BAX 855 is an extended half-life, pegylated full-length recombinant factor VIII (PEG-rFVIII) built on ADVATE and is approved for prophylaxis and the treatment of bleeding in hemophilia A. Safety data from 7 clinical studies were integrated to evaluate single, short-term, and long-term exposure with BAX 855. These clinical trials included the following patients: previously treated adult, adolescent, and pediatric patients (PTPs) and previously untreated patients (PUPs). Immunogenicity, adverse events (AEs), and clinical laboratory parameters were assessed during prophylaxis, treatment of bleeding, perioperative management, and PK evaluations. Of 243 patients, the mean ±SD (range) age was 23.4 ±15.84 (0-61) years, there was 1 female; 74.9% of patients were White, 21.4% were Asian, and 2.5% were Black. Overall, 97 million IUs of BAX 855 were infused, resulting in a median (Q1; Q3) of 111 (73-196) exposure days (EDs) per patient, which ranged from 1 to 322 EDs. No patient developed inhibitory antibodies to FVIII (≥0.6BU) at any time. The 95% confidence intervals for developing inhibitory antibodies based on exposure are as follows: 0-0.19 for 191 PTPs with ≥50 EDs, 0-0.027 for 135 patients with ≥100 EDs, 0-0.37 for 98 patients with ≥150 EDs, and 0-0.68 for 52 patients with ≥200 EDs. At the time of the last blood sample analyzed, no patient had any antibodies to CHO proteins or persistent binding antibodies to FVIII, PEG-FVIII, or PEG. Binding antibodies were either pre-existing (28 patients) or transient (13 patients). No conclusion can be drawn as yet for 5 patients who developed binding antibodies shortly before or at the data cut-off for the analysis. The presence of binding antibodies could not be correlated to an altered PK or impaired efficacy. The only AE considered related to BAX 855 occurring in ≥1% of patients was headache; other related AEs (nausea; diarrhea, flushing, rash, and hypersensitivity) were observed in <1% of patients. No SAEs related to the use of BAX 855 were reported. One PUP discontinued due to a treatment-related AE: a mild, non-serious AE of hypersensitivity (a rash), which resolved. In total, 819 AEs were reported in 182/243 subjects administered ≥1 BAX 855 infusion. The overall rate of AEs/infusion was 2.7% (819 AEs/30,865 infusions), for non-serious AEs 2.5% (773 AEs/30,865), and for serious AEs 0.1% (46/30,865). No trends were observed in laboratory parameters or in vital signs. This safety update for BAX 855 confirms that the safety profile of BAX 855 is consistent with the safety profile of ADVATE. Overall, short- and long-term treatment with BAX 855 was safe and well tolerated in 243 pediatric, adolescent and adult subjects with severe hemophilia A from 3 completed and 4 ongoing studies. As experience with BAX 855 grows, this integrated safety update continues to confirm the safe use of BAX 855 for prophylaxis, the treatment of bleeding episodes, and perioperative management.

Introduction and Objective: Patients with severe hemophilia A repeatedly bleed into joints and subsequently develop target joints and arthropathy. BAX 855, a polyethylene glycol pegylated, full-length, recombinant factor VIII built on ADVATE, demonstrates an extended half-life, efficacy, and safety for prophylaxis and the treatment of bleeding in patients with severe hemophilia A. Target joint status was evaluated in an ad-hocanalysis of integrated efficacy data from previously treated adolescent and adult patients who participated in the pivotal (completed) and continuation (ongoing) studies.

Current management of hemophilia A includes prophylaxis with factor VIII (FVIII) replacement every 2 to 3 days. BAX 855, Baxalta's pegylated full-length recombinant FVIII (rFVIII), was designed to increase half-life and, thus, reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy. BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years. A phase 1 study compared the pharmacokinetic (PK) profile of BAX 855 with that of licensed rFVIII (Advate). In a pivotal study, the annualized bleeding rate (ABR), PK parameters, and efficacy of bleeding treatment were assessed. In the phase 1 study, the mean half-life (T1/2) and the mean residence time of BAX 855 compared with Advate were 1.4- to 1.5-fold higher. These results were confirmed in the pivotal study. The pivotal study met its primary endpoint: Prophylaxis with BAX 855 resulted in an ABR that was significantly lower than half the ABR of on-demand treatment (P < .0001). The median ABR was 1.9, and 39.6% of compliant subjects had no bleeding episodes during prophylaxis, whereas subjects treated on-demand had a median ABR of 41.5. BAX 855 was also efficacious for the treatment of bleeding episodes, with 95.9% of bleeding episodes treated with 1 to 2 infusions and 96.1% having efficacy ratings of excellent/good. No FVIII inhibitory antibodies or safety signals were identified. These studies provide evidence that BAX 855 was safe and efficacious for on-demand treatment and prophylaxis administered twice weekly in patients with hemophilia A. The trials were registered at www.clinicaltrials.gov as #NCT01736475 and #NCT01599819.

BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on rFVIII (ADVATE) with an extended half-life and is intended for prophylaxis and the treatment of bleeding in patients with hemophilia A.1 This phase 3 surgery study is evaluating the efficacy and safety of BAX 855 for the perioperative control of hemostasis. Patients' informed consent and appropriate ethics committee approvals were obtained. Elective procedures were prospectively classified (major or minor) by the investigator/surgeon and major emergency surgeries were excluded. The target trough FVIII levels for major and minor surgeries were to be ≥80% and 30-60%, respectively. Each patient's pharmacokinetic (PK) profile was used to guide the BAX 855 dose and infusion frequency. BAX 855 PK were consistent with previous PK assessments with terminal half-life ranging from 8.81 to 18.06 hours for the 15 patients in this study.

BAX 855 is a pegylated, full-length, recombinant factor VIII (PEG rFVIII) built on ADVATE with an extended half-life that is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. This safety evaluation was derived from an integrated analysis of 5 clinical studies in previously treated patients (PTPs) who were treated with BAX 855 for prophylaxis, bleeding episodes, or perioperative management, or who received a single-dose for a pharmakokinetic (PK) evaluation. Two studies have been completed (pivotal phase 2/3 and phase 1) and 3 are ongoing (continuation, surgery, and pediatric). In all studies, adverse events (AEs) (including hematology and clinical chemistry laboratory values deemed AEs by the investigator) and immunogenicity (inhibitory and binding antibodies) were assessed. Shifts in laboratory values to clinically abnormal over the course of the study and changes in pre- and post-infusion vital signs were also assessed.

Erik Berntorp,1 Gerald Spotts,2 Lisa Patrone,2 Bruce M Ewenstein2 1Malmö Centre for Thrombosis and Haemostasis, Lund University, Skåne University Hospital, Malmö, Sweden; 2Baxter Healthcare Corporation, Westlake Village, CA, USA Abstract: Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t1/2), recovery, and clearance appeared to differ between patients aged <6 years and 10–65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10–65 years. The weekly frequency of dosing and adherence to dosing were both significantly and inversely related to the rate of bleeding (young children, P<0.0001 for both all bleeds and joint bleeds; older patients, P<0.0001 for all bleeds and P<0.05 for joint bleeds), as was adherence to dosing frequency (P<0.0001 for all comparisons). A postmarketing randomized study of prophylaxis demonstrated that a PK-guided dosing regimen, based on an individual patient’s rAHF-PFM PK (infusion interval, estimated t1/2, and recovery), was as effective as standard prophylaxis and that both prophylactic regimens were superior to episodic treatment with respect to ABR and quality of life measures. Thus, compared with standard prophylaxis, the PK-guided regimen achieved comparable efficacy with fewer weekly infusions. A two-compartment population PK model describes the PK data across the entire age range and forms the basis for future PK-guided therapy with rAHF-PFM. The model confirmed a shorter t1/2 and faster clearance of rAHF-PFM in children <6 years of age versus patients ≥10 years and predicted similar PK parameters with either a full or reduced blood sampling schedule, offering the potential for the use of PK-guided, individualized treatment in the routine clinical care setting. Keywords: rAHF-PFM, ADVATE, FVIII, prophylaxis, pharmacokinetics, individualized

Detailed analysis of data from studies of recombinant antihemophilic factor produced using a plasma/albumin-free method (rAHF-PFM) in previously treated patients showed a substantial level of interpatient variation in pharmacokinetics (PKs), factor VIII dosing, and annualized bleed rate (ABR), suggesting that individual patient characteristics contributed to outcome. For example, plasma half-life (t(1/2)), recovery, and clearance appeared to differ between patients aged <6 years and 10-65 years. Prophylaxis resulted in lower ABRs than episodic treatment in both age groups; better adherence to the prophylactic regimen resulted in a lower ABR in patients aged 10-65 years. The weekly frequency of dosing and adherence to dosing were both significantly and inversely related to the rate of bleeding (young children, P<0.0001 for both all bleeds and joint bleeds; older patients, P<0.0001 for all bleeds and P<0.05 for joint bleeds), as was adherence to dosing frequency (P<0.0001 for all comparisons). A post-marketing randomized study of prophylaxis demonstrated that a PK-guided dosing regimen, based on an individual patient's rAHF-PFM PK (infusion interval, estimated t(1/2), and recovery), was as effective as standard prophylaxis and that both prophylactic regimens were superior to episodic treatment with respect to ABR and quality of life measures. Thus, compared with standard prophylaxis, the PK-guided regimen achieved comparable efficacy with fewer weekly infusions. A two-compartment population PK model describes the PK data across the entire age range and forms the basis for future PK-guided therapy with rAHF-PFM. The model confirmed a shorter t(1/2) and faster clearance of rAHF-PFM in children <6 years of age versus patients >= 10 years and predicted similar PK parameters with either a full or reduced blood sampling schedule, offering the potential for the use of PK-guided, individualized treatment in the routine clinical care setting.

Background: Dose tailoring of coagulation factors requires reliably estimated and reproducible pharmacokinetics (PK) in the individual patient. Objectives: To investigate the contribution of both biological and methodological factors to the observed variability of factor VIII (FVIII) PK, with the focus on differences between children and adults, and to examine the implications for dosing. Patients: Data from 52 1-6-year-old and 100 10-65-year-old patients with hemophilia A (FVIII < 2 IU dL-1) in three clinical studies were included. Results: In vivo recovery was lower, weight-adjusted clearance was higher and FVIII half-life was on average shorter in children than in adults. However, a reduced blood sampling schedule for children was estimated to account for up to one half of the total observed differences. Intrapatient variance in PK was smaller than interpatient variance in 10-65-year-olds. Age and ratio of actual to ideal weight only showed weak relationships with PK parameters. Variance in PK caused large variance in the calculated dose required to maintain a target FVIII trough level during prophylactic treatment. Conclusion: Differences in blood sampling schedules should be taken into account when results from different PK studies are compared. However, even with this consideration, PK cannot be predicted from observable patient characteristics but must be determined for the individual. Because the influence of reducing the blood sampling was minor in comparison to the true variance between patients, a reduced blood sampling protocol can be used. Low intrapatient variability supports the use of PK measurements for dose tailoring of FVIII.

BACKGROUND:Hemophilia A is an X-linked bleeding disorder that results from insufficient levels of factor VIII (FVIII) coagulant activity. OBJECTIVE:To evaluate the efficacy and safety of ADVATE rAHF-PFM (Baxter Healthcare Corporation), a recombinant FVIII concentrate manufactured without human or bovine blood-derived additives, and to assess the effect of compliance with prophylactic use in preventing bleeding episodes (BEs). METHODS:Clinical data were integrated from six prospective studies. Two hundred thirty-four hemophilia A subjects (FVIII levels < or = 2%) (median age 14.7 (range: 0.02 - 72.7) years) were included. RESULTS:BEs were managed with one or two infusions and nearly all (1953/1956) responded to treatment. Compliance with a prophylactic treatment regimen significantly reduced the incidence of BEs (p = 0.0061) and prevented non-traumatic joint BEs (median annualized BE rate was 0). One previously treated subject developed an inhibitor; no other safety concerns were observed. CONCLUSIONS:These results reinforce the efficacy and safety of rAHF-PFM and suggest that compliance is an essential contributor to the effectiveness of prophylaxis in the treatment of hemophilia A.