Favorable Immunologic Response to Recombinant Thrombin Application in Surgery among Subjects with Pre-Existing Antibodies to Bovine Thrombin.

Recombinant thrombin (rThrombin) is an active topical hemostat that is approved by the FDA as an aid to hemostasis. The safety, immunogenicity, and efficacy of rThrombin have been demonstrated in 1 Phase 1 study, 5 Phase 2 studies, and 1 randomized, double-blind Phase 3 study. No safety observations have been deemed clearly causally related to exposure to rThrombin; favorable immunologic response to rThrombin was observed in these trials. Treatment with thrombin derived from bovine sources has occasionally been associated with adverse events which appear to be related to the formation of antibodies against bovine thrombin and/or Factor V. A boxed product warning indicates that patients with antibodies to bovine thrombin preparations should not be re-exposed to these products. Secondary immune responses to bovine thrombin re-exposure may occur in patients with antibodies to bovine thrombin product. This Phase 3b open-label, single-group, multisite study was designed to evaluate the immunogenicity and safety of rThrombin among subjects at increased risk for having anti-bovine thrombin product antibodies as a result of prior surgery with a high likelihood of bovine thrombin exposure (N=209). Topical rThrombin was applied during a single spinal or vascular surgical procedure. Immunogenicity was evaluated by enzyme-linked immunosorbent assay at baseline and Day 29; safety measures were evaluated through Day 29. Subjects were eligible for participation if they had definite or highly likely prior exposure to bovine thrombin within the previous 3 years. Preliminary results from 162 subjects enrolled and evaluated as of the cut-off date (28 July 2008) are presented herein; complete study results will be available at the meeting. Of the subjects evaluated to date, 78 (48%) had definite prior exposure to bovine thrombin; prior exposure was highly likely for 85 subjects (52%) and unknown for 1 subject. At baseline, 139 subjects (86%) were seronegative and 23 (14%) were seropositive for anti-bovine thrombin product antibodies. Anti-rThrombin product antibodies did not develop through Day 29 post-treatment in any subject; thus, the rate of antibody formation to rThrombin was the same regardless of anti-bovine thrombin product antibody status. Of the 4 subjects who had anti-rThrombin product antibodies at baseline, none had a change in titer ≥1.0 unit at Day 29. Common adverse events (AEs; reported by ≥10% of subjects) were consistent with the post-surgical setting and with prior studies of rThrombin in these surgical populations. Common AEs included incision site pain, procedural pain, nausea, constipation, anemia, muscle spasms, hypotension, and pyrexia. Topical application of rThrombin was well tolerated, and there was no difference in the formation of antibodies to rThrombin at Day 29 in subjects with or without pre-existing antibodies to bovine thrombin product. The results from this study provide additional information about the immunologic safety of rThrombin and suggest that rThrombin can be safely applied as an aid to hemostasis in patients with pre-existing antibodies to bovine thrombin.