编者按：欧洲血友病和相关疾病协会（EAHAD）始终肩负着促进教育、支持研究，以及提升遗传性或后天性出血性疾病患者临床护理水平、改善其生活质量的重要使命。2025年2月4日至7日，第18届EAHAD年会在意大利米兰盛大举行。

ORO1 I FRONTIER3: Safety and Efficacy Of Mim8Prophylaxis in Paediatric Patients with Haemophilia A

FRONTIER3：Mim8在血友病A患儿中预防治疗的安全性和有效性研究

J.Mahlangu等

背景：；Mim8（NNC0365-3769/denecimig）是一种处于临床开发阶段的模拟凝血VIII因子（FVIIIa）的双特异性抗体，用于血友病A（HA）伴或不伴抑制物（HAwI）患者的皮下（SC）预防治疗。本中期分析报告了3期、开放标签的FRONTIER3儿科研究（NCT05306418）在所有患者完成第1部分时的研究结果。

方法：FRONTIER3研究纳入任何严重程度的HA/HAwI的患儿（年龄1-11岁），接受第1部分（已完成）为期26周的每周一次（QW）皮下注射Mim8治疗，然后可选择在第2部分（进行中）接受为期26周的QW或每月一次（QM）的Mim8治疗。对于之前接受过预防治疗的患者，该研究纳入了至少 26 周的导入期。主要终点是治疗期间出现的不良事件（TEAE）数量。次要终点包括治疗出血次数、出血亚型、抗药物抗体（ADA）、注射部位反应（ISR）和Mim8血浆浓度。

结果：共有70例患儿（n=36例1-5岁；n=34例6-11岁）纳入并完成第1部分；大多数（n=60，85.7%）患有严重HA [n=8（11.4%）为中型，n=2（2.9%）为轻度]；14例（20%）患有HAwI。在第2部分，38例患儿继续QW注射Mim8，31例转为QM注射。

【摘要原文】：

Introduction: Mim8 (denecimig) is a Factor VIII mimetic bis-pecific antibody in clinical development for subcutaneous (SC)prophylaxis in haemophilia A (HA) with inhibitors (HAwI) or without. This interim analysis reports results from the Phase 3,open-label FRONTIER3 paediatric study (NCT05306418) when all patients completed Part 1.

Methods: FRONTIER3 enroled patients with HA/HAwI (aged 1–11 years) of any severity to receive 26 weeks of SC Mim8 once weekly (QW) in Part 1 (completed), then the option of 26weeks of Mim8 QW or once monthly (QM) in Part 2 (ongoing).The study included a run-in period of at least 26 weeks for patients previously treated with prophylaxis. Primary endpoint was the number of treatment-emergent adverse events (TEAEs).Secondary endpoints included number of treated bleeds, bleed subtypes, anti-drug antibodies (ADAs), injection site reactions (ISRs) and Mim8 plasma concentration.

Results: In total, 70 patients (n = 36 aged 1–5 years; n = 34 aged 6–11 years) enroled in and completed Part 1; most (n = 60, 85.7%)had severe HA [n = 8 (11.4%) had moderate, n = 2 (2.9%) had mild]; 14 (20%) had HAwI. In Part 2, 38 patients continued Mim8 QW, and 31 switched to Mim8 QM. 198 TEAEs were reported in 58 (82.9%) patients across Parts 1 and 2 [total exposure time (TET): 59.6 years]. No TEAEs were severe, and no hypersensitivity reactions or TEAEs of special interest (including thromboembolic events such as thrombotic microangiopathy) were reported. ISRs occurred in 6 (8.6%) patients; 0.97% of injections led to ISRs. No evidence of neutralising ADAs was observed. In Part 1, estimated mean annualised bleeding rate (ABR; negative binomial model) for treated bleeds with Mim8 QW was 0.53 (95% CI: 0.30;0.94);median observed ABR was 0.00; TET was 35.4 years; 74.3% of patients had zero treated bleeds. In Part 2, estimated mean ABR for treated bleeds was 0.37 (95% CI: 0.15;0.90) for Mim8 QW and 0.21 (0.05;0.85) for Mim8 QM; median ABR was 0.00 in both groups; TET was 14.7 and 9.5 years; and 86.8% and 93.5%of patients had zero treated bleeds, respectively. Among patients with HAwI (n = 14), none reported treated bleeds across Parts 1 and 2. Mim8 plasma concentration was within the expected range.

OR02 |Efanesoctocog Alfa for the Perioperative Management of Patients with Severe Haemophilia A: 4 Years of Experience in the XTEND Clinical Program

Efanesoctocog Alfa用于重型血友病A患者围手术期管理：XTEND四年临床经验总结

A.K. C. Chan等

背景：Efanesoctocog Alfa是一种首创的高效持续型凝血因子VIII替代治疗，能够克服血管性血友病因子所限制的半衰期上限。XTEND-1（NCT04161495）和XTEND-Kids（NCT04759131）研究显示，Efanesoctocog Alfa（50 IU/kg）每周一次治疗在重型血友病A患者手术期间具有较高的疗效且耐受性良好。完成这些研究的参与者可以继续在XTEND-ed（NCT04644575）A组进行Efanesoctocog Alfa预防治疗。本研究报告了从基线至XTEND-ed第二次中期分析的四年手术数据。

方法：本研究包括来自母研究的XTEND-ed A组参与者，以及在B组（中国）和C组（计划手术）中刚开始接受预防治疗的患者。患者按照方案在术前接受50 IU/kg的药物剂量；对于大型手术，术后每2-3天根据需要给予30或50 IU/kg的剂量。允许短期围手术期血栓栓塞预防。描述了维持止血所需的注射次数和剂量、总消耗量、失血/输血量及研究者的疗效评估。数据截止日期为2024年2月22日。

结果：45名男性（平均年龄35.6岁）接受了62次大型手术（其中31例为骨科手术）；47名患者（平均年龄33.1岁）接受了56次小型手术。对于大型手术，56例（90.3%）的患者在术前1天到手术当日之间通过1次注射维持止血；维持止血的平均总剂量为50.4（SD 11.5）IU/kg。术前1天到术后14天的围手术期平均消耗量为176.2（SD 54.6）IU/kg，平均注射次数为4.1（SD 1.7）次。估算的术中平均失血量为125.4（SD 210.5）mL[骨科手术为219.0（SD 250.6）mL；非骨科手术为14.3（SD 28.2）mL]。95.2%的病例止血效果被评为良好/优秀，仅2例（3.2%）大型手术需要输血（均为骨科手术）。对于小型手术，47例（83.9%）患者在术前1天到手术当日之间通过1次注射维持止血；9例患者不需要术前给药。维持手术过程中止血的平均总剂量为50.5（SD 5.2）IU/kg。术前1天到术后7天的围手术期平均消耗量为94.3（SD 31.8）IU/kg，平均注射次数为1.9（SD 0.8）次。

结论：这些数据进一步证明，对于各种手术中的重型A型血友病患者围手术期管理，Efanesoctocog Alfa疗效显著且耐受性良好。围手术期因子总使用量较低。

【摘要原文】：

Introduction: Efanesoctocog alfa is a first-in-class high-sustained Factor VIII replacement therapy that overcomes the von Willebrand factor-imposed half-life ceiling. XTEND-1 (NCT04161495) and XTEND-Kids (NCT04759131) showed once-weekly efanesoctocog alfa (50 IU/kg) was highly efficacious and well tolerated during surgery in people with severe haemophilia A. Participants completing these studies could continue efanesoctocog alfa prophylaxis in XTEND-ed (NCT04644575)Arm A. We report 4 years of surgical data from parent studies baseline through the 2nd interim analysis of XTEND-ed.

Methods: XTEND-ed Arm A participants from parent studies and those newly initiating prophylaxis in Arms B (China) and C (planned surgery) were included. Patients received 50 IU/kg preoperatively per protocol; 30 or 50 IU/kg was administered every 2–3 days (D) postoperatively for major surgeries as needed. Short-term perioperative thromboembolic prophylaxis was allowed. The number and dose of injections to maintain haemostasis, total consumption, blood loss/transfusions and investigator assessment of response are described. Datacut 22 February 2024.

Results: Forty-five males (mean age 35.6 years) had 62 major surgeries (31 orthopaedic); 47 (mean age 33.1 years) had 56 minor surgeries. For major surgeries, haemostasis was maintained (D-1 to 0) with 1 injection in 56 (90.3%) cases; mean (SD) total dose to maintain haemostasis was 50.4 (11.5) IU/kg. Mean (SD)perioperative consumption (D-1 to 14) was 176.2 (54.6) IU/kg with a mean (SD) of 4.1 (1.7) injections. Mean (SD) estimated intraoperative blood loss was 125.4 (210.5) mL [orthopaedic 219.0 (250.6) mL; nonorthopaedic 14.3 (28.2) mL]. Haemostatic response was rated good/excellent in 95.2% of cases. Transfusions were required for 2 (3.2%) surgeries (both orthopaedic). For minor surgeries, haemostasis was maintained (D-1 to 0) with 1 injection in 47 (83.9%) cases; 9 did not require a preoperative dose. Mean (SD) total dose to maintain haemostasis during surgery was 50.5(5.2) IU/kg. Total mean (SD) perioperative consumption (D-1 to 7) was 94.3 (31.8) IU/kg with a mean (SD) of 1.9 (0.8) injections.

OR03 |Pharmacodynamics (PD)and Pharmacokinetics(PK) of Dirloctocogene Samoparvovec in People With Severe to Moderately Severe Haemophilia A (HA)

Dirloctocogene Samoparvovec（SPK-8011）在中重型至重型血友病A（HA）患者中的药效学（PD）与药代动力学（PK）研究

L. George等

结果：共有25名患者被纳入四个剂量组[5×1011（n=2），1×1012（n=3），2×1012（n=9），和1.5×1012（n=11）vg/kg]。截至数据截止日期（2024年3月8日），自给药后的中位时间为4.6年（范围：1.25-6.5年）。所有患者均出现治疗反应，表现为给药后FVIII活性较基线（BL）初始升高。各剂量组FVIII活性达到峰值的中位时间为49天（范围：26-321天）。在两个最高剂量组中，中位FVIII活性峰值（OSA法）的中位数在2×1012剂量组为38.7%（范围：7-209），在1.5 ×1012剂量组为55.1%（范围：31-112）。在5×1011剂量组的两名患者中，FVIII活性峰值（OSA法）分别为10.8%和12.1%，在1×1012剂量组的三名患者中，峰值FVIII活性（OSA法）分别为6.3%、20.0%和24.2%。在2×1012剂量组的两名患者中，观察到暂时性超生理水平的FVIII表达（OSA/CSA结果>150%），FVIII活性峰值（OSA法）分别为194%和209%；这些超生理水平并未持续，且未与血栓事件相关。

【摘要原文】：

Introduction: Dirloctocogene samoparvovec is a low-dose inves-tigational adeno-associated viral vector gene therapy for HA. In the Phase 1/2 program (NCT03003533/NCT03432520), dirloctoco-gene samoparvovec demonstrated a favourable safety profile and durable Factor (F)VIII expression for up to 6.5 years, with most participants (pts) stabilising within the mild HA range (George,ISTH 2024). PD and PK of dirloctocogene samoparvovec are described.

Methods: Adult males with moderate–severe HA (<2%) and no pre-existing anti-capsid neutralising antibodies received a single dose of dirloctocogene samoparvovec (George, NEJM 2021).Transgene PD measures were FVIII activity assessments [chro-mogenic substrate assay (CSA) and one-stage assay (OSA)]. PK was assessed as vector shedding in peripheral blood mononuclear cells (PBMCs), saliva, semen, serum and urine.

Results: A total of 25 pts were enroled across four dose cohorts [5 × 1011(n = 2), 1 × 1012 (n = 3), 2 × 1012 (n = 9), and 1.5 × 1012 (n = 11) vg/kg]. At data cutoff (8 March 2024), median time since dosing was 4.6 years (range: 1.25–6.5). All pts responded, as evidenced by an initial increase from baseline (BL) FVIII activity after dosing. The median time to peak FVIII activity was 49 days (range: 26–321) across all cohorts. In the two highest dose cohorts,median peak FVIII activity (OSA) was 38.7% (2 × 1012 cohort;range: 7–209) and 55.1% (1.5 × 1012 cohort; 31–112). The two pts in the 5 × 1011 cohort had peak FVIII activity (OSA) of 10.8% and 12.1%, and the three in the 1 × 1012 cohort had peak activity (OSA) of 6.3%, 20.0% and 24.2%. Transient supraphysiologic FVIII expression (OSA/CSA result >150%) was observed in two pts[2 × 1012 cohort; peak FVIII activity (OSA): 194% and 209%]; these levels were not sustained or associated with thrombotic events.The median time to absence of detectable vector was 5.5 weeks (wks; range: 3–12) in PBMCs (n = 22), 2.0 wks (1–2) in saliva (n = 21), 2.0 wks (1–3) in semen (n = 17), 2.0 wks (2–3) in serum (n = 23) and 1.0 wk (1–2) in urine (n = 23).

OR04 |Immune Tolerance Induction (ITI) in Haemophilia A Inhibitor Patients: MOTIVATE First Per Protocol Interim Analysis

血友病A抑制物患者的免疫耐受诱导（ITI）：MOTIVATE研究首次中期分析

C. Escuriola Ettingshausen等

【摘要原文】：

Introduction: Inhibitor eradication to restore Factor VIII (FVIII)efficacy is the treatment goal for persons with severe haemophilia A (HA) and inhibitors. Emicizumab can prevent bleeding in patients with inhibitors but does not eradicate them. ITI therapy (repeated FVIII administration) is the only clinically proven way to eliminate inhibitors. MOTIVATE investigates real-life management of haemophilia A patients with inhibitors and evaluates the efficacy and safety of ITI, emicizumab prophylaxis and ITI with emicizumab prophylaxis.

Methods: MOTIVATE is an investigator-initiated, international,multicentre, prospective study (NCT04023019). Males of any age with haemophilia A and FVIII inhibitors, with or without prior unsuccessful ITI attempts, were included. Patient groups were Group 1: ITI (FVIII only); Group 2: FVIII ITI alongside emicizumab prophylaxis; Group 3: routine emicizumab prophy-laxis without ITI. The primary outcome for Groups 1 and 2 was ITI success (negative inhibitor titre, FVIII recovery and half-life). Secondary outcomes included time to ITI success and frequency/severity of bleed events (BEs).

Results: As of June 2024, 46/56 patients were eligible for interim analysis: Group 1/2/3: n = 7/22/17. Total treatment duration [median years (range)] was 2.8 [1.5–5.0], 2.0 [0.7–5.0] and 3.5 [0.3–5.1], respectively. Negative inhibitor titre was achieved in 6/7Group 1 and 10/22 Group 2 patients; reached in a median of 8 and 19 months. The median FVIII dose at ITI initiation was 394.1 and 225.9 IU/kg/week, respectively. 6/6 (Group 1) and 16/20 (Group 2)high-responder patients (titre ≥ 5 BU/mL) were on primary ITI,of which 5/6 and 6/16 achieved negative inhibitors. Two Group 2 patients failed ITI and switched to Group 3. There were 151 BEs in 35/45 patients. Major BEs: Group 2/3: n = 6/1. Moderate BEs: Group 1/2/3: n = 4/13/35; 50% (26/52) were joint bleeds and 85%(22/26) were in Group 3. Minor BEs: Group 1/2/3: n = 31/18/43.One mild adverse drug reaction related to emicizumab was recorded with no discontinuation. No thrombotic or thrombotic microangiopathy events were reported.

OR05 Elevating Levels of Endogenous Circulating vonWillebrand Factor (VWF): The Potential of HMB-002 as a Prophylactic Treatment of von Willebrand Disease (VWD)

提高内源性循环von Willebrand因子（VWF）水平：HMB-002作为von Willebrand病（VWD）预防治疗的潜力

H. Ostergaard等

方法：通过酶联免疫吸附实验（ELISA）、VWF-ristocetin辅助活性（VWF:RCo）和胶原结合（VWF:CB）试验、VWF多聚体分析、全血流试验评估HMB-002对VWF的影响，并在对食蟹猴单剂量给药后进行相关检测。

结果：通过表面等离子体共振（SPR）分析和X射线晶体学，证明了HMB-002可与VWF的C端CK结构域表位具有高亲和力结合。体外和离体试验表明，在HMB-002存在时，VWF保持了关键功能，包括与FVIII、血小板糖蛋白1b（GP1b）和胶原的结合，以及被ADAMTS13酶切处理的能力。对食蟹猴给予HMB-002后，VWF抗原的稳态水平随时间积累并升高。VWF抗原的积累伴随着VWF:RCo和FVIII抗原成比例增加，而VWF多聚体模式基本保持不变。

结论：HMB-002延长了内源性VWF的半衰期，促使VWF和FVIII在功能保留的情况下积累。通过提高循环中VWF和FVIII的水平，HMB-002旨在通过提供便捷、低频率的皮下预防治疗，减轻VWD患者的出血症状，满足未被满足的治疗需求，提高患者依从性并改善治疗效果。

【摘要原文】：

Introduction: VWD is the most common inherited bleeding dis-order affecting about 1% of the global population. It results from a deficiency or defect in VWF, a protein crucial for hemostasis.Symptoms range from frequent small-volume mucocutaneous bleeding to severe hemorrhagic episodes and heavy menstrual bleeding, often leading to iron deficiency anemiaall of which pose significant yet often overlooked health equity concerns.Current VWD treatments are limited, with on-demand therapies unsuitable for long-term use and VWF replacement requiring fre-quent intravenous infusion. An ideal VWD therapy would enable effective and durable prophylaxis with reduced administration frequency, improving adherence and outcomes. HMB-002 aims to offer convenient subcutaneous (SC) prophylaxis by binding to and elevating levels of endogenous circulating VWF and thereby also increasing FVIII. It is a human, monovalent antibody designed to bind VWF across the spectrum of VWD mutations while retaining VWF function. Here, we investigate the functional properties of HMB-002.

Methods: The effect of HMB-002 on VWF was evaluated by ELISA, VWF ristocetin cofactor activity (VWF:RCo) and collagen-binding (VWF:CB) assays, VWF multimer analysis, and whole-blood flow assays, and after single-dose administration to cynomolgus monkey.

Results: High-affinity binding of HMB-002 to an epitope in the C-terminal CK domain of VWF was demonstrated by surface plas-mon resonance (SPR) analysis and X-ray crystallography. Using in vitro and ex vivo assays, VWF retained key functions in presence of HMB-002, including binding to FVIII, platelet GP1b and collagen, as well as processing by ADAMTS13. Administration of HMB-002 to cynomolgus monkey resulted in a time-dependent accumulation and elevation of the steady-state level of VWF antigen. Accumulation of VWF antigen was accompanied by a proportional increase in VWF:RCo and FVIII antigen, while the VWF multimer pattern remained essentially unchanged.

Discussion/Conclusion: HMB-002 extends the half-life of endogenous VWF, leading to the accumulation of VWF and FVIII with retained function. By increasing the levels of VWF and FVIII in circulation, HMB-002 aims to mitigate the bleeding in VWD by providing convenient, infrequent SC prophylaxis, addressing unmet needs and improving adherence and outcomes.