Oral Presentations


OR01

Implementation of the French primary long-term prophylaxis guidelines: A real-world prospective study of the FranceCoag PUPs cohort

P. Saultier1,2,*, Y. Guillaume1, V. Demiguel3, C. Berger4, A. Borel-Derlon5, S. Claeyssens6, A. Harroche7, C. Oudot8, A. Rafowicz9, M. Trossaert10, B. Wibaut11, M. Boucekine12, K. Baumstarck12, S. Meunier13, T. Calvez14, H. Chambost1,2, on behalf of FranceCoag PUPs / CoMETH Prophylaxis Study Group

1CHU Timone Enfants, Department of pediatric hematology and oncology, APHM, Marseille, France; 2NORT, Aix Marseille Univ, INSERM, INRA, Marseille, France; 3Santé Publique France, French national public health agency, Saint-Maurice, France; 4Hematology and Oncology Pediatric Unit, Saint-Etienne University Hospital, Saint Etienne, France; 5Center for bleeding disorders, La Côte de Nacre University Hospital, Caen, France; 6Center for bleeding disorders, Purpan University Hospital, Toulouse, France; 7Necker University Hospital, Center for bleeding disorders, Assistance Publique - Hôpitaux de Paris, Paris, France; 8Hematology and Oncology Pediatric Unit, Limoges University Hospital, Limoges, France; 9Bicêtre University Hospital, Center for bleeding disorders, Assistance Publique - Hôpitaux de Paris, Le Kremlin Bicêtre, France; 10Center for bleeding disorders, Nantes University Hospital, Nantes, France; 11Center for bleeding disorders, Lille 2 University Hospital, Lille, France; 12EA 3279, Self-perceived Health Assessment Research Unit, School of Medicine, Aix-Marseille Univ, Marseille, France; 13Lyon University Hospital, Center for bleeding disorders, HCL, Lyon, France; 14Institut Pierre Louis d’Épidémiologie et de Santé publique (IPLESP UMRS 1136), Sorbonne Universités, UPMC Univ Paris 06, Inserm, Paris, France

Introduction: Primary long-term prophylaxis (LTP) efficiently prevents arthropathy in children with severe hemophilia. In early 2000s, the French group of hemophilia treaters (CoMETH) published their first LTP guidelines. Several issues may impair the actual LTP use in young patients. However, real-world evaluations of the implementation of such guidelines are scarce. This study aimed at prospectively analyzing the LTP guidelines implementation in France and at identifying factors modulating the LTP initiation.

Methods: The study group consisted of 395 boys from the FranceCoag PUPs cohort. All included patients had severe hemophilia A or B (FVIII/FIX <1%) and were born in 2000-2009 (i.e. after the French LTP guidelines dissemination). Sociodemographic, clinical, biological, genetic, and therapeutic data were prospectively recorded during medical visits in the hemophilia treatment center (HTC). The study group was compared to a historical group of 44 registered boys with severe hemophilia born in 1996 (retrospective data collection).

Results: In the study group, the median age at first joint bleed was 1.9 years (IQR 1.1-3.0). The cumulative incidence of primary LTP use according to age was dramatically higher in the study group compared to the historical group (e.g. cumulative incidence of LTP use 59.2% versus 8.5% at three years of age, respectively). The prevalence of ineligibility to the guidelines, delay or absence of LTP initiation, anticipated LTP initiation, and timely LTP initiation according to guidelines was 20.8%, 9.9%, 38.5% and 30.9%, respectively. A multivariate analysis showed that two factors were significantly associated with anticipated or timely versus delayed or absent LTP initiation: the year of birth (OR 1.2 per each additional year, 95% CI 1.1-1.3, P < .001) and the HTC location (OR 6.4, 95% CI 1.4-29.2, P = .02 and OR 6.2, 95% CI 2.0-19.4, P = .002 for Northwest and Southeast part of France, respectively).

Discussion/Conclusion: This analysis provides pivotal data to evaluate the adherence to early LTP guidelines and to identify barriers for their implementation. CoMETH guidelines dissemination was associated with a dramatic increase in early LTP use. The study highlights the capacity of FranceCoag device to assess critical variables and evaluate therapeutic practice in one of the largest national PUPs cohort worldwide.

Disclosure of interest: None declared.

OR02

Within-patient comparison of treatment patterns before and after switching to rFVIIIFc: A report from the UK national haemophilia database

M. Scott1,*, X. Hua2, P. W. Collins3, C. R. M. Hay1, on behalf of UKHCDO

1Clinical Haematology, Manchester Royal Infirmary, Manchester, UK; 2UK National Haemophilia Database, Manchester, UK; 3School of Medicine, Cardiff University, University Hospital of Wales, Cardiff, UK

Introduction: Extended half-life (EHL) FVIII products may permit a reduction of infusion frequency (IF) and clotting factor consumption (CFC) whilst improving bleeding outcomes in haemophilia A (HA). Direct comparisons with standard rFVIII do not exist. We compared IF and CFC in patients using FVIII prophylaxis before and after switching to rFVIIIFc using data from the UK National Haemophilia Database.

Methods: rFVIIIFc was introduced in the UK from September 2016 using a restricted NHS England protocol. This assumed effective FVIII prophylaxis could be provided using at least one fewer infusion/wk of rFVIIIFc than previously required using rFVIII. All UK patients who used rFVIIIFc 01/09/16-30/06/2017 were identified. Patients with ≥4-weeks compliant post-switch Haemtrack (HT) home-therapy diary data were analysed. Individual IF and weekly CFC were calculated for 12-months pre-switch and the post-switch period and compared using summary statistics and Wilcoxon signed rank test.

Results: 236 patients used rFVIIIFc during the study period; 172 were excluded (76 non-HT users; 13 trial participants; 15 new treatment non-switchers; 22 treated on-demand; and 46 poor compliance/short follow-up). Of those remaining, 54 had severe; 9 moderate (all with FVIII = 0.01 IU/mL) and one mild (FVIII = 0.11 IU/mL) HA. Median (IQR) age was 16 (7-38) years. Median (IQR) post-switch follow-up was 18 (12-23) wks. IF for the group fell from a median (IQR) of 3.5 (3.0-3.7) to 2.4 (2.2-3.6) infusions/wk, (−27%; P < .0001), reducing in 81% of patients. CFC for the group reduced from a median (IQR) of 5445 (3497-7304) to 4811 (2604-6377) IU/wk (−16%; P < .0001), reducing in 72% of patients. Preliminary data suggest that switching to rFVIIIFc is associated with a reduction in bleed rate even using this conservative dosing schedule. This requires confirmation with longer follow-up and more subjects.

Discussion/Conclusion: We have shown a significant reduction in IF and CFC (−27% and −16%, respectively) associated with switching from rFVIII to rFVIIIFc. CFC compares favourably to indirect comparisons (CFC with rFVIIIFc ranges −38% to +17% relative to rFVIII in one study) and median IF is consistent with previous clinical trials. This is the first within-patient direct comparison of rFVIII and rFVIIIFc prophylaxis, providing further evidence that EHL rFVIII products can reduce treatment burden.

Disclosure of interest: M. Scott Grant/Research support from: Bayer, Sobi, X. Hua: None declared, P. Collins Consultant for: Sobi, C. Hay Consultant for: Sobi, Speaker Bureau of: Sobi.

OR03

Inhibitor incidence in pups with severe haemophilia B is higher than usually reported; data from the PedNet registry

M. Van Den Berg1,*, M. Carcao2, E. Santogostino3, H. Chambost4, K. Fischer5, M. Williams6, R. Ljung7, on behalf of PedNet study group

1PedNet Haemophilia Research Foundation, Baarn, The Netherlands; 2Division of Haematology/Oncology, Hospital for Sick Children, Toronto, Canada; 3A. Bianchi Bonomi Hemophilia and Thrombosis Centre, Institute of Internal Medicine IRCCS Ospedale Maggiore, Milano, Italy; 4Service d'Hématologie Pédiatrique CHU Timone, Marseille, France; 5Van Creveld Kliniek, Internal Medicine, Utrecht, The Netherlands; 6Birmingham Children's Hospital NHS Trust, Birmingham, UK; 7Department of Pediatrics, Lund University, Malmo, Sweden

Introduction: Inhibitor incidence in severe haemophilia B has usually been reported to be about 3%-5%, much lower than the 25%-30% rate reported in haemophilia A Few comparative data exist on host-related and treatment-related risk factors and on the immunological processes associated with FIX inhibitors due to the low patient numbers that hinder the collection of sufficient data. Objective. To investigate inhibitor incidence in a large unselected group of severe haemophilia B patients.

Methods: All severe haemophilia B patients in the PedNet registry born in the time period 2000-2009 were included. Inhibitors were considered present if confirmed by at least two positive inhibitor assays. High-titre inhibitors were defined as an inhibitor titre >5 BU/mL.

Results: Of the 85 patients identified, 93% had reached at least 50 EDs. Surprisingly, ten (11.8%, 95% CI 4.9-18.7) patients developed inhibitors (5 high and 5 low titre); 7 of these occurred within the first 50 EDs and 3 after 75 EDs. All late inhibitors were low-titre, whilst all high titre inhibitors developed within the first 14 EDs. Of the 5 high-titre inhibitors, 4 occurred in patients with large deletions (>50 bp) and the other occurred in a patient in whom no mutation was found. One of 5 large deletions was associated with a low-titre inhibitor (table).

Discussion/Conclusion: Inhibitor incidence in severe haemophilia B is higher than usually reported. All high-titre inhibitors developed in the first 14 ED and most of these in patients with large deletions.

Disclosure of Interest: None declared.

OR04

Comorbidities explain the age-related increase of Von Willebrand factor in patients with type 1 Von Willebrand disease

F. Atiq1,*, K. Meijer2, J. Eikenboom3,4, K. Fijnvandraat5, E. P. Mauser-Bunschoten6, K. P. M. van Galen6, M. R. Nijziel7, P. F. Ypma8, J. de Meris9, B. A. P. Laros-van Gorkom10, J. G. van der Bom11,12, M. P. M. de Maat1, M. H. Cnossen13, F. W. G. Leebeek1, on behalf of WiN Study Group

1Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands; 2Hematology, University Medical Center Groningen, Groningen, The Netherlands; 3Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands; 4Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands; 5Pediatric Hematology, Emma Children's Hospital-Academic Medical Center, Amsterdam, The Netherlands; 6Hematology, Van Creveldkliniek-University Medical Center Utrecht, Utrecht, The Netherlands; 7Hematology, Catharina Hospital, Eindhoven, The Netherlands; 8Hematology, Haga Hospital, The Hague, The Netherlands; 9Netherlands Hemophilia Society, Leiden, The Netherlands; 10Hematology, Radboud University Medical Center, Nijmegen, The Netherlands; 11Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; 12Jon J van Rood Center for Clinical Transfusion Medicine, Sanquin Research, Leiden, The Netherlands; 13Pediatric Hematology, Sophia Children's Hospital-Erasmus University Medical Center, Rotterdam, The Netherlands

Introduction: Von Willebrand factor (VWF) levels rise with increasing age in patients with von Willebrand disease (VWD). VWF levels are also increased in patients with several diseases. Therefore, we assessed the influence of comorbidities on the age-related increase of VWF levels in VWD patients.

Methods: We performed a nationwide multicenter cross-sectional study in patients with moderate and severe VWD in the Netherlands; “the WiN-study”. All patients completed a questionnaire on comorbidities, use of medication and bleeding history (Tosetto bleeding score [BS]). Blood samples were collected at study inclusion. Statistical analysis was performed using multiple regression analysis.

Results: We included 536 patients older than 16 years with type 1 and type 2 VWD in whom data on comorbidities were available. In type 1 VWD, higher VWF:Ag was seen in patients with hypertension (n = 75, β = 0.23 IU/mL, P < .001), diabetes mellitus (n = 14, β = 0.11 IU/mL, P = .093), cancer (n = 15, β = 0.14 IU/mL, P = .017) and thyroid dysfunction (n = 15, β = 0.13 IU/mL, P = .036) than in patients without these comorbidities (all corrected for age, sex and blood group). Similar results were observed for VWF:Act and FVIII:C. In type 1 VWD, aging was associated with higher VWF:Ag, VWF:Act and FVIII:C, respectively with β = 0.03 IU/mL (P = .001), β = 0.04 IU/mL (P < .001) and β = 0.03 IU/mL (P = .002) per decade. After adjustment for relevant comorbidities there was no longer an association between age and VWF:Ag, VWF:Act or FVIII:C, respectively β = 0.01 IU/mL (P = .343), β = 0.02 IU/mL (P = .202) and β = 0.01 IU/mL (P = .321) per decade. In type 1 VWD, presence of comorbidities was associated with higher BS (β = 1.9, P = .043) (corrected for age, sex and blood group), and patients with comorbidities had more often a bleeding episode one year prior to inclusion in the study, 29.2% vs 18.4% (P = .030). In patients with type 2 VWD, there was no association between comorbidities and VWF levels or bleeding phenotype.

Discussion/Conclusion: This is the first study to demonstrate that comorbidities increase VWF and FVIII levels and explain the age-related increase of VWF levels in patients with type 1 VWD. Despite the higher VWF and FVIII levels, VWD patients with comorbidities had more bleeding episodes than those without comorbidities, indicating that hemostatic treatment remains necessary in these individuals.

Disclosure of interest: F. Atiq: None declared, K. Meijer: None declared, J. Eikenboom Grant/Research support from: CSL Behring, K. Fijnvandraat: None declared, E. Mauser-Bunschoten Grant/Research support from: CSL Behring, Bayer, Baxter, Grifols, Novo Nordisk, Pfizer, Biovitrum, Biotest and Sanquin, K. van Galen Grant/Research support from: CSL Behring and Bayer, M. Nijziel: None declared, P. Ypma: None declared, J. de Meris: None declared, B. Laros-van Gorkom Grant/Research support from: Baxter and CSL Behring, Speaker Bureau of: Sanquin, J. van der Bom Speaker Bureau of: Bayer, M. de Maat: None declared, M. Cnossen: None declared, F. Leebeek Grant/Research support from: CSL Behring for performing the Willebrand in the Netherlands (WiN) study, Consultant for: CSL Behring and Shire.

OR05

Phase 1/2 trial of single and multiple dose subcutaneously administered factor IX variant CB 2679d/ISU304: Pharmacokinetics, activity and safety

C. W. You1,*, H. Levy2, H.-J. Shin3, J. S. Kim4, J. W. Han4, S.-J. Kim4, M. Lee5, J. Park6, S.-B. Hong6, S. Kim6, J. E. Siegel2

1Eulji University Hospital, Daejeon, Korea, Republic Of; 2Catalyst Biosciences, South San Francisco, CA, USA; 3Pusan National University Hospital, Busan, Korea, Republic Of; 4Yonsei University College of Medicine, Severance Hospital, Seoul, Korea, Republic Of; 5Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA, USA; 6ISU Abxis, Seongnam-si Gyeonggi-do, Korea, Republic Of

Introduction: CB 2679d/ISU304 was developed using rational protein design to enable administration by subcutaneous (SQ) injection for use as prophylaxis and has resistance to ATIII inhibition, increased catalytic activity and affinity for FVIIIa, 20-fold enhanced potency by clotting activity and tail clip model, and 8-fold increased duration of aPTT activity compared to wt-FIX. This study was conducted to determine intravenous (IV) and SQ pharmacokinetics and safety.

Methods: Cohort 1 received 75 IU/kg IV BeneFIX followed by 75 IU/kg IV CB 2679d. Cohort 2 and 3 received CB 2679d 75 IU/kg IV followed by 75 or 150 IU/kg SQ. Cohort 4 dose escalation was not required and omitted. Cohort 5 received 150 IU/kg SQ daily for 6 days. Safety measures were performed 2 weeks after dosing. FIX antigen (VisuLizeTM Factor IX Antigen KitAG (Affinity Biologicals)) and activity (one-stage clotting assay by ACL TOP 700 and Instrumentation Laboratories reagents), anti-drug antibody and neutralizing antibody were measured at Haematologic Technologies. AUC was based on the trapezoidal rule. For the additional area for AUC0-inf, the log-linear regression line for the last three time points was fit and extrapolated to the x-intercept. Half-life (t1/2) calculation was by Demitasse 2000 that uses an iterative piecewise fitting algorithm based on a robust (M-regression) log-linear model. Activity data were adjusted for baseline assuming exponential falloff of IV administration and a t1/2 of 20 hours. Bioavailability was calculated from the AUC0-t activity data.

Results: IV CB 2679d has 22-fold greater potency, longer beta t1/2 27.2 ± 2.7 vs 21.0 ± 1.1 hours (P = .007) and mean residence time 35.8 ± 2.7 vs 25.1 ± 1.5 hours (P = .0004) over BeneFIX. SQ bioavailability was 19.2% (range 15.9%-23.6%) and t1/2 was 70.4 ± 31.0 hours. Median Tmax was 24 hours. One subject reported moderate generalized ache and mild SQ injection site discomfort (both possibly related) and 2 other subjects had brief mild adverse events.

Discussion/Conclusion: SQ PK data supports the aim of achieving normal FIX activity levels with daily SQ CB 2679d dosing.

Complete bioavailability, steady-state PK and activity after daily dosing will be reported.

Disclosure of Interest: C. W. You: None declared, H. Levy Shareholder of: Catalyst Biosciences, Employee of: Catalyst Biosciences, H.-J. Shin: None declared, J. Kim: None declared, J. Han: None declared, S.-J. Kim: None declared, M. Lee Consultant for: Catalyst Biosciences, J. Park Employee of: ISU Abxis, S.-B. Hong Employee of: ISU Abxis, S. Kim Employee of: ISU Abxis, J. Siegel Employee of: Catalyst Biosciences.

OR06

Perioperative management for patients with congenital factor XI deficiency

C. Chai-Adisaksopha1,*, S. Afraz1, T. Rattanathammethee2, A. Iorio1

1Medicine, McMaster University, Hamilton, ON, Canada; 2Medicine, Chiang Mai University, Chiang Mai, Thailand

Introduction: A perioperative management in patients with congenital factor (F) XI deficiency is challenging because the poor relation between bleeding phenotype and residual FXI activities. The aim of this study is to investigate the treatment modalities and outcomes of perioperative treatment in these patient populations.

Methods: We conducted a retrospective, chart-review of pediatric and adult patients who were diagnosed with FXI deficiency and who underwent surgical procedures between January 2002 and August 2017. We collected treatment modalities during the surgeries. We carried out a systematic review of studies investigating perioperative management of patients with FXI deficiency and reporting individual patients’ data. Primary outcome was hemostatic achievement during the surgeries and secondary outcome was thromboembolic complications. 

Results: A retrospective study and a systematic review yielded a total of 297 surgical procedures. FXI concentrates was used in 102 procedures (34.5%), plasma 82 (27.7%), rFVIIa 40 (13.5%), tranexamic acid alone 26 (8.78%), desmopressin 11 (3.72%) and aPCC 2 (0.7%). Good or excellent hemostatic control was achieved in 85.4%-100% of patients. Among patients who did not received hemostatic agent perioperatively, poor hemostatic control was observed in 18.2% of procedures. Thromboembolic complications were reported in 5 patients (4.90%) who received FXI concentrates and 6 patients (15.0%) who received rFVIIa.

Discussion/Conclusion: Concern with thromboembolic complications, we recommend plasma over factor XI concentrate or rFVIIa for patients with congenital FXI deficiency who undergo surgical procedures. Tranexamic acid monotherapy may be considered only in dental procedures.

Disclosure of Interest: None declared.

OR07

Occurrence and impact of pain among patients living with hemophilia: An analysis from the patient reported outcomes, burdens and experiences (PROBE) study

D. Noone1,*, C. Chai-Adisaksopha2, R. Curtis3, N. Frick4, M. Nichol5, B. O'Mahony1,6, D. Page7, J. Stonebraker8, A. Iorio9, M. W. Skinner10, on behalf of Patient Reported Outcomes Burdens and Experiences (PROBE) Investigator Group

1Irish Haemophilia Society, Dublin, Ireland; 2Department of Medicine, McMaster University, Hamilton, ON, Canada; 3Factor VIII Computing, Berkeley, CA, USA; 4National Hemophilia Foundation, New York City, NY, USA; 5University of Southern California, Sol Price School of Public Policy, Los Angeles, CA, USA; 6Trinity College, Dublin, Ireland; 7Canadian Hemophilia Society, Montreal, QC, Canada; 8Poole College of Management, North Carolina State University, Raleigh, NC, USA; 9Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada; 10Institute for Policy Advancement Ltd., Washington, DC, USA

Introduction: Hemophilia significantly impacts quality of life through acute and chronic pain, mobility reduction, and limitation on activities of daily living (ADL). The PROBE questionnaire was developed by people with hemophilia (PWH) to examine outcomes that matter to them in a way that allows comparison to a cohort without hemophilia (controls). An aim of PROBE was to investigate the occurrence, pattern and impact of pain in PWH compared to controls.

Methods: Participants were recruited through national hemophilia patient associations. The PROBE questionnaire asks about the presence of acute and chronic pain, the occurrence of pain in association with activities, its interference with activities, the use of pain medication and health-related quality of life (HRQL) measured by EQ-5D-5L. The prevalence of pain, its impact on ADL and HRQL were compared between PWH and controls. The association between participants’ characteristics and occurrence of pain was investigated using the logistic regression model.

Results: There were 1287 respondents from 21 countries. Of these, 867 provided information on presence of hemophilia and severity. The mean ages for controls, mild/moderate and severe hemophilia were 44, 35 and 37. Acute pain was reported as significantly higher among PWH (mild/moderate-70.19% and severe-70.94%) compared with controls-38.44%. Chronic pain was significantly higher among PWH (mild/moderate-65.43% and severe-75.28%) as compared to controls-41.06%. Pain had a negative impact on physical and emotional function in both cohorts; however, PWH reported these more frequently than controls. In respective models, reporting of acute pain was not associated with reporting of chronic pain. For those reporting acute pain in the control, mild/moderate and severe groups, the mean EQ-5D utilities were 0.88, 0.73 and 0.66. For those reporting chronic pain in the control, mild/moderate and severe groups, the mean EQ-5D utilities were 0.85, 0.70 and 0.65.

Discussion/Conclusion: Acute and chronic pain are much more prevalent among PWH as compared to controls. The occurrence of pain, its interference with daily activities and its psychological aspects are different between PWH and controls. The results show that pain management in PWH needs improvement. The differences of frequency and pattern of pain in PWH warrant a disease-specific pain control program. 

Disclosure of Interest: D. Noone: None declared, C. Chai-Adisaksopha: None declared, R. Curtis: None declared, N. Frick: None declared, M. Nichol: None declared, B. O'Mahony: None declared, D. Page: None declared, J. Stonebraker: None declared, A. Iorio: None declared, M. Skinner Grant/Research support from: PROBE is an independent investigator led research project with grant / research support from: Baxalta, now part of Shire; Bayer; Bioverativ; CSL Behring; Novo Nordisk, Roche and Sobi with administrative support provided by the US National Hemophilia Foundation.

OR08

Perioperative management in patients with hemophilia receiving fitusiran, an investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia

C. Negrier1,*, M. V. Ragni2, P. Georgiev3, T. J. Lissitchkov4, A. Monpara5, H. Van Nguyen5, K. Madigan5, K. J. Pasi6

1Hopital Louis Pradel - Unite d'hemostase clinique/CRTH, Bron, France; 2c/o Hemophilia Center of Western PA, University of Pittsburgh, Pittsburgh, PA, USA; 3University Multiprofile Hospital for Active Treatment “Sveti Georgi” and Medical University, Plovdiv, Bulgaria; 4University Hospital for Hematology, Sofia, Bulgaria; 5Alnylam Pharmaceuticals, Cambridge, MA, USA; 6Royal London Haemophilia Centre, Barts and the London School of Medicine and Dentistry, London, UK

Introduction: Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting antithrombin (AT) as a means to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or B with and without inhibitors. Monthly administration of fitusiran has led to dose dependent AT lowering, improved TG and decreased bleeding frequency. Management of operative procedures while on novel therapies for hemophilia, such as fitusiran, is of clinical interest. Perioperative hemostatic management during procedures in patients with hemophilia receiving fitusiran in a clinical trial will be described.

Methods: The fitusiran Ph 1 study followed by the Ph 2 open-label extension (OLE) study included patients with hemophilia A or B with and without inhibitors. After Ph 1, patients eligible to continue dosing in the OLE received monthly, fixed SC doses of fitusiran, 50 or 80 mg. Data on perioperative hemostatic treatment and response were collected and reported by study investigators for procedures while AT was lowered on study.

Results: Four patients, 27-53 yrs, with severe hemophilia A (2 with inhibitors) underwent 5 procedures: endoscopic cholecystectomy and septoplasty; thoracotomy/partial lung segmentectomy; molar teeth extraction; premolar tooth extraction. Prior to procedures, AT level for all patients was <20% (range: 10.7%-19%) of baseline. At Investigators’ discretion, perioperative hemostatic treatments (FVIII, rFVIIa, and/or aPCC) were administered for 4/5 procedures. Duration of hemostatic treatment varied depending on type of procedure: 15 hours post-procedure (premolar tooth extraction), 7 days post-procedures (endoscopic cholecystectomy and septoplasty), and 13 days post-procedure (thoracotomy/partial lung segmentectomy). No thromboprophylaxis was used in any procedure. All procedures were rated by the respective investigator as resulting in minimal blood loss or blood loss similar to a patient without hemophilia. Further details on perioperative treatment regimens and hemostatic responses will be presented.

Discussion/Conclusion: Successful perioperative hemostatic management of patients in the context of AT lowering with fitusiran was observed; the number of procedures is limited and additional data are needed to further define appropriate perioperative hemostatic management plans.

Disclosure of Interest: None declared.

OR09

Pharmacokinetics (PK), pharmacodynamics (PD) and PK/PD relationships of emicizumab in persons with haemophilia a (PWHA) with inhibitors from adolescent/adult (HAVEN 1) and paediatric (HAVEN 2) phase 3 studies

C. Schmitt1,*, J. Adamkewicz2, J. Xu2, T. Chang2, C. Petry1, A. Calatzis3, G. Young4, C. Negrier5, S. Meeks6, M. Callaghan7, G. G. Levy2

1Dept of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland; 2Genentech Inc., South San Francisco, CA, USA; 3Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität München, Munich, Germany; 4Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 5Louis Pradel Cardiology Hospital, University Claude Bernard, Lyon, France; 6Aflac Cancer and Blood Disorders Center, Atlanta, GA, USA; 7Children's Hospital of Michigan, Detroit, MI, USA

Introduction: Emicizumab, a monoclonal antibody in development for treatment of PwHA with/without inhibitors, bridges FIXa and FX, restoring missing FVIIIa function. Weekly subcutaneous emicizumab prophylaxis significantly decreased bleeds vs bypassing agents in PwHA with inhibitors in the HAVEN 1 (NCT02622321) and 2 (NCT02795767) studies. We assessed emicizumab PK and effects on targeted coagulation parameters in children, adolescents and adults from these studies and present a comparison of PK and PK/PD relationships between age groups.

Methods: The following tests were determined: emicizumab concentration (ELISA); FVIII activity (chromogenic assay containing human factors [Hyphen Biophen FVIII:C]); thrombin generation (TG); aPTT; PT/INR; antigen levels of FIX, FX, D-dimer and prothrombin fragment 1.2 (PF1.2); FVIII inhibitor titres (chromogenic Bethesda assay). Data are presented for 172 PwHA; median (range) emicizumab exposures: 42 (3-74) weeks in HAVEN 1 and 8 (1-41) weeks in HAVEN 2; median (range) ages: 28.5 (12-75) years in HAVEN 1 and 7.1 (1.2-15.7) years in HAVEN 2.

Results: Mean trough emicizumab concentrations of ˜50 mg/mL were maintained over >1 year of treatment; similar PK profiles were found across age groups. The PD markers FVIII:C and TG peak height increased with loading doses to achieve ˜25% for FVIII:C and ˜110 nM for TG during maintenance dosing. Reported FVIII activity and TG strongly correlated with emicizumab concentration; similar PK/PD was found across age groups. Emicizumab target antigens FIX and FX were not affected by treatment. INR, D-dimer and PF1.2 were largely within normal limits and not correlated to emicizumab levels. Elevated baseline aPTT normalised after first emicizumab dose and showed no further concentration-response. Inhibitor titres remained stable or slightly declined with time.

Discussion/Conclusion: Emicizumab exhibited similar PK across age groups, as well as similar PK/PD relationships measured by TG and FVIII:C activity. aPTT was normalised at sub-therapeutic emicizumab levels. FIX and FX antigen levels and markers of activated coagulation were unaffected by emicizumab. PK/PD data collected over longer term exposure confirmed sustainability of emicizumab procoagulant effect in paediatric, adolescent and adult PwHA.

Disclosure of Interest: C. Schmitt Employee of: Roche, J. Adamkewicz Employee of: Genentech Inc., J. Xu Employee of: Genentech Inc., T. Chang Shareholder of: Genentech Inc., Employee of: Genentech Inc., C. Petry Employee of: Roche, A. Calatzis Consultant for: Genentech Inc., G. Young Consultant for: Alnylam, Bayer, Bioverativ, Genentech, Kedrion, Novo Nordisk, Roche, Shire, CSL Behring, C. Negrier Grant/Research support from: Alnylam, Baxalta/Shire, Bayer, Biogen/SOBI, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Speaker Bureau of: Baxalta/Shire, Bayer, Biogen/SOBI, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, Roche, S. Meeks Consultant for: Genentech, Bayer, Bioverativ, CSL Behring, Shire, HEMA Biologics, M. Callaghan Shareholder of: Alnylum, Grant/Research support from: Pfizer , Consultant for: Roche/Genentech, Sancilio, Global Blood Therapeutics, Baxalta, Biogen, Grifols, CSL Behring, Bayer, Shire, Pfizer, Octapharma, Bioverativ, Speaker Bureau of: Roche/Genentech, Baxalta, Shire, Novo Nordisk, G. Levy Employee of: Genentech Inc.

OR10

Emicizumab prophylaxis in paediatric persons with haemophilia A (PWHA) with inhibitors: Impact on health-related outcomes and caregiver burden in the HAVEN 2 study

M. E. Mancuso1,*, J. Mahlangu2, R. F. Sidonio Jr3, P. C. Trask4, S. von Mackensen5, M. Shima6, M. Uguen7, T. Chang8, G. Young9, J. Oldenburg10

1Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; 2Haemophilia Comprehensive Care Centre, Faculty of Health Sciences, University of the Witwatersrand and NHLS, Johannesburg, South Africa; 3Pediatrics, Emory University and Children's Healthcare of Atlanta, Atlanta, GA, USA; 4Patient Centered Outcomes Research, Genentech, Inc, South San Francisco, CA, USA; 5Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; 6Department of Pediatrics, Nara Medical University, Kashihara, Japan; 7F. Hoffmann-La Roche Ltd, Basel, Switzerland; 8Genentech Inc., South San Francisco, CA, USA; 9Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA; 10Universitätsklinikum Bonn, Bonn, Germany

Introduction: Established treatments for PwHA who develop FVIII inhibitors are associated with suboptimal efficacy and high treatment burden. The burden can be especially high for children and their caregivers. Emicizumab is a recombinant, humanized, monoclonal antibody that restores missing FVIIIa function by bridging FIXa and FX. In an interim analysis of a Phase 3, single-arm study of paediatric PwHA with inhibitors (HAVEN 2; NCT02795756), prophylaxis (Px) with once-weekly subcutaneous emicizumab was well tolerated and, amongst pts on study ≥12 weeks (n = 23), the annualised bleed rate (95% CI) for treated bleeds was 0.2 (0.06; 0.62) and 87% (66.4; 97.2) had zero treated bleeds. Here we present effects of emicizumab Px on health-related (HR) outcomes and caregiver burden in HAVEN 2.

Methods: Paediatric PwHA with inhibitors were enrolled if they were previously treated with BPAs to control/prevent bleeds and were: age ≥2 to <12 years; age 12-17 years and <40 kg; or age <2 years with high unmet medical need. All pts received emicizumab 3.0 mg kg−1 wk−1 for 4 weeks and 1.5 mg kg−1 wk−1 thereafter. Outcomes included: Haemo-QoL-SF (age 8-11 years; range 0-100); Adapted InhibQoL with Aspects of Caregiver Burden (range 0-100); days of day care/school missed; and number of days hospitalised.

Results: At data cutoff (8 May 2017), 57 pts age <12 years, (22 pts age 8-11) were enrolled. Nineteen pts (10 pts age 8-11) reached Week 25. Change from baseline (BL) was only reported for pts with data at both BL and Week 25. At Week 25, mean (SD) change from BL in Haemo-QoL-SF (n = 7) was −10 (11) for Total score and −20 (25) for Physical Health (PH) domain. Notable improvements (mean [SD]) were seen in Feeling (−14 [18]) and Treatment (−14 [24]) domains. For aspects of caregiver burden, mean (SD) change from BL in Adapted InhibQoL (n = 16) was −22 (12) for Total score and −32 (22) for PH domain. Notable improvements were seen in Dealing (−27 [15]) and Family Life (−26 [24]) domains. In pts <12 years who answered the questionnaire, the proportion with no days away from day care/school during the previous 4 weeks was 28% (14/51) at BL and 83% (15/18) at Week 25.

Discussion/Conclusion: Once-weekly emicizumab Px substantially decreased bleeding in paediatric PwHA with inhibitors. This interim analysis suggests these clinical benefits may be accompanied by improvements in HRQoL and aspects of caregiver burden.

Disclosure of interest: M. Mancuso Consultant for: Bayer Healthcare, CSL Behring, Novo Nordisk, Sobi/Biogen Idec, Pfizer, Kedrion, Roche, Speaker Bureau of: Bayer Healthcare, CSL Behring, Baxalta/Shire, Novo Nordisk, Sobi/Biogen Idec, Pfizer, Octapharma, J. Mahlangu Grant/Research support from: Alnylam, Bayer, Biogen, Catalyst Biosciences, CSL Behring, Novo Nordisk, Roche,, Consultant for: Alnylam, Baxalta, Biogen, CSL Behring, Novo Nordisk, Roche, Shire, Speaker Bureau of: Alnylam, Amgen, Bayer, Biotest, Biogen, CLS, Roche, R. Sidonio Jr. Grant/Research support from: Shire, Bioverativ, Grifols, Consultant for: Shire, CSL Behring, Bioverativ, Novo Nordisk, Bayer, Genentech, P. Trask Shareholder of: Genentech Inc., Employee of: Genentech Inc., S. von Mackensen Consultant for: Roche, M. Shima Grant/Research support from: Bayer, Novo, Pfizer, Baxalta, Chugai, CSL., Consultant for: Bayer, Novo, Pfizer, Biogen, Baxalta, Chugai, Kaketsuken, CSL., Speaker Bureau of: Baxalta, Chugai., M. Uguen Employee of: Roche, T. Chang Shareholder of: Genentech Inc., Employee of: Genentech Inc., G. Young Consultant for: Alnylam, Bayer, Bioverativ, Genentech, Kedrion, Novo Nordisk, Roche, Shire, CSL Behring, J. Oldenburg Grant/Research support from: Baxter, Bayer, Biotest, CSL, Grifols, Novo, Octapharma, Baxalta, Consultant for: Baxter, Bayer, Biotest, Biogen, CSL, Grifols, Novo, Octapharma, Chugai, Pfizer, Roche, Baxalta, Sobi, Speaker Bureau of: Baxter, Bayer, Biotest, Biogen, CSL, Grifols, Novo, Octapharma, Chugai, Pfizer, Roche, Baxalta, Sobi.

OR11

Achievement of normal factor viii activity following BMN 270 AAV5-FVIII gene transfer: Long-term efficacy and safety from a phase 1/2 study in patients with severe hemophilia A

J. Pasi1,*, S. Rangarajan2, B. Kim3, W. Lester4, D. Perry5, B. Madan6, F. Tavakkoli3, K. Yang3, G. Pierce7, W. Y. Wong3

1Royal London Hospital, London, UK; 2Basingstoke and North Hampshire Hospital NHS Foundation Trust, Basingstoke, UK; 3BioMarin Pharmaceutical Inc, Novato, CA, USA; 4Queen Elizabeth Hospital Birmingham, Edgbaston, UK; 5Addenbrooke's Hospital, Cambridge, UK; 6St. Thomas’ Hospital, London, UK; 7Consultant, La Jolla, San diego, CA, USA

Introduction: As a single gene disorder of Factor VIII (FVIII), hemophilia A (HA) is an ideal candidate for gene therapy. We present results from an ongoing Phase 1/2 study of AAV5-FVIII gene transfer in patients with severe HA.

Methods: As of 28 July 2017, 13 subjects (6E13 vg/kg, n = 7; 4E13 vg/kg, n = 6) received a single intravenous dose of an AAV5 vector containing the B-domain-deleted FVIII gene (BMN 270). Safety, efficacy, immunogenicity, and other clinically relevant endpoints are being evaluated.

Results: FVIII activity is presented as median levels over 4-week intervals. In the 6E13 vg/kg cohort, FVIII activity plateaued by Week 20 post-BMN 270, with median levels between Weeks 20-64 in the normal range (NR; 86-122 IU/dL); at Week 64, median FVIII activity was 86 IU/dL (interquartile range [IQR] 65-107 IU/dL). In the 4E13 vg/kg cohort, median [IQR] FVIII activity continue to steadily increase toward the NR (Week 20 [n = 6]: 34 [28-40] IU/dL; Week 32 [n = 3]: 51 [48-54] IU/dL). Median [IQR] annualized FVIII infusions in the 6E13 and 4E13 vg/kg cohorts declined from 139 [122-157] and 156 [112-183] to 0 [0-0] in both cohorts 4 weeks post-BMN 270 infusion through last follow-up visit. Subjects previously on prophylactic therapy (n = 6 in each dose cohort) had a median [IQR] annualized bleeding rate of 0 [0-0] with 5 subjects in each cohort reporting no bleeding episodes. Mild, grade 1, asymptomatic alanine aminotransferase (ALT) increases were reported in all 7 (6E13 vg/kg) and 4 of 6 subjects (4E13 vg/kg). Peak ALT levels ranged from 44-141 U/L (upper limit of normal = 43 U/L). All but 1 subject (4E13 vg/kg) currently have a normal ALT level, and all but 1 subject (4E13 vg/kg) are off of corticosteroid therapy.

Discussion/Conclusion: AAV5-FVIII gene transfer in subjects with severe HA resulted in sustained, clinically relevant FVIII activity that profoundly reduced self-reported bleeding and exogenous FVIII use >1.2 years post-gene transfer in the 6E13 vg/kg cohort. FVIII activity in the 4E13 vg/kg cohort continues to rise, reaching the lower end of NR >0.6 years post-gene transfer. BMN 270 was well-tolerated. Both doses enabled achievement of long-term normalization of FVIII activity and prevention of hemophilia-related bleeding, with a favorable safety profile. BMN 270 will be further evaluated in upcoming Phase 3 clinical trials.

Disclosure of interest: J. Pasi Grant/Research support from: BioMarin Pharmaceutical Inc.; Octapharma, Alnylam Pharmaceuticals,, Consultant for: Alnylam Pharmaceuticals, Inc; Biogen Idec Inc.; BioMarin Pharmaceutical, Paid Instructor at: Roche, Novo Nordisk, Pfizer, Speaker Bureau of: Bayer HealthCare; Biotest; Novo Nordisk; Pfizer Inc.; Roche, S. Rangarajan Grant/Research support from: Shire, Pfizer, Novo Nordisk, BioMarin, Grifols, Alnylam, LFB, B. Kim Employee of: BioMarin Pharmaceutical Inc, W. Lester: None declared, D. Perry Grant/Research support from: BioMarin, B. Madan: None declared, F. Tavakkoli Employee of: BioMarin Pharmaceutical Inc, K. Yang Employee of: BioMarin Pharmaceutical Inc, G. Pierce Consultant for: BioMarin, Roche, W. Y. Wong: None declared.

OR12

SPK-9001: Adeno-associated virus mediated gene transfer for hemophilia B—sustained fix activity and persistent prophylactic benefit at 1 year

L. A. George1,*, M. E. Carr2, S. K. Sullivan3, A. Giermasz4, B. J. Samelson-Jones5, J. M. Ducore6, J. M. Teitel7, A. E. Cuker5, S. V. Mackensen8, S. Majumdar9, C. E. McGuinn10, A. R. Runoski11, J. F. Wright12, S. E. Dasen13, K. E. Barber13, Y. E. Chen13, D. J. Hui13, R. E. Patel12, Y. E. Liu12, K. E. Wachtel14, D. Takefman14, L. B. Couto12, K. Reape13, X. M. Anguela12, K. A. High13

1Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; 2Research and Development, Spark Therapeutics, Inc., Philadelphia, PA, USA; 3Pediatric Hematology/Oncology, Mississippi Center for Advanced Medicine, Madison, MS, USA; 4Hematology, University of California Davis, Davis, CA, USA; 5Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 6Pediatric Hematology/Oncology, University of CA Davis Medical Center, Sacramento, CA, USA; 7St. Michael's Hospital, University of Toronto, Toronto, ON, Canada; 8Department of Medical Psychology, University Medical Centre Hamburg-Eppendorf, Hamburg, GA, USA; 9Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC, USA; 10Weill Cornell Medical College, New York, NY, USA; 11Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA USA; 123737 Market Street, Suite 1300, Philadelphia, PA, USA; 13Research and Development, Spark Therapeutics, Inc., Philadelphia, PA, USA; 14Regulatory Affairs, Spark Therapeutics, Inc., Philadelphia, PA, USA

Introduction: Levels of FIX:C obtained with long term expression of FIX after AAV8-mediated gene transfer in hemophilia B (HB) have fallen short of values that may be required (≥12%) to eliminate spontaneous hemarthrosis. We seek to develop a recombinant AAV (rAAV) gene transfer agent that will, at low doses, achieve FIX:C adequate to prevent bleeding.

Methods: SPK-9001 combines a liver specific, bioengineered AAV capsid (Spark100) and a single-stranded cassette encoding FIX-Padua. FIX-Padua has enhanced (˜5-10 fold) specific activity. Subject baseline characteristics and FIX:C were compared to vector post-infusion data. We report 1 year follow up in 9 subjects infused with 5 × 1011 vg/kg.

Results: As of 10/15/17, 9 subjects completed 1 year follow up after a SPK-9001 dose of 5 × 1011 vg/kg. Subjects were males ages 18-52 with FIX:C ≤2%. No vector related serious adverse events (SAEs) or FIX inhibitors occurred. Mean FIX:C at 12 weeks following vector (30.0 ± 17.6%) did not significantly differ from FIX:C at 52 weeks (35.4 ± 21.8%). One subject had pre-treatment Spark100 neutralizing antibody (NAb) titer of 1:1 and the remaining were <1:1. FIX:C for subjects with <1:1 NAb was 38.6 ± 21.1% at 52 weeks and 12% for the subject with NAb 1:1. FIX:C in the five subjects with a history of HCV and stage 1-2 liver fibrosis (44.0 ± 26.1%) or with combined HIV and HCV exposure (26%) did not differ significantly from other participants. All subjects discontinued prophylaxis. Use of factor concentrate occurred in one subject who infused for self-reported joint bleeding. Baseline characteristics in two subjects with suspected T-cell mediated capsid immune responses did not differ from the cohort. Both subjects were treated with a steroid taper, and have stable, sustained FIX:C (15% and 78%) with no bleeding post vector.

Discussion/Conclusion: These data represent the highest, most consistent and sustained vector derived FIX:C following gene transfer in the largest cohort of HB subjects treated using the same vector and dose with 1 year follow up. Despite heterogenous baseline characteristics, all subjects achieved consistent clinical results including no serious AEs, improved QoL, termination of prophylaxis, near complete elimination of bleeding and factor use. Low grade liver fibrosis and prior HCV exposure did not appear to affect achieved FIX:C.

Disclosure of interest: L. George Grant/Research support from: Principal Investigator Ongoing Spark Phase I/II trials, Consultant for: Pfizer, M. Carr Shareholder of: Pfizer, Spark Therapeutics, Inc., Employee of: Spark Therapeutics, Inc., S. Sullivan: None declared, A. Giermasz: None declared, B. Samelson-Jones: None declared, J. Ducore Grant/Research support from: Octapharma, Consultant for: Bayer, Shire, Hema Biologics, Bioverativ, Octapharma, Spark Therapeutics, J. Teitel: None declared, A. Cuker: None declared, S. Mackensen Consultant for: Spark Therapeutics Inc., S. Majumdar: None declared, C. McGuinn: None declared, A. Runoski: None declared, J. Wright Shareholder of: Spark Therapeutics, Employee of: Spark Therapeutics, Inc., S. Dasen Employee of: Spark Therapeutics, Inc., K. Barber Employee of: Spark Therapeutics, Inc., Y. Chen Employee of: Spark Therapeutics, Inc., D. Hui Employee of: Spark Therapeutics, Inc., R. Patel Employee of: Spark Therapeutics, Inc., Y. Liu Employee of: Spark Therapeutics, Inc., K. Wachtel Employee of: Spark Therapeutics, Inc., D. Takefman Employee of: Spark Therapeutics, Inc., L. Couto Employee of: Spark Therapeutics, Inc., K. Reape Employee of: Spark Therapeutics, Inc., X. Anguela Employee of: Spark Therapeutics, Inc., K. High Shareholder of: Spark Therapeutics, Employee of: Spark Therapeutics, Inc.

OR13

SPK-8011: Preliminary results from a phase 1/2 trial of investigational gene therapy for hemophilia A

L. A. George1,*, M. Ragni2, S. K. Sullivan3, J. C. Barrett4, B. J. Samelson-Jones1, A. Cuker5, G. Cole6, F. Wright6, Y. Chen7, D. J. Hui8, Y. Liu8, K. Wachtel9, D. Takefman9, L. B. Couto8, K. Reape6, M. E. Carr6, X. M. Anguela6, K. A. High6

1The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 2Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 3Pediatric Hematology/Oncology, Mississippi Center for Advanced Medicine, Madison, MS, USA; 4Central Virginia Center for Coagulation Disorders, Virginia Commonwealth University, Richmond, VA, USA; 5Hematology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 6Research and Development, Spark Therapeutics, Inc., Philadelphia, PA, USA; 73737 Market Street, Suite 1300, Spark Therapeutics, Inc., Philadelphia. PA, USA; 83737 Market Street, Suite 1300., Philadelphia. PA, USA; 9Regulatory Affairs, Spark Therapeutics, Inc., Philadelphia, PA, USA

Introduction: Current hemophilia A (HA) therapy is based on administration of FVIII protein. While improving outcomes in HA, prophylaxis has a high (43%) non-compliance rate. Recombinant adeno-associated viral (rAAV) vectors, in development for >25 years with no major safety concerns in >160 clinical trials, may offer a way to achieve sustained expression of clinically relevant FVIII levels. The objective of this work is to obtain consistent, predictable and sustained FVIII activity (FVIII:C) adequate to prevent spontaneous bleeding without the need for prophylactic FVIII infusions.

Methods: SPK-8011 is a rAAV vector composed of a hepatotropic bio-engineered capsid (AAV-Spark200) and a codon-optimized expression cassette encoding a B-domain-deleted (BDD) human FVIII gene. The phase 1/2 trial is an open-label, non-randomized, dose-escalation study of SPK-8011 (starting dose 5 × 1011 vg/kg) in adult HA males (FVIII:C ≤2%). Laboratory data, bleeding frequency, and FVIII use before vector infusion are compared to post infusion values.

Results: As of 10/15/17, we infused 5 subjects: 2 at 55 × 1011, 2 at 15 × 1012, 1 at 25 × 1012 vg/kg. Subjects were 28-52 years with Spark200 NAb titer of <1:1. Subjects infused with 55 × 1011 vg/kg have FVIII:C of 11% and 14% at 30 and 17 weeks after infusion. Subjects infused at 15 × 1012 vg/kg have not reached steady state, but the subject >6 weeks post vector infusion has a FVIII level >10%. As of 10/15, data was unavailable on the 25 × 1012 vg/kg subject. ELISPOT reactivity to capsid peptides revealed early (week 1-5) transient (resolved by week 6) positivity in 1 subject. Hepatic transaminases increases have not occurred. All subjects discontinued FVIII prophylaxis. One subject experienced fever and myalgias that resolved within 24 hours of vector infusion. After 518 cumulative follow up days, there have been no additional vector related adverse events or FVIII inhibitors. There have been 10 factor infusions (5 prophylactic during the first week) and 5 to treat 3 bleeds (1 spontaneous elbow, 1 traumatic ankle, 1 dental extraction).

Discussion/Conclusion: Preliminary results in this phase 1/2 study demonstrate FVIII:C levels sufficient to prevent spontaneous bleeding without exogenous factor use. Therapeutic transgene-derived FVIII:C was achieved at the lowest vector dose thus far reported in HA trials. As of this report, no safety concerns have been observed.

Disclosure of interest: L. George Grant/Research support from: Principal Investigator Ongoing Spark Phase I/II trials, Consultant for: Pfizer, M. Ragni: None declared, S. Sullivan: None declared, J. Barrett: None declared, B. Samelson-Jones: None declared, A. Cuker: None declared, G. Cole Employee of: Spark Therapeutics, Inc., F. Wright Shareholder of: Spark Therapeutics, Inc, Employee of: Spark Therapeutics, Inc., Y. Chen Employee of: Spark Therapeutics, Inc., D. Hui Employee of: Spark Therapeutics, Inc., Y. Liu Employee of: Spark Therapeutics, Inc., K. Wachtel Employee of: Spark Therapeutics, Inc., D. Takefman Employee of: Spark Therapeutics, Inc., L. Couto Employee of: Spark Therapeutics, Inc., K. Reape Shareholder of: Spark Therapeutics, Inc, Employee of: Spark Therapeutics, Inc., M. Carr Shareholder of: Spark Therapeutics, Inc, Employee of: Spark Therapeutics, Inc., X. Anguela Shareholder of: Spark Therapeutics, Inc, Employee of: Spark Therapeutics, Inc., K. High Shareholder of: Spark Therapeutics, Inc, Employee of: Spark Therapeutics, Inc.

OR14

Endogenous fix expression and reduced annual bleed rate following AMT-060 (AAV-HFIX) in adults with severe or moderate-severe hemophilia B: Interim results up to 1.5 years from a phase I/II dose-escalation study

W. Miesbach1,*, K. Meijer2, M. Coppens3, P. Kampmann4, R. Klamroth5, R. Schutgens6, G. Castaman7, E. Seifreid8, J. Schwable8, H. Boeig1, E. Sawyer9, F. Leebeek10

1Universitatsklinikum Frankfurt, Frankfurt, Germany; 2University Medical Center Groningen, Groningen, The Netherlands; 3Academic Medical Centre, Amsterdam, The Netherlands; 4Rigshospitalet, Copenhagen, Denmark; 5Vivantes Klinikum, Berlin, Germany; 6University medical Centre, Utrecht, The Netherlands; 7Azienda ospedaliera Universitaria Careggi, Florence, Italy; 8German Red Cross Blood Service Baden Wuerttemberg-Hessen, Institute Frankfurt, Frankfurt, Germany; 9uniQure biopharma, Amsterdam, The Netherlands; 10Erasmus University Medical Center, Rotterdam, The Netherlands

Introduction: Gene transfer for hemophilia offers the potential to convert the disease from severe to mild with a single treatment. AMT-060 comprises an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized wildtype human factor IX (FIX) gene under control of a liver-specific promoter.

Methods: Multi-national, open-label, dose-escalating Phase I/II safety and efficacy study of AMT-060 in adult males with FIX activity ≤2% of normal and a severe bleeding phenotype (prophylactic exogenous FIX; or on-demand exogenous FIX, plus ≥4 bleeds/year or hemophilic arthropathy). Pts received either 5 × 1012 gc/kg (Cohort 1; n = 5) or 2 × 1013 gc/kg (Cohort 2; n = 5) of AMT-060 iv. Efficacy assessments include endogenous FIX activity (measured ≥10 days after last exogenous FIX); exogenous FIX use; and annualized bleeding rates (ABR). Safety assessments include treatment-related adverse events, immunological and inflammatory biomarkers.

Results: There were no screening failures due to AAV5 NABs; 3 pts were later found to test positive using a novel highly-sensitive assay, with no association with treatment outcome. Cohorts 1 and 2 had 1.5 and 1 years of follow-up post-AMT-060 available, respectively. Mean (95% CI) FIX activity was 4.6 IU/dL (1.6-7.6) in Cohort 1, and 7.1 IU/dl (3.2-11.1) in Cohort 2, with an activity:antigen ratio of approximately 1 in evaluable pts (n = 7; 3 pts presumed cross-reactive material positive). 8/9 pts on FIX prophylaxis discontinued use. Annualized exogenous FIX consumption declined 85% in Cohort 1 and 68% in Cohort 2. Mean ABR decreased 54% and 64% compared to 1 year before AMT-060 for Cohorts 1 and 2 (n = 4, historical data unavailable for 1 pt), respectively, while mean spontaneous ABRs decreased 58% and 84%. 3 pts experienced mild, temporary elevations in alanine transaminase (ALT) levels and received a tapering course of prednisolone. ALT elevations were not associated with changes in FIX activity, NAB status at screening, or capsid-specific T-cell responses.

Discussion/Conclusion: Pts continue to show sustained endogenous FIX activity with no T-cell activation ≥1 year after a single infusion of AMT-060. Modifying AMT-060 with a hyperactive FIX variant may offer FIX activity in near-curative ranges at similar protein levels while maintaining safety attributes.

Disclosure of interest: W. Miesbach Grant/Research support from: Uniqure, Consultant for: Novo-Nordisk, Bayer, Shire, Biotest, Pfizer, Octapharma, LFB, CSL Behring, SOBI, Biogen and BPL, K. Meijer Consultant for: Uniqure, Speaker Bureau of: Bayer, Sanquin, Baxter, Pfizer Boehringer Ingelheim, BMS, Aspen, M. Coppens Consultant for: Uniqure, CSL Behring, Bayer, P. Kampmann Grant/Research support from: UniQure, R. Klamroth Grant/Research support from: Shire/Baxalta, Bayer, CSL Behring, Pfizer, Consultant for: SOBI, Biotest, Chiesi, Octapharma, Novo Nordisk, R. Schutgens Grant/Research support from: Uniqure, G. Castaman Grant/Research support from: Uniqure, Consultant for: Kedrion, Novo-Nordisk, Shire, SOBI, CSL Behring, Pfizer, Bayer, E. Seifreid: None declared, J. Schwable: None declared, H. Boeig: None declared, E. Sawyer Employee of: Uniqure, F. Leebeek Grant/Research support from: Uniqure, CSL Behring, Baxalta/Shire.

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