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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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The Impact of Recombinant Versus Plasma-Derived Factor VIII Concentrates on Inhibitor Development in Previously Untreated Patients With Hemophilia A: A 2021 Update of a Systematic Review and Meta-Analysis
Kohar K, Prayogo SA, Wiyono L
Cureus. 2022;14(6):e26015
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Abstract
Hemophilia A, the most common hereditary disorder, is caused by clotting factor deficiency. Challenges encountered in the current treatment of hemophilia A [factor VIII (FVIII) replacement therapy] due to inhibitor development have caused ineffective treatment as well as morbidity and mortality among patients. However, there are no studies comparing the two types of FVIII treatments in terms of inhibitor development rate. Therefore, we conducted this systematic review to devise a better treatment option with a lower risk of inhibitor development. The systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and by searching several databases. Data extraction on study characteristics and outcomes was conducted. Reviewers also conducted a risk of bias assessment on all studies. All eligible studies for quantitative analysis were then processed using RevMan 5.4.1 and the data was extrapolated into cumulative outcomes and expressed in forest and funnel plots. Nine studies were included in the meta-analysis, involving a total of 2,531 hemophilia A patients who were followed up from birth until death. A higher incidence of inhibitor development was found to be associated with recombinant FVIII (rFVIII) [odds ratio (OR)=1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)=1.89, 95% CI: 1.15-3.12]. The same trend was also found for high-responding inhibitors (OR=1.38, 95% CI: 0.70-2.70; HR=1.42, 95% CI: 0.84-2.39). rFVIII is associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived FVIII (pdFVIII).
PICO Summary
Population
Children and adults with haemophilia A (9 studies, n= 2,531).
Intervention
Plasma-derived factor VIII.
Comparison
Recombinant factor VIII.
Outcome
Most of the included participants in the studies were children. A higher incidence of inhibitor development was found to be associated with recombinant factor VIII (odds ratio (OR)= 1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)= 1.89, 95% CI: 1.15-3.12). The same trend was also found for high-responding inhibitors (OR= 1.38, 95% CI: 0.70-2.70; HR= 1.42, 95% CI: 0.84-2.39). Recombinant factor VIII was associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived factor VIII.
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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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Indirect Treatment Comparison of Damoctocog Alfa Pegol versus Turoctocog Alfa Pegol as Prophylactic Treatment in Patients with Hemophilia A
Vashi P, Batt K, Klamroth R, Mancuso ME, Majewska R, Tiede A, Mantovani LG
Journal of blood medicine. 2021;12:935-943
Abstract
PURPOSE To assess the efficacy and FVIII consumption of BAY 94-9027 versus N8-GP in prophylaxis in adolescent and adult patients with severe hemophilia A (HA). PATIENTS AND METHODS A systematic literature review was conducted to identify studies on the efficacy of BAY-94-9027 and N8-GP for prophylaxis in patients with HA aged ≥12 years without a history of inhibitors. Eight studies met systematic literature review inclusion criteria, but only data from PROTECT VIII on BAY 94-9027 and PATHFINDER 2 on N8-GP could be used for an indirect comparison. Matching-adjusted indirect comparison (MAIC) and simulated treatment comparison were performed. RESULTS No significant differences (unadjusted and adjusted) were observed in the mean annualized bleeding rate (ABR) for any bleed and proportion of patients with zero bleeds when comparing BAY 94-9027 to N8-GP. The adjusted treatment difference [incidence rate ratio (IRR)] in terms of ABR was 1.11 (95% CI, 0.85-1.44). The odds ratio (OR) of any bleed, measuring the relative effect of BAY 94-9027 versus N8-GP on the proportion of patients with zero bleeds, was 1.03 (95% CI, 0.60-1.77). FVIII consumption was significantly lower in BAY 94-9027 [mean adjusted difference=-1292.57 IU/kg/year (95% CI, ‒2152.44 to ‒432.70)]; a 26.7% reduction in consumption of BAY-94-9027. The results of the sensitivity analyses were similar to the main analysis for mean ABRs, percentages of patients with zero bleeds, and significant reduction in rFVIII consumption. For patients on BAY 94-9027 every-5-days and every-7-days, no differences versus every-4-days N8-GP were observed for the mean ABR for any bleed [IRR=0.90 (95% CI, 0.68‒1.20)] and proportion of patients with zero bleeds [OR=1.06 (95% CI, 0.56‒2.02)]. CONCLUSION BAY 94-9027 prophylaxis demonstrated 26.7% lower annual consumption when compared to N8-GP with similar efficacy in terms of ABR and percentage of patients with zero bleeds.
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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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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.
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Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A
Villar A, Aronis S, Morfini M, Santagostino E, Auerswald G, Thomsen HF, Erhardtsen E, Giangrande PL
Haemophilia. 2004;10((4):):352-9.
Abstract
To establish the pharmacokinetic profile of activated recombinant coagulation factor VII (rFVIIa; NovoSeven in children with haemophilia A, and to compare it with the pharmacokinetic profile in adults with haemophilia A. Twelve children (2-12 years) received one single dose of rFVIIa 90 and 180 micrograms kg(-1) in randomized order separated by a washout period of 48 h to 1 month. Six adults (18-55 years) received a single dose of rFVIIa 90 micrograms kg(-1). The pharmacokinetic analyses were based on a non-compartmental method. In children, the plasma level of FVII increased proportionally with the dose. The total body clearance normalized for body weight was significantly faster in children than in adults (FVII:C, 58 vs. 39 mL kg(-1) h(-1) and FVIIa, 78 vs. 53 mL kg(-1) h(-1), P < 0. 05). A trend towards a larger volume of distribution at steady-state in children than in adults was observed (P > 0. 05). Dose proportionality was established for plasma concentrations of FVII in children with haemophilia A at the dose levels investigated (90 and 180 micrograms kg(-1) rFVIIa). Following administration of rFVIIa 90 micrograms kg(-1), significantly faster clearance was observed in children compared with adults, suggesting that higher doses of rFVIIa may be needed to achieve the same plasma levels as in adults.
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Superior in vivo response of recombinant factor VIII concentrate in children with hemophilia A
Kelly KM, Butler RB, Farace L, Cohen AR, Manno CS
Journal of Pediatrics. 1997;130((4):):537-40.
Abstract
OBJECTIVE Our previous experience with highly purified plasma-derived factor VIII (pdFVIII) concentrates showed that adult dosage recommendations were not applicable to children. In this study, we compared the in vivo response and recovery of recombinant factor VIII (rFVIII) with those of highly purified pdFVIII concentrate in children with hemophilia A. STUDY DESIGN Ten boys with severe factor VIII deficiency and no concurrent bleeding episodes participated in a masked, prospective, crossover study comparing factor VIII coagulant activity after infusion of 50 units of pdFVIII and rFVIII products per kilogram of body weight. RESULTS Mean peak factor VIII response with rFVIII was 1.91% +/- 0.14%, significantly better than the response observed with highly purified pdFVIII of 1.5% +/- 0.15% (p = 0.007). Mean peak factor VIII recovery was 100.5% with rFVIII versus 78.7% with pdFVIII (p = 0.007). Positive correlations between response to rFVIII and body surface area (r = 0.734, p = 0.015), body weight (r = 0.762, p = 0.01), and plasma volume (r = 0.659, p = 0.03) were observed. CONCLUSIONS Infusion of rFVIII produced a significantly better response and recovery in vivo than infusion of highly purified pdFVIII in children. The response in children after infusion of rFVIII was similar to the response previously observed in adults.