Turoctocog alfa pegol provides effective management for major and minor surgical procedures in patients across all age groups with severe haemophilia A: Full data set from the pathfinder 3 and 5 phase III trials.

INTRODUCTION: Turoctocog alfa pegol is a glycoPEGylated recombinant factor VIII (FVIII) with an extended half-life developed for prophylaxis, treatment of bleeds and perioperative management in patients with haemophilia A. AIM: Evaluate the efficacy and safety of turoctocog alfa pegol treatment for major and minor surgeries in the pathfinder 3 and 5 phase III trials. METHODS: Adults/adolescents aged ≥12 years with severe haemophilia A (FVIII <1%) received perioperative turoctocog alfa pegol treatment planned to achieve FVIII activity levels >80% during major surgery (pathfinder 3). The primary end point was haemostatic efficacy during surgery; secondary end points were blood loss, haemostatic effect postsurgery, consumption, transfusions, safety and health economics. Children (0-11 years) undergoing minor surgeries received 20-75 IU/kg turoctocog alfa pegol at Investigator's discretion (pathfinder 5). RESULTS: pathfinder 3 included 35 patients undergoing 49 major surgeries. Haemostasis was successful in 47/49 (95.9%) surgeries; two had moderate haemostatic responses. Median (mean) blood loss during major surgery was 75 (322.6) mL. Four bleeds were reported postsurgery; three were successfully treated with turoctocog alfa pegol (one was not evaluated). On the day of surgery, overall mean (median) dose was 75.5 (74.5) IU/kg and mean (median) number of doses was 1.7 (2.0). Five procedures required 11 transfusions on the day of surgery or days 1-6. No safety concerns or inhibitors were identified. Forty-five minor surgeries in 23 children were performed without complications. CONCLUSION: Turoctocog alfa pegol was effective for perioperative haemostatic management of major and minor surgeries in patients across age groups with severe haemophilia A.

Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: Safety and efficacy results from pathfinder 2 (randomized phase III trial).

INTRODUCTION: Turoctocog alfa pegol (N8-GP) is a site-specific, 40 kDa glycoPEGylated recombinant factor VIII (FVIII) product with an extended half-life. The comprehensive main phase of the pivotal pathfinder 2 trial showed N8-GP dosed every 4 days (Q4D) provided favourable safety and efficacy for preventing bleeds in 175 patients with haemophilia A. AIM AND METHODS: We investigated the safety and efficacy of N8-GP prophylaxis when administered weekly (Q7D) for 24 weeks to patients with low bleeding rates in the pathfinder 2 extension trial. Patients (≥12 years) with ≤2 bleeds during the preceding 6 months of the pathfinder 2 main phase were eligible for randomization to receive N8-GP 50 IU/kg Q4D or 75 IU/kg Q7D. Safety and efficacy endpoints were incidence of FVIII inhibitors and annualized bleeding rate (ABR), respectively. RESULTS: Fifty-five of 143 (38.5%) patients on prophylaxis who continued into the extension phase were randomized to receive 50 IU/kg Q4D (n = 17) or 75 IU/kg Q7D (n = 38). Nine patients in the Q7D cohort reverted to 50 IU/kg Q4D. No inhibitors were detected. In both cohorts, >50% of patients experienced no bleeds. Median ABR for overall, joint, spontaneous, traumatic and muscle was 0.00 for both cohorts. Overall estimated success rate for treating bleeding episodes was 87.5%; 94.7% of bleeds were controlled with ≤2 injections. CONCLUSIONS: Weekly N8-GP was well tolerated and efficacious and may benefit selected "low bleeder" patients with haemophilia A.

Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Hemorrhage.

Background: Despite a range of available treatments, it is still sometimes challenging to treat patients with severe post-partum hemorrhage (sPPH). Objective: This study evaluated the efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 (NCT04723979), OS-2, OS-3, and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligations, arterial embolization, or hysterectomy) and safety (incidence of thromboembolic events (TE) and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa-exposed women only. Results: A total of 446 women exposed to rFVIIa and 1717 non-exposed controls were included. In the RCT, fewer rFVIIa-exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio: 0.11; 95% confidence interval: 0.03-0.35). In OS-1, more rFVIIa-exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio: 2.46; 95% confidence interval: 1.06-5.99). In OS-2, 17% (3/18) of rFVIIa-exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio: 0.33; 95% confidence interval: 0.03-1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa-exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa on the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment.

Nordic Haemophilia Council's practical guidelines on diagnosis and management of von Willebrand disease.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder characterized by spontaneous or tissue injury-related, mostly mucocutaneous, bleeding events. VWD affects both males and females and is caused by quantitative or qualitative deficiency of Von Willebrand factor. The diagnostic procedure is complicated because VWD is highly heterogeneous, and differential diagnosis from platelet disorders may be challenging. Moreover, these defects may even coexist, impacting the bleeding phenotype. Mild and moderate VWD can be difficult to distinguish from the normal population, and VWD subtyping may also be problematic. This article summarizes the guidelines of the Nordic Haemophilia Council (NHC), which are intended to serve as a practical tool and provide the standards for diagnosing and treating VWD patients. The complete Nordic Guidelines on VWD are available at the NHC Web site (http://nordhemophilia.org).

Long-term safety and efficacy of N8-GP in previously treated pediatric patients with hemophilia A: Final results from pathfinder5.

BACKGROUND: N8-GP (turoctocog alfa pegol; Esperoct® , Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated, extended half-life human recombinant factor VIII (FVIII). OBJECTIVE: Here, we report end-of-trial safety and efficacy results from the completed N8-GP pathfinder5 trial. METHODS: pathfinder5 (NCT01731600) was a multi-national, open-label, single-arm, non-randomized, non-controlled trial in previously treated male patients aged <12 years old with severe hemophilia A that comprised a main and an extension phase. During the main phase, patients received twice-weekly N8-GP 60 IU/kg for 50 exposure days (~26 weeks). During the extension phase, patients received the same regimen until the end of trial (first patient in main phase, 20 February 2013; trial end, 28 September 2018). RESULTS: Sixty-eight patients were exposed to N8-GP for a median time of ~4.9 years on regimen. Of the 63 patients who started in the extension phase, 62 completed the trial. No FVIII inhibitors (≥0.6 BU) or other safety concerns were detected. The overall estimated annualized bleeding rate was 1.08 (median 0.81), and nearly 20% of patients had no bleeds during the entire trial. The proportion of patients with no annual bleeds increased with time, with 56% of patients experiencing no bleeds and 86% experiencing no spontaneous bleeds during the fourth year of exposure. All baseline target joints of patients who participated in both phases of this trial were resolved in slightly over 2 years. CONCLUSION: Overall, data from the completed pathfinder5 trial show that long-term (median 4.9 years) N8-GP treatment was efficacious and well tolerated in previously treated pediatric patients with severe hemophilia A.

Long-term safety and efficacy of N8-GP in previously treated adults and adolescents with hemophilia A: Final results from pathfinder2.

BACKGROUND: N8-GP (turoctocog alfa pegol; Esperoct® , Novo Nordisk A/S, Bagsvaerd, Denmark) is a glycoPEGylated human recombinant factor VIII with a half-life of ~1.6-fold of standard FVIII products. pathfinder2 (NCT01480180) was a multi-national, open-label trial of N8-GP in previously treated adolescent and adult patients with severe hemophilia A. OBJECTIVE: We report end-of-trial efficacy and safety of N8-GP from pathfinder2. METHODS: pathfinder2 main phase and extension phase part 1 results have been previously reported. During extension phase part 2, patients could switch from N8-GP prophylaxis 50 IU/kg every fourth day (Q4D) or 75 IU/kg once weekly (Q7D), depending on bleeding status. Extension phase part 2 collected long-term safety and efficacy data for all regimens until trial end (first patient in main phase, 30 January 2012; trial end, 10 December 2018). RESULTS: Overall, 186 patients were exposed to N8-GP for up to 6.6 years (median 5.4 years). The estimated annualized bleeding rate (ABR) was 2.14 (median 0.84) for the Q4D prophylaxis arm and 1.31 (median 1.67) for the Q7D prophylaxis arm. Nearly 30% of patients experienced zero bleeds throughout the entire duration of the trial, the hemostatic response was 83.2% across all treatment arms, and patient-reported outcomes were maintained or slightly improved. No safety concerns were detected. CONCLUSION: Data from the completed pathfinder2 trial, one of the largest and longest-running clinical trials to investigate treatment of severe hemophilia A, demonstrate the efficacy and safety of N8-GP in previously treated adolescent and adult patients.

Health-related quality-of-life and treatment satisfaction of individuals with hemophilia A treated with turoctocog alfa pegol (N8-GP): a new recombinant extended half-life FVIII.

BACKGROUND: Prophylactic treatment regimens lead to improvements in health-related quality-of-life (HRQoL) among individuals with hemophilia. Turoctocog alfa pegol (N8-GP) provides the benefit of extending the duration of protection from bleeding and reducing the number of injections, which is expected to impact HRQoL and treatment satisfaction (TS). AIM: To investigate the HRQoL and TS of patients with severe hemophilia A from two phase III trials evaluating the safety and efficacy of N8-GP. METHODS: HRQoL was assessed using the Haemo-QoL (reported by children and their parents) and Haem-A-QoL (reported by adults). TS was assessed using Hemo-Sat. Domain and total scores for all questionnaires ranged from 0 to 100, with lower scores indicating a better HRQoL or TS. A negative change in score indicates an improvement in HRQoL/TS. RESULTS: Mean changes in HRQoL scores were reported for 14 children aged 4-7 years, 21 children aged 8-11 years, 10 adolescents aged 13-16 years, and 163 adults (17 years and above). Mean changes in children/adolescents-reported Haemo-QoL total score were -14.0 for ages 4-7 years, -3.6 for ages 8-11 years, and -0.1 for ages 13-16 years. Mean changes in parent-reported Haemo-QoL total scores were -11.5 for 4-7 years, -8.6 for ages 8-11 years, and -4.0 for 13-16 years. Adults' mean change in Haem-A-QoL total score was -3.1 for those receiving on-demand treatment and -2.3 for those receiving prophylaxis treatment. High levels of TS with N8-GP were reported by parents of children/adolescents and the adults at the end of the trial. CONCLUSION: While most patients reported a relatively good baseline HRQoL when entering the respective trials, the HRQoL of patients was either maintained or further improved when treated with N8-GP. Adults and parents of children and adolescents reported a high level of treatment satisfaction with N8-GP.

Changes in bleeding patterns in von Willebrand disease after institution of long-term replacement therapy: results from the von Willebrand Disease Prophylaxis Network.

Clinically, the leading symptom in von Willebrand disease (VWD) is bleeding, chiefly of mucosal type, for example, epistaxis, gingival, or gastrointestinal bleeding, and menorrhagia. In severe forms of VWD with secondary deficiency of factor VIII, spontaneous joint bleeding, resembling that observed in severe haemophilia A, may also be observed. The bleeding patterns of VWD can affect quality of life, and may be life-threatening. The von Willebrand Disease Prophylaxis Network is an international study group formed with the goal of investigating the role of prophylaxis in clinically severe VWD. The objective of the present study is to investigate the response to prophylaxis focusing primarily on epistaxis, joint bleeding, gastrointestinal bleeding, and heavy bleeding associated with menses. Data from 105 subjects, 10 enrolled in a prospective study and 95 in a retrospective study between 2008 and 2013, were available for analysis. The median annualized rate reductions in bleeding were significant for epistaxis (P < 0.0001), gastrointestinal bleeding (P = 0.0003), joint bleeding (P < 0.0001), and menorrhagia (P = 0.008). Doses on a group level were approximately the same prior to and during prophylaxis, but more patients with gastrointestinal bleeding had prophylaxis three or more times per week as well as higher dosages. Our study, which primarily used retrospective data, indicates that prospective studies are needed to better delineate the doses and dose intervals that should be used for prophylactic treatment of VWD.