Yeung P K
Dalhousie University, Pharmacokinetics and Metabolism Laboratory, School of Pharmacy, Burbridge Building, Halifax, NS B3H-3J5, Canada.
IDrugs. 2000 Jun;3(6):669-73.
ATIII LLC, a joint venture between Genzyme Transgenics (GTC) and Genzyme General, is developing transgenic recombinant human antithrombin III (rhAT-III) as a potential treatment for sepsis and other disorders involving thrombosis. It is in phase III clinical trials in the US and Europe as an anticoagulant in patients undergoing elective cardiac surgery requiring cardiopulmonary bypass (CPB). GTC has a license from Behringwerke (Hoechst Marion Roussel; now Aventis Pharma) to develop transgenic AT-III. Behringwerke retains exclusive worldwide marketing rights to the product, but has to purchase its entire supply of transgenic AT-III from GTC [156364]. In March 1997, GTC signed an agreement with SMIG, a joint venture formed by GTC and Sumitomo Metals, under which SMIG has the rights to develop rhAT-III in Asia in return for US dollar 4.4 million in additional funding for the continued transgenic development of rhAT-III. The dollar 4.4 million will be paid upon reaching certain milestones, which GTC expected to complete in 1997 [240202]. In December 1998, US-05843705 was issued covering rhAT-III production in transgenic goats [302263]. In January 2000, the results of the European phase III trial, which were significant in meeting the trial's primary endpoint of reduction in the use of fresh frozen plasma were reported. The trial was also significant in two of three secondary endpoints, maintenance of normal AT-III levels and changes in D-dimer and fibrin monomer [352041,353372]. Three phase III trials were initiated in the second quarter of 1998. Two identical trials, one in Europe and one in the US, evaluated the safety and efficacy of rhAT-III compared to placebo in restoring heparin sensitivity to heparin-resistant patients scheduled for elective cardiac surgery requiring CPB. The third trial, in both the US and Europe, will determine whether rhAT-III matches, at equivalent doses, the ability of plasma-derived AT-III to restore heparin sensitivity among heparin-resistant patients undergoing CPB [292235,292861]. Full enrollment onto the US trial was complete by the end of first quarter 2000 [363589], and the companies aim to complete trials and submit a filing by the end of 2000 [353372]. Clinical trials of the proteins in Japan were expected to begin in 1998 [286086].
ATIII有限责任公司是Genzyme转基因公司（GTC）与Genzyme通用公司的合资企业，正在研发转基因重组人抗凝血酶III（rhAT-III），作为治疗败血症和其他涉及血栓形成疾病的潜在疗法。它在美国和欧洲正处于III期临床试验阶段，用于接受需要体外循环（CPB）的择期心脏手术患者的抗凝治疗。GTC拥有拜耳公司（赫斯特·马里恩·罗氏公司；现为安万特制药公司）授予的开发转基因AT-III的许可。拜耳公司保留该产品在全球的独家营销权，但必须从GTC购买其全部转基因AT-III产品[156364]。1997年3月，GTC与SMIG签署了一项协议，SMIG是GTC与住友金属公司组建的合资企业，根据该协议，SMIG有权在亚洲开发rhAT-III，作为回报，将额外提供440万美元资金用于rhAT-III的持续转基因开发。这440万美元将在达到某些里程碑时支付，GTC预计在1997年完成这些里程碑[240202]。1998年12月，美国专利US-05843705发布，涵盖转基因山羊生产rhAT-III的方法[302263]。2000年1月，欧洲III期试验结果公布，该试验在达到减少新鲜冰冻血浆使用这一主要试验终点方面具有显著意义。该试验在三个次要终点中的两个方面也具有显著意义，即维持正常AT-III水平以及D-二聚体和纤维蛋白单体的变化[352041,353372]。1998年第二季度启动了三项III期试验。两项相同的试验，一项在欧洲，一项在美国，评估了rhAT-III与安慰剂相比，在恢复计划接受需要CPB的择期心脏手术的肝素抵抗患者的肝素敏感性方面的安全性和有效性。第三项试验同时在美国和欧洲进行，将确定rhAT-III在等效剂量下是否与血浆来源的AT-III在恢复接受CPB的肝素抵抗患者的肝素敏感性方面的能力相当[292235,292861]。美国试验在2000年第一季度末完成全部入组[363589]，各公司的目标是在2000年底完成试验并提交申请文件[35337]。预计该蛋白在日本的临床试验将于1998年开始[286086]。
