Corporate Presentation JANUARY 2019

Transcription

1 Corporate Presentation JANUARY 2019

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, 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 presentation. 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, development of product candidates, 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 6, 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. DELIVERING GENE THERAPY TO PATIENTS JANUARY

3 Our mission To deliver curative, one-time therapies that transform the lives of patients. DELIVERING GENE THERAPY TO PATIENTS JANUARY

4 Our strategic imperatives Pipeline Manufacturing Enabling Technologies Intellectual Property Develop a proprietary pipeline of gene therapy candidates focused on liver-directed and CNS disorders Maintain leadership in commercial-scale manufacturing of AAV gene therapies Invest and leverage next-generation technologies that optimize and expand the applicability of gene therapy to patients Expand and maintain our leading IP portfolio Commercialization Retain valuable commercial rights DELIVERING GENE THERAPY TO PATIENTS JANUARY

5 A pioneer in AAV gene therapy +20 years of experience in AAV gene therapy DELIVERING GENE THERAPY TO PATIENTS JANUARY

6 Leading the way in AAV manufacturing Large-scale AAV Manufacturing Based in Lexington, MA, expanding to 80,000 ft 2 3 rd generation insect cell, baculovirus Demonstrated 500L stirred-tank production Scalable up to 2 x 2,000L Strong intellectual property position Benefits Control and flexibility Consistent process from preclinical to commercial Highly scalable, cost-effective High-volume capacity Consistent, stable, high-quality product DELIVERING GENE THERAPY TO PATIENTS JANUARY

7 Leveraging AAV5: a potentially best-in-class vector AAV5 Clinically demonstrated tolerability and outcomes AAV5 Vector Long-term follow-up data demonstrating safety and tolerability 25 patients have received AAV5 across 4 clinical studies 1 Demonstrated clinical outcomes in the liver and brain Lowest prevalence of pre-existing neutralizing antibodies 2 Favorable immunogenicity profile for systemic, intravenous delivery No confirmed T-cell-mediated immune responses to capsid 1 Clinical trials in Hemophilia B, Sanfilippo B and Acute Intermittent Porphyria 2 Boutin et al 2014 DELIVERING GENE THERAPY TO PATIENTS JANUARY

8 Investing in proprietary enabling technologies Expression Biodistribution Immunogenicity Delivery Increase expression of genetic material Improve uniformity of transduction Mitigate immune activation Optimize targeting and administration BEST-IN-CLASS GENE THERAPIES Increased patient eligibility Applicability to more diseases Improved safety & efficacy DELIVERING GENE THERAPY TO PATIENTS JANUARY

9 Expanding our proprietary pipeline DELIVERING GENE THERAPY TO PATIENTS JANUARY

10 Hemophilia B AMT-061 DELIVERING GENE THERAPY TO PATIENTS JANUARY

11 Executing in Hemophilia B Target product profile Potential for functionally-curative increases in FIX activity Hemophilia B AMT K patients in US/EU >$1B market in Near-term goal: Complete enrollment in pivotal study Durable and predictable outcomes Low risk of immune responses Greater patient eligibility due to low levels of NABs Strong intellectual property Potential to be first to market 1 GlobalData report 2016 DELIVERING GENE THERAPY TO PATIENTS JANUARY

12 AMT-061: dose-confirmation study Characteristics of the Participants at Baseline Age (years) Weight (kg) HIV Status Negative Positive, controlled Positive, controlled Hep B / Hep C Hep C; resolved Hep C; resolved Hep C; resolved Hemophilia B status Pre-screening FIX treatment ABR 1 year prior to screening Severe FIX Deficiency (<1%) Severe FIX Deficiency (<1%) Severe FIX Deficiency (<1%) Prophylactic Prophylactic Prophylactic DELIVERING GENE THERAPY TO PATIENTS JANUARY

13 AMT-061: efficacy perspective with 24 weeks of cumulative patient data At six weeks after the administration of AMT-061, patients achieved a mean FIX activity level of approximately 31% of normal All patients experienced increasing and sustained FIX activity No reported bleeding events No infusions of FIX replacement therapy No immunosuppression required DELIVERING GENE THERAPY TO PATIENTS JANUARY

14 AMT-061: estimated FIX activity in humans (1) FIX activity at 6 to 8 weeks after gene transfer expected to be 65% to 70% of peak 6 to 8 Weeks 52 Weeks ESTIMATED PATIENT VARIABILITY 20-35% 30-50% // (1) Interim and steady state FIX estimates based on AMT-061 and AMT-060 animal data and AMT-060 Phase I/II clinical data (at one year follow-up) DELIVERING GENE THERAPY TO PATIENTS JANUARY

15 AMT-061: summary of top-line data at 24 weeks of cumulative patient observation AMT-061 has been generally safe and well-tolerated with no serious adverse events occurring during or after vector infusion All patients achieved therapeutic 1 levels of FIX activity 6 weeks after treatment, with mean FIX activity of 31% of normal No participants reported bleeds or required any infusions of factor replacement therapy No patients required any immunosuppression or experienced loss of FIX activity 1 Epidemiological data indicate that factor activity above 12% of normal is associated with substantial reduction or elimination of spontaneous bleeds and factor usage. Den Uijl IE et al Haemophilia 2011; 17(6): DELIVERING GENE THERAPY TO PATIENTS JANUARY

16 AMT-061: HOPE-B Phase III pivotal study Open label, single-dose, multi-center, multi-national trial Approximately 50 patients with severe and moderately-severe hemophilia B Patients with AAV5 antibodies will not be excluded Patients will serve as their own control; 6-month lead-in to establish baseline Study objectives: Increase FIX activity Reduce frequency of bleeding episodes Decrease use of FIX replacement therapy Assess efficacy and safety DELIVERING GENE THERAPY TO PATIENTS JANUARY

17 Huntington s Disease AMT-130 DELIVERING GENE THERAPY TO PATIENTS JANUARY

18 Executing in Huntington s Disease Target product profile One-time administration of disease-modifying therapy Huntington s AMT per 100K people 1 No treatments available Strong preclinical data Near-term goal: Initiate clinical study in 2019 Proprietary miqure TM silencing platform Strong mhtt knockdown in both deep structures and cortex Preclinically shown to be generally safe and well-tolerated Potential to be first to market 1 Rawlins, MD. Neuroepidemiology 2016;46: DELIVERING GENE THERAPY TO PATIENTS JANUARY

19 AMT-130: Huntington s disease Huntington s disease Caused by expansion of CAG trinucleotide in exon 1 No disease-modifying therapies available Prevalence of 60,000 to 70,000 patients in US and EU Significant additional patients undiagnosed Huntington s Disease Pathway Degenerated regions Preserved Regions Therapeutic Targeting mhtt leads to damage in the striatum, and in later stage disease, in parts of the cortex Therapeutic targeting of striatum (caudate nucleus and putamen), globus pallidus and cortex (sensorimotor) Ross CA., et al. Nat Rev Neurol Apr;10(4): DELIVERING GENE THERAPY TO PATIENTS JANUARY

20 AMT-130: treating Huntington s disease AMT-130 gene therapy for Huntington s disease (HD) AMT-130 Putamen Caudate nucleus Non-selective knockdown of huntingtin protein (HTT) in the brain Utilizes proprietary mirna that binds to and degrades HTT mrna One-time injection in the striatum, the primary affected structure in HD AAV5 has been shown to have widespread distribution in brain, including cortex MRI-guided stereotactic administration directly into deep structures of brain Demonstrated preclinical PoC in multiple small and large animal models AMT-130 leverages same manufacturing platform and process used for AMT-061 DELIVERING GENE THERAPY TO PATIENTS JANUARY

21 AMT-130: widespread distribution in brain Penetration throughout NHP brain Vector DNA distribution Vector genome copies per g DNA 1 Samaranch L. et al, Gene Ther Apr;24(4): Figure 3 1 Lower Limit of Detection DELIVERING GENE THERAPY TO PATIENTS JANUARY

22 AMT-130: strong reduction of mhtt Libechov transgenic (tghd) minipigs: Life-span: years Body weight: kg Brain weight: g Highly developed immune system Mutant huntingtin protein knockdown at 6 months 47.0% 67.5% 28.2% 46.5% 12.0% 40.7% MRI-guided CED caudate putamen N=12 N=21 N=9 N=9 N=12 N=6 N=12 Median. Each dot represents the average value of 3 tghd minipig animals DELIVERING GENE THERAPY TO PATIENTS JANUARY

23 AMT-130: considerations for Phase I/II dose escalation study Early manifest / stage 1 patients 44 HTT CAG repeats 3 surgical sites in U.S. At least 2 non-surgical sites Randomized, double-arm, blinded study with sham control CSF mhtt protein, mihtt, other biomarkers measured over 9-18 months Other exploratory endpoints DELIVERING GENE THERAPY TO PATIENTS JANUARY

24 AMT-130: considerations for Phase I/II dose escalation study HD patients Screening / Randomization CSF levels at baseline and over time will be monitored with other exploratory parameters Clinical Parameters (e.g. UHDRS, HD- CAB) Quantitative Motor Function Measurements over 9-18 months Volumetric MRI and MRS Biomarkers of neuronal injury Patient-reported outcomes 1M 3M 6M 9M 12M 15M 18M Sham controls Open-label access DELIVERING GENE THERAPY TO PATIENTS JANUARY

25 AMT-130: status and next steps Current Status Next Steps Established pre-clinical proof of concept Completed safety toxicology studies Clearance of IND for AMT-130 Begin first-in-human clinical study Granted Orphan Drug Designation by FDA Granted Orphan Medicinal Drug Designation by EMA DELIVERING GENE THERAPY TO PATIENTS JANUARY

26 Research Pipeline Expansion DELIVERING GENE THERAPY TO PATIENTS JANUARY

27 AMT-180: Super9 A new approach to hemophilia A Long-term and stable expression Effective in all hemophilia A patients Compatible with bypass agents Comparable with emicizumab Hepatocyte-friendly Stable long-term expression Non-immunogenic Sufficient thrombin generation to stop bleeding episodes Not neutralized by FVIII inhibitors Safe in combination with rfviia and/or FEIBA and emicizumab Comparable efficacy in HemA with and without inhibitors DELIVERING GENE THERAPY TO PATIENTS JANUARY

28 AMT-180: expression levels in NHPs expected to translate to therapeutically relevant FVIII mimetic activity in humans male Cynomolgus macaque n=2 IV, 9 e 13 gc/kg adapted delivery 1) AAV5-LP1-Super9 2) AAV5-P-IDAV 3) AAV5-P-Super hfix protein (%) in NHPs vehicle AAV5-LP1-Super9 AAV5-P-IDAV AAV5-P-Super9 1 vehicle treated NHP Wk 13: FEIBA injection Wk 15: FVIIa injection weeks post-injection DELIVERING GENE THERAPY TO PATIENTS JANUARY

29 AMT-180: preclinical data findings Sufficient thrombin generation Hepatocytefriendly Not immunogenic Manufacturability Expected to prevent bleeding Long-term expression in mice Proven record manufacturing FIX mutant proteins DELIVERING GENE THERAPY TO PATIENTS JANUARY

30 AMT-190: Fabry disease, a lysosomal storage disease In Fabry disease Gb3 and lyso-gb3 accumulate in tissues throughout the body, resulting in a wide range of debilitating symptoms Patients suffer from pain, angiokeratomas, hypohidrosis, corneal opacity, gastrointestinal tract disorder, hearing loss, renal failure, cardiac involvement and cerebrovascular disorder Two Fabry phenotypes depending on the α-gal A levels: Classic Fabry: <1% of α-gal A activity: early onset Variant Fabry: >1% of α-gal A activity: late onset in black: early symptoms in red: late symptoms DELIVERING GENE THERAPY TO PATIENTS JANUARY

31 AMT-190: injection of the modified NAGA protein in Fabry mice, superior GLA activity in the liver, kidneys and heart Wild type Fabry Modified NAGA Fabrazyme Replagal Tajima Y et al. Am J Human Genetics 2009 DELIVERING GENE THERAPY TO PATIENTS JANUARY

32 AMT-190: preclinical data findings AAV/modNAGA causes therapeutic GLA activity and gb3 reduction More stable in plasma and better end-organ distribution Preclinical Proof of Concept Non-immunogenic longterm replacement product for Fabry Potentially more effective than current replacement therapy Ready for toxicology studies DELIVERING GENE THERAPY TO PATIENTS JANUARY

33 AMT-150: halt brain degeneration in SCA3 patients Cause Damage Symptoms Unmet need CAG repeat expansion in ATXN3 gene: Ataxin-3 protein acquires toxic properties Brain degeneration Cerebellum and Brainstem More widespread in later stages Ataxia Dystonia/Rigidity Muscular atrophy Paralysis No medication that slows the progressive course of the lethal disease DELIVERING GENE THERAPY TO PATIENTS JANUARY

34 AMT-150: 65% ataxin-3 lowering in brainstem of SCAconcept3 mice after cisterna magna injection of miqure SCA3 mouse model miqure TM Up to 65% ataxin-3 lowering in SCA3 mice N = 3 per group In-life 6 weeks Mutant ataxin-3 protein (%) Relative to control SCA3 mouse brainstem * * Control miqure_a miqure_b miqure_c DELIVERING GENE THERAPY TO PATIENTS JANUARY

35 AMT-150: halt ataxia with our proprietary miqure therapy Strong target engagement No off-target effects Ataxin-3 lowering in SCA3 mice Widespread brain transduction Candidate selection Proof-of-mechanism Enhancing intrathecal delivery DELIVERING GENE THERAPY TO PATIENTS JANUARY

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