By Mary Welch
Genzyme Transgenics Corp. and Genzyme Corp., in a joint venture, have started three Phase III trials with recombinant human antithrombin III (rhATIII), a transgenically produced anticlotting drug.
"It's a great achievement because it's the first time a transgenically human recombinant therapeutic will enter Phase III trials," said Genzyme Transgenics Director of Corporate Development Patricia Dimond. "It's the first one ever."
Two of the three trials will evaluate the safety and efficacy of rhATIII vs. placebo in restoring heparin sensitivity to heparin-resistant patients who are having heart surgery and will be put on a cardiopulmonary bypass (CPB) — a heart-lung machine. Patients undergoing such surgery require anticoagulation with heparin to prevent clotting that occurs when blood comes into contact with the foreign surface of the CPB circuit.
Heparin is an anticlotting substance that works in conjunction with rhATIII to prevent clotting. ATIII is a naturally occurring blood protein that helps control the body's normal clotting mechanisms. Unfortunately, some patients on CPB are heparin resistant, which means they don't reach a defined level of anticoagulation following heparin administration.
Currently ATIII is extracted from human blood plasma, which is not only expensive, but susceptible to disease transmission. Genzyme Transgenics inserts human DNA into goat cells so that the targeted protein is secreted in the milk of female offspring. The transgenic protein drug is produced in a 168-acre commercial production facility in central Massachusetts. ATIII is freeze-dried and kept in a vial until it is reconstituted and put in a fluid bag to be fed to the patient intravenously.
"The body always wants to be in a state of homeostasis, or checks and balances," said Dimond. "Heparin and ATIII work together. When you go on a CPB, for instance, your ATIII levels drop about 30 to 40 percent and you overcome that by giving the patient heparin. But some people can't take heparin, and even in those who can, you have to find the right dosage to achieve harmony. Now, in order to give the patient the needed ATIII, you order up some fresh frozen human plasma and pump in a unit."
Trials Target Heparin Resistance
The degree of anticoagulation is monitored by the activated clotting time (ACT), which must reach a specified level before the patient can be put on bypass. These two Phase III trials will try to show that giving ATIII to heparin-resistant patients will restore heparin responsiveness and, as a result, decrease the need for fresh frozen plasma. Each of the trials will be separate, double-blind and randomized and will involve 52 patients. One multicenter trial will take place in this country, the other in Europe.
"It's very measurable and definable," said Dimond.
The third trial matches the ability of rhATIII to restore heparin sensitivity among heparin-resistant patients undergoing CPB with that of equivalent doses of plasma-derived ATIII.
Patients will be randomly assigned to receive rhATIII at one of two dosage levels or plasma-derived ATIII at a dose equal to the lower recombinant version. Two dosage levels are being tested to compare the effects of high and low doses of rhATIII on heparin sensitivity and thrombin inhibition in patients receiving the same heparin dose.
"We only have to prove that the results are the same, not better," Dimond pointed out. "That's important, because rhATIII is easier than using blood plasma. And while the blood supplies are safe, a transgenically produced ATIII does take away any worries about diseases. One person getting hepatitis C from a blood transfusion is one too many."
The trials should last a year and rhATIII should be introduced in 2000, Dimond said.
Genzyme Transgenics and Genzyme are 50-50 partners in the joint venture to commercialize the product. Both contribute manufacturing, marketing and other resources but Genzyme provides 70 percent of the development costs, up to a maximum of $33 million. Any expenses above that will be equally shared. Genzyme owns 43 percent of Genzyme Transgenics.
Genzyme Transgenics' stock (NASDAQ:GZTC) closed Wednesday at $11, up $0.25. Genzyme (NASDAQ:GENZ) ended the day at $30.125, down $0.50. *