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。
 

血友病及其他出血性疾病，对患者的生活质量与健康造成了严重影响。尽管治疗领域持续取得进步，但在这些疾病的治疗方面，依旧存在诸多亟待攻克的挑战，众多需求尚未得到满足。在EAHAD 2025年会上，10项精彩的口头报告（Oral）吸引了众多目光。这些报告内容广泛且深入，从血友病A患儿的Mim8预防治疗，到重型血友病A患者围手术期的精细管理；从基因治疗药物的药效学与药代动力学探究，到血管性血友病、Hermansky-Pudlak综合征等相关疾病的治疗新探索。各项研究从独特视角出发，为改善出血性疾病的治疗现状提供了宝贵的新证据与新思路，犹如点点星光，为临床治疗的发展指引方向，意义重大。《血液时讯》精心整理了此次会议全部口头报告的摘要，以飨读者。

 

OR06 Screening and Surveillance Pathway for Patients with Hermansky–Pudlak Syndrome at Risk of Pulmonary Fibrosis

Hermansky-Pudlak综合征患者肺纤维化风险的筛查与监测路径

J. Collins等

 

背景

 

Hermansky-Pudlak综合征（HPS）是一组常染色体隐性遗传性血小板功能障碍疾病，其特征为因致密颗粒缺乏导致的出血以及眼皮肤白化病(OCA)。HPS-1、HPS-2和HPS-4亚型患者还存在肺纤维化（PF）风险。预计所有HPS-1患者都会不可避免地发展为进行性且最终致命的肺纤维化，典型发病年龄在30至40岁之间，但也有早至25岁发病的报道。肺移植是目前唯一的治愈方法；然而，酪氨酸激酶抑制剂尼达尼布的抗纤维化治疗已被证实可减缓纤维化间质性肺疾病的进展速度，是HPS继发肺纤维化的一种获批治疗选择。肺纤维化在出现临床症状之前就已发生，因此早期识别有风险的患者有可能延长生存期。
 

方法

 

在这个单中心试点筛查项目中，对转诊的HPS患者进行基因分型，以识别患有HPS-1、HPS-2或HPS-4的患者，并纳入一项新的肺功能和影像学监测项目。从25岁开始，有风险的患者将接受专科临床评估和胸部X线基线检查。根据评估结果，对于有肺纤维化相关特征的患者，直接进行高分辨率计算机断层扫描（HRCT）；若未发现已确诊的肺部疾病证据，则将患者纳入年度肺功能测试监测。

 

结果

 

通过对中心19例HPS患者的基因特征分析，识别出9例有高肺纤维化风险的患者。所有患者HPS1基因均存在双等位基因致病性变异，其中7例女性、2例男性，中位年龄为27岁（范围8-41岁）。这些有风险的患者已被转诊至新的监测路径。

 

结论

 

进展性肺纤维化是HPS-1、HPS-2和HPS-4严重且危及生命的并发症。我们首次报道了这项前瞻性的筛查项目，旨在早期识别有肺纤维化风险的患者，并将其纳入个性化的监测路径，从而使患者能够更早获得延长生命的治疗。

 

【摘要原文】：（上下滑动查看更多）

Introduction: Hermansky–Pudlak syndrome (HPS) comprises a group of autosomal recessive platelet function disorders, characterised by bleeding due to dense granule deficiency and oculocutaneous albinism; patients with subtypes HPS-1, HPS-2 and HPS-4 are also at risk of pulmonary fibrosis (PF). It is expected that all patients with HPS-1 will develop inexorably progressive and invariably fatal PF, with typical onset between 30 and 40 years of age, but reported as early as 25 years .Lung transplantation is the only current cure; however, anti-fibrotic therapy with the tyrosine kinase inhibitor nintedanib is proven to slow the rate of progression in fibrotic interstitial lung disease and is a licensed treatment option for PF secondary to HPS. The onset of PF precedes clinical symptoms, therefore early identification of at-risk patients has the potential to prolong survival.

Methods: In this single-centre pilot screening programme,patients referred with HPS were genotyped to identify those with HPS-1, -2 or -4, for enrolment into a newly devised lung function and radiology surveillance programme. Starting at the age 25 years, at-risk patients will have a specialist clinical review and baseline chest x-ray. This stratifies those with concerning features for PF to upfront high-resolution computed tomography, and if no evidence of established lung disease, individuals are entered into annual lung function test surveillance.

Results: Through the genetic characterisation of 19 patients with HPS in our centre, we have identified a cohort of nine patients at high risk of PF. All have biallelic pathogenic variants in HPS1; seven female and two male patients with a median age of 27 years (range 8–41 years). These at-risk patients have been referred to our new surveillance pathway.

Discussion/Conclusion: Progressive PF is a devastating and life-limiting complication of HPS-1, HPS-2 and HPS-4. We present the first reported prospective screening programme,designed to identify early those patients at risk of PF and enrol them into a bespoke surveillance pathway, thus facilitating earlier access to life-prolonging treatment.

 

OR07 Factor VIII Activity Elevations Above Normal Ranges Post-Giroctocogene Fitelparvovec:Characterisation and Clinical Management in the Phase 3 AFFINE Trial

Giroctocogene Fitelparvovec治疗后VIII因子活性升高超过正常范围：III期AFFINE临床试验中的特征描述与临床管理

L. Frenzel等

 

背景

 

Giroctocogene fitelparvovec是一种基于腺相关病毒6型（AAV-6）的基因疗法，旨在增加内源性FVIII表达，从而防止或减少患有A型血友病患者的出血情况。我们描述了在III期AFFINE临床试验中，部分患者在治疗后FVIII活性短暂升高超过正常上限（ULN）的临床管理情况、FVIII活性随时间的变化，以及FVIII活性高水平预测因素的初步数据。
 

方法

 

在III期AFFINE试验（NCT04370054）中，75名中重型至重型（FVIII ≤1%）HA成年男性患者接受了单次静脉注射的Giroctocogene fitelparvovec，剂量为3或13 vg/kg。FVIII活性通过发色底物法（CA）和一期法（OSA）测定。对于FVIII活性超过设定阈值的情况，根据研究建议并由研究者酌情决定，采用预防性口服直接抗凝药物（DOAC）进行管理，即根据检测方法（CA或OSA）和风险因素设定不同的阈值。研究者使用一个专有的生成式AI工具，并经过审阅后制定了初步草案。
 

结果

 

患者在输注后，FVIII活性的中位峰值为148.8%（范围：16.9–1354.2），达到峰值的中位时间为98天（范围：20–627天）。37例患者（49.3%）的FVIII活性在≥1次CA测定中超过150%，其中中位首次达到150%的时间为42天（范围：15–540天）；中位累计超过150%的时间为56天（范围：4–953天）。20例患者（26.6%）的FVIII活性在≥1次CA测定中超过230%，其中中位首次达到230%的时间为60天（范围：19–186天）；中位累计超过230%的时间为62天（范围：3–647天）。

 

在23名患者（30.7%）中启动了DOAC治疗，启动的中位时间为57天（范围：28–370天）；DOAC治疗的中位总时间为84天（范围：7–944天），且治疗耐受良好。根据患者基线（BL）特征与峰值FVIII活性进行分组：（1）组1：≥2次连续CA测定超过150%，n=31；（2）组2：≥2次CA测定超过230%，n=17；对照组，n=44。发现基线VWF水平可能是预测FVIII活性升高超过ULN的潜在因素。与对照组（108.4%）相比，组1（134.2%）和组2（151.7%）的平均基线VWF水平在统计学上显著更高（两组P＜0.05）。

结论

 

在输注后观察到FVIII活性水平存在波动。FVIII活性超过ULN的现象是短暂的，且通过预防性DOAC治疗可成功管理。基线VWF水平可能是预测FVIII活性升高超过ULN的潜在因素。

 

【摘要原文】：（上下滑动查看更多）

Introduction: Giroctocogene fitelparvovec is an AAV-6-based gene therapy designed to increase endogenous Factor VIII (FVIII) expression to prevent or reduce bleeding in individuals with haemophilia A (HA). We describe the clinical management of participants (pts) with transient elevated FVIII activity levels above the upper limit of normal (ULN), the evolution of FVIII activity over time and preliminary data for predictors of high levels.

Methods: Adult men (N = 75) with moderately severe to severe HA (FVIII ≤1%) received a single intravenous 3 and 13 vg/kg infusion of giroctocogene fitelparvovec in the pivotal Phase 3 AFFINE (NCT04370054) trial. FVIII activity was measured via chromogenic (CA) and one-stage (OSA) assays. FVIII activity above defined thresholds was managed with prophylactic direct oral anticoagulant (DOAC) per study recommendations and investigator discretion [i.e., different thresholds depending on assay (CA or OSA) and risk factors]. A proprietary genera-tive AI tool was used with author review to develop the first draft.

Results: Pts achieved median peak FVIII activity of 148.8% (range 16.9–1354.2) post-infusion; median time to peak was 98 (range 20–627) days. Transient FVIII activity (≥1 CA measurement) >150% was reached in 37 (49.3%) pts [median time to first >150%, 42 (range 15–540) days; median cumulative time >150%, 56 (range 4–953) days]. CA FVIII activity >230% (≥1 measurement) was reached in 20 (26.6%) pts [median time to first >230%, 60 (range 19–186) days; median cumulative time >230%, 62 (range 3–647)days]. DOAC was initiated in 23 (30.7%) pts [median time to initiation, 57 (range 28–370) days; median total time on DOAC, 84 (range 7–944) days] and was well tolerated. Grouping pt baseline (BL) characteristics by peak FVIII activity [group (G) 1: ≥2 consecutive CA measurements >150%, n = 31; G2: ≥2 CA measurements >230%, n = 17; control, n = 44] identified BL von Willebrand factor (VWF) level as a potential predictor of FVIII elevations >ULN. Mean BL VWF was statistically significantly higher in G1 (134.2%) and G2 (151.7%) versus control (108.4%;p < 0.05 for both).

Discussion/Conclusion: Variability in FVIII activity levels was observed post-infusion. FVIII activity >ULN was transient and successfully managed with prophylactic DOAC. BL VWF level is a potential predictor of FVIII activity elevations >ULN.

 

OR08 Activated Prothrombin Complex Concentrate in Patients Receiving Non-Factor Therapies: from Evidence to Clinical Practice

接受非因子疗法患者使用活化凝血酶原复合物浓缩物：从循证到临床实践

R. F. Sidonio Jr等

 

背景

 

Emicizumab是出血预防的标准治疗药物，其他非因子疗法（NFTs）也不断涌现。然而，旁路治疗剂[BPAs；活化凝血酶原复合物浓缩物（aPCC）和重组活化因子VII（rFVIIa）]在具有抑制物的先天性A型血友病患者（CHAWI）发生突破性出血和重大手术时仍然不可替代。早期关于aPCC与emicizumab联合使用时出现的罕见血栓性并发症的报告，导致了对该方案使用的限制。然而，目前已有更多关于aPCC与emicizumab联合使用的安全性的证据。由于这些药物在不同地区的可及性/可用性以及患者反应的差异，因此两种旁路制剂对于CHAWI患者的治疗均有必要。医学界应了解如何在接受NFT治疗的患者中使用BPAs的最佳方法。
 

方法

 

本叙述性综述评估了公开的证据，探讨了在接受NFT预防治疗的CHAWI患者中，使用aPCC处理急性临床情况的管理方法。
 

结果

 

临床试验和真实世界证据（RWE）表明，接受NFT治疗的患者发生突破性出血的发生率存在差异。对于emicizumab的研究报告显示，约三分之一的患者出现突破性出血。在emicizumab处方信息中报告的四项临床试验的汇总分析中，37名接受emicizumab治疗的CHAWI患者发生了130次出血事件使用了aPCC治疗，且大多数（96%）患者未出现血栓性并发症。99次（76%）出血事件使用了≤100 U/kg/day的aPCC治疗，且在任何治疗时长下均未发生血栓性并发症。31次（24%）出血事件使用了>100 U/kg/day的aPCC治疗；在使用此剂量超过48小时的10例病例中，3例发生了血栓性微血管病，其中2例还额外使用了rFVIIa治疗相同的出血事件。

 

结论

 

接受NFT治疗的CHAWI患者仍会发生突破性出血事件。在这种情况下，使用每日≤100 U/kg的aPCC进行出血管理，未出现血栓并发症。随着更多NFT成为CHAWI患者的出血预防治疗选择，处理急性临床情况仍需同时使用两种BPAs。重要的是，需考虑可能影响BPA选择的因素，如出血类型/部位、临床反应、剂量和使用时长，以及可及性/可用性。
 

【摘要原文】：（上下滑动查看更多）

Introduction: Emicizumab is a standard of care for bleed pro-phylaxis, with other non-factor therapies (NFTs) also emerging.Yet, bypassing agents [BPAs; activated prothrombin complex con-centrate (aPCC) and recombinant activated Factor VII (rFVIIa)] remain irreplaceable for the management of breakthrough bleeds and major surgeries in patients with congenital haemophilia A with inhibitors (CHAWI). Early reports of rare thrombotic complications led to restricted use of aPCC with emicizumab;however, additional evidence on the safety of aPCC use with emicizumab is now available. Both BPAs are needed to support patients with CHAWI, owing to regional differences in their accessibility/availability and variable patient responses; there-fore, it is critical for the medical community to understand how BPAs can be used optimally in patients receiving NFTs.

Methods: This narrative review evaluated publicly available evidence on the management of acute clinical situations with aPCC in patients with CHAWI receiving NFT prophylaxis.

Results: Clinical trial and real-world evidence (RWE) indicate that breakthrough bleed rates in patients receiving NFTs vary;studies of emicizumab report breakthrough bleeds in more than a third of patients on average. In a pooled analysis of four clinical trials reported in the emicizumab prescribing information, 130 bleeds in 37 patients with CHAWI receiving emicizumab were treated with aPCC, with no thrombotic complications in the majority (96%) of cases. 99 (76%) bleeds were treated with ≤100 U/kg/day of aPCC, with no thrombotic complications at any treatment duration. Thirty-one (24%) bleeds were treated with >100 U/kg/day of aPCC; thrombotic microangiopathy occurred in 3/10 cases in which this dose was used for >48 h (2/3 were additionally treated with rFVIIa for the same bleeding event).

Discussion/Conclusion: Patients with CHAWI receiving NFTs continue to experience breakthrough bleeds. In this context,aPCC has been used for bleed management at ≤100 U/kg/day without thrombotic complications. As more NFTs become avail-able for bleed prophylaxis in patients with CHAWI, both BPAs will be needed for the management of acute clinical situations,and it is important to consider the factors that may influence BPA selection, such as bleed type/location, clinical response, dosing and duration of use, and accessibility/availability.

 

OR09 Outcomes by Dose Escalation Criteria in Participants with Haemophilia A or B Without Inhibitors Receiving Marstacimab in the Basis Trial

在BASIS试验中，无抑制物的A型或B型血友病患者按剂量递增标准的治疗结果

L. Frenzel等

 

背景

 

1/2期临床研究已证明Marstacimab在A型（HA）或B型（HB）血友病患者中，450 mg每周一次（QW）的剂量有效且安全。3期BASIS研究（NCT03938792）显示，在无抑制物的血友病患者中，Marstacimab 150 mg QW的治疗方案有效。本研究评估了符合剂量递增标准（DE）患者的治疗结局。
 

方法

 

在6个月的观察期（OP）中，根据因子替代治疗方案[按需治疗（OD）或常规预防治疗（RP）]对患者进行分类。在12个月的积极治疗期（ATP）中，患者接受单次皮下注射300 mg（2×150 mg）Marstacimab，之后每周150 mg治疗。完成ATP的患者可进入开放标签扩展期（OLE）。对于符合方案规定标准（体重≥50 kg，且6个月内≥2次需要治疗的自发性出血）的患者，研究者可在第180天后自行决定将剂量递增至每周300 mg。年化出血率（ABR）用于总结无抑制物患者的治疗结果（抑制物队列研究仍在进行中）。本研究使用了生成式AI工具，并经过作者审阅后制定了初稿。
 

结果

 

共128名无抑制物的患者进入OP阶段，中位年龄30岁，（范围：13–66岁），其中116名进入ATP阶段（RP组：n=83，OD组：n=33；），平均治疗时间12个月（范围：1–13个月），数据截至2023年10月，107名患者继续进入OLE阶段（RP组：n=75，OD组：n=32；），治疗持续时间为12个月（范围：1–23个月）。在OP阶段，RP组和OD组的平均ABR分别为7.9（95%CI：5.1–10.6）和38.0（95%CI：31.0–46.5）。在BASIS研究中，有47名患者（40.5%；RP组：n=33，OD组：n=14）符合DE标准，其中14名患者（RP组：n=11，OD组：n=3）在ATP阶段增加了剂量。

 

对于RP组患者，DE后的ABR有早期改善：在OP阶段，ABR为14.0（范围：3.8–24.3）；在ATP阶段DE前为14.1（范围：9.0–19.2），DE后为3.3（范围：1.4–5.2），在OLE阶段为4.9（范围：1.8–8.0）。

 

对于未进行DE的RP组患者，ABR在OLE阶段持续改善：OP阶段ABR为10.2（范围：4.2–16.2），ATP阶段为9.6（范围：5.7–13.6），OLE阶段为6.1（范围：1.9–10.4）。对于未进行DE的OD组患者，ABR在ATP阶段得到改善，并在OLE阶段保持：OP阶段ABR为45.8（范围：34.4–61.2），ATP阶段为4.2（范围：3.1–5.7），OLE阶段为4.2（范围：2.3–7.6），由于样本量有限，未对剂量递增的按需治疗患者进行数据估计。DE未引发安全性问题。
 

结论

 

Marstacimab的剂量递增治疗能迅速降低ABR，这可能改善出血频繁患者的治疗结局。符合剂量递增标准但仍使用150 mg Marstacimab的患者，其ABR随时间推移有所下降。
 

【摘要原文】：

Introduction: Phase 1/2 studies demonstrated marstacimab efficacy and safety up to 450 mg once weekly (QW) in participants (pts) with haemophilia A (HA) or B (HB). The Phase 3 BASIS study (NCT03938792) demonstrated efficacy of marstacimab 150mg QW in pts without inhibitors. We evaluated outcomes in pts who met criteria for dose escalation (DE).

 

Methods: Pts were categorised by factor replacement treatment [on-demand (OD) or routine prophylaxis (RP)] in a 6-month observational phase (OP). Pts received a single subcutaneous 300 mg (2×150 mg injections) marstacimab dose followed by QW 150 mg in the 12-month active treatment phase (ATP). Pts who completed ATP could enrol in the open-label extension (OLE).

Dose could be increased at the investigator discretion to 300 mg QW after Day 180 for pts who met protocol-specified criteria (weight ≥50 kg, ≥2 spontaneous bleeds requiring treatment in 6 months). Annualised bleeding rates (ABR) are summarised for pts without inhibitors (the inhibitor cohort is ongoing). A proprietary generative AI tool was used with author review to develop the first draft; authors take full responsibility for the content.

Results: Overall, 128 pts [median age 30 (range 13–66) years]without inhibitors entered OP, 116 entered ATP [RP: n = 83,OD: n = 33; mean (range) duration: 12 (1–13) months], and 107continued in OLE [data cutoff: October 2023; RP: n = 75, OD:n = 32; duration: 12 (1–23) months]. In the OP, mean (95%CI)ABR was 7.9 (5.1–10.6) vs. 38.0 (31.0–46.5) for RP vs. OD pts. Of 47 pts (40.5%; RP: n = 33; OD: n = 14) who qualified for DE in BASIS, 14 (RP: n = 11; OD: n = 3) increased dose in ATP. For RP pts, ABR improved early after DE: mean (95%CI) was 14.0 (3.8–24.3) in OP, 14.1 (9.0–19.2) in ATP before DE, 3.3 (1.4–5.2) in ATP after DE, and 4.9 (1.8–8.0) in OLE. For RP pts who did not DE,ABR improved into OLE: mean (95%CI) was 10.2 (4.2–16.2) in the OP, 9.6 (5.7–13.6) in ATP, and 6.1 (1.9–10.4) in OLE. For OD pts who did not DE, ABR improved in ATP and was maintained in OLE: mean (95%CI) was 45.8 (34.4–61.2) in OP, 4.2 (3.1–5.7) in ATP and 4.2 (2.3–7.6) in OLE (data not estimated for DE OD pts due to limited sample size). No safety concerns were associated with DE.

Discussion/Conclusion: Marstacimab DE led to a rapid ABR reduction, which may improve outcomes in pts with a greater number of bleeds. ABR decreased over time in pts who met DE criteria but remained on marstacimab 150 mg.

 

OR10 Efficacy and Safety of ETX-148 in Murine Models of Haemophilia A and B

ETX-148在A型和B型血友病小鼠模型中的疗效与安全性

N. Pursell等
 

背景

 

血友病患者（PwH）仍然面临反复性关节出血或血肿的困扰。尽管最近获批了一些新的治疗方案，但对于安全有效的预防性治疗，且治疗负担更低以提升生活质量的需求，仍有很大未被满足。e-Therapeutics公司利用其HepNet计算平台，识别出蛋白Z依赖性蛋白酶抑制剂（ZPI）是一种参与止血过程的新型肝脏表达的血液凝固相关目标基因。最近的研究表明，抑制血友病患者血浆中的ZPI能够增加凝血酶生成，进一步支持ZPI作为治疗出血性疾病的治疗靶点。通过计算设计了针对ZPI的强效小干扰RNA（siRNA），并在体内进行验证，最终筛选出GalOmic siRNA——ETX-148，目前该药物正被开发用于治疗包括血友病在内的罕见出血性疾病。
 

方法

 

在非人灵长类动物（NHPs）中检测排名靠前的siRNA的药效学活性。为了评估ETX-148在血友病中的潜在治疗作用，在A型血友病（HA）和B型血友病（HB）小鼠模型中测试了一种对小鼠有效的ETX-148替代siRNA（mETX -148）。首先在严重关节积血的小鼠模型中测试mETX-148，对血友病小鼠预先给予mETX-148处理，然后对单侧膝关节进行损伤处理。随后在10天内监测小鼠有无出血迹象，之后进行终末组织病理学分析。为证明预防性使用ETX-148治疗与紧急治疗的兼容性，进一步测试了在血友病小鼠中单独使用mETX-148或与按需治疗联合使用，以评估血栓形成风险。最后，为了展示持续ZPI敲除的安全性，向C57BL/6小鼠长期给予高剂量的mETX-148。

 

结果

 

ETX-148在非人类灵长类动物中表现出对ZPI mRNA和蛋白的深度且持续的抑制作用，支持在血友病患者中采用每季度一次的给药方案。在关节积血模型中，用mETX-148治疗HA和HB小鼠，可使关节病理状况显著改善。单独使用mETX-148或与紧急治疗联合使用时，耐受性良好，无血栓形成风险增加的迹象。

 

结论

 

尽管血友病治疗在近年来取得了进展，但仍然存在大量未满足的需求。上述结果突显了ETX-148作为一种安全且有效的血友病预防性治疗方法的潜力，其每季度一次的皮下注射治疗方案对患者更为友好。

 

【摘要原文】：

Introduction: People with haemophilia (PwH) continue to be plagued by recurrent haemarthroses, or joint bleeds. Despite recent approvals, a high unmet need remains for safe and effective prophylactic treatments with a lower treatment bur-den to improve quality of life. e-Therapeutics used its HepNet computational platform to identify protein Z-dependent protease inhibitor (ZPI) as a novel liver-expressed target gene involved in haemostasis. Inhibition of ZPI in plasma from PwH has recently been shown to increase thrombin generation, further supporting ZPI as a therapeutic target for the treatment of bleeding disorders. Potent siRNAs targeting ZPI were designed in silico and tested in vivo to select the lead GalOmic siRNA, ETX-148, which is being developed for the treatment of rare bleeding disorders, including haemophilia.

Methods: Pharmacodynamic activity of top-ranked siRNAs was measured in non-human primates (NHPs). To establish the disease-modifying potential of ETX-148 in haemophilia, a mouse-active ETX-148 surrogate siRNA (mETX-148) was tested in mouse models of haemophilia A (HA) and haemophilia B (HB). mETX-148 was first tested in a mouse model of severe haemarthrosis where haemophilia mice were pre-treated with mETX-148 and subjected to injury of a single knee joint. Mice were then monitored for 10 days for evidence of bleeding before termi-nal histopathological analysis. To demonstrate compatibility of prophylactic ETX-148 treatment with emergency treatments, mETX-148 was further tested in haemophilia mice alone or in combination with on-demand therapies to assess thrombosis risk. Lastly, high-dose mETX-148 was chronically administered to C57BL/6 mice to demonstrate the safety of sustained ZPI knockdown.

Results: ETX-148 demonstrated deep and sustained knockdown of ZPI mRNA and protein in NHPs, supporting a quarterly dosing regimen in PwH. Treatment of HA and HB mice with mETX-148 resulted in significant improvement in joint pathology in the hemarthrosis model. Administration of mETX-148 was well-tolerated alone and in combination with emer-gency treatments, with no evidence of increased thrombosis risk.

Discussion/Conclusion: Despite recent advances in the treat-ment of haemophilia, high unmet need remains. These results highlight the potential of ETX-148 as a safe and effective prophy-lactic treatment for haemophilia with a patient-friendly quarterly,subcutaneous dosing regimen.