The development of neutralizing antibodies to factor VIII or IX therapeutic concentrates remains the most serious and challenging complication in the management of patients with haemophilia A and B. FEIBA, Anti-Inhibitor Coagulant Complex, is an activated prothrombin complex concentrate that has been used to treat patients with such complications for almost 30 years. The mechanism of action of FEIBA has been proposed to involve simultaneous FVIII/FIX inhibitor bypassing action in the common, intrinsic and extrinsic coagulation pathways. FEIBA is derived from human plasma that undergoes stringent viral screening followed by significant viral inactivation and removal. To date, there have been no confirmed reports of transmission of hepatitis A, B or C, or of human immunodeficiency viruses associated with the use of the current, vapour-heat-treated FEIBA concentrate. The incidence of thrombotic adverse events recorded in the Baxter pharmacovigilance database for the 10-year postmarket period (1990-99) was approximately 4 : 100,000 infusions of FEIBA. Almost all documented thrombotic events with FEIBA occurred with doses that exceeded dosing recommendations, and known risk factors for cardiovascular disease were evident in more than 80% of the patients involved. Overall, clinical data have shown FEIBA to be safe and well-tolerated for use in a wide variety of clinical settings, including treatment of bleeding episodes, management of surgical procedures, home therapy, long-term prophylaxis, and prophylaxis during immune tolerance induction, when used according to dosing guidelines.

Postauthorization safety surveillance of factor VIII (FVIII) concentrates is essential for assessing rare adverse event incidence. We determined safety and efficacy of ADVATE [antihaemophilic factor (recombinant), plasma/albumin-free method, (rAHF-PFM)] during routine clinical practice. Subjects with differing haemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. Among 408 evaluable subjects, 386 (95%) received excellent/good efficacy ratings for all on-demand assessments; the corresponding number for subjects with previous FVIII inhibitors was 36/41 (88%). Among 276 evaluable subjects receiving prophylaxis continuously in the study, 255 (92%) had excellent/good ratings for all prophylactic assessments; the corresponding number for subjects with previous FVIII inhibitors was 41/46 (89%). Efficacy of surgical prophylaxis was excellent/good in 16/16 evaluable procedures. Among previously treated patients (PTPs) with >50 exposure days (EDs) and FVIII≤2%, three (0.75%) developed low-titre inhibitors. Two of these subjects had a positive inhibitor history; thus, the incidence of de novo inhibitor formation in PTPs with FVIII≤2% and no inhibitor history was 1/348 (0.29%; 95% CI, 0.01-1.59%). A PTP with moderate haemophilia developed a low-titre inhibitor. High-titre inhibitors were reported in a PTP with mild disease (following surgery), a previously untreated patient (PUP) with moderate disease (following surgery) and a PUP with severe disease. The favourable benefit/risk profile of rAHF-PFM previously documented in prospective clinical trials has been extended to include a broader range of haemophilia patients, many of whom would have been ineligible for registration studies.

Continuous infusion of factor VIII (FVIII) concentrates during surgical procedures offers the potential for improved hemostatic control and reduced FVIII consumption, but requires stable FVIII concentrates. The stability of ADVATE, Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (rAHF-PFM), was examined using various simulated conditions. Experiments performed with a multi-therapy 6060 pump showed FVIII recoveries of 95% or more after 48 h for multiple lots of high-potency and mid-potency rAHF-PFM, with or without heparin. Non-infused controls maintained at the same temperature showed similar FVIII recovery, demonstrating that the infusion system did not cause loss of FVIII activity. Supportive data generated using single lots of mid-potency or high-potency rAHF-PFM infused through a MEDEX or HARVARD syringe pump, or a CADD Pump-1, demonstrated FVIII recoveries of 83% or more at 24 or 48 h under all conditions tested. Additionally, rAHF-PFM was stable immediately after dilution in saline or saline/dextrose solutions, and after a 10-h exposure to ultraviolet and visible light. Taken together, these data demonstrate that rAHF-PFM is stable under conditions typically encountered during continuous infusion, and suggest that rAHF-PFM should be safe and effective when used for FVIII replacement by continuous infusion in patients with hemophilia A.

3670 Introduction: Development of neutralizing antibodies to FVIII is the most serious complication in the management of hemophilia A today. Eradication of the inhibitor with ITI therapy is a common treatment practice however, there are few reports of controlled studies, and much of the current ITI experience is reported from international registries and small site-based case studies. A previous case-series demonstrated successful tolerance in 9/12 (75%) patients using ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM). Data on the safety and efficacy of rAHF-PFM in ITI therapy have now been formally captured in the recently completed Previously Untreated Patient (PUP-ITI) study, a retrospective chart review (PRE-PAIR), and an ongoing Prospective ADVATE ITI Registry (PAIR). Objectives: To provide a critical assessment of the safety and efficacy of rAHF-PFM in ITI therapy through a review of the cumulative data from PUP-ITI, PRE-PAIR, and PAIR. Methods: PUP study was a prospective, multicenter, open-label, clinical study in PUPs <6 years of age with severe or moderately severe hemophilia (FVIII level ≤2%) who underwent on-demand or prophylactic treatment with rAHF-PFM. Subjects who developed inhibitors against rAHF-PFM could enter the PUP-ITI study and receive ITI. PRE-PAIR was a multicenter, retrospective, chart review of PTPs of any age and any severity of hemophilia A with history of ITI with rAHF-PFM. PAIR is an ongoing non-interventional safety surveillance registry of subjects prescribed rAHF-PFM for ITI. In all three studies, the choice of ITI regimen was at the discretion of the investigator; however, for the PUP-ITI study, the ITI regimen was based on site-specific ITI data and/or institutional guidelines, or as described in peer reviewed literature. The primary endpoints for PUP-ITI and PRE-PAIR were the success rate of ITI. The PAIR report was an interim safety assessment that did not examine efficacy endpoints. For PUP-ITI and PRE-PAIR, the definitions of success required the subject to have achieved 2 consecutive negative inhibitor test results and if data available, demonstrated normalized FVIII recovery. For PRE-PAIR, partial success was defined as achieving negative titer but without normalized recovery. Results: In PUP-ITI, a total of 11 subjects initiated ITI; 3 withdrew and 8 completed ITI. In PRE-PAIR, 35 subjects were enrolled, 30 of which were evaluable per protocol. Of these 30 subjects, 20 had moderately severe to severe hemophilia A (FVIII ≤2%), and high-titer (>5 BU) inhibitor. As of Sept 4, 2010, 18 subjects had been enrolled in PAIR and were included in an interim safety assessment. Over all 3 studies, most commonly prescribed initial dose regimen in subjects with high inhibitor titer prior to initiation of ITI was 100 IU/kg QD (17/37 [46%]), followed by 200 IU/kg QD (11/37 [30%]), and any dose at a frequency of <1/day (9/37 [24%]). In the low titer inhibitor subjects the most commonly prescribed regimen were various doses with a frequency of <1/day (13/22 [59%] subjects). Of the 11 subjects in the PUP study who participated in the PUP-ITI study, 3 withdrew and 8 (72.7%) achieved success (95% CI: 43.4%, 90.3%). All 8 subjects (100%) achieved success, with 1st negative titer at a median time of 1.8 months (0.0 - 4.1 months) and the 2nd negative titer at 3.0 months (1.1 – 9.0 months). In PRE-PAIR, sum of complete and partial success rates gave a total success rate of 76.7% (23/30) in subjects who met inclusion criteria (95% CI: 59.1, 88.2%). During these 3 studies, there were no SAEs related to rAHF-PFM ITI therapy and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM (diarrhea, vomiting, pain following bleed, mild urticaria, and mild fever). Conclusions: In 2 clinical studies of rAHF-PFM therapy in ITI treatment, rAHF-PFM was found to be efficacious in a variety of dosing regimens reflective of current standards of practice in hemophilia care. Overall success rates ranged from 72.7% in PUP-ITI to 76.7% in PRE-PAIR. Success rates in these 2 rAHF-PFM studies are similar to those reported in published literature. In all 3 ITI studies, there were no product related SAEs and 6 non-serious AEs in 3 subjects considered to be related to rAHF-PFM, suggesting that rAHF-PFM used for ITI has a similar risk profile established in routine clinical use. These data suggest that ITI treatment with rAHF-PFM was both effective and safe. Disclosures: Spotts: Baxter Bioscience: Employment. Off Label Use: ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] (rAHF-PFM)use in ITI therapy. Abbuehl:Baxter Bioscience: Employment. Luu:Baxter Bioscience: Employment. Song:Baxter Bioscience: Employment. Dyck-Jones:Baxter Bioscience: Employment. Guzman-Becerra:Baxter Bioscience: Employment. Wu:Baxter Bioscience: Employment. Oh:Baxter Bioscience: Employment. Zoerer:Baxter Bioscience: Employment. Sosa:Baxter Bioscience: Employment. Stephens:Baxter Bioscience: Employment. Yamamoto:Baxter Bioscience: Employment. Ewenstein:Baxter Bioscience: Employment.

1404 Poster Board I-426 Objectives: The primary objective of this study was to compare the Health-Related Quality of Life (HRQOL) burden of severe hemophilia A patients relative to a healthy sample of people, a general sample of the population, and to patients with other burdensome chronic conditions. The secondary objective was to determine the HRQOL impact of having at least one target joint. Methods: All adult patients with severe hemophilia A who were enrolled in the Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (Advate) Post-Authorization Safety Surveillance (PASS) study and completed the SF-36v2 at their baseline assessment were selected for this research. Analysis of variance was used to assess the relative HRQOL burden of these hemophilia A patients as compared to a healthy US population sample, a normal US population sample and patients reporting either chronic back pain, rheumatoid arthritis, or cancer. This comparison data was collected from the 1998 US National Survey of Functional Health Status. These comparisons groups were adjusted to the age and sex distribution of the severe hemophilia A sample using OLS regression models, with each SF-36v2 scale/summary score as a dependent variable. Finally, multivariate analysis of covariance (controlling for age) tested the impact of target joint absence (TJ-) or presence (TJ+) on SF-36v2 scores. Results: 141 adult patients (ages 18–78; median age=35) were identified. These severe hemophilia A patients scored worse than the US healthy population and US general population on all four physical domain scales and lower than chronic back pain patients on three out of the four physical domain scales (all p<0.01). The mean physical component summary (PCS) score was 41.6 for these hemophilia A patients and 54.3, 51.3, and 47.4 for the US healthy population, US general population and chronic back pain patients (all p<0.01); all exceeding this measure's established minimal important difference (MID) of 3 points. Hemophilia A patients reported no differences in physical HRQOL on the SF-36v2 when compared to patients with rheumatoid arthritis and cancer (p>0.05). Interestingly, hemophilia A patients reported significantly a higher score on both the vitality domain and mental component summary (MCS) score when compared to all patient groups except the US healthy population (all p<0.01). In addition, the difference on the MCS between hemophilia A patients and patients with chronic back pain, rheumatoid arthritis, and cancer were larger than the MID (50.6 vs 45.2, 44.4, and 44.7, respectively). Forty-six (32.6%) severe hemophilia A patients enrolled in the PASS study did not have a target joint. Hemophilia A patients without target joints showed significantly better HRQOL than patients with at least one target joint on the physical functioning scale (p<0.05), the general health scale (p<0.01) and the PCS score (p<0.01). The difference between the mean PCS score exceeded the MID (44.8/40.1 for TJ-/TJ+ groups, p<0.01). There were no differences between hemophilia A patients with and without target joints for any of the mental scales or the MCS score (p>0.05). Conclusion: These comparisons demonstrate that severe hemophilia A patients have significantly significant and clinically meaningful lower physical HRQOL compared to the general public and people suffering from chronic back pain. The physical burden that these severe hemophilia A patients reported was similar to those who were living with rheumatoid arthritis or cancer. If target joints are prevented, hemophilia A patients may be able to experience significantly better physical HRQOL than if they developed a target joint. Finally, this research demonstrated that hemophilia A patients were unique compared to the other three chronic conditions studied, because hemophilia A patients reported significantly higher mental HRQOL than patients with chronic back pain, rheumatoid arthritis and cancer. Disclosures: Epstein: Baxter BioScience: Employment. Luu: Baxter BioScience: Employment. Yarlas: Baxter BioScience: Consultancy. Hammond: Baxter BioScience: Consultancy.