GTC Biotherapeutics (fka GTCB)

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Jan 2000 - (HR) First Phase III Trial for Transgenically Produced Protein Meets Primary Endpoint

http://www.medscape.com/viewarticle/411424

New York (MedscapeWire) Jan 12 — The results of a phase III trial evaluating the ability of transgenically produced recombinant human antithrombin III (rhATIII) to restore heparinsensitivity in heparin-resistant patients undergoing elective heart surgeryrequiring cardiopulmonary bypass (CPB) are now available, according to Genzyme Transgenics and Genzyme General. The results were statistically significant (P<.001) in meeting the trial's primary endpoint — reduction in the use of fresh frozen plasma.

These results mark the first time a transgenic drug candidate has advanced to and successfully completed a phase III clinical trial evaluation.

"The data indicate that transgenically produced rhATIII has the potential to support an extremely important function, anticoagulation, in heparin resistant patients undergoing cardiopulmonary bypass," said Jerrold Levy, MD, director of cardiothoracic anesthesiology, Emory University School of Medicine. "The prospect of an unlimited supply of this unique therapeutic protein may enable physicians to avoid the need for donor blood products. Transgenic proteins have the potential to provide a new and exciting treatment option for the future."

Patients undergoing cardiopulmonary bypass require anticoagulation with heparin to prevent clotting, which can occur when blood comes into contact with the tubing and artificial surfaces of the heart-lung machine used to take over the heart's function during surgery. Treatment of heparin-resistant patients with fresh frozen plasma is one option available to restore heparin sensitivity and achieve adequate anticoagulation to permit initiation of cardiopulmonary bypass.

The results of the study demonstrated that in heparin-resistant patients, 6 (21%) of 28 patients in the rhATIII-treated group required fresh frozen plasma to manage their heparin resistance, compared with 22 (92%) of 24 patients in the placebo group.

The double-blinded, randomized, placebo-controlled study evaluated 52 patients at 6 medical centers in Germany and the United Kingdom. This trial is the first of 2 identical phase III trials.

"We are pleased that the data demonstrate the biological activity of rhATIII in this setting and show its potential value," said Sandra Nusinoff Lehrman, MD, president and chief executive officer of Genzyme Transgenics. "This result is a significant milestone in the advancement of transgenic technology and we await the results of the second phase III trial to confirm these results. In the future, we plan to conduct additional studies to further evaluate this compound for other potential uses."

In addition to achieving statistical significance on the primary endpoint, the trial also achieved statistical significance on 2 of 3 secondary endpoints. Secondary endpoints included maintenance of normal ATIII levels and changes in 2 biochemical markers of coagulation: D-dimer and fibrin monomer.

In the treatment group, ATIII blood levels increased to 103% of normal 30 minutes after the start of surgery, and were at 104% of normal at the end of CPB. In contrast, ATIII levels in placebo patients who received fresh frozen plasma were 41% of normal within 30 minutes after the start of bypass, and 42% of normal at the end of CPB.

The researchers report that they did not note any significant differences between the rhATIII and placebo groups with respect to safety parameters. There was no evidence of antibody formation in the patients treated with rhATIII.

ATIII deficiency is a key factor in heparin resistance, since heparin requires ATIII for effective anticoagulation. Administration of fresh frozen plasma, which contains ATIII, is one approach to managing heparin resistance. This trial was designed to evaluate the potential efficacy of rhATIII to reduce the need for treatment with fresh frozen plasma.

The degree of anticoagulation during cardiopulmonary bypass is measured by the activated clotting time (ACT). An ACT of 480 seconds or greater reflects adequate anticoagulation for initiation and maintenance of CPB. In this study, after receiving a total of 400 U/kg heparin before CPB, patients whose ACT was still less than 480 seconds were randomized into either rhATIII (75U/kg) or placebo groups. Following treatment, patients whose activated clotting time remained below 480 seconds were given fresh frozen plasm






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