Factor IX inhibitor formation is the most serious complication of replacement therapy for the bleeding disorder hemophilia B, exacerbated by severe allergic reactions occurring in up to 60% of patients with inhibitors. Low success rates of immune tolerance induction therapy in hemophilia B necessitate the search for novel immune tolerance therapies. Skin-associated lymphoid tissues have been successfully targeted in allergen-specific immunotherapy.

Objectives:

We aimed to develop a prophylactic immune tolerance protocol based on intradermal administration of FIX that would prevent inhibitor formation and/or anaphylaxis in response to replacement therapy.

Methods:

We measured FIX inhibitor, anti-FIX immunoglobulin G1, and immunoglobulin E titers using the Bethesda assay and enzyme-linked immunosorbent assay after 4 weeks of twice-weekly intradermal FIX or FIX-Fc administration followed by 5 to 6 weeks of weekly systemic FIX injections in C3H/HeJ hemophilia B mice. We also measured skin antigen-presenting, follicular helper T, and germinal center B cell frequencies in skin-draining lymph nodes after a single or repeat intradermal FIX administration.

Results:

Intradermal administration enhanced FIX inhibitor formation in response to systemic administration. We further found that intradermal administration alone triggers inhibitor formation, even at a low dose of 0.4 IU/kg, which is 100-fold lower than the intravenous dose of 40 IU/kg typically required to induce inhibitor development in hemophilia B mice. Also, intradermal administration triggered germinal center formation in skin-draining lymph nodes and sensitized mice to systemic administration. Factor IX-Fc fusion protein did not modulate inhibitor formation.

Conclusion:

Intradermal FIX administration is highly immunogenic, suggesting that the skin compartment is not amenable to immune tolerance induction or therapeutic delivery of clotting factors.

2023-05-01·Research and practice in thrombosis and haemostasis

Extended half-life factor IX prophylaxis up to every 21 days in hemophilia B: a longitudinal analysis of the efficacy and safety in selected adult patients

Article

作者: Li, Yanyan ; Seifert, Wilfried ; Lissitchkov, Toshko ; Mancuso, Maria Elisa ; Lepatan, Lynda Mae ; Nagao, Asuza ; Pabinger, Ingrid

Background:

Extended half-life factor IX (FIX) products have revolutionized prophylactic treatment for patients with hemophilia B as patients maintain protective FIX levels with minimal occurrence of spontaneous bleeding. rIX-FP is an extended half-life FIX product that allows prolonged dosing intervals.

Objectives:

To assess individualized and prolonged prophylactic dosing interval up to 21 days in adult patients (≥18 years) with hemophilia B in the rIX-FP clinical trial program.

Methods:

Patients who were included in the PROLONG-9FP phase III study or who received rIX-FP during surgery could continue into an extension study for long-term assessment. Patients began 7-day prophylaxis with rIX-FP, and after 6 months, they could extend dosing intervals to every 14 days. In the extension study, adult patients could switch to a 21-day regimen if well-controlled on a 14-day regimen.

Results:

Eleven patients transitioned from a 7-day prophylaxis regimen to a 14-day regimen and finally to a 21-day regimen, 5 of whom were treated on demand at enrollment. Patients who switched to the 21-day regimen had a median annualized spontaneous bleeding rate of 0.0 across all regimens. The median observed FIX activity remained >5 IU/dL until day 21 after a single 100-IU/kg dose of rIX-FP. After 6 months on the 21-day regimen, 2 patients switched back to a 14-day regimen. No inhibitors, anaphylactic reactions, or thromboembolic events occurred.

Conclusion:

Patients who are well controlled on a once-weekly regimen might extend their treatment interval to 14 days, and in adult patients, further extension to up to 21 days (100 IU/kg) may be considered.

2023-04-25·JAMA

Efficacy and Safety of Early Administration of 4-Factor Prothrombin Complex Concentrate in Patients With Trauma at Risk of Massive Transfusion: The PROCOAG Randomized Clinical Trial.

Article

作者: Bosson, Jean-Luc ; Riou, Bruno ; Courvalin, Elie ; Marcotte, Guillaume ; Gauss, Tobias ; Duranteau, Jacques ; Payen, Jean-Francois ; Pottecher, Julien ; Charbit, Jonathan ; Abback, Paer-Selim ; David, Jean-Stephane ; Levrat, Albrice ; Sourd, Dimitri ; Huet-Garrigue, Delphine ; Leone, Marc ; Asehnoune, Karim ; Bouzat, Pierre ; Adolle, Anais ; Delhaye, Nathalie

Importance:

Optimal transfusion strategies in traumatic hemorrhage are unknown. Reports suggest a beneficial effect of 4-factor prothrombin complex concentrate (4F-PCC) on blood product consumption.

Objective:

To investigate the efficacy and safety of 4F-PCC administration in patients at risk of massive transfusion.

Design, Setting, and Participants:

Double-blind, randomized, placebo-controlled superiority trial in 12 French designated level I trauma centers from December 29, 2017, to August 31, 2021, involving consecutive patients with trauma at risk of massive transfusion. Follow-up was completed on August 31, 2021.

Interventions:

Intravenous administration of 1 mL/kg of 4F-PCC (25 IU of factor IX/kg) vs 1 mL/kg of saline solution (placebo). Patients, investigators, and data analysts were blinded to treatment assignment. All patients received early ratio-based transfusion (packed red blood cells:fresh frozen plasma ratio of 1:1 to 2:1) and were treated according to European traumatic hemorrhage guidelines.

Main Outcomes and Measures:

The primary outcome was 24-hour all blood product consumption (efficacy); arterial or venous thromboembolic events were a secondary outcome (safety).

Results:

Of 4313 patients with the highest trauma level activation, 350 were eligible for emergency inclusion, 327 were randomized, and 324 were analyzed (164 in the 4F-PCC group and 160 in the placebo group). The median (IQR) age of participants was 39 (27-56) years, Injury Severity Score was 36 (26-50 [major trauma]), and admission blood lactate level was 4.6 (2.8-7.4) mmol/L; prehospital arterial systolic blood pressure was less than 90 mm Hg in 179 of 324 patients (59%), 233 patients (73%) were men, and 226 (69%) required expedient hemorrhage control. There was no statistically or clinically significant between-group difference in median (IQR) total 24-hour blood product consumption (12 [5-19] U in the 4F-PCC group vs 11 [6-19] U in the placebo group; absolute difference, 0.2 U [95% CI, -2.99 to 3.33]; P = .72). In the 4F-PCC group, 56 patients (35%) presented with at least 1 thromboembolic event vs 37 patients (24%) in the placebo group (absolute difference, 11% [95% CI, 1%-21%]; relative risk, 1.48 [95% CI, 1.04-2.10]; P = .03).

Conclusions and Relevance:

Among patients with trauma at risk of massive transfusion, there was no significant reduction of 24-hour blood product consumption after administration of 4F-PCC, but thromboembolic events were more common. These findings do not support systematic use of 4F-PCC in patients at risk of massive transfusion.

Trial Registration:

ClinicalTrials.gov Identifier: NCT03218722.

项与乾燥濃縮人血液凝固第Ⅸ因子(一般社団法人日本血液製剤機構) 相关的新闻（医药）

2023-10-18

·美通社

信念医药与武田中国宣布在华达成B型血友病领域独家商业化合作

将为中国患者带来基因治疗新选择 2023年10月17日信念医药集团（以下简称信念医药）与武田中国今日宣布达成独家合作协议，信念医药授权武田中国在中国内地、中国香港和中国澳门负责其在研产品BBM-H901注射液的商业化经营。双方将结合各自领域的优势和资源，加速推动该产品的商业化进程，助力B型血友病患者获得创新治疗新选择，共同促进基因疗法的产业发展。信念医药联合创始人、董事长兼首席科学家肖啸博士表示："信念医药专注深耕前沿基因治疗领域，产品管线广泛涵盖罕见病与常见病，致力填补大量未被满足的临床需求。BBM-H901注射液是信念医药自主研发和生产的重磅产品之一，亦是国内首个进入注册临床试验的B型血友病的腺相关病毒（AAV）基因治疗药物。非常高兴在2023上海国际生物医药产业周期间，信念医药与武田中国达成此次战略合作，相信依托信念医药扎实的临床开发实力以及武田中国强大的商业化能力，必将助力双方进一步夯实管线策略及市场布局，强强联手，互信合作，聚力将更多创新治疗方案带给广大中国患者。" B型血友病是一种遗传性凝血功能障碍疾病，由于患者血液中缺乏凝血因子Ⅸ（FIX）所致，其特点为反复的、自发性的关节、肌肉和软组织出血，如长时间反复出血，还可能导致患者关节畸形、肌肉萎缩甚至死亡。我国已注册登记的B型血友病患者约3800人[1]。目前，中国B型血友病患者仍面临着治疗选择有限、诊疗不规范等挑战，患者多使用凝血酶原复合物（PCC）用于替代治疗，存在感染风险和给药不便等问题。同时，由于治疗不充分或不规范，中重度患者常见关节出血和畸形，患者的医疗需求仍未得到满足。 BBM-H901注射液由信念医药自主研发和生产，以静脉给药的方式将人凝血因子IX基因导入B型血友病患者体内持续表达，提高并长期维持患者的凝血因子水平，用于预防B型血友病成年患者出血。该产品是国内首个获批进入注册临床试验的B型血友病的AAV基因治疗药物，目前已经顺利完成Ⅲ期注册临床试验的受试者给药[2]。2022年，BBM-H901注射液相关临床研究结果先后发表于国际权威期刊《柳叶刀-血液病学》和《新英格兰医学杂志》，同年被国家药监局药品审评中心纳入"突破性治疗品种"名单。《柳叶刀-血液病学》发表的临床研究（NCT04135300）是一项研究者发起、单中心、单臂的临床试验，旨在评估单次静脉输注BBM-H901的安全性和有效性。根据其研究结果，18岁以上、FIX残留水平≤2IU/ dl的B型血友病患者在接受BBM-H901注射液治疗后，58周随访显示：患者中位年化出血率从12次减少至0次（p=0.0092），中位靶关节数从1.5个减少至0个（p=0.0031），中位凝血因子IX药物年输注次数从53.5次减少至0次（p[3]。 "与信念医药的合作是一个重要的里程碑，将进一步丰富我们现有的产品组合和疗法。我们期待联合信念医药的研发技术、以及武田中国在商业化领域丰富的经验和专业知识，能加速让更多患者从突破性的基因疗法中获益。"武田制药全球高级副总裁、武田中国总裁单国洪表示，"以信念医药为代表的本土基因治疗技术正在日益崛起，我们深信未来中国的医药创新也将加速融入全球，成为全球生物医药技术的创新策源地。" 信念医药是一家集基因治疗产品研发、生产和临床应用为一体的高科技企业，治疗领域广泛覆盖血友病、帕金森病、关节炎、神经肌肉病等多种重大、未被满足临床需求的疾病。本次合作建立在双方的互信与协作的基础上，将大大加速信念医药在血友病治疗领域基因疗法在中国的商业化，为更多患者点亮生命之光，为中国基因治疗行业的蓬勃发展增添力量。注释说明: [1] Demographics, clinical profile and treatment landscape of patients with hemophilia B in China [J]. Haemophilia, 2022 Mar, 28(2): e56-e60 [2] https://www.cde.org.cn/main/xxgk/listpage/4b5255eb0a84820cef4ca3e8b6bbe20c [3] Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial [J]. The Lancet, 2022 May, 9(7): E504-E513 内容来源于网络，如有侵权，请联系删除。

基因疗法临床3期

100 项与乾燥濃縮人血液凝固第Ⅸ因子(一般社団法人日本血液製剤機構) 相关的药物交易

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