Perioperative Efficacy of an Extended Half-Life, Pegylated, Full-Length, Recombinant Factor VIII (BAX 855) in Individual Procedures

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2299-2299
Author(s):  
Brigitte Brand ◽  
Ralph A. Gruppo ◽  
Tung T. Wynn ◽  
Laimonas Griskevicius ◽  
Maria Fernanda Lopez Fernandez ◽  
...  
Keyword(s):  
Blood Loss ◽  
Factor Viii ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Full Length ◽  
Recombinant Factor Viii ◽  
Employment Equity ◽  
Major Procedure ◽  
Equity Ownership

Abstract 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. In this interim analysis, 15 male previously treated patients (PTPs) ranging from 19 to 52 years of age have undergone 15 procedures in 7 countries. Individual procedure profiles are compiled to evaluate the control of hemostasis for BAX 855. There were 11 major procedures: 6 orthopedic (3 knee replacements, 2 arthroscopic synovectomies, 1 elbow cyst extirpation) and 5 non-orthopedic procedures (3 dental [root canals for 2 teeth, 2 extractions of ≥4 teeth, 1 radicular cyst removal], 1 cardiovascular [mediport placement], 1 abdominal [gastric band insertion]). The 4 minor surgeries comprised 1 synoviorthesis, 1 dental, 1 dermatological and 1 endoscopy (radiosynovectomy) procedure. Efficacy was evaluated by the surgeon or investigator's rating of hemostatic control using 4-point scale which was based on blood loss and by comparing actual blood loss with predicted blood loss which was specified by the surgeon for non-hemophilia patients prior to the procedure. For all procedures, the hemostatic control of BAX 855 was rated "excellent" for the intraoperative (during the procedure), postoperative (24 hours after completion of the procedure), and perioperative (from start of the procedure until discharge or day 14) periods, except for 1 minor dental procedure in which postoperative efficacy was rated "good" and 1 minor procedure in which a postoperative rating was not provided (for both of these procedures intra- and perioperative ratings were "excellent"). Actual blood loss (ABL) for the intraoperative and postoperative periods were compared with predicted average and maximum values. Intraoperative ABL for all minor and major procedures was less than or equal to predicted averages and maximums, except for 1 minor procedure in which the ABL was greater than the predicted average and maximum and 1 major procedure which did not have ABL recorded. Postoperative ABL was less than or equal to predicted averages and maximums for 4/4 minor procedures and 5 major procedures. For 4 major procedures, postoperative ABL was greater than or equal to predicted average, but less than predicted maximums. For the remaining major procedure (synovectomy with general anesthesia) with reported ABL, postoperative ABL was greater than the predicted the average and maximum - the efficacy assessments at all periods for this procedure were considered "excellent". These results demonstrate the efficacy of BAX 855 for the perioperative control of hemostasis in patients with severe hemophilia A. 1 Konkle BA, Stasyshyn O, Chowdary P et al. Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A. Blood. 2015; Link to Publisher's site: http://www.bloodjournal.org/content/bloodjournal/early/2015/07/08/blood-2015-03-630897.full.pdf Disclosures Brand: CSL Behring: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biotest: Consultancy. Gruppo:Baxalta: Consultancy, Research Funding; Novo Nordisk: Consultancy; Pfizer: Consultancy; Alexion: Speakers Bureau. Wynn:Baxalta: Research Funding. Griskevicius:Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Fernanda Lopez Fernandez:Baxalta: Research Funding. Dvorak:Baxalta: Employment, Equity Ownership. Patrone:Baxalta: Employment, Equity Ownership. Abbuehl:Baxalta: Employment, Equity Ownership.

Target Joint Status in Patients with Hemophilia a during 18 Consecutive Months of Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2592-2592
Author(s):  
Werner Engl ◽  
Lisa Patrone ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Treatment Period ◽  
Half Life ◽  
Hemophilia A ◽  
Full Length ◽  
Adult Patients ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Equity Ownership

Abstract 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. Methods: The number of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, were analyzed over 3 consecutive 6-month periods in patients who received twice weekly BAX 855 prophylaxis at 40-50 IU/kg. Results: After approximately 6 months of twice weekly prophylaxis during the pivotal study, 101 adolescent and adult patients continued treatment in the continuation study, 51 of whom were treated with twice weekly prophylaxis for 18 consecutive months. At screening 29.4% (15/51) of these patients had no target joints, 19.6% (10) had 1 target joint, 21.6% (11) had 2, and the remaining 29.4% (15) had 3 or more. After the first 6-month treatment period, the percent of patients with no target joints increased to 66.7% (34 patients), including 19 patients in whom 1 or more target joints had resolved and 15 patients who remained target joint-free from screening. Of note, for the 15 patients with 3 or more target joints at screening, all of their target joints resolved after the first 6 months of treatment with BAX 855. This trend was maintained after the second 6-month treatment period. After the third 6-month period of twice weekly prophylaxis, the percent of patients with no target joints further increased to 82.4% (42), which included the 15 patients who remained target joint-free from screening. Nine patients had 1 or more unresolved target joint after 18 months of twice weekly prophylaxis, and in 6 of these patients, 1 to 3 other target joints had resolved. Overall, there were 89 target joints at screening which reduced to 14 after 18 months of twice weekly prophylaxis. Of those, 10 target joints changed status (eg, were present, resolved, and then re-appeared) and only 4 target joints (in 4 patients) persisted as unresolved through each of the 3 consecutive 6-month treatment periods. Conclusions: These results demonstrate the efficacy of continuous twice weekly prophylaxis with BAX 855 for preventing and resolving the majority of target joints. Disclosures Engl: Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Patrone:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.

An Evaluation of Safety with an Extended Half-Life, Pegylated, Full-Length Recombinant Factor VIII (BAX 855) in the Treatment of 243 Patients with Hemophilia a

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3801-3801
Author(s):  
Werner Engl ◽  
Lisa Patrone ◽  
Dyck-Jones Jacqueline ◽  
Srilatha D. Tangada ◽  
Brigitt E. Abbuehl
Keyword(s):  
Factor Viii ◽  
Safety Profile ◽  
Half Life ◽  
Perioperative Management ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Employment Equity ◽  
Equity Ownership ◽  
Inhibitory Antibodies

Abstract 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. Disclosures Engl: Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Patrone:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Jacqueline:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Tangada:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.

Joint Bleeding Patterns in Patients Treated Prophylactically with an Extended Half-Life, Pegylated, Full-Length Recombinant Factor VIII (BAX 855)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2300-2300 ◽  
Author(s):  
Marilyn J. Manco-Johnson ◽  
Alice D. Ma ◽  
Robert Klamroth ◽  
Werner Engl ◽  
Lorena Griparic ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Recombinant Factor Viii ◽  
Employment Equity ◽  
Advisory Committees ◽  
Bleeding Episodes ◽  
Equity Ownership ◽  
The Mean

Abstract BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In a pivotal trial, 101 previously treated patients (PTPs) received BAX 855 for prophylaxis twice weekly (in the per protocol analysis set). At screening, 67/101 (66.3%) of patients had arthropathy (reported in medical history or history of joint surgery) and 69/101 (68.3%) had at least 1 target joint. A target joint was defined as a single joint (ankle, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period. Overall, among these 101 PTPs, the mean (standard deviation) annualized joint bleeding rate (AJBR) was 1.8 (3.0) and 57.4% of patients had zero joint bleeding episodes. There were 32, 40, and 29 subjects with 0, 1-2, and ≥3 target joints, respectively, at screening. Patients with more target joints at screening experienced higher AJBRs: with mean AJBRs of 1.15, 1.84, and 2.58 for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Of the individual joints, ankle and knee joints had highest AJBRs. BAX 855 demonstrated efficacy in the treatment of joint bleeding, with the majority of joint bleeding episodes, irrespective of target joint status, treated with 1-2 infusions: 92.8%, 91.9% and 94.4% for patients with 0, 1-2, and ≥3 target joints, respectively, at screening. Hemostatic efficacy of BAX 855 at 24 hours was rated as excellent or good in >90% of patients, regardless of target joint status at screening. Patients with 0 target joints at screening had 57.1% of joint bleeding episodes considered mild in severity, while patients with 1-2 or ≥3 target joints had 59.5% and 66.7% of joint bleeding episodes, respectively, rated moderate in severity. There were few joint bleeding episodes considered severe. Similar doses per infusion of BAX 855 were used to treat joint bleeding episodes: the mean dose per BAX 855 infusion was 35, 33.8, and 36.2 IU/kg for patients with 0, 1-2, and ≥3 target joints, respectively. In conclusion, BAX 855 demonstrated a favorable efficacy profile in the treatment of breakthrough joint bleeding episodes, and twice-weekly use was efficacious in prevention of bleeding, with the lowest overall AJBRs achieved in patients in the trial without target joints. Disclosures Manco-Johnson: Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Ma:Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees. Klamroth:Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau; Biogen and SOBI: Honoraria, Speakers Bureau. Engl:Baxalta: Employment, Equity Ownership. Griparic:Baxalta: Employment. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

Pharmacokinetics Of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Pediatric Subjects With Hemophilia A: An Interim Analysis Of The Kids A-LONG Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3609-3609
Author(s):  
Guy Young ◽  
Johnny Mahlangu ◽  
Beatrice Nolan ◽  
Simon Brown ◽  
Leonard A. Valentino ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Interim Analysis ◽  
Research Funding ◽  
Hemophilia A ◽  
Additional Time ◽  
Employment Equity ◽  
Advisory Committees ◽  
Age Cohorts ◽  
Equity Ownership

Abstract Introduction Prophylactic factor VIII (FVIII) administration is the standard of care for patients with severe hemophilia A; however, frequent injections are required to maintain protective factor levels. To reduce injection frequency, we developed a long-lasting recombinant FVIII Fc fusion protein (rFVIIIFc) consisting of one rFVIII molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1). rFVIIIFc had a 1.53-fold higher half-life and a 36% reduction in clearance (CL) versus FVIII (Advate®) in a phase 3 study of adults and adolescents (J Thromb Haemost. 2013;11[2]:169). The Kids A-LONG study (NCT01458106) was designed to investigate the pharmacokinetics (PK), safety, and efficacy of rFVIIIFc in pediatric subjects with hemophilia A who were previously treated with FVIII products. The objective of this planned interim analysis was to determine the PK parameters of rFVIIIFc in pediatric subjects and compare these parameters to those of the subjects' prescribed FVIII products. Methods This multi-center, open-label, phase 3 study is currently enrolling previously-treated subjects aged<12 years with severe hemophilia A (≤1 IU/dL endogenous FVIII), at least 50 exposure days (EDs) to FVIII products, and no history of or current inhibitors to FVIII. Subjects are stratified into two age cohorts (<6 years and 6 to<12 years). All subjects are started on a twice-weekly rFVIIIFc prophylactic regimen 25 IU/kg on day 1 and 50 IU/kg on day 4 with subsequent dosing adjustment based on PK data and bleeding frequency. The primary endpoint is the incidence of inhibitor development. A sequential PK analysis is performed to compare the PK parameters of rFVIIIFc with that of the prescribed FVIII product. Subjects undergo a washout period of at least 72 hours before receiving the first dose of either FVIII or rFVIIIFc. For FVIII PK analysis, subjects receive 50 IU/kg of their currently prescribed FVIII product with sampling at baseline and at 4 additional time points after for up to 48 hours. For rFVIIIFc PK assessment, subjects receive 50 IU/kg rFVIIIFc, with sampling prior to rFVIIIFc administration and at 5 additional time points after for up to 72 hours. PK parameters were derived from FVIII activity-over-time profiles estimated by the non-compartmental analysis using the PK data analysis software Phoenix™ WinNonlin 6.2.1.51. FVIII activity was measured by the one-stage clotting assay calibrated against a commercially available FVIII plasma standard. A data cut-off date of 8 February 2013 was used to report PK data in this interim analysis. Results At the time of this analysis, 52 subjects were enrolled and received at least one dose of FVIII and/or rFVIIIFc. Of 37 subjects with evaluable PK profiles, 30 received both FVIII and rFVIIIFc. For PK assessment of FVIII, 7 different FVIII products were used, of which Advate ®, Haemosolvate®, and Kogenate FS® were the most common. A comparison of PK parameters for rFVIIIFc versus FVIII for both age cohorts demonstrated that rFVIIIFc had a longer half-life (∼1.5 fold increase) and a lower CL (30% to 50% reduction) than FVIII (Table 1). Conclusion In comparison to currently available FVIII products, rFVIIIFc had an extended half-life and reduced CL in children. These results are in agreement with those previously observed in adults and adolescents. The final analysis of the Kids A-LONG study will provide additional PK information and evaluate the safety and efficacy of rFVIIIFc in children. Disclosures: Young: Novo Nordisk: Consultancy, Honoraria; Biogen Idec, Baxter, Kedrion: Consultancy. Mahlangu:Bayer, Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Research Funding. Brown:Novo Nordisk, Biogen Idec, Baxter: Membership on an entity’s Board of Directors or advisory committees. Valentino:Baxter, Bayer, Biogen Idec, GTC Biotherapeutics, Inspiration Biopharmaceuticals, Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Liesner:Bayer, Baxter, Novo Nordisk, Pfizer: Consultancy, Sponsorship Other; Octapharma: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Inspiration Biopharmaceuticals: Research Funding. Dong:Biogen Idec: Employment, Equity Ownership. Diao:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Nugent:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.

scholarly journals An Integrated Analysis of Long Term Safety of an Extended Half-Life, Pegylated, Full-Length Recombinant Factor VIII (BAX 855) in the Treatment of Hemophilia a

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3522-3522
Author(s):  
Pratima Chowdary ◽  
Barbara Konkle ◽  
Tadashi Matsushita ◽  
Werner Engl ◽  
Lisa Patrone ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Vital Signs ◽  
Integrated Analysis ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract 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. Of the 169 unique patients (most participated in more than 1 study), 3 were <6 years of age, 1 was 6 to <12, 25 were 12 to <18, and 140 were ≥18. The mean (SD) age was 30.1 (13.0) years and all were male. Overall, 133 (78.7%) patients were White, 34 (20.1%) were Asian, 1 (0.6%) was Black, and 1 (0.6%) was "other". These 169 patients received nearly 46 million IUs of BAX 855; 117 patients started treatment in the pivotal study and transitioned to the continuation study, for an overall median (Q1;Q3) exposure of 96 (48.0;110) days. A total of 300 AEs were reported in 96 of 169 patients during or after treatment with at least 1 infusion of BAX 855. The overall rate of AEs by infusion was 2.2% (300 AEs/13,579 infusions), the rate of nonserious AEs by infusion was 2.1% (283 AEs/13,579 infusions), and the rate of SAEs by infusion was 0.1% (16 SAEs/13,579 infusions). Common AEs considered related to BAX 855 (in ≥1% of patients) were headache and nausea; diarrhea, flushing, and blood pressure increase occurred once in 1 patient each. None of the 16 SAEs reported were considered related to the use of BAX 855. No treated patient has discontinued from a study due to a treatment related AE (or SAE). None of the patients exposed to BAX 855 developed an inhibitory antibody to FVIII of ≥0.6 BU/mL by the Bethesda assay, including 120 patients with ≥50 EDs (95% CI: 0.000 to 0.030) and 48 with ≥100 EDs (95% CI: 0.000 to 0.074). None of the 169 treated patients developed a persistent binding antibody against FVIII, PEG-FVIII, PEG, or CHO protein. Pre-existing and transient binding antibodies were detected in 21 patients; however, these were not detectable at subsequent visits or at completion of the study and appeared to have no apparent impact on efficacy or temporal association with an AE. No remarkable trends were observed in changes in laboratory parameters from baseline to last study visit or in vital signs evaluated pre- and post-infusions given at the study site (eg, PK assessments). From this integrated analysis, BAX 855 was safe and well tolerated in 169 PTPs with severe hemophilia A. The common adverse events considered related to BAX 855 treatment were consistent with the safety profile of ADVATE. Disclosures Chowdary: Sobi: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding. Konkle:Baxalta: Consultancy, Research Funding; CSL Behring: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy; Octapharma: Research Funding; Biogen: Consultancy, Research Funding. Matsushita:Baxalta: Research Funding. Engl:Baxalta: Employment, Equity Ownership. Patrone:Baxalta: Employment, Equity Ownership. Abbuehl:Baxalta: Employment, Equity Ownership.

Phase I, Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation Study of the rFVIIa Variant (BAY 86–6150) In Hemophilia A or B with or without Inhibitors.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3679-3679 ◽  
Author(s):  
J.N. Mahlangu ◽  
M.J. Coetzee ◽  
M. Laffan ◽  
J. Windyga ◽  
T. T. Yee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Employment Equity ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Bleeding Episodes ◽  
Equity Ownership

Abstract Abstract 3679 Bleeding episodes in hemophilia A or B patients with inhibitors to factors VIII or IX are commonly managed with bypassing agents such as recombinant factor VIIa (rFVIIa). However, currently available rFVIIa treatment is associated with variable response rates and a short elimination half-life, often necessitating the administration of multiple doses to control bleeding. BAY 86–6150, a human rFVIIa variant, was developed to provide a longer-acting and more potent activated factor VII in the management of bleeding episodes in patients with hemophilia who developed inhibitors. The safety, tolerability, pharmacodynamic/pharmacokinetic (PD/PK) profiles, and immunogenicity of BAY 86–6150 in nonbleeding patients with hemophilia was investigated in a phase I, randomized, double-blind, placebo-controlled, single-dose escalation study. The patient population comprised nonbleeding men aged 18–65 years with moderate or severe hemophilia A or B with or without inhibitors. 16 patients were randomized 3:1 to escalating doses of BAY 86–6150 at 6.5, 20, 50, or 90 μg/kg (n=3 each) or placebo (n=4). Patients were followed for 50 days postdose. The objective of the trial was to evaluate the safety and tolerability of BAY 86–6150, with adverse events (AEs) as the primary endpoint. Other endpoints included PK parameters, the effects of BAY 86–6150 on hemostasis markers and coagulation, and the immunogenicity of the compound. BAY 86–6150 was not associated with clinically significant AEs or dose-limiting toxicities and the PK parameters were linear over the dose range, with a half-life of 5–7 hours. Patients demonstrated consistent, dose-dependent thrombin generation ex-vivo in platelet-poor plasma (mean peak effect 26–237 nM thrombin from 6.5–90 μg/kg). Peak thrombin levels over time paralleled the presence of BAY 86–6150 by PK analysis, indicating that the drug in circulation retained activity. There were corresponding decreases in time and duration in the activated partial thromboplastin and prothrombin time testing. In contrast, there was no dose response seen in the thrombogenicity markers evaluated including antithrombin III, prothrombin fragment 1+2, TAT, and D-dimer. One patient demonstrated antibody activity to both BAY 86–6150 and to rVIIa as determined by ELISA testing at baseline. The level of inhibition and titer remained constant when evaluated in follow-up on day 29 and day 49. The data safety monitoring board recommended progression to the highest proposed dose (90 μg/kg). The phase II/III studies are designed to evaluate the clinical efficacy and safety as well as corresponding laboratory markers. Results of the present study suggest that the novel rFVIIa agent BAY 86–6150 is safe and has increased potency and a longer half-life compared with the currently available rFVIIa therapy. BAY 86–6150 may therefore have the potential to improve the treatment of bleeding episodes in hemophilic patients with inhibitors. Disclosures: Mahlangu: Bayer Helathcare: Consultancy, Honoraria, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Speakers Bureau; IAVI: Consultancy; Maxygen: Consultancy. Coetzee:Bayer Schering Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Laffan:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Windyga:Bayer HealthCare Pharmaceuticals: Research Funding; Bayer, Baxter, Behring, NovoNordisk, Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yee:Bayer HealthCare Pharmaceuticals: Research Funding. Schroeder:Bayer Schering Pharma AG: Employment, Equity Ownership. Haaning:Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. Siegel:Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. Lemm:Bayer Schering Pharma AG: Employment, Equity Ownership.

MODERN POSSIBILITIES OF SUBSTITUTION THERAPY AND HEMOPHILIA A PREVENTION IN CHILDREN

2021 ◽  
Vol 100 (2) ◽  
pp. 182-187
Author(s):  
P.A. Zharkov ◽  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Safety Data ◽  
Residual Activity ◽  
Recombinant Factor Viii ◽  
Substitution Therapy ◽  
Life Effectiveness ◽  
Intravenous Injections ◽  
Prophylactic Use

Currently, the prophylactic use of factor VIII concentrate is the «gold standard» for treatment of an uncomplicated severe hemophilia A without inhibitors. However, there are a number of difficulties associated with frequent intravenous injections to maintain the activity of factor VIII above 1% in children and adolescents, which cannot but affect the adherence of patients to this type of treatment. The article discusses modern approaches to extend the half-life of recombinant factor VIII allowing to reduce the frequency of infusions and increase the residual activity of the deficient factor. On the example of efmoroctocog alpha, the first recombinant factor VIII concentrate registered in our country with a prolonged half-life, effectiveness and safety data of this class of drugs approved for use in children is presented.

scholarly journals Factor VIII Use in the Treatment of Breakthrough Bleeds in Hemophilia A Patients without Inhibitors on Emicizumab Prophylaxis: The Phase 3 HAVEN 3 Study Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2395-2395
Author(s):  
Michael Callaghan ◽  
Benjamin Trzaskoma ◽  
Richard H. Ko ◽  
Lucy Lee ◽  
Anisha M. Patel ◽  
...  
Keyword(s):  
Factor Viii ◽  
Exposure Time ◽  
Cumulative Dose ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 3 ◽  
Breakthrough Bleeding ◽  
On Demand ◽  
Equity Ownership ◽  
The Individual

Introduction HAVEN 3 was a phase 3 study investigating the use of emicizumab as prophylaxis in adult and adolescent (≥12 years old) persons with hemophilia A (PwHA) without factor VIII (FVIII) inhibitors (NCT02847637; Mahlangu et al. 2018). HAVEN 3 demonstrated that emicizumab prophylaxis once weekly or every two weeks was safe and highly effective in bleed prevention. The primary analysis of HAVEN 3 included an intrapatient comparison of 48 participants who received FVIII prophylaxis in a non-interventional study (NIS) prior to enrollment in HAVEN 3. Compared with emicizumab prophylaxis during the HAVEN 3 study, emicizumab prophylaxis resulted in an annualized bleed rate that was 68% lower than the rate with previous FVIII prophylaxis (1.5 vs 4.8, p<0.001). No dosing guidance was provided regarding the use of on-demand FVIII in HAVEN 3, and investigators prescribed FVIII at their own discretion. In this subsequent analysis, we characterize the dose and frequency of replacement FVIII used for the treatment of breakthrough bleeding in these 48 participants. Methods The primary comparisons in our analyses are focused on on-demand FVIII use for breakthrough bleeding while participants were on FVIII prophylaxis during the NIS versus its use while on emicizumab prophylaxis during HAVEN 3. Any use of on demand FVIII other than to manage breakthrough bleeding (e.g. prior to activity) was not included in our analyses. Given that, collectively, the total exposure time to emicizumab during HAVEN 3 was more than twice the exposure time to FVIII prophylaxis during the NIS (75.8 vs 28.6 years respectively), any treatment comparisons are drawn on an annualized basis. Annualized on-demand FVIII use was calculated by dividing by the number of days in the efficacy period and multiplying the resulting daily consumption by 365.25 days. The number of infusions and cumulative doses of on-demand FVIII use are described at the participant level as well as at the individual bleed level and are presented descriptively for both the NIS and HAVEN 3 exposure periods. No formal statistical inferences (i.e. calculation of p-values) have been conducted. All analyses were based on an October 2018 data cutoff. Results A total of 48 participants who were treated with FVIII prophylaxis during the NIS were then treated with emicizumab prophylaxis during HAVEN 3 and thus make up the total cohort for our analyses. Annualized infusion rates of on-demand FVIII per participant and cumulative doses of on-demand FVIII (in international units [IU] per kilogram) per participant were higher during the FVIII prophylaxis period when compared with the emicizumab exposure period (mean 15.3 vs 7.2; median 3.6 vs 0.6 annual infusions per participant and mean 602.4 IU/kg vs 209.0 IU/kg; median 75.5 IU/kg vs 19.1 IU/kg, respectively). At the individual bleed level, FVIII infusions and total cumulative dose suggested that participants were administered a similar amount of medication to treat bleeds during both the NIS and HAVEN 3 study periods: median number of infusions per bleed were 1.0 (interquartile range [IQR]=1.0) versus 2.0 (IQR=3.0) and median cumulative doses were 43.5 (IQR=35.1) versus 50.0 (IQR=72.7) IU/kg, respectively (Table 1). Conclusions This analysis revealed a lower annualized infusion rate and a correspondingly lower annualized cumulative dose of FVIII for treatment of breakthrough bleeds during emicizumab prophylaxis compared with FVIII prophylaxis. At the individual bleed level, the amount of on-demand FVIII used per bleeding episode was comparable between NIS and HAVEN 3 exposure periods. Thus, based on this single analysis, it appears that patients received less on-demand FVIII during emicizumab prophylaxis compared with FVIII prophylaxis, as a result of overall reduction of bleed frequency, while the treatment of individual bleeds appeared similar regardless of the prophylaxis therapy administered. Disclosures Callaghan: Octapharma: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Bayer: Consultancy, Speakers Bureau; Alnylum: Equity Ownership; Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Roche/Genentech: Speakers Bureau; Shire/Takeda: Speakers Bureau; Pfizer: Research Funding; Roche: Research Funding. Trzaskoma:Genentech: Employment, Equity Ownership. Ko:Genentech, Inc.: Employment. Lee:Genentech, Inc.: Employment. Patel:Genentech: Employment; Roche/Genentech: Equity Ownership. Tzeng:Genentech, Inc.: Employment. Shah:Genentech: Employment. Chang:Genentech, Inc.: Employment; Genentech/Roche: Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Dhalluin:F. Hoffmann-La Roche Ltd: Employment. Mahlangu:Sanofi: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Biomarin: Research Funding; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; Unique: Research Funding.

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