Transgenic antithrombin III (Genzyme).

Abstract

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].