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.

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.

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.

scholarly journals Enhancing the Acute Hemostatic Efficacy in Cynomolgus Monkeys By Targeting Activated Coagulation Factor VII to Platelets

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1488-1488
Author(s):  
Siyuan Tan ◽  
Joe Salas ◽  
Kai Chen ◽  
Tamera Ashworth ◽  
Sarah Smith ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Whole Blood ◽  
Half Life ◽  
Hemophilia A ◽  
Factor Vii ◽  
Employment Equity ◽  
Cynomolgus Monkeys ◽  
Hemostatic Activity ◽  
Equity Ownership ◽  
Inhibitory Antibodies

Abstract Recombinant activated factor VII (rFVIIa) is used for controlling bleeds in hemophilia A and B patients with inhibitory antibodies against factor VIII or factor IX. The hemostatic effect of rFVIIa at pharmacological doses is believed to be mediated by activating the tenase complex on platelets directly at the site of injury to promote thrombin generation. To increase the hemostatic activity of rFVIIa, we sought to target rFVIIa to platelets by fusing a single chain variable region of a monoclonal antibody against human platelet receptor αIIbβ3. The resulting fusion protein, FVII-189, displays higher affinity to human platelets and about 50-fold higher hemostatic activity than that of rFVIIa in whole blood from hemophilia A patients by rotational thromboelastometry (ROTEM). Here we investigated the safety, pharmacokinetics, and pharmacodynamics of FVII-189 in cynomolgus monkeys. First, we confirmed that FVII-189 cross-reacted to platelets from cynomolgus monkeys. When spiked in the monkey whole blood, FVII-189 could bind platelets in a dose-dependent manner, as measured by flow cytometry using fluorescently labeled antibodies against FVII, whereas platelet-binding by rFVIIa was not detectable in the same assay. More importantly, increased hemostatic activity of FVII-189 was observed by ROTEM in acquired hemophilic monkey blood where factor VIII activity was neutralized by the inhibitory antibodies. We then evaluated FVII-189 in cynomolgus monkeys following a bolus intravenous administration (n=3) at an equal molar dose to the pharmacological dose of rFVIIa (~2 nmol/kg). rFVIIa was included as a comparator. Both FVII-189 and rFVIIa appeared to be well tolerated with no abnormal clinical observations that could be attributed to the dosing. No apparent effects on platelet count in whole blood, as well as other hematology and coagulation parameters except for a temporary decrease in prothrombin time over a few hours, which was an expected pharmacological effect of rFVIIa and FVII-189. Compared to rFVIIa, FVII-189 cleared more rapidly in plasma, and distributed more to the platelets. The half-life of FVII-189 antigen on platelets was found to be several fold longer than that of rFVIIa antigen in plasma, as measured by ELISA of the platelet-rich plasma, or by flow cytometry of platelet-associated FVII-189 antigen. Despite the lower initial recovery and faster clearance of FVII-189 in plasma, directing FVII-189 to platelets resulted in much higher hemostatic activity of the whole blood 5 minute and 1 hour after dosing, as measured by ex vivo ROTEM assay. In conclusion, these results indicate that in cynomolgus monkeys, 1) FVII-189 is safe and does not affect the platelet clearance, 2) FVII-189 protein is targeted to platelets with fast clearance in plasma and prolonged half-life on platelets and 3) FVII-189 could be more efficacious in controlling acute bleeds than rFVIIa. Disclosures Tan: Biogen Idec: Employment, Equity Ownership. Salas:Biogen Idec: Employment, Equity Ownership. Chen:Biogen Idec: Employment, Equity Ownership. Ashworth:Biogen Idec: Employment, Equity Ownership. Smith:Biogen Idec: Employment, Equity Ownership. Kistanova:Biogen Idec: Employment, Equity Ownership. Moore:Biogen Idec: Employment, Equity Ownership. Acosta:Biogen Idec: Employment, Equity Ownership. Kole:Biogen Idec: Employment, Equity Ownership. Light:Biogen Idec: Employment, Equity Ownership. Peters:Biogen Idec: Employment. Jiang:Biogen Idec: 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.

Enhanced Half-Life Recombinant Factor VIII Concentrates for Hemophilia A: Final Results from Extension Studies

2021 ◽  
Author(s):  
Matteo Nicola Dario Di Minno ◽  
Alessandro Di Minno ◽  
Ilenia Calcaterra ◽  
Ernesto Cimino ◽  
Francesco Dell'Aquila ◽  
...  
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Factor Viii Concentrates

scholarly journals Perioperative Management of Hemophilia A Using Recombinant Factor VIII in Patients Undergoing Major or Minor Surgery

2019 ◽  
Author(s):  
Atsushi Okamoto ◽  
Kenta Yamamoto ◽  
Go Eguchi ◽  
Yoshitaka Kanai ◽  
Terufumi Yamaguchi ◽  
...  
Keyword(s):  
Factor Viii ◽  
Perioperative Management ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Minor Surgery

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIFc) in Adults/Adolescents with Severe Hemophilia a

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1413-1413
Author(s):  
Barbara Konkle ◽  
K John Pasi ◽  
David J Perry ◽  
Johnny Mahlangu ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Treatment Group ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Dosing Intervals

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylaxis with conventional FVIII products usually requires frequent intravenous injections (3-4 times/week). The safety, efficacy, and prolonged half-life of rFVIIIFc in previously treated adults and adolescents (≥12 y) with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01181128, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in study participants as of the second interim data cut (8 Dec 2014). Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the second interim data cut 8 Dec 2014) for subjects treated with ≥1 dose of rFVIIIFc. A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on Day 1 and 50 IU/kg on Day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment (ET). Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or ET groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) group. Subjects could change treatment groups at any point during ASPIRE. Efficacy analyses were performed using data summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL identified and confirmed on 2 separate samples drawn approximately 2-4 weeks apart and performed by the central laboratory as measured by the Nijmegen-modified Bethesda assay), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic consumption and dosing interval compared to pre-A-LONG (prestudy). Results: Of 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE; at the time of this second interim data cut, 97 subjects were ongoing in ASPIRE, 40 subjects had completed the study, and 13 subjects withdrew. Cumulatively, subjects had 38,662 rFVIIIFc exposure days (EDs), inclusive of surgery. As of this second interim data cut (8 Dec 2014), no inhibitors were observed; the type and incidence of adverse events (AEs) observed were typical of previous hemophilia A populations studied. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were lower with rFVIIIFc compared with prestudy FVIII for subjects on prestudy prophylaxis or ET (Figure). In the IP group, the median (interquartile range [IQR]) spontaneous ABRs in Years 1, 2, and 3 on-study were 0.0 (0.0, 2.0), 0.0 (0.0, 1.0), and 0.0 (0.0, 1.0), respectively. In the WP treatment group, the median (IQR) spontaneous ABRs in Years 1, 2, and 3 on-study were 1.0 (0.5, 3.0), 0.5 (0.0, 2.1), and 0.0 (0.0, 1.0), respectively. Overall, 88.5% and 97.0% of bleeding episodes were controlled with 1 or ≤2 intervenous injections, respectively. Among subjects treated with FVIII prophylaxis prestudy (n = 79), 86% were dosed at least 3 times/week prestudy. Compared with prestudy dosing intervals, dosing intervals with rFVIIIFc were extended in 96.2% of subjects, were shortened in 2.5% of subjects, and were unchanged in 1.3% of subjects. The median (IQR) total weekly prophylactic consumption was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.8] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE confirm long-term safety, with no inhibitors observed in any subject. Low median ABRs were maintained, and rFVIIIFc demonstrated efficacy in the prevention and treatment of bleeding episodes. Prophylactic dosing intervals were extended, without an increase in median prophylactic factor consumption. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Pasi: Biogen: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Bayer: Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Roche: Consultancy, Research Funding; Baxalta: Consultancy. Rangarajan:Baxter: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Biogen: Consultancy; Biotest: Research Funding; Grifols: Consultancy, Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding. Brown:Baxter: Consultancy; Biogen: Consultancy; Novo Nordisk: Consultancy. Hanabusa:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pabinger:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: 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. Cristiano:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Glazebrook:Biogen: Employment, Equity Ownership. Lethagen:Sobi: Employment. Jackson:Biogen: Consultancy, Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta/Shire: Research Funding; Novo Nordisk: Research Funding; Baxter: Consultancy, Research Funding.

scholarly journals Long-Term Safety and Efficacy of rFVIIIFc in Adults and Adolescents with Severe Hemophilia A: A Longitudinal Analysis of A-LONG and ASPIRE

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1087-1087 ◽  
Author(s):  
K John Pasi ◽  
David J Perry ◽  
Johnny Mahlangu ◽  
Barbara A Konkle ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Treatment Group ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Treatment Groups ◽  
Equity Ownership

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylactic treatment with conventional FVIII products usually requires frequent intravenous infusions (3-4 times/week). Recombinant FVIII Fc fusion protein (rFVIIIFc), which is produced in a human cell line, binds the neonatal Fc receptor and utilizes the natural IgG recycling pathway to prolong the half-life of FVIII. The safety, efficacy and prolonged half-life of rFVIIIFc in adults and adolescents with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01027377, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in participants in these studies. Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the interim data cut, 6 January 2014) for subjects treated with ≥1 dose of rFVIIIFc (n=164). A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on day 1 and 50 IU/kg on day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment. Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or episodic treatment groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) treatment group. Subjects could change treatment groups at any point during ASPIRE. For efficacy analyses, data were summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one treatment group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay at a central laboratory, confirmed upon retesting within 2 to 4 weeks), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic dose and dosing interval. Results: Of the 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE. At the time of the interim data cut, 140 subjects were ongoing in ASPIRE. Cumulatively, subjects had a median (IQR) of 25.5 (24.6, 26.7) months of rFVIIIFc treatment, and a median (IQR) of 183.0 (120.5, 232.5) rFVIIIFc exposure days (EDs). No inhibitors were reported. The estimated inhibitor incidence rate (95% CI) was 0.0% (0.0, 2.2) overall (N=164), and 0.0% (0.0, 2.7) in subjects with ≥100 rFVIIIFc EDs (n=136). The type and incidence of AEs observed were consistent with those expected for the general hemophilia population. 84.8% of subjects reported ≥1 AE on study, with the majority assessed by the investigator as mild and unrelated to rFVIIIFc treatment. 17.7% of subjects experienced at least 1 SAE; none were assessed by the investigator as related to rFVIIIFc. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were generally lower with rFVIIIFc treatment compared with prestudy FVIII (Figure). In the IP treatment group, the year 1 and year 2 median spontaneous ABRs were 0.0. Overall, 89.1% of bleeding episodes were controlled with 1 infusion; 97.3% with 1 or 2 infusions. Among subjects treated with FVIII prophylaxis prior to entering A-LONG (n=79), 86% were dosed at least 3 times/week. With rFVIIIFc, 96% of these subjects extended their dosing interval compared with their prestudy product, while the median (IQR) total weekly prophylactic dose was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.2] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE demonstrate long-term safety, with no inhibitors observed in any subjects, and efficacy in the prevention and treatment of bleeding. Low median ABRs were maintained with extended prophylactic dosing intervals, without an increase in median prophylactic factor consumption. Figure 1. Figure 1. Disclosures Pasi: Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria; Octapharma: Research Funding. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Roche: Research Funding; Biotest: Speakers Bureau; Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Konkle:Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; CSL Behring: Consultancy, Other: IDMC chair; Pfizer: Other: IDMC member; Octapharma: Research Funding; Novo Nordisk: Consultancy. Rangarajan:Grifols, Pfizer, and Baxter: Research Funding; Grifols: Honoraria; Sobi: Membership on an entity's Board of Directors or advisory committees; LFB: Other: Conference support. Brown:Biogen, Novo Nordisk, Baxter, and Pfizer: Other: Sponsorship to meeting. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Jackson:Biogen: Honoraria, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Dong:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Allen:Biogen: Employment, Equity Ownership.

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