AMT-061 (AAV5-Padua hFIX variant) an Enhanced Vector for Gene Transfer in Adults with Severe or Moderate-Severe Hemophilia B: Follow-up up to 9 Months in a Phase 2b trial Steven W. Pipe1, Adam Giermasz2, Giancarlo Castaman3, Nigel S. Key4, Susan Lattimore5, Frank W.G. Leebeek6, Wolfgang Miesbach7, Michael Recht5, Alison Long8, Robert Gut8, Annette Von Drygalski9 1University of Michigan, MI, USA. 2University of California Davis, Sacramento, USA. 3Azienda Ospedaliera Universitaria Careggi, Florence, Italy. 4University of North Carolina, Chapel Hill, USA. 5Oregon Health & Science University, Portland, USA. 6Erasmus University Medical Center, Rotterdam, the Netherlands. 7University Hospital Frankfurt, Frankfurt, Germany. 8uniQure Inc, Lexington, USA. 9University of California San Diego, San Diego, USA. CRA 22 INTRODUCTION AIMS Table 1. AMT-061 baseline demographics Reduction in bleeds and FIX replacement with ■■1 participant experienced three isolated elevations Participant AMT-061 above the upper limit of normal in aspartate ■■Gene transfer for severe hemophilia B can shift the ■■To confirm the efficacy and safety of AMT-061 aminotransferase (AST): Characteristic 1 2 3 disease phenotype to moderate (Factor IX [FIX] (2 x 1013 genome copies (gc)/kg) for the Phase 3 study– ■■In the year prior to screening and the screening Age (years) 43 50 47 ■■43 U/L (week 2), 48 U/L (week 4) and 90 U/L (week 31). 1%–5% of normal), mild (FIX >5% to <40%) or Health Outcomes with Padua gene; Evaluation in period (approximately 4 weeks) the participants 8 Weight (kg) 89 81 82 ■■Resolved quickly without treatment or impact on 1,2 Hemophilia B (HOPE-B, NCT03569891). experienced a total of 10 bleeds (Table 2). normal (FIX ≥40%) and significantly reduce or Positive, Positive, HIV Status Negative FIX activity. abrogate bleed risk.3,4 controlled controlled ■■During the 36-week interim analysis there have been ■■No participants required immunosuppression. METHODS Hep C; Hep C; Hep C; Hep B / Hep C no bleeds post-treatment and no requirement for FIX ■■AMT-060 (adeno-associated virus 5 [AAV5]-wildtype resolved resolved resolved Trial design replacement aside from protocol-specified use for [wt] human FIX) has demonstrated efficacy and Hemophilia B status FIX = 1% FIX <1% FIX <1% CONCLUSION ■■Phase 2b, open-label, single-dose, single-arm, perioperative management in participant 3. Pre-screening FIX Prophylaxis Prophylaxis Prophylaxis safety in an ongoing Phase 1/2 trial in hemophilia B 9 ■■AMT-061 resulted in increased FIX activity, with multicenter trial (NCT03489291). treatment (EHL FIX) (EHL FIX) (EHL FIX) (CT-AMT-060-01).3,5 mean FIX of 45.0% at 36 weeks. 13 Annualized bleed rate Table 2. Reduction in bleeds ■■Single intravenous administration 2x10 gc/kg of 3 1 5 1-year prior to screeninga Bleeds ■■AMT-061 was safe and well-tolerated. ■■Mean FIX activity over 3 years was 7.5 IU/dL with AMT-061. Neutralizing antibody ■■Based on these favorable results, the efficacy and the 2x1013 genome copies (gc)/kg dose of AMT-060. Positive Positive Positive activity (AAV5) Participant Pre-AMT-061 Post-AMT-061 Study participants 48 44 25 safety of AMT-061 will be further characterized in the (Luciferase assay)b ■■AMT-060 was safe and well tolerated: 1 3 spontaneous (severe) 0 pivotal HOPE-B study. ■■Three adult hemophilia B participants with FIX AAV, adeno-associated virus; EHL, extended half-life; FIX, Factor IX; Hep, hepatitis; HIV, human immunodeficiency virus; NAb, neutralizing 2 1 spontaneous (moderate) 0 ■■The majority of treatment-related adverse events activity ≤2%. For more information, please visit antibody. Participants 2 and 3 were excluded from another AAV-based 6 spontaneous* (moderate [n=2] www.ClinicalTrials.gov NCT03569891 or contact (TRAEs) occurred in the first 3.5 months post gene therapy trial for hemophilia B based on anti-AAV NAb titer. aTotal 3 0 ■■Controlled HIV, cleared hepatitis B/C, and no FIX and mild [n=4]) uniQure at [email protected] treatment. bleeds (treated + untreated). bAAV5 NAb data from screening visit, inhibitors. considered positive if titer is ≥2. Table includes all bleeds (treated and untreated). *1 bleed occurred after REFERENCES ■■One new TRAE during the last 12 months of ■■Pre-existing neutralizing antibodies (NAbs) to AAV5 enrollment but prior to dosing. 1. White GC, et al. Thromb Haemost 2001;85:560; 2. Blanchette VS, et al. J observation post treatment. FIX activity with AMT-061 Thromb Haemost 2014;12:1935-9; 3. Miesbach W, et al. Blood. 2018;131:1022- were evaluated but were not an exclusion criterion. 1031; 4. George LA, et al. N Engl J Med. 2017;377:2215-2227; 5. Leebeek ■■The study achieved the primary endpoint of FIX General safety F, et al. Res Pract Thromb Haemost 2019;3(S1):81; 6. Cantore A, et al. ■■AMT-061 (AAV5-Padua hFIX) was developed by Outcomes Blood 2012;120:4517-20; 7. Kao CY, et al. Thromb Haemost. 2013;110:244- activity >5% at 6 weeks (Figure 2): ■■AMT-061 was well tolerated. 56; 8. ClinicalTrials.gov. HOPE-B: Trial of AMT-061 in Severe or Moderately introducing a 2-nucleotide change into the transgene ■■Primary efficacy was assessed by FIX activity at 6 Severe Hemophilia B Patients. Accessed at: https://clinicaltrials.gov/ct2/show/ ■■Participant 1: 37.8%. NCT03569891 on 14 March 2019; 9. ClinicalTrials.gov. Dose Confirmation coding sequence of AMT-060, resulting in the weeks (central one-stage clotting assay). ■■1 participant experienced two adverse events (AE), ■■Participant 2: 23.9%. Trial of AAV5-hFIXcoPadua. Accessed at: https://clinicaltrials.gov/ct2/show/ naturally occurring highly active Padua FIX variant possibly related to AMT-061, that resolved without NCT03489291?term=AMT-061&rank=2 on 14 March 2019 ■■Historical bleeds and FIX use were assessed from 6 ■■Participant 3: 30.0%. intervention: DISCLOSURES (Figure 1). medical records. ■■By week 36, mean FIX activity was 45.0%. Steven W. Pipe reports fees paid to his institution from uniQure B.V. during the conduct ■■AMT-061 is expected to result in 6- to 7-fold higher ■■Transient, self-limiting headache and slightly. of the study; consultant fees from Shire, Novo Nordisk, Bioverativ, CSL Behring, Pfizer, ■■From screening participants recorded bleeds and FIX Genentech/Roche, Alnylam, Apcintex, Biomarin, uniQure, Bayer, Freeline, Spark levels of FIX activity versus AMT-060.7 elevated C-reactive protein. Therapeutics, Catalyst Biosciences, HEMA Biologics; research grant from Shire. Adam use in their e-diary. Figure 2. FIX activity post-AMT-061 treatment Giermasz reports fees paid to his institution from uniQure B.V. during the conduct of ■■No loss of FIX activity. the study; consultant fees from Bioverativ, Genentech/Roche, Biomarin and uniQure; ■■52-week follow-up to assess FIX activity, bleeding 0 speaker's fees from Bioverativ and Genentech/Roche. Giancarlo Castaman reports a Figure 1. Comparison of AMT-060 (AAV5-wild trial-related fee from UniQure B.V. during the conduct of the study; personal fees from type hFIX) and AMT-061 (AAV5-Padua hFIX) rates and FIX replacement, and safety will be 60 ■■No FIX inhibitor development. Novo Nordisk, Shire, Sobi, CSL Behring, Pfizer, Bayer, Kedrion, Roche, and research 54.1 grants to his institution from CSL Behring, Sobi and Pfizer outside the submitted work. monitored for five years. 50.9 50 ■■Participant 3: hip surgery due to worsening of pre- Nigel S. Key reports consultant fees from uniQure B.V. for participation on the Steering AAV5 capsid Liver-specific promoter Committee for this study. Susan Lattimore reports consultant fees from uniQure B.V. human FIX gene ■■This poster includes 36-week data from an interim 40 existing condition (avascular necrosis): during the conduct of the study. Frank W.G. Leebeek reports fees paid to his institution from UniQure B.V. during the conduct of the study; he has received research grants analysis. 30 30.1 from CSL Behring and Baxalta/Shire, outside the submitted work. Wolfgang Miesbach (% of normal) ■■Reported as SAE deemed unrelated to AMT-061. reports consultant fees from UniQure. B.V. during the conduct of the study; grants and 20 Participant 1 personal fees from Novo-Nordisk, personal fees from Bayer, Shire, Biotest, Pfizer, AMT-061 FIX activity one-stage aPTT Participant 2 Liver-specific safety Octapharma, LFB, CSL Behring, SOBI, Biogen, and BPL outside the submitted work. RESULTS 10 AGG to CTG at Participant 3 Michael Recht reports research support to his institution position 338 ■■AMT-061 (AAV5-Padua hFIX): Changes to the from Bioverativ, Genentech, NovoNordisk, and Shire. In 0 ■■No clinically significant ALT elevations above upper addition, he reports consultant fees from Bioverativ, CSL vector-transgene construct result in improvements in 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 limit of normal after dosing: Behring, Genentech, Kedrion, NovoNordisk, Pfizer, Shire, Week and uniQure. He is the immediate past chair, Board of FIX activity. Directors, American Thrombosis and Hemostasis Network. aPTT, activated partial thromboplastin time; FIX, Factor IX. No ■■Participant 1 had an isolated, slight elevation in Alison Long and Robert Gut are uniQure employees. AMT-060 - wildtype ■■Baseline demographics are shown in Table 1. immunosuppression required. †The week 0 time point reflects FIX Annette Von Drygalski reports consultant fees from AMT-061 - Padua variant ALT at week 22 (44 U/L), which resolved without UniQure, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, (epected 6- 7-fold increase in activity) activity before AMT-061 treatment.*Samples may include activity from ■■Notably, all 3 had low titers of NAbs to AAV5 at baseline. exogenous FIX replacement. intervention or loss of efficacy. Biomarin, Shire, Spark and CSL Behring.

Presented at the National Hemophilia Foundation's 71st Bleeding Disorders Conference, Anaheim, California, October 3 - October 5, 2019