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BAY 81-8973 Efficacy and Safety in Previously Untreated and Minimally Treated Children with Severe Hemophilia A: The LEOPOLD Kids Trial
Ljung, R., Chan, A. K. C., Glosli, H., Afonja, O., Becker, B., Tseneklidou-Stoeter, D., Mancuso, M. E., Saulyte-Trakymiene, S., Kenet, G.
Thrombosis and Haemostasis. 2023;123(1):27-39
Abstract
INTRODUCTION BAY 81-8973, a full-length recombinant factor VIII for hemophilia A treatment, has been extensively evaluated in previously treated patients in the LEOPOLD (Long-Term Efficacy Open-Label Program in Severe Hemophilia A Disease) clinical trials. AIM: To assess BAY 81-8973 efficacy and safety when used for bleed prophylaxis and treatment in previously untreated/minimally treated patients (PUPs/MTPs). METHODS In this phase III, multicenter, open-label, uncontrolled study, PUPs/MTPs (<6 years old) with severe hemophilia A received BAY 81-8973 (15-50 IU/kg) at least once weekly as prophylaxis. Primary efficacy endpoint was the annualized bleeding rate (ABR) within 48 hours after prophylaxis infusion. Adverse events and immunogenicity were assessed. Patients who developed inhibitors were offered immune tolerance induction (ITI) treatment in an optional extension phase. RESULTS Fifty-two patients were enrolled, with 43 patients (mean age: 13.6 months) treated. Median (interquartile range) ABR for all bleeds within 48 hours of prophylaxis infusion was 0.0 (0.0-1.8) among patients without inhibitors (n = 20) and 0.0 (0.0-2.2) among all patients. As expected, inhibitors were the most frequent treatment-related adverse event (high titer: 17 [39.5%] patients; low titer: 6 [13.9%] patients). Six of 12 patients who underwent ITI treatment in the extension phase (high titer [n = 5], low titer [n = 1]) achieved a negative inhibitor titer. CONCLUSION BAY 81-8973 was effective for bleed prevention and treatment in PUPs/MTPs. The observed inhibitor rate was strongly influenced by a cluster of inhibitor cases, and consequently, slightly higher than in other PUP/MTP studies. Overall, the BAY 81-8973 benefit-risk profile remains unchanged and supported by ongoing safety surveillance. Immune tolerance can be achieved with BAY 81-8973.
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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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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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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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Comparative evaluation of the safety and efficacy of recombinant FVIII in severe hemophilia A patients
Abolghasemi H, Panahi Y, Ahmadinejad M, Toogeh G, Karimi M, Eghbali A, Mirbehbahani NB, Dehdezi BK, Badiee Z, Hoorfar H, et al
Journal of Pharmacopuncture.. 2018;21((2)):76-81.
Abstract
Objective: This study compared the safety and efficacy of Safacto versus xyntha in patients with severe hemophilia A. Methods: Thirty-three male patients with severe hemophilia A were randomly divided into two groups. Seventeen patients received Safacto and 16 patients received Xyntha for four consecutive times. The dosage of FVIII was 40-50 IU/kg for each injection. Plasma level of FVIII activity was evaluated before every injection, 15 minutes after the injection and one month after the start of the trial. The rate of factor VIII activity, pain and joint motion were also assessed before and after the treatment. Results: Plasma level of FVIII clotting activity in Safacto and Xyntha were 1.96+/-0.5 IU/dl and 1.63+/-0.5 IU/dl and increased to 88.84+/-25.2 IU/dl and 100.09+/-17.8 IU/dl, respectively (P<0.001). Pain score and range of motion improvement were 9.3+/-0.9 and 8.7+/-0.1 in Safacto (P=0.17); and 9.4+/-0.8 and 8.8+/-0.3 in Xyntha (P=0.35), respectively. No allergic or other unfavorable reactions was observed with either of the preparations. Conclusion: This study showed that Safacto has a favorable efficacy and safety profile.
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Source of factor VIII replacement (PLASMATIC OR RECOMBINANT) and incidence of inhibitory alloantibodies in previously untreated patients with severe hemophilia a: the multicenter randomized sippet study
Peyvandi F, Mannucci PM, Garagiola I, Elalfy M, El-Beshlawy A, Ramanan MV, Eshghi P, Hanagavadi S, Varadarajan R, Karimi M, et al
Blood. 2015;126((23)): Abstract No. 5.
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Effect on joint health of routine prophylaxis with Bayer’s sucrose-formulated recombinant factor VIII (rFVIII-FS) in adolescents and adults previously treated on demand: MRI analyses from the 3-Year Spinart study
Lundin B, Hong W, Raunig D, Engelen S, Peterfy C, Werk, Manco-Johnson MJ
Blood. 2014;124((21)): Abstract No. 2854
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A comparison of efficacy between recombinant activated factor VII (ARYOSEVEN TM) and NOVOSEVEN® in patients with hereditary FVIII deficiency with inhibitor
Faranoush M, Abolghassemi H, Toogeh G, Karimi M, Eshghi P, Managhchi M, Hoorfar H, Keikhaei DB, Mehrvar B, Khoein B, et al
Blood. 2014;124((21)): Abstract No. 4299
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Evaluation of two secondary prophylaxis regimens of recombinant factor IX (r-IX) in moderately severe to severe (FIX <=2%) hemophilia B patients
Rendo P, Barrette-Grischow M-K, Smith L, Korth-Bradley JM, Charnigo R, Shafer FE
Blood. 2012;120((21):): Abstract No. 4628.
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Direct costs of children with haemophilia A undergoing prophylaxis or episodic treatment: Results from the ESPRIT study
Gringeri A, Fusco F, Riva S, Von MacKensen S, Mantovani LG
Journal of Thrombosis and Haemostasis. 2011;9((Suppl 2):):927. Abstract No. P-TH-510.
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A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study)
Gringeri A, Lundin B, Von Mackensen S, Mantovani L, Mannucci PM
Journal of Thrombosis and Haemostasis. 2011;9((4):):700-10.
Abstract
Background: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. Objective:This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. Methods: Forty-five children with severe hemophilia A, aged 1-7years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25IUkg-1 3x week) or episodic therapy with >=25IUkg-1 every 12-24h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Results:Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P<0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P< 0.05). Prophylaxis was more effective when started early (<=36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. Conclusion:This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. 2011 International Society on Thrombosis and Haemostasis.