Abstract: Background: Etranacogene dezaparvovec is an investigational gene therapy for hemophilia B (HB) comprising an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with a liver specific promoter. In a Phase 2b study, a single dose of etranacogene dezaparvovec provided mean FIX activity of 41.0% sustained at 1yr post-dose in 3 participants (pts). Although most gene therapy clinical studies exclude pts with pre-existing neutralizing antibodies (NAbs) to the capsid serotype, early clinical studies and nonhuman primate data suggest that generally prevalent titers of anti-AAV5 NAbs may not preclude successful transduction with etranacogene dezaparvovec. Aims: A Phase 3, Health Outcomes with Padua gene; Evaluation in Hemophilia B (HOPE-B; NCT03569891) was established to further assess efficacy and safety of etranacogene dezaparvovec in adults with HB with a wide range of pre-existing NAbs to AAV5. Here we report outcomes at 26 weeks (wks). Methods: HOPE-B is a Phase 3, open-label, single-dose, single-arm, multi-national trial in adult males with severe or moderate-severe HB (FIX≤2%). All pts received routine FIX prophylaxis prior to study. Pts were not excluded based on pre-existing NAbs to AAV5. Pts entered a prospective lead-in period of at least 6 months during which bleeding/factor use was monitored, then received a single intravenous dose of etranacogene dezaparvovec (2x1013 gc/kg). Pts will be followed for 5yrs. Primary endpoints comprised FIX activity (one stage) at 26 and 52wks after dosing and 52wk annualized bleeding rate. For pts with no clean post-treatment FIX samples (≥10d post exogenous FIX), factor activity was imputed as baseline value based on historic disease severity. Secondary endpoints include factor replacement use, adverse events (AEs), and reactive use of corticosteroids. Results: 75 pts were screened, of whom 67 entered lead-in. 54 pts were dosed (44 severe, 10 moderately severe HB) and completed 26wks of follow-up. Mean age (±SD) was 41.5 (15.8) yrs. 38/54 pts (70.4%) had bleeds (n=123) during the lead-in despite prophylaxis, and 23/54 (42.6%) had NAbs to AAV5 at baseline (max titer: 3212.3). Following treatment, FIX activity increased rapidly to a mean (SD; min,max) of 37.2% (±19.6; 1.0, 97.1) at wk26, representing a mean (SD; min,max) change from baseline of 36.0% (±19.7; 0, 96.1 p & lt;0.0001, confirmed by per-protocol sensitivity analysis). No correlation of pre-existing NAbs with FIX activity was identified up to a titer of 678.2; n=52, R2 = 0.078); a single pt had a NAb titer of 3212.3 and did not respond. In addition to this pt, one other pt received a partial dose and remained on prophylaxis; all other pts (96.3%) successfully discontinued routine prophylaxis. 39/54 (72.2%) pts reported 0 bleeds in the first 26wks post-treatment; 15 pts reported a total of 21 bleeds. Mean (SD) annualized FIX consumption (IU/yr/pt) was 292,304 (±171,079) during lead-in, decreasing to 12,622 (±36,466) at wk26 (96.0% reduction, N=54). Overall, 37/54 (68.5%) pts had any treatment-related AE post-treatment, the majority of which were mild (81.5%). No deaths occurred and no treatment-related SAEs were reported. 7 pts had infusion-related reactions; the infusion was discontinued in 1 pt. Treatment-related elevations in liver enzymes were reported in 9 pts and received steroids per protocol. All discontinued steroid use prior to wk26 and FIX activity was preserved in the mild range. In addition to these, the most frequent treatment-related AEs were headache (13.0%) and influenza-like illness (13.0%). No inhibitors to FIX were reported. No relationship between safety and NAbs was observed. Conclusions: The first co-primary endpoint of this study was met. This is the first report of a Phase 3 study in HB and the largest gene therapy trial cohort to date. Following a single dose of etranacogene dezaparvovec, FIX activity increased, without the need for prophylactic immunosuppression, into the mild-to-normal range at 26wks in pts with severe/moderately severe HB. Importantly, this included pts with titers of pre-existing anti-AAV5 NAbs. Pts were able to discontinue prophylaxis and bleeding was abolished in the majority. The safety profile was consistent with early phase AAV5 studies and together these data support a favorable safety and efficacy profile for etranacogene dezaparvovec Disclosures Pipe: HEMA Biologics: Consultancy, Other; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; ApcinteX: Consultancy; Bayer: Consultancy, Other: Contracted Research; BioMarin: Consultancy, Other: Contracted Research; Takeda: Consultancy; uniQure: Consultancy, Other; Siemens: Other; Pfizer: Consultancy; Freeline Therapeutics: Consultancy, Other: Contracted Research; Novo Nordisk: Consultancy, Other: Contracted Research; Roche/Genentech: Consultancy, Other: Contracted Research; Sangamo Therapeutics: Consultancy; Sanofi Genzyme: Consultancy, Other; Spark Therapeutics: Consultancy. Recht:CSL Behring: Consultancy, Other: personal fees; Genentech: Consultancy, Other: personal fees, Research Funding; Pfizer: Consultancy, Other: personal fees, Research Funding; BioMarin: Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; uniQure: Consultancy, Other: personal fees, Research Funding; Novo Nordisk: Consultancy, Other: personal fees, Research Funding; Spark: Research Funding; Bayer: Research Funding; Grifols: Research Funding; Hema Biologics: Consultancy, Research Funding; LFB: Research Funding; Octapharma: Research Funding; Catalyst Biosciences: Consultancy; Kedrion: Consultancy; Sanofi: Consultancy, Research Funding. Key:Uniqure: Consultancy; Grifols: Research Funding; Takeda: Research Funding; Novo Nordisk: Other: Chair of Grants Committee. Leebeek:Shire/Takeda: Research Funding; uniQure: Consultancy; Shire/Takeda: Consultancy; BioMarin: Consultancy; SOBI: Other: Travel grant; Roche: Other: DSMB member for a study; CSL Behring: Research Funding. Castaman:Bayer, Roche, Sobi, Grifols, Novo Nordick, Werfen, Kedrion: Consultancy, Honoraria, Speakers Bureau; CSL Behring, Pfizer, Sobi: Research Funding; Ablynx, Alexion, Bayer, Takeda, CSL Behring, Novo Nordisk, Pfizer, Roche,Sanofi, SOBI, uniQure: Membership on an entity's Board of Directors or advisory committees. Lattimore:uniQure: Other: Study Steering Committee member. Van Der Valk:Baxalta: Research Funding. Peerlinck:Bayer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Roche: Research Funding; Sobi: Consultancy; Takeda: Consultancy, Research Funding. Coppens:Roche: Research Funding; Portola/Alexion: Research Funding; Sanquin Blood Supply: Research Funding; uniQure: Research Funding; NovoNordisk: Consultancy; Pfizer: Consultancy; Sobi: Consultancy; Medcon International: Consultancy; MEDtalks: Consultancy; Bayer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Daiichi Sankyo: Research Funding. O'Connell:uniQure: Consultancy; F. Hoffmann-La Roche Ltd, Novo Nordisk, SOBI: Speakers Bureau; SOBI: Research Funding. Pasi:Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; uniQure: Other: Grants and nonfinancial support , Research Funding; ApcinteX: Consultancy, Other: Personal fees ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Roche: Honoraria, Other; Sobi: Consultancy, Honoraria, Other; Tremeau: Consultancy. Kampmann:Uniqure: Research Funding, Speakers Bureau; Shire Pharmaceuticals: Speakers Bureau. Meijer:Pfizer: Research Funding; Sanquin: Speakers Bureau; Bayer: Speakers Bureau; Sanquin: Research Funding; Bayer: Research Funding; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. von Drygalski:Biomarin: Consultancy; Bioverativ/Sanofi Genzyme: Consultancy; NovoNordisk: Consultancy; Pfizer: Consultancy; uniQure: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees. Young:Genentech/Roche, Grifols, and Takeda: Research Funding; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Bayer, CSL Behring, Freeline, UniQure: Consultancy. Hermans:WFH: Other; EAHAD: Other; LFB: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; CAF-DCF: Consultancy, Speakers Bureau; Biogen: Consultancy, Speakers Bureau; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire, a Takeda company: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Kedrion: Speakers Bureau. Astermark:Bayer, CSL Behring, Novo Nordisk, Octapharma, Roche, Sobi, Spark, Takeda, uniQure: Consultancy; uniQure: Research Funding. Klamroth:Bayer: Consultancy, Research Funding, Speakers Bureau; Biomarin: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche/Chugai: Consultancy, Speakers Bureau; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Biotest: Speakers Bureau; LEO: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Lemons:uniQure: Research Funding. Visweshwar:Biogen Idec: Membership on an entity's Board of Directors or advisory committees. Escobar:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biomarin, Genetech/Roche, CSL Behring, Kedrion, Magellan Healthcare: Honoraria. Gomez:Global Blood Therapeutics: Speakers Bureau. Kruse-Jarres:CSL Behring, Genentech, Inc., Spark: Research Funding; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Honoraria; F. Hoffmann-La Roche Ltd: Speakers Bureau; Biomarin, Chugai Pharmaceutical Co., CSL Behring, CRISPR Therapeutics, Genentech, Inc.: Consultancy. Kotowski:uniQure: Research Funding. Quon:Orthopaedic Institute for Children: Current Employment; Bayer: Honoraria; Biomarin: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Octapharma: Honoraria; Shire/Takeda: Speakers Bureau. Wang:Bayer: Honoraria; Takeda: Honoraria; Genentech: Honoraria; Biomarin: Honoraria; CSL Behring: Honoraria; Bioverativ Inc: Honoraria; Catalyst Biologics: Consultancy; NovoNordisk: Consultancy; Hema biologics / LFB: Consultancy. Wheeler:Takeda: Membership on an entity's Board of Directors or advisory committees; uniQure: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Sawyer:uniQure: Current Employment, Current equity holder in publicly-traded company. Verweij:uniQure: Current Employment. Colletta:uniQure: Current Employment. Bajma:uniQure: Current Employment. Gut:uniQure: Current Employment. Miesbach:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Consultancy, Membership on an entity's Board of Directors or advisory committees; Freeline: Consultancy, Membership on an entity's Board of Directors or advisory committees; LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; uniQure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Etranacogene dezaparvovec is an investigational gene therapy

Abstract: Acquired hemophilia A (AHA) is a rare autoimmune disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII:C). Immunosuppressive treatment may result in remission of disease over a period of days to months. Until remission, patients are at high risk of bleeding and complications from immunosuppression. Prognostic parameters to predict remission and the time needed to achieve remission could be helpful to guide treatment intensity, but have not been established so far. GTH-AH01/2010 was a prospective multicenter cohort study using a standardized immunosuppressive treatment protocol. The primary study endpoint was time to achieve partial remission (PR, defined as FVIII:C activity 〉 50 IU/dl after cessation of any hemotherapy for 〉 24h, and no active bleeding). Secondary endpoints were time to achieve complete remission (CR, defined as PR plus negative FVIII:C inhibitor, steroid tapered to 〈 15 mg/d prednisolone, and cessation of any other immunosuppressive treatment), and overall survival (OS). Enrolment was strictly prospective and only allowed within 7 days of starting immunosuppression. Outcome data were recorded in all patients enrolled. The treatment protocol consisted of prednisolone (100 mg/d from day 1 to the day of PR, then tapered down to 〈 15 mg/d over 5 weeks), oral cyclophosphamide (150 mg/d, from day 21-42, unless PR was achieved), and rituximab (375 mg/m2 weekly for 4 weeks starting on day 43, unless PR was achieved). If AHA was first diagnosed in patients previously on prednisolone 〉 15 mg/d, or equivalent, they received prednisolone (100 mg/d) and rituximab from day 1. If cyclophosphamide was contraindicated, patients received prednisolone (100 mg/d) and rituximab from day 21. One hundred twenty-four patients from 21 treatment centers in Germany and Austria were enrolled between April 2010 and April 2013 (36 months). The patients from two centers not compliant with the treatment protocol were excluded (N=18), as were patients in whom AHA was not confirmed (N=2) or follow-up was too short at the time of this analysis (N=7). The remaining 97 patients from 17 centers were followed for a median of 256 days (interquartile range [IQR] 84-561). Median age was 74 years (IQR 64-82). AHA was associated with other autoimmune disorders (19%), malignancy (12%), pregnancy or puerperium (5%), but was most often idiopathic (66%). The median FVIII:C activity at baseline was 1 IU/dl (IQR 〈 1-3), and the median inhibitor titer was 20 BU/ml (IQR 7.7-78). PR and CR were achieved after a median time of 35 and 102 days, respectively. Patients achieving PR prior to day 21 (N=22) compared with patients not achieving PR within 21 days (N=75) had a higher baseline FVIII:C activity (median 3 vs. 〈 1 IU/dl, p 〈 0.01) and a lower FVIII:C inhibitor (median 12 vs. 29 BU/ml, p 〈 0.05). Multivariate analysis with adjustment for age, sex, underlying disorder, and WHO performance status on admission demonstrated that baseline FVIII:C activity ( 〈 1 IU/dl vs. 〉 =1 IU/dl) had a strong impact on the time to achieve PR (HR 2.76 [95% confidence interval 1.73-4.42] , p 〈 0.001) and CR (HR 2.36 [1.34-4.14], p 〈 0.01). Baseline FVIII:C activity was also a predictor of PR and CR when other cutoffs were used (2 or 3 IU/dl instead of 1 IU/dl), or when it was analyzed as a continuous variable in Cox regression analysis. In contrast, FVIII:C inhibitor titer assessed by the local laboratory did not affect time to PR or CR significantly. OS after 300 days, estimated by the Kaplan Meier method, was 69%. Age, WHO performance status, and FVIII:C activity at baseline were independent predictors of OS. In summary, GTH-AH 01/2010 is the largest prospective study of patients with AHA treated according to a standardized protocol. The study demonstrated a robust effect of baseline FVIII:C activity on the time needed to achieve PR and CR. Baseline FVIII:C activity, together with age and performance status, also affected OS. Therefore, baseline FVIII:C activity may be considered to guide individually tailored immunosuppression in future studies. Disclosures: Tiede: Baxter: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy; CSL Behring: Consultancy, Honoraria, Research Funding. Off Label Use: Prednisolone, cyclophosphamid, and rituximab for immunosuppression in acquired hemophilia. Klamroth:Bayer: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding. Gottstein:Novo Nordisk: Honoraria; Baxter: Honoraria. Holstein:Baxter: Honoraria, Speakers Bureau. Scharf:CSL Behring: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Biotest: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria, Research Funding. Huth-Kühne:SRH Kurpfalz Hospital and Hemophilia Center: Consultancy, Employment, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Greil:Roche: Consultancy, Honoraria, Research Funding. Miesbach:Novo Nordisk: Consultancy, Honoraria, Research Funding; Baxter: Consultancy, Honoraria, Research Funding. Trappe:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel Other; AMGEN: Research Funding, Travel, Travel Other; CSL Behring: Honoraria, Research Funding, Speakers Bureau, Travel, Travel Other; Mundipharma: Research Funding, Travel, Travel Other; Takeda: Consultancy, Research Funding, Travel Other; Novartis: Consultancy, Research Funding, Travel, Travel Other; Novartis: Research Funding, Travel Other; Cellgen: Travel, Travel Other. Knoebl:Novo Nordisk: Consultancy, Honoraria; Baxter: Consultancy, Honoraria.

Abstract: Introduction: The development of gene transfer for hemophilia is advancing rapidly and offers the potential to shift the disease severity from severe to mild with a single treatment. AMT-060 consists of an AAV5 vector with a gene cassette containing an LP1 liver specific promoter and codon-optimized wild type hFIX gene that has previously been shown to result in durable increases in FIX activity of at least 4 years1. This phase 1/2 study aims to investigate the safety and efficacy of AMT-060 in adult patients with severe hemophilia B. Methods: This is a multi-national, multi-center, open-label, dose-escalating study in patients with FIX activity ≤ 2% of normal, and a severe bleeding phenotype. To be eligible, patients had to require either prophylactic exogenous FIX, or on-demand exogenous FIX with more than 4 bleeds per year or suffer from hemophilic arthropathy. Ten patients were treated in two subsequent, escalating dose cohorts, with AMT-060 5x 1012 gc/kg (n=5) or 2x 1013 gc/kg (n=5). Patients received AMT-060 via a single intravenous infusion over 30 minutes. Efficacy assessments include endogenous FIX activity, measured at least 10 days after the most recent administration of exogenous FIX; reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events and immunological assessments, including T-cell response to capsid antigens. Results : There were no screen failures for pre-existing antibodies against AAV5. The age of enrolled patients ranged from 33 to 72 years. At enrollment, nine patients were on FIX prophylaxis, and one patient in the high dose cohort used on-demand FIX therapy. At the time of submission, all ten patients have received AMT-060. The mean of all endogenous FIX activity values after cessation of prophylaxis in the low-dose cohort was 5.4% (95% CI 5.0-5.8%, range 3.1-6.7%; n=4), and stable during the 39 weeks of follow-up. Four out of five patients in the low-dose cohort were able to stop FIX prophylaxis. These patients demonstrated a mean reduction in annualized total FIX usage of 82% after treatment with AMT-060. For all five patients in the low-dose cohort, the mean annualized total FIX usage declined 75% after treatment with AMT-060. Following AMT-060 administration, one patient in the lower dose cohort had a mild, asymptomatic, elevation of ALT at week 10 that resolved with a seven weeks course of tapering prednisolone. No change in FIX activity, and no T-cell response or other possibly associated immunogenicity or inflammatory abnormalities were seen during the ALT elevation. Efficacy and safety results will be updated up to 52 weeks of follow up for the low-dose cohort. Initial efficacy and safety results from the higher-dose cohort up to 26 weeks of follow up will also be presented. Conclusions: Follow up of patients with severe hemophilia B who received either the low or higher dose of AMT-060 is ongoing. A single infusion of AMT-060 was generally well-tolerated. FIX activity increased to levels sufficient to provide endogenous prophylaxis in four of five patients in the low-dose cohort, relieving them from the need for exogenous FIX prophylaxis and resulting in marked decrease of FIX usage. 1Nathwani et al. NEJM 2014; 371:1994-2004 Disclosures Leebeek: UniQure: Consultancy; Netherlands Hemophilia Foundation: Research Funding; CSL Behring: Research Funding; Baxter: Research Funding. Tangelder:uniQure: Employment. Meijer:Baxter: Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bristol-Myers Squibb: Honoraria. Castaman:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta-Shire: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Cattaneo:Chiesi: Employment. Coppens:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; BMS/Pfizer: Consultancy, Honoraria, Research Funding; Sanquin: Consultancy, Honoraria, Research Funding. Klamroth:SOBI: Other: honoraria for advisory boards and speaker fees; uniqure: Other: honoraria for advisory boards and speaker fees; pfizer: Other: honoraria for advisory boards and speaker fees; NovoNordisk: Other: honoraria for advisory boards and speaker fees; Octapharma: Other: honoraria for advisory boards and speaker fees; Baxalta: Other: honoraria for advisory boards and speaker fees ; Bayer: Other: honoraria for advisory boards and speaker fees; Biogen Idec: Other: honoraria for advisory boards and speaker fees; CSL Behring: Other: honoraria for advisory boards and speaker fees. Schutgens:CSL Behring: Research Funding; Sanquin: Research Funding. Hendriks:uniQure: Employment. Corzo:uniQure: Employment. Miesbach:Grifols: Honoraria; CSL Behring: Research Funding; Pfizer: Honoraria; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Background: Gene therapy aims to provide long-term therapeutic benefit from a single administration. AMT-060 is an adeno-associated virus serotype 5 (AAV5) vector with a codon-optimized wildtype human factor IX (FIX) gene and liver-specific promoter. AMT-060 is being evaluated in an ongoing study of 10 participants with severe/moderate-severe hemophilia B (Phase 1/2 study, NCT02396342) over 5 years. Aim: To describe efficacy and safety outcomes from an analysis at up to 5-years post-AMT-060. Methods: Adult males with FIX activity ≤2% and a severe bleeding phenotype received a single intravenous infusion of AMT-060 (5x1012 gc/kg, Cohort 1, n=5) or (2×1013 gc/kg, Cohort 2, n=5). Assessments included FIX activity, FIX replacement use, annualized bleeding rate (ABR), treatment-related adverse events (TRAE), immunological and inflammatory biomarkers up to 5 years (Cohort 1) and 4.5 years (Cohort 2). Results: As of November 2019, for Cohort 1 the mean FIX activity (at 4.0 years) was 5.1% as compared to 4.4% in the first year, 6.8% in the second year, 7.3% in the third year and 7.0% in the fourth year. Mean FIX activity for Cohort 2 was 7.5% as compared to 7.1% in the first year, 8.4% in the second year 7.9% in the third year, and 7.4% in the fourth year. Eight of 9 participants using prophylaxis at baseline were able to discontinue use. During the last 12, and 6 months of observation respectively, the mean annualized bleed rate (ABR) was 3.3. for Cohort 1 and 0.0 for Cohort 2. These represent, respectively, a reduction in mean ABR to the year prior to treatment of 77% and 100% for Cohort 1 and Cohort 2. During this same period the consumption of FIX replacement therapy declined 90% and 100% relative to pre-treatment, respectively for Cohort 1 and Cohort 2. No participants developed FIX inhibitors or signs of sustained AAV5 capsid-specific T-cell activation. As previously reported, TRAE were mainly reported in the first 3.5 months after treatment, including three participants who experienced transient mild elevations in alanine aminotransferase. One additional TRAE (joint swelling post-exercise) was observed during the last 12 months of observation post-treatment. Updated data, up to 5-years of observation, will be presented for the first time. Conclusions: Long-term stable endogenous FIX activity and reductions in ABR and FIX replacement use were sustained over multiple years following a single treatment with AMT-060. There were no additional safety concerns with longer term follow-up. This data supports the ongoing Phase 3 study of the enhanced construct etranacogene dezaparvovec (AMT-061), which encodes the highly active Padua FIX variant. Disclosures Meijer: Bayer: Research Funding; Sanquin: Research Funding; Pfizer: Research Funding; Bayer: Speakers Bureau; Sanquin: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; BMS: Speakers Bureau; Aspen: Speakers Bureau; Uniqure: Consultancy. Kampmann:Uniqure: Speakers Bureau; Shire Pharmaceuticals: Speakers Bureau. Klamroth:CSL Behring: Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Takeda/Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Consultancy, Speakers Bureau; Biotest: Speakers Bureau; Grifols: Speakers Bureau; Biomarin: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau. Castaman:Novo Nordisk: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding; Ablynx: Honoraria; Alexion: Honoraria; Bayer: Honoraria; CSL Behring: Honoraria, Research Funding; Kedrion: Speakers Bureau; Sobi: Honoraria, Research Funding, Speakers Bureau; Uniqure: Honoraria, Membership on an entity's Board of Directors or advisory committees; Werfen: Speakers Bureau; Baxalta/Shire: Honoraria. Bönig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Healthineers: Current equity holder in publicly-traded company; Sandor-Hexal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Polyphor: Research Funding; Miltenyi: Honoraria, Research Funding; Erydel: Research Funding; Chugai: Honoraria, Research Funding; Bayer: Research Funding; Terumo BCT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiadis: Honoraria; Uniqure: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Stage: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fresenius: Honoraria; medac: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Sawyer:uniQure: Current Employment. Miesbach:UniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioMarin Pharmaceutical Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: AMT-060 = AAV5 vector gene therapy in subjects with moderate to severe hemophilia B

Abstract: Die Gentherapie hat sich in den vergangenen Jahren zu einer realistischen Behandlungsoption für Patienten mit Hämophilie entwickelt. Unter Berücksichtigung der verfügbaren Literatur und der persönlichen Erfahrungen aus klinischen Studien diskutieren wir hier wesentliche Aspekte der Gentherapie der Hämophilie A und B mit Vektoren auf Basis des Adeno-assoziierten Virus (AAV) einschließlich zu erwartender Ergebnisse, Risiken, Nebenwirkungen und Auswirkungen auf patientenrelevante Endpunkte. Überlegungen zur Auswahl von Patienten, zum Aufklärungs- und Einwilligungsprozess, zur ambulanten Durchführung und Überwachung der Gentherapie sowie zur Erfassung von Daten werden dargestellt. Die Notwendigkeit interdisziplinärer Zusammenarbeit mit der Hepatologie und anderen Fachgruppen wird dargelegt. Besondere Berücksichtigung finden strukturelle und organisatorische Voraussetzungen der Zentren, die Gentherapie durchführen (Dosierungszentren oder „Hub“), und der heimatnahen Zentren, die Patienten der Gentherapie zuführen und die Nachsorge übernehmen („Spoke“). Wir geben eine Empfehlung zur Nutzung einer elektronischen Plattform zum sicheren und verzögerungsfreien Datenaustausch zwischen diesen Zentren und den Patienten. Diese elektronische Plattform wird auch die Primärdatenquelle sein für Pharmakovigilanz, Studien, nationale und internationale Register sowie für die frühe Nutzenbewertung dieser neuen Therapieform. Überlegungen zur Finanzierung der Gentherapie sowie zur möglichen zukünftigen Nutzung bei Jugendlichen und Kindern werden diskutiert. In einem sich rasch entwickelnden wissenschaftlichen Umfeld sollen diese Empfehlungen den betreuenden Einrichtungen und Kostenträgern erste Orientierung in Vorbereitung auf die Anwendung der Gentherapie nach ihrer Zulassung geben.