Target Selection in the area of Gene Therapy Harald Petry, PhD

Transcription

1 Target Selection in the area of Gene Therapy Harald Petry, PhD Chief Scientific Officer

2 Forward-looking statements This presentation contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, contained in this presentation, including statements regarding our strategy, future operations, future financial position, future revenues, projected costs, prospects, plans and objectives of management, are forward-looking statements. The words anticipate, believe, estimate, expect, intend, may, plan, predict, project, target, potential, will, would, could, should, continue, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements we make. The forward-looking statements contained in this presentation reflect uniqure s current views with respect to future events, and uniqure assumes no obligation to update any forward-looking statements except as required by applicable law. These forward-looking statements include, but are not limited to, statements regarding the risk of cessation or delay of any of the ongoing or planned clinical studies and/or development of our product candidates, the risk of delay or failure to successfully commercialize or obtain further regulatory approval of Glybera, and the risk that our collaborations with Chiesi or our other collaboration partners will not continue or will not be successful. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, risks associated with our clinical development activities, regulatory oversight, product commercialization, intellectual property claims, and the risks, uncertainties and other factors described under the heading Risk Factors in uniqure s form 20-F and the prospectus dated February 5, 2014, both documents filed with the Securities and Exchange Commission. 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, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, except as required by law. 2

3 Gene therapy THE USE OF GENETIC MATERIAL TO MODIFY A PATIENT S CELLS FOR THE TREATMENT OF AN INHERITED OR ACQUIRED DISEASE. THE ULTIMATE GOAL IS TO CURE OR PREVENT DEVELOPMENT OF GENETIC DISEASES.

4 DNA Delivery Systems

5 The State of the Gene Therapy Industry Recent Successes and Failures - SANFILIPPO B (LSD) PH 1/2 - POC SICKLE CELL DISEASE - BETA THALASSEMIA - MULTIPLE PRECLINICAL SUCCESSES (INCL. S100A1) - HEMOPHILIA FIX TO THE LIVER GLYBERA APPROVAL BY EMA - JEAN ERICKSON FIRST CLINICAL BENEFIT IN PARKINSON S AVALANCHE AMD PHASE 3 [?] - CELADON CVD PHASE 2B - RESTORED IMMUNE SYSTEMS IN 17 SCID PATIENTS STARTING IN Before - FAILED HEMOPHILIA FIX TRIAL - FAILED X-SCID TRIAL IN

6 Gene Therapy Exponential Growth Clinical Trial #s and Market Cap of Listed Companies Exploded Over Past 10 Years $6.7 bn 7 Open Clinical Trials (clinicaltrials.gov) 2 7 # Public Companies 1) 1) 2005: TGEN, OXB; 2015: AAVL, BLUE, QURE, ONCE, AGTC, ARWR, CLDN $.1 b n Market Cap Public Co s (as of 09/23/2015) 6

7 Grows of uniqure Over the Last Two Years Employees Partners Academic collaborations BMS, Chiesi 4D Therapeutics (Next Gen Vectors) Synpromics (Promotors), Treeway Academic collaborations Locations Amsterdam, NL Amsterdam, NL Lexington, Mass. US Heidelberg, Germany Clinical Programs Glybera (EU-approved) Glybera (commercial) Glybera (commercial) Hemophilia B Sanfilippo B, Parkinson s Disease 7

8 Severe hemophilia Spontaneous bleeds Arthropathy Quality of Life Compliance Cost 8

9 Factor IX Factor IX Hemophilia gene therapy versus rfactor concentrate FACTOR REPLACEMENT THERAPY Spontaneous bleeding bl 5% PROMISE GENE THERAPY 5% > No spontaneous serious or life-threatening bleeding > No prolonged bleeding with minor trauma > Marked reduction in use of FIX concentrate > Improved Quality of Life 9

10 AAV-based product for Hemophilia B > AAV VECTOR WITH HIGH LIVER TROPISM FIX > THE GENE CASSETTE INCLUDES: > LP1 liver-specific promoter > Codon-optimised FIX gene > SINGLE ADMINISTRATION VIA PERIPHERAL VEIN (30 min administration) LP1 Promoter Expression cassette 10

11 % Expression of normal AAV8/FIX Single Intervention Results in Marked Clinical Improvements SUSTAINED, DOSE DEPENDENT EFFECT OVER > 4 YEARS AFTER A SINGLE INTERVENTION UC London Low-dose Mid-dose High-dose Patient Patient 10 Disease severity Mild Moderate Severe In the high dose cohort, FIX mean expression, 5% Except for patient 5, factor IX concentrate usage down >85% Except for patient 5, annualized bleeding rate was reduced >93% 11 Nathwani AC et al. N Engl J Med 2014

12 AAV for different targets AAV-1 AAV-5 Viral Vector AAV-6 AAV-1 AAV-8 AAV-1 AAV-5 AAV-8 12

13 2015 and beyond Entry indications Building an AAV-based Portfolio Indications and technological requirements Monogenetic Disorders i.e. LPLD, HemB, LSDs 1 st generation AAVs; localized administration Expression of wt genes Constitutive (life long) expression 1st and 2 nd generation raavs;. Inducible expression system? Acquired diseases (PD, CHF)

14 Target Finding Project Methodology 14

15 Technology Still influences Target Selection Part I GENE PROCESS & ANALYTICAL NON-CLINICAL Vector Part II CLINICAL Lead optimization Development Promoter Manufacturing VECTOR CAPSID PROMOTER PROCESS CONTROL > HIGH VECTOR YIELDS/SCALABLE > REPRODUCIBLE/CONSIS TENT > GMP AND REGULATORY COMPLIANCE > SAFE BY DESIGN > COST EFFECTIVE Manufacturing Vector Promoter Manufacturing 15

16 AAV-Capsid Glybera - Expression Cassette AAV1-capsid VP1 VP2 VP3 ITR CMV LPL S447X WPRE p A ITR AAV2-LPL S447X

17 Evolution of Gene Therapy Technology Improved delivery (vector), higher expression efficiency and specificity (promoters) GOAL/EVOLUTION PRESENT FUTURE VECTOR Specific & efficient delivery of DNA Natural viruses e.g. raav Designer viruses e.g. AAV-based DVs* PROMOTER Specific & efficient gene expression, long term/life long Natural control elements e.g. Natural promoter Designed control elements e.g. short synthetic promoters * DVs Designer Vehicles Vector Promoter Manufacturing 17

18 Evolution of AAV Vector Delivery Technology New Targets dependent on better delivery vectors Directed Evolution Natural Serotyps Rational Designed Serotypes DESIGNED VECTORS PRESENT Potency / Specificity Vector Promoter Manufacturing FUTURE 18

19 4D Molecular THerapeutics Directed Evolution Input AAV Capsid Sequences Diversity Generation of Variants Selection Package into Functional Vectors Sequence SELECTED VARIANT Evaluate Individual Variants VALIDATION STUDIES 2 nd half 2016 HIGH-POTENCY (HP) - AAV Novel Library ~10 8 unique variants Vector Promoter Manufacturing 19

20 Evolution of AAV Gene Promoter Expression Technology uniqure s strategy is to optimize expression efficiency, size and specificity Optimization EXPRESSION EFFICIENCY REDUCED PROMOTER SIZE SPECIFICITY Vector Promoter Manufacturing 20

21 Partnership with Synpromics to optimize promoters Synpromics will develop synthetic promoters to enable > Expression to a specific cell type, for improved safety and efficacy > Decreased promoter size facilitating increased packaging capacity TECHNOLOGY Enhancer Elements: (Confer Specificity) Enhancer Elements: (Randomly Assembled) Core TSS Promoter Proximal Promoter +1 Core TSS Promoter +1 Information about endogenous Promoter/ Enhancer Synthetic Promoter Vector Promoter Manufacturing 21

22 Technical Ingredients of Success vector, promoter, manufacture VECTOR (CAPSID) > Delivery into the cell PROMOTER > Expression efficiency ADMINISTRATION MANUFACTURING > High vector yields scalability. > Safe by design Vector Promoter Manufacturing 22

23 AAV2: Efficient transport of GDNF following AAV2 gene delivery in the Putamen 75ml AAV2-GDNF (1.1 x 10e13 vg/ml) Substantia Nigra CNS: Rhesus Monkeys 23 Kells et, al.,2011

24 AAV5 in the brain - intraparenchymal injection ANTEROGRADE AND RETROGRADE (thalamus) TRANSDUCTION cortex striatum thalamus Substantia nigra 24

25 Technical Ingredients of Success vector, promoter, manufacture VECTOR (CAPSID) > Delivery into the cell PROMOTER > Expression efficiency ADMINISTRATION MANUFACTURING > High vector yields scalability. > Safe by design Vector Promoter Manufacturing 25

26 Consistent & scalablity Industrial applicability Progress towards improved quality and larger markets From 1st to 2 nd to 3rd generation processes uniqure uniqure AMT/uniQure Glybera AMT-021 AMT-060 AMT-110 NIH 1st generation Insect cell// Plasmid-Mammaliancell Glybera 2nd generation Insect Cell 3rd generation Insect Cell EMA / CHMP Approvable Vector Promoter Manufacturing 26

27 uniqure s Leading Baculovirus Manufacturing Platform AAV manufacturing unit in Boston, US LEXINGTON, MA, USA 2 x 500 L (scalable to 2 x 2000 L) Copy/scale of existing technology Estimated time of completion for GMP batches H AMSTERDAM, NL 2 x 50 L EMA approved facility Vector Promoter Manufacturing 27

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