IntroductionBAX 855 is a pegylated full‐length recombinant factor VIII (rFVIII) with an extended half‐life, built on a licensed rFVIII (ADVATE®). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A.AimThis phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery.MethodsElective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively.ResultsA total of 15 male patients (aged 19–52 years) underwent 15 procedures (11 major and four minor). The overall intra‐ and perioperative haemostatic efficacy of BAX 855 was ‘excellent’ in all 15 subjects (100%). Postoperatively, evaluated at postoperative Day 1, all treatments were ‘excellent’ except for one minor (dental) procedure which was rated ‘good’. No related adverse events, allergic reactions, thrombotic events, nor signs of immunogenicity in terms of induction of binding antibodies to FVIII, PEG or PEG‐VIII, or FVIII inhibitors were observed.ConclusionThese results demonstrate that BAX 855 is safe and haemostatically effective in patients with severe haemophilia A undergoing surgery.

SummaryThe benefits of prophylaxis of haemophilia A patients regarding joint health and quality-of-life are well established. However, adherence to an up to every-other-day infusion regimen is a barrier to widespread adoption of prophylaxis. BAY 79–4980 is an investigational drug consisting of rFVIII-FS (sucrose-formulated recombinant FVIII) reconstituted with liposome solvent. Previous clinical studies showed extended protection from bleeding after a single injection of BAY 79–4980 (13.3 ± 6.2 days) compared with rFVIII-FS (7.2 ± 1.7 days). The effect of once-a-week prophylaxis with BAY 79–4980 (35 IU/kg) compared with three times-per-week rFVIII-FS (25 IU/kg) in previously treated, severe haemophilia A patients was evaluated in a 52-week, double-blind, two-arm, randomised, controlled study. The primary and secondary endpoints were protection from total bleeds and joint bleeds, respectively. Short- and long-term safety and tolerability of BAY 79–4980 including effects on lipid levels were assessed. A total of 139 and 131 subjects were evaluable for safety and efficacy analyses, respectively. A large difference in efficacy between treatment groups was observed with 72.1% (49/68) in the rFVIII-FS control group demonstrating <9 bleeds/year compared with 38.1% (24/63) of BAY 79–4980-treated subjects. A similar difference was seen in annualised joint bleeds, with 43 subjects (63.2%) in the control group demonstrating <5 joint bleeds/year compared with 24 subjects (38.1%) treated with BAY 79–4980. The distribution of bleeds seven days post-prophylactic treatment with BAY 79–4980 showed that 61% of bleeds occurred after day 4 post dosing. There were no safety concerns identified. The investigational treatment arm was prematurely discontinued due to failure to achieve the primary endpoint.

Background: Inhibitors are a serious complication for patients with severe hemophilia A. Immune tolerance induction (ITI) is the primary method for eradicating these inhibitors. The role of type of concentrate and in particular the use of von Willebrand factor-containing, plasma-derived factor VIII (VWF/pd-FVIII) concentrate in primary or rescue ITI remains unclear. Objectives: To report retrospective collection of data on the use of a single VWF/pd-FVIII concentrate in primary and rescue ITI. Methods: Retrospective chart review of hemophilia A inhibitor patients at 11 US institutions who received VWF/pd-FVIII concentrate in primary or rescue ITI. Results: Primary ITI was carried out in eight inhibitor patients with a 75% complete and partial success. Secondary ITI was carried out in 25 inhibitor patients, with 52% attaining complete or partial success. Conclusions: This report represents the largest group of primarily pediatric, high-titer inhibitor patients treated with a single VWF/pd-FVIII concentrate. It adds retrospective data to the use of VWF-containing plasma-derived factor VIII concentrate in primary and rescue ITI, particularly in those patients with characteristics of poor response to ITI.

BDDrFVIII [moroctocog alfa (AF-CC), Xyntha] is manufactured by a modified process designed to enhance viral safety relative to currently licensed ReFacto. Efficacy and safety of BDDrFVIII for management of surgical hemostasis has been evaluated in a completed, open-label study of previously treated patients, age 12 years or older, with severe hemophilia A (FVIII:C ≤ 2%) undergoing elective major surgery. BDDrFVIII was to be administered for at least 6 postoperative days by bolus injection (BI) or by continuous infusion (CI) at the investigator's discretion, and up to a maximum of 6 weeks following surgery. Twenty-two (22) patients treated by BI received a median of 42 infusions per patient (range 16 to 72) for a median total dose of 85,008 IU per patient (range 36,500 to 231,044) over a median 33 total exposure days (EDs) per patient (range 15 to 40). Eight (8) patients designated for treatment by CI, including 1 patient who received 1 dose for PK assessment only, received a median total dose of 74,409 IU per patient (range 4,405 to 96,251) over a median 29 total EDs per patient (range 1 to 37). Of the 30 patients treated with BDDrFVIII, 29 patients underwent major surgery and completed the study; 25 were evaluable for hemostatic efficacy. These 25 patients had the following procedures: 11 total knee replacements, 5 synovectomies, 1 left ulnar nerve transposition/release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, 1 stapes replacement, 1 ankle arthrodesis, 1 pseudotumor excision, 1 hip arthroplasty, 1 hip arthroplasty revision, and 1 revision/debridement of the knee after total knee replacement. Investigator ratings for surgical hemostasis efficacy at the end of surgery, the primary efficacy endpoint, were 72% excellent (18/25) and 28% good (7/25). At the end of the initial postoperative period, postsurgical day 7, the surgical hemostasis efficacy ratings were 92% excellent (23/25) and 8% good (2/25). Blood loss was assessed for the intra- and post-operative periods. Twenty-four (24) efficacy-evaluable patients had intraoperative blood loss; for all subjects, blood loss was rated normal. Thirteen (13) efficacy-evaluable patients had postoperative blood loss; in 10 cases the postoperative blood loss was rated normal, 1 case was rated abnormal due to hemorrhage following surgical trauma to the epigastric artery, 1 due to an 800 mL blood loss after hip replacement surgery and 1 after an elbow synovectomy, but the blood loss could not be quantitated by the investigator. Nine (9) of 25 efficacy-evaluable patients were prospectively predicted to require transfusions during the intraoperative period; of those 9 only 1 was transfused. Of the other 16 efficacy-evaluable patients, 2 had intraoperative transfusions of packed red blood cells (PRBCs), for both, blood loss was reported as normal. During the postoperative period 4 efficacy-evaluable patients received transfusions, including 1 patient who received PRBCs following excessive hemorrhage associated with trauma to the epigastric artery during surgery. All 30 patients were assessed for safety. Treatment emergent adverse events (AEs) reported in 3 or more patients were fever, pain, infection, headache, flu syndrome, hypertension, nausea, anemia, thrombocythemia, peripheral edema, arthralgia, upper respiratory infection, and local reaction to procedure. The general AE profile was considered consistent with AEs reported in the surgical setting. Three (3) AEs were reported as related to BDDrFVIII. There was an AE of hemorrhage at the operative site during the postoperative period in 1 patient, and clinically silent low titer inhibitors were detected in two patients during routine protocol-specified surveillance testing. One inhibitor was detected pre-operatively (maximum observed titer 1.51 BU/mL) and the other inhibitor (0.63 BU/mL) was detected only on the patient's final study visit with corresponding negative ELISA tests for anti- Factor VIII antibodies. This study has demonstrated that BDDrFVIII is effective and safe when used for surgical prophylaxis in hemophilia A patients undergoing major surgery.

The K121Q polymorphism of the glycoprotein PC-1 gene was recently reported to associate with insulin resistance (IR) in an all-Caucasian, Sicilian population. Given black-white differences in plasma insulin and IR, we compared the prevalence of the KK, KQ, and QQ genotypes and their associations with insulin and IR in 2 large, biracial pediatric samples: 1 hospital-based (n = 301, 137 blacks and 164 whites) and 1 school-based (n = 639, 344 blacks and 295 whites). The Q allele frequencies in the hospital-based and school-based cohorts in black children were 0.80 and 0.77 and in the white children, 0.15 and 0.13. The K allele frequencies in the hospital-based and school-based cohorts in black children were 0.20 and 0.23 and in the white children, 0.85 and 0.87. Differences in allelic frequencies were highly significant (chi square test, P <.0001) for both the hospital-based cohort and the school-based cohort. Both cohorts were in Hardy-Weinberg equilibrium. Within race, after covariance adjusting for age and body mass index (BMI), there were no significant differences (P >/=.10) among the 3 PC-1 genotypes for insulin, glucose, or homeostasis model assessment (HOMA) IR. After covariance adjusting for age and BMI, black girls had higher insulin (P =.0007) and higher HOMA IR (P =.0002) than white girls. The K121Q polymorphism was not associated with insulin, glucose, or HOMA IR measures in black or white children. However, the QQ genotype was population-specific, encompassing most black children versus 1% to 3% of white children. As such, K121Q genotyping should be useful in epidemiology, population genetics, and forensic anthropology.

PURPOSE:To compare results of low-dose tissue plasminogen activator (TPA) in children with arterial and venous thrombi relative to standard published dosing. METHODS:Subjects consisted of all consecutive children with objectively confirmed thrombi for whom TPA thrombolysis was clinically ordered by the authors. Initial dosing used published standard dose (0.1-0.5 mg/kg per hour). With experience, a low-dose regimen (0.01-0.06 mg/kg per hour) was given in an attempt to derive a minimal effective dose. RESULTS:Thirty-five children were treated with TPA. Either standard or low-dose infusions of TPA resulted in complete thrombolysis of 28 of 29 (97%) acute thrombi, while all 6 chronic thrombi had a partial response. In contrast to the recommended adult-derived dosages of 0.1 to 0.5 mg/kg per hour, the authors found that initial doses of less than 0.01 mg/kg per hour were effective in 12 of 17 patients with acute thrombosis. Neonates required 0.06 mg/kg per hour. Route of administration (local or systemic) did not affect efficacy. Major bleeding occurred in only one extremely preterm infant. Minor bleeding, primarily oozing at intravenous sites, occurred in 27% of children during TPA infusions. Prophylactic unfractionated or low-molecular-weight heparin was infused concomitant with TPA in 42% of the children and did not increase the risk of bleeding. CONCLUSIONS:TPA in very low doses appears to be safe and effective for thrombolysis of acute thromboses in most children, given appropriate patient selection.

Effective treatment of bleeding episodes in hemophilia with high titer inhibitors (HTI) remains a challenge, despite the fact that the therapeutic armamentarium has expanded considerably over the past few years. Treatment safety has improved with the availability of porcine factor VIII (FVIII) and bypassing products such as recombinant factor VIIa (rFVIIa), and plasma‐derived activated Prothrombin Complex Concentrates (aPCCs) that are virally inactivated. The major drawbacks of rFVIIa and aPCCs are their unpredictable hemostatic effect, lack of laboratory assays to monitor efficacy and dosing frequency, and the risk of thrombosis. The proceedings of a one‐day workshop of physicians who specialized in treating patients with hemophilia held in Vienna on May 13, 2000 have been summarized. In making a decision regarding the choice of product, physicians often consider the type of bleeding episode (life or limb threatening), age of the patient, volume of the reconstituted product, previous exposure to plasma derived products, cost, efficacy, and safety. For plasma naïve patients, to achieve rapid hemostasis a majority of the panelists used porcine FVIII (for patients who lack porcine inhibitory antibodies) or rFVIIa. For patients previously treated with plasma derived factors, in addition to the above concentrates, aPCCs were recommended. Although no data exists regarding safety and efficacy, switching products was routinely practiced either because of availability or cost. Furthermore, the panelists were uncertain about the efficacy of bypassing agents in the prevention of joint disease in inhibitor patients. The workshop participants felt that future research offers the best solution to resolve some of the dilemmas faced by clinicians and may help individualise treatment in a hemophilia patient with a high titer inhibitor. Am. J. Hematol. 67:240–246, 2001. © 2001 Wiley‐Liss, Inc.