV5-miHTT AAV5-miHTT PBS+ 5%sucrose PBS+ 5%sucrose * * * * * * * * * * * 3 ) 2 . 0 5 1 0 D A R P P - 3 2 l e s i o n ( m m H T T a g g r e g a t e s 1 . 5 4 1 0 1 . 0 3 1 0 0 . 5 0 . 0 2 1 0 1 0 1 0 1 0 1 0 P B S + 6 . 5 x 1 0 g c 6 . 5 x 1 0 g c P B S + 6 . 5 x 1 0 g c 6 . 5 x 1 0 g c 5 % s u c r o s e A A V 5 - G F P A A V 5 - m i H T T 5 % S u c r o s e A A V 5 - G F P A A V 5 - m iH T T M A Y 1 2 , 2 0 1 7 | 12 Miniarikova et al., Gene Therapy, accepted
1x10 13 gc AAV5-GFP: 1. PBS + 5%sucrose 4. 1x10 13 gc AAV5-miHTT 2. 3x10 13 gc AAV5-miHTT 3. thalamus striatum * * striatum thalamus * * * * * * * * GFP GFP Evers MM, ASGCT 2017 presentation 536 M A Y 1 2 , 2 0 1 7 | 13
1 3 g c A A V 5 - m iH T T 1 x 1 0 1 3 g c A A V 5 - m iH T T 3 x 1 0 microRNA vector DNA 8 1 0 1 0 0 V e c t o r g e n o m e c o p i e s 7 1 0 M a t u r e m i H T T m o l e c u l e s / c e l l p e r g D N A 1 0 6 1 0 5 1 0 1 4 L L O D 1 0 3 1 0 0 . 1 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 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 M A Y 1 2 , 2 0 1 7 | 14
mutant huntingtin protein mutant HTT mRNA ( n o r m a l i z e d b y s s G A P D H , r e l a t i v e t o c o n t r o l ) m u t a n t h u n t i n g t i n p r o t e i n ( % ) h H T T m R N A e x p r e s s i o n ( % ) 1 5 0 1 5 0 * * * * * * ( r e l a t i v e t o P B S + 5 % s u c r o s e ) 1 0 0 1 0 0 * * * 5 0 5 0 * * * * * * * 0 0 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 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 P B S + 5 % S u c r o s e P B S + 5 % S u c r o s e 1 3 g c A A V 5 - m iH T T 1 3 g c A A V 5 - m iH T T 1 x 1 0 1 x 1 0 1 3 g c A A V 5 - m iH T T 1 3 g c A A V 5 - m iH T T 3 x 1 0 3 x 1 0 M A Y 1 2 , 2 0 1 7 | 15
• 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 | 16
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 | 17
Impact of neutralizing antibodies (NAB) directed against AAV5 on efficacy of liver directed gene delivery in non-human primates (NHP) 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). M A Y 1 2 , 2 0 1 7 | 18
M A Y 1 2 , 2 0 1 7 | 19
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• 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 | 21
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