美国西北血液中心Barbara A. Konkle团队研究了BIVV001融合蛋白作为因子Ⅷ替代治疗A型血友病的疗效。2020年9月10日，该研究发表在《新英格兰医学杂志》上。

因子Ⅷ替代品可改善A型血友病患者的治疗，但这些产品的半衰期较短，影响了患者的生活质量。由于血管性血友病因子伴侣效应，重组因子Ⅷ的半衰期为15-19小时。BIVV001是一种新型融合蛋白，旨在克服这一半衰期上限，并维持长时间较高的因子Ⅷ活性水平。然而，单剂量BIVV001的安全性和药代动力学尚不明确。

在这项临床1-2a期、开放标签试验中，研究组招募了16例18-65岁、先前治疗过、严重血友病（因子Ⅷ活性小于1%）男性，将其随机分组，分别接受静脉注射重组因子Ⅷ剂量25（低剂量组）或65 IU/kg体重（高剂量组）。注射后至少有3天的洗脱期。这些患者随后接受了相应剂量的BIVV001单次静脉注射，分别为25或65 IU/kg体重。

在单剂量BIVV001注射后28天内，所有患者均未检测到因子Ⅷ抑制，也未发生超敏或过敏事件。BIVV001的几何平均半衰期是重组因子Ⅷ的3-4倍，其中低剂量组分别为37.6小时和9.1小时，高剂量组则分别为42.5小时和13.2小时；两剂量组药物暴露曲线下面积（AUC）分别是重组因子Ⅷ的6-7倍。高剂量组注射BIVV001后，第4天时平均因子Ⅷ水平处于正常范围（超过51%），第7天为17%，提示可间隔一周治疗。

总之，对于重度A型血友病男性，单次静脉注射BIVV001可维持较长时间的高Ⅷ因子活性水平，其半衰期是重组因子Ⅷ的4倍，可作为每周治疗一次的新型Ⅷ因子替代疗法。

附：英文原文

Title: BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A

Author: Barbara A. Konkle, M.D.,, Amy D. Shapiro, M.D.,, Doris V. Quon, M.D., Ph.D.,, Janice M. Staber, M.D.,, Roshni Kulkarni, M.D.,, Margaret V. Ragni, M.D., M.P.H.,, Ekta S. Chhabra, Ph.D.,, Stacey Poloskey, M.D.,, Kara Rice, M.S.,, Suresh Katragadda, Ph.D.,, Joachim Fruebis, Ph.D.,, and Craig C. Benson, M.D.

Issue&Volume: 2020-09-10

Abstract:

Background

Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients’ quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001.

Methods

In this phase 1–2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed.

Results

No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments.

Conclusions

In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration.

DOI: 10.1056/NEJMoa2002699

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2002699