Surgery
Recombinant Human Thrombin as Topical Surgical Hemostat
By Akanksha, Pharmacology Correspondent
Feb 10, 2005, 13:26

ZymoGenetics today announced summary results of its four Phase 2 clinical studies of recombinant human Thrombin (rhThrombin).In these randomized,controlled trials,130 patients undergoing peripheral artery bypass surgery,spinal surgery,arteriovenous graft construction or liver resection surgery had areas of intraoperative bleeding treated with gelatin sponges containing a solution of either rhThrombin or placebo.

The primary objective of these studies was to establish the initial potential safety profile of rhThrombin as a topical surgical hemostat.Secondary objectives included evaluating immunogenicity and developing point estimates of time to hemostasis with intraoperative use of rhThrombin.

The study results showed that rhThrombin is potentially safe and well tolerated. No serious adverse events were observed that were deemed related to administration of rhThrombin. The rate of adverse events observed in patients treated with rhThrombin was generally comparable to that observed in patients receiving placebo, and was consistent with the expected rate of adverse events following these types of surgery.

"With these initial Phase 2 findings, we are optimistic about the prospect of offering rhThrombin to surgeons and patients as an alternative to current animal-derived products that stop surgical bleeding," said Bruce L.A. Carter, Ph.D., President and Chief Executive Officer of ZymoGenetics.

There was no evidence that rhThrombin increased the incidence of antibody formation relative to placebo.Only one of the eighty-three patients evaluated after treatment with rhThrombin tested positive for anti-thrombin antibodies,and none of the five patients who entered the study with established antibodies to thrombin showed increased antibody levels after rhThrombin treatment.These outcomes contrast with published results of studies involving bovine thrombin, in which over forty percent of treated patients generated antibodies to the bovine product.

Among point estimates for time-to-hemostasis in these studies, rhThrombin + gelatin sponge was found to be superior to placebo + gelatin sponge in aggregate in all indications. Both hemostasis at 10 minutes and mean time to hemostasis showed a positive trend in favor of patients treated with rhThrombin.Furthermore, ninety-five percent (19/20) of patients who did not achieve hemostasis after treatment with blinded study drug achieved successful hemostasis after application of rhThrombin.

"We were pleased that rhThrombin demonstrated its potential for safety and low immunogenicity in all four rhThrombin Phase 2 trials," commented Douglas E. Williams, Ph.D., Executive Vice President and Chief Scientific Officer of ZymoGenetics. "We look forward to working with the FDA to establish the safety and efficacy of rhThrombin in our pivotal Phase 3 study."

"We're excited about the positive findings from the Phase 2 studies with rhThrombin," said Jan K. Ohrstrom, M.D., Senior Vice President & Chief Medical Officer. "The market for thrombin is growing, and we project increasing demand in the coming years. Our market research shows that the medical community is interested in a topical hemostat with low potential for antigenicity and negligible risk of viral transmission."

The results of these studies will guide ZymoGenetics in an End of Phase 2 meeting with the U.S. Food and Drug Administration, which will be aimed at creating a mutually acceptable design for a Phase 3 pivotal trial, expected to begin in the second half of this year. Based on the results of the Phase 2 studies, the company currently expects to enroll approximately 400 to 600 patients in a Phase 3 pivotal study designed to demonstrate the superiority of rhThrombin + gelatin sponge to placebo + gelatin sponge. This outlook is subject to future guidance from the FDA.

ZymoGenetics is developing rhThrombin for the control of bleeding associated with surgical procedures. Thrombin is used in over 500,000 surgeries per year in the United States. Currently, only thrombin derived from bovine blood is available in the U.S. as a stand-alone thrombin product. Bovine-derived thrombin has been associated with the development of antibodies that may cross-react with human blood proteins. In some cases, these antibodies lead to serious bleeding complications. Recombinant proteins, such as rhThrombin, can be manufactured to higher levels of purity and consistency than proteins purified from human or animal blood. Furthermore, the production of recombinant proteins is not dependent on the availability of blood from human or animal donors and can be scaled-up to meet market demands. For these reasons, ZymoGenetics believes that rhThrombin represents a potential preferred alternative to the bovine-derived product.

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