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Eptacog beta efficacy and safety in the treatment and control of bleeding in paediatric subjects (<12 years) with haemophilia A or B with inhibitors
Pipe SW, Hermans C, Chitlur M, Carcao M, Castaman G, Davis JA, Ducore J, Dunn AL, Escobar M, Journeycake J, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2022
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Abstract
INTRODUCTION Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS Using a randomised crossover design, subjects received initial doses of 75 or 225 μg/kg eptacog beta followed by 75 μg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 μg/kg initial dose regimen (IDR) and 60% in the 225 μg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 μg/kg IDR and 98% for the 225 μg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION Both 75 and 225 μg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.
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The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors
Escobar M, Castaman G, Boix SB, Callaghan M, de Moerloose P, Ducore J, Hermans C, Journeycake J, Leissinger C, Luck J, et al
Haemophilia : the official journal of the World Federation of Hemophilia. 2021
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Abstract
INTRODUCTION Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. AIM: To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. METHODS Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. RESULTS Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. CONCLUSION Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.
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BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A
Konkle BA, Shapiro AD, Quon DV, Staber JM, Kulkarni R, Ragni MV, Chhabra ES, Poloskey S, Rice K, Katragadda S, et al
The New England journal of medicine. 2020;383(11):1018-1027
Abstract
BACKGROUND Factor VIII replacement products have improved the care of patients with hemophilia A, but the short half-life of these products affects the patients' quality of life. The half-life of recombinant factor VIII ranges from 15 to 19 hours because of the von Willebrand factor chaperone effect. BIVV001 (rFVIIIFc-VWF-XTEN) is a novel fusion protein designed to overcome this half-life ceiling and maintain high sustained factor VIII activity levels. Data are lacking on the safety and pharmacokinetics of single-dose BIVV001. METHODS In this phase 1-2a open-label trial, we consecutively assigned 16 previously treated men (18 to 65 years of age) with severe hemophilia A (factor VIII activity, <1%) to receive a single intravenous injection of recombinant factor VIII at a dose of 25 IU per kilogram of body weight (lower-dose group) or 65 IU per kilogram (higher-dose group). This injection was followed by a washout period of at least 3 days. The patients then received a single intravenous injection of BIVV001 at the same corresponding dose of either 25 IU or 65 IU per kilogram. Adverse events and pharmacokinetic measurements were assessed. RESULTS No inhibitors to factor VIII were detected and no hypersensitivity or anaphylaxis events were reported up to 28 days after the injection of single-dose BIVV001. The geometric mean half-life of BIVV001 was three to four times as long as that of recombinant factor VIII (37.6 hours vs. 9.1 hours in the lower-dose group and 42.5 vs. 13.2 hours in the higher-dose group); the area under the curve (AUC) for product exposure was six to seven times as great in the two dose groups (4470 hours vs. 638 hours × IU per deciliter in the lower-dose group and 12,800 hours vs. 1960 hours × IU per deciliter in the higher-dose group). After the injection of BIVV001 in the higher-dose group, the mean factor VIII level was in the normal range (≥51%) for 4 days and 17% at day 7, which suggested the possibility of a weekly interval between treatments. CONCLUSIONS In a small, early-phase study involving men with severe hemophilia A, a single intravenous injection of BIVV001 resulted in high sustained factor VIII activity levels, with a half-life that was up to four times the half-life associated with recombinant factor VIII, an increase that could signal a new class of factor VIII replacement therapy with a weekly treatment interval. No safety concerns were reported during the 28-day period after administration. (Funded by Sanofi and Sobi; ClinicalTrials.gov number, NCT03205163.).
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Long-term orthopedic effects of delaying prophylaxis in severe hemophilia A until age 6 years: results of the Joint Outcome Study continuation (JOSc)
Manco-Johnson MJ, Manco-Johnson ML, Blades TA, Funk S, Lane H, McRedmond K, Dunn AL, Recht M, Shapiro AD, Valentino LA, et al
Blood. 2013;122((21):):210.
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Pharmacokinetic behavior of IB1001, an investigational recombinant factor IX, in patients with hemophilia B: Repeat pharmacokinetic study and subgroup analysis
Martinowitz U, Shapiro AD, Quon DV, Escobar MA, Kempton CL, Collins P, Chowdary P, Makris M, Mannucci PM, Morfini M, et al
Blood. 2011;118((21):): Abstract No. 2267.
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Significant improvement in health-related quality of life with prophylaxis in severe hemophilia A: results from the rAHF-PFM randomized, controlled prophylaxis study
Shapiro AD, Santagostino E, Epstein JD, Schroth P, Wong W-Y
Journal of Thrombosis and Haemostasis. 2011;9((Suppl 2):):827. Abstract No. P-TH-184.
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Recombinant human von Willebrand Factor (rhVWF): first-in-human study evaluating pharmacokinetics, demonstrating safety and tolerability in Type 3 von Willebrand Disease
Suiter T, Laffan M, Mannucci PM, Kempton CL, Romond EH, Shapiro AD, Birschmann I, Gill JC, Ragni MV, Turecek P, et al
Blood. 2010;116((21):): Abstract No. 237.
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Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, et al
The New England Journal of Medicine. 2007;357((6):):535-44.
Abstract
BACKGROUND Effective ways to prevent arthropathy in severe hemophilia are unknown. METHODS We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI). RESULTS Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0. 006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6. 1 (95% confidence interval, 1. 5 to 24. 4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0. 001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. CONCLUSIONS Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials. gov number, NCT00207597 [ClinicalTrials. gov]. ).
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Pharmacokinetic analysis of plasma-derived and recombinant F IX concentrates in previously treated patients with moderate or severe hemophilia B
Ewenstein BM, Joist JH, Shapiro AD, Hofstra TC, Leissinger CA, Seremetis SV, Broder M, Mueller-Velten G, Schwartz BA, Mononine Comparison Study Group
Transfusion. 2002;42((2):):190-197.
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Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery
Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA
Thrombosis & Haemostasis. 1998;80((5):):773-8.
Abstract
Recombinant factor VIIa (rFVIIa: NovoSeven; Novo Nordisk) has proven efficacy in the treatment of haemophilic patients with inhibitors. This prospective, double-blind study compared rFVIIa (35 vs. 90 microg/kg) in the initiation and maintenance of haemostasis during and after elective surgery. Patients with inhibitors (FVIII, n = 26; FIX, n = 3) received rFVIIa immediately prior to incision; intraoperatively as needed; every 2 h for the first 48 h; and every 2-6 h for the following 3 days. Haemostasis was evaluated during surgery, at 0, 8, 24 and 48 h and 3, 4 and 5 days after wound closure. After day 5, open-label rFVIIa (90 microg/kg) was available for maintenance. Intraoperative haemostasis was achieved in 28/29 patients. All high-dose patients and 12/15 low dose patients had satisfactory haemostasis during the first 48 h. Twenty-three patients (13/14 high dose) successfully completed the study. Although the 35 microg/kg dose is probably sub-optimal for post-operative management, at least in major procedures, rFVIIa 90 microg/kg is an effective first-line option in surgery for patients with inhibitors.