Efficacy, safety and tolerability of recombinant factor VIII (REFACTO®) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria

An open-label, multicentre, postmarketing surveillance study conducted in Germany and Austria with recombinant factor VIII (REFACTO) has enrolled 217 patients (mean age 26.3 years) from 38 haemophilia centres during the first 4.8 years. Most patients (188/217; 86.6%) had severe to moderately severe haemophilia A, of whom 153 completed sufficient diary information for the main efficacy analysis. These 153 patients experienced a median of 6.6 (interquartile range 1.4-18.6) bleeding episodes per year. Patients treated with prophylaxis experienced a median of 4.4 (1.1-9.3) bleeds per year, while patients treated on-demand experienced a median of 22.8 (11.3-29.0) bleeds per year. Overall, most physicians (41/43 [95.3%]) were 'very satisfied' or 'satisfied' with the efficacy of REFACTO in the treatment of bleeding episodes. A total of 137 non-serious adverse events have been reported in 52/217 patients (24.0%) to date. In addition, 129 serious adverse events in 87 patients (40%) were reported, including 41 cases of 'less than expected therapeutic effect' (LETE). Of these, 39 LETE cases were reported in one centre; however, patients in this centre experienced considerably fewer bleeding episodes per year than patients outside this centre. Overall, six patients (2.8%) have developed de novo inhibitors, three of which were considered high titre. Four of these patients were at high risk (0-50 exposure days [ED]) of inhibitor formation, one was at intermediate risk (51-100 ED) and one was at low risk (>100 ED). These results emphasize the benefit of postmarketing surveillance and, overall, this study confirms the efficacy, safety and tolerability of REFACTO in the treatment of patients with haemophilia A.     

Clinical efficacy, safety and pharmacokinetic properties of the factor VIII concentrate Haemoctin® SDH in previously treated patients with severe haemophilia A

Clinical efficacy, safety and pharmacokinetic properties of the high-purity double-virus inactivated plasma-derived factor VIII concentrate Haemoctin SDH (pdFVIII) were evaluated in three prospective open-label uncontrolled studies in previously treated patients (PTPs) with severe haemophilia A. The pharmacokinetic properties assessed at baseline and after 3 months of treatment are in accurate accordance with published data and remain unchanged over time (study A, n = 12). Mean terminal elimination half-life was 11.8 and 11.9 h, mean incremental recovery (IU dL(-1)/IU kg(-1)) was 2.3 and 2.0, respectively. Long-term efficacy and safety, in particular the potential immunogenicity, were investigated in a total of 53 PTPs (studies A and B) treated prophylactically and on-demand, as required. PdFVIII has shown to be effective in preventing and controlling bleeding episodes; 23.5% of patients were free of bleeding events. A total of 177 haemorrhages occurred with 74.0% resolving after a single infusion, 87.6% within two infusions. 98.3% of responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy has been demonstrated in 10 surgical procedures including general and severe orthopaedic interventions (study C). No complication occurred in any surgery. Few adverse events were reported, one patient developed a high-titre FVIII inhibitor without clinical relevance. In all three studies, over 6 million units were administered in nearly 4300 infusions, approximately 94% units or infusions were given for prophylaxis and only 6% for treatment on-demand. In conclusion, pdFVIII has shown to be effective, safe and well tolerated in long-term prophylaxis and treatment on-demand as well as after minor and major surgical procedures.     

In vivo recovery and safety of human factor VIII product AAFACT® in patients with haemophilia A

AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT, were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe.     

Clinical safety surveillance study of the safety and efficacy of long-term home treatment with ReFacto® utilizing a computer-aided diary: a Nordic multicentre study

Summary.  A Nordic multicentre, open-label, non-interventional postmarketing surveillance study was carried out during a period of 24 months evaluating safety and efficacy of ReFacto as prophylactic or on-demand replacement therapy in patients with haemophilia A treated by self-medication. Fifty-seven patients were enrolled and studied for safety; efficacy was evaluated in 39 patients who received ReFacto for 24 months and recorded sufficient diary data on a hand-held computer. The compliance of using the device was good in small children, variable in adults and poor in teenagers. The fact that the overall compliance was low constituted a limitation of the number of patients with reliable diary data. Overall safety was rated as excellent or good by the clinicians for all patients at all visits and overall efficacy at 24 months evaluated to be excellent (74%) or good (26%). It was noticed that ≥50% of patients/parents reported no absences from school or work owing to bleeding episodes during the study period. Among patients on regular prophylaxis, 6 of the 30 patients (20%) receiving ReFacto experienced no bleeding episodes. A median of four bleeding episodes occurred during the 24-month study period, and 93% of the episodes were resolved with ≤2 ReFacto infusions. In the 7 on-demand patients, there was a median of 18 bleeding episodes, 87% of which resolved with ≤2 ReFacto infusions. Interestingly, 42% of the ReFacto infusions taken by the patients classified to the on-demand group were registered as prophylactic treatment. In conclusion, ReFacto demonstrated good safety and efficacy in prophylaxis as well as treatment of bleeding episodes.     

Efficacy and safety of the B-domain-deleted TQG202 for on-demand treatment in moderate and severe haemophilia A patients: A multicentre,single-arm trial

Introduction

On-demand treatment is the most common treatment strategy for haemophilia A in China.

Aim

This study aims to evaluate the efficacy and safety of a human-derived B-domain-deleted recombinant factor VIII (TQG202) in the on-demand treatment of bleeding episodes in moderate/severe haemophilia A patients.

Methods

This multicentre, single-arm clinical trial enrolled moderate/severe haemophilia patients previously treated with FVIII concentrates for ≥50 exposure days (EDs) from May 2017 to October 2019. TQG202 was injected intravenously on-demand for bleeding episode management. The primary endpoints were the infusion efficiency at 15 and 60 min after the first administration and haemostatic efficacy of the first bleeding episode. Safety was also monitored.

Results

Fifty-six participants were enrolled with a median age of 24.5 (range: 12–64) years old. The median total dose of TQG202 was 29,250 IU per participant (range: 1750–2,02,500), and the median number of administrations was 24.5 (2–116). The median infusion efficiency at 15 and 60 min after the first administration was 155.4% and 145.2%, respectively. Among the 48 first bleeding episodes evaluated, 47 (83.9%, 95% CI: 71.7%–92.4%) had a haemostatic efficacy rating of excellent or good. Eleven (19.6%) participants had treatment-related adverse events (TRAEs), but no ≥grade 3 TRAE was observed. Inhibitor development (0.6BU) was observed in one participant (1.8%) after 22 EDs, but was undetectable after 43 EDs.

Conclusion

TQG202 for on-demand treatment in moderate/severe haemophilia A shows effective control of the bleeding symptoms, with a low incidence of adverse events and inhibitors development.     

Results from a large multinational clinical trial (guardian™1) using prophylactic treatment with turoctocog alfa in adolescent and adult patients with severe haemophilia A: safety and efficacy

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open‐label, non‐controlled trial investigated the safety and efficacy of turoctocog alfa, a new rFVIII product. The primary objective was to evaluate safety. A total of 150 patients (24 adolescents and 126 adults) with severe haemophilia A (FVIII activity ≤1%), with at least 150 exposure days (EDs) to any FVIII product and no history of inhibitors were enrolled, and 146 patients (97%) completed the trial. All patients received prophylaxis with turoctocog alfa for approximately 6 months and had a mean of 85 EDs during the trial. None of the patients developed FVIII inhibitors, there were no indications of early FVIII inhibitor development and no safety concerns were identified. A total of 225 adverse events were reported in 100 (67%) patients, with the most common being events associated with dosing procedures, headaches, and nasopharyngitis. A total of 499 bleeding episodes were reported during the trial, the majority (89%) were controlled with 1–2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as ‘excellent’ or ‘good’ haemostatic response) for treatment of bleeding episodes was 81%. The overall median annualized bleeding rate was 3.7 (interquartile range: 8.7) bleeds/patient/year. In conclusion, turoctocog alfa provides a new, safe and effective alternative for prophylaxis and treatment of bleeding episodes in patients with haemophilia A.     

Effective and safe use of recombinant factor VIIa (NovoSeven®) in elderly mild haemophilia A patients with high-titre antibodies against factor VIII

Three patients with mild haemophilia A who developed high-titre antibodies against factor VIII at high age are reported. These patients had only a limited number of exposure days of FVIII concentrates in the past. The patients had to undergo surgery or presented with recurrent bleeding episodes. Treatment with recombinant FVIIa (rFVIIa) was effective and safe. Despite the high age and the presence of coronary heart disease in one of the patients, no adverse events or thrombotic complications occurred. These cases illustrate that the physician should always be alert on the development of inhibitors, also in elderly patients with mild haemophilia, in whom FVIII inhibitors had never been detectable before and that treatment with rFVIIa was effective and well-tolerated.     

Experience with a third generation recombinant factor VIII concentrate (Advate®) for immune tolerance induction in patients with haemophilia A

Summary.  The development of an inhibitor represents one of the most challenging complications in patients with haemophilia A. Optimal management is immune tolerance induction (ITI), typically through the administration of high doses of factor VIII (FVIII) concentrate. Among 12 patients who underwent ITI using Advate, a third-generation recombinant FVIII product that is free of animal and human protein additives, tolerance was achieved in nine (75%), including seven of 10 patients (70%) with high-titre inhibitors. ITI is ongoing in two patients and not yet successful; immune tolerance failed in the third patient. The median time to success was 4.0 months for group as a whole and for patients with high-titre inhibitors. Treatment was well tolerated, and no adverse events were observed. Advate was found to be equivalent to other FVIII products with regard to both ITI success rates and the incidence of adverse effects when used in these immune tolerance regimens.     

Factor VIII recovery after a single infusion of recalibrated ReFacto® in 14 severe haemophilia A patients

A recent multicentre collaborative study showed higher estimates of ReFacto potency when assayed with ReFacto Laboratory Standard(TM) (RLS) in comparison when standards consisting of full-length factor VIII (FVIII) were used. The RLS was hence recalibrated, leading to a 20% increase in the amount of ReFacto per vial without change in the labelled potency. The primary objective of this study was to determine the incremental and in vivo recovery of the recalibrated ReFacto in patients with severe haemophilia A. Fourteen male severe haemophilia A patients (FVIII < 1 IU dL(-1)) with a cumulative previous exposure days to any FVIII product >150 were administered an intravenous infusion 50 +/- 5 IU kg(-1) of ReFacto over a 5-min period. Blood samples were collected before infusion and after 15, 30 and 60 min. FVIII clotting activity (FVIII:C) was assessed in a central laboratory by the chromogenic substrate assay. After ReFacto infusion, peak FVIII:C was obtained within 15 min for 10 patients and within 30 min for the remaining four. Mean FVIII:C at peak was 117.7 +/- 17.3 IU dL(-1). Mean incremental recovery was 2.22 +/- 0.27 IU dL(-1) per IU kg(-1) while mean in vivo recovery was 105.9 +/- 14.6%. One patient reported three mild adverse events rated as 'unrelated' to the study drug. FVIII recovery after recalibrated ReFacto infusion falls within the expected range and is similar to the values reported for other FVIII concentrates.     

In vitro evaluation of B-domain deleted recombinant factor VIII (ReFacto®) stability during simulated continuous infusion administration

The administration of factor VIII (FVIII) by continuous infusion (CI) to manage severe haemorrhage or during major surgery appears pharmacokinetically and economically favourable when compared with intermittent bolus infusions. Successful clinical use of FVIII delivered by CI, however, requires a thorough assessment of product stability under conditions encountered during CI such as prolonged exposure to the delivery devices at ambient temperature and the low FVIII concentrations. This investigation has identified conditions under which ReFacto, a recombinant human B-domain deleted FVIII, can be successfully delivered under dilute conditions when using large volume parenteral polyvinyl chloride (PVC) bags without the addition of stabilizers or as an undiluted preparation delivered by ambulatory infusion pumps. ReFacto is stable for 36 h when stored in large volume parenteral PVC reservoirs at 3 and 8 IU mL(-1) or 72 h when delivered undiluted at 62 IU mL(-1) by CADD infusion pumps. The greatest concern with the delivery of ReFacto by CI is adsorptive losses to the contact surfaces of the delivery system. There was no significant binding of ReFacto to the PVC reservoirs overtime; however, there was appreciable binding to the administration set under certain conditions. The binding was influenced by the ionic strength of the solution, residence time in the tubing and protein concentration. The recovery and stability profile of ReFacto under certain conditions appears favourable when compared with that of full-length recombinant FVIII products, observed by other investigators.     

Results from a large multinational clinical trial (guardian™3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety,efficacy and pharmacokinetics

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open‐label, non‐controlled trial investigated the safety, efficacy and pharmacokinetics (PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0–5 years) and 32 older children (6–11 years), with ≥50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25–50 IU kg^?1 every second day or 25–60 IU kg^?1 three times weekly). PK assessments of turoctocog alfa and the patients’ previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (≥0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1–2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as ‘excellent’ or ‘good’ haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient^?1 year^?1. PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients.     

Long-term immunogenicity,efficacy and tolerability of simoctocog alfa in patients with severe haemophilia A who had completed the NuProtect study in previously untreated patients

Background

The NuProtect study reported data on the immunogenicity, efficacy and tolerability of simoctocog alfa (Nuwiq^®) in 108 previously untreated patients with severe haemophilia A planned to be treated for ≥100 exposure days or up to 5 years. The NuProtect-Extension study collected long-term prophylaxis data in children with severe haemophilia A.

Methods

Patients who completed the NuProtect study according to the protocol were eligible for the NuProtect-Extension study, a prospective, multinational, non-controlled, Phase 3b study.

Results

Of 48 patients who entered the extension study, 47 (median age 2.8 years) received prophylaxis with simoctocog alfa for a median of 24 months, with 82%–88% on a twice-weekly or less regimen. No patient developed FVIII inhibitors during the extension study. The median (IQR) annualized bleeding rate (ABR) during prophylaxis was 0 (0–0.5) for spontaneous bleeding episodes (BEs) and 1.00 (0–1.95) for all BEs. ABRs estimated using a negative binomial model were .28 (95% CI: .15, .53) for spontaneous and 1.62 (95% CI: 1.09, 2.42) for all BEs. During the median follow-up of 24 months, 34 (72%) patients had zero spontaneous BEs and 46 (98%) had zero spontaneous joint BEs. Efficacy in treating BEs was excellent or good for 78.2% of rated BEs, and efficacy of surgical prophylaxis was excellent for two rated surgeries. No treatment-related adverse events were reported.

Conclusion

No FVIII inhibitors developed during long-term prophylaxis in the NuProtect-Extension study. Prophylaxis with simoctocog alfa was efficacious and well-tolerated, and is therefore an attractive long-term option for children with severe haemophilia A.     

Clinical observation on safety and efficacy of a plasma‐ and albumin‐free recombinant factor VIII for on‐demand treatment of Chinese patients with haemophilia A

Summary. Recombinant FVIII (rFVIII) has become the best choice for treating bleeding of haemophilia A patients. A plasma‐ and albumin‐free recombinant FVIII (rAHF‐PFM, ADVATE^®), as the third generation rFVIII, virtually eliminates the risk of blood‐borne disease transmission by excluding all human blood derived additives throughout cell culture, purification and formulation. In this multicentre prospective clinical study we evaluated the efficacy, safety and immunogenicity of ADVATE^® in Chinese patients with haemophilia A. Fifty‐eight patients enrolled and received ADVATE^® treatment. Of the patients enrolled, eight (13.79%) had severe haemophilia, 45 (77.59%) had moderate haemophilia and five (8.62%) had mild haemophilia. Fifty‐four patients completed 6 months of observation. A total of 781 bleeds occurred in these 58 subjects, all evaluable per‐protocol. A total of 984 infusions were administered with a mean of 17.0 ± 11.1 infusions per patient. On average, each patient received a mean of 15030.2 ± 7972.7 IU ADVATE^® (median 13 625 IU, range 9500–19 750 IU) during 6 months. The majority of bleeding episodes (95.9%) were successfully treated with one or two infusions of ADVATE^®. Overall, response to the first ADVATE^® treatment was rated as either ‘excellent’ (82.8%) or ‘improved’ (17.2%) in all subjects. All patients tolerated ADVATE^® infusions well. One patient (1/58, 1.7%) developed an inhibitor of 4 Betheseda units at day 180 visit. The results of this clinical observational study support that ADVATE^® is efficacious, safe and well tolerated in the treatment of Chinese patients with haemophilia A.     

Safety and efficacy of KOGENATE® Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs)

Summary.  Safety and efficacy of KOGENATE^® Bayer (Kogenate^® FS), a second-generation full-length recombinant factor VIII formulated with sucrose as stabilizer and produced without the addition of human albumin during purification and the final formulation, was assessed in a prospective, international clinical trial including 31 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe haemophilia A in home therapy and surgery. Factor VIII inhibitor development was monitored and mutation type profiles were analysed. As of 30 June 2000, the patients received a total of 2.729 infusions (mean 88; range 6–274) for bleeding episodes, surgery or prophylactic treatment. No unexpected drug-related adverse events were observed. Four patients developed an inhibitor after 3–12 exposure days (EDs). One patient successfully underwent immune tolerance treatment; inhibitors in two patients disappeared spontaneously with on-demand treatment, while the inhibitor titre remains low in one patient. Twenty-nine patients (93%) with more than 20 EDs can be regarded as at low risk for inhibitor development. In conclusion, KOGENATE^® Bayer is efficacious and well-tolerated for treatment of children with severe haemophilia A. The incidence of inhibitor formation is not different to that observed with other recombinant or plasma-derived products.     

A survey of factor prophylaxis in boys with haemophilia followed in North American haemophilia treatment centres

Summary.  A survey was conducted in 2002 to determine the pattern of factor prophylaxis use in boys ≤18 years of age with haemophilia followed in North American treatment centres. Responses were obtained from 4553 cases (74% haemophilia A, 26% haemophilia B). The frequency of prophylaxis, defined as factor infusion greater than or equal to once per week for ≥45 weeks per year, was significantly higher for haemophilia A vs. haemophilia B cases (51% vs. 32%, P < 0.0001), and for boys with severe haemophilia A living in Canada vs. the USA (77% vs. 47%, P < 0.0001). Use of full-dose prophylaxis, defined as the infusion of 25–40 IU kg⁻¹ of factor VIII on alternate days (minimum three times per week) or 25–40 IU kg⁻¹ of factor IX twice weekly, was similar for boys ≤5 years of age in both Canada and the USA (30% and 33% haemophilia A and 35% and 13% haemophilia B). Reasons for initiating prophylaxis included a history of joint bleeding (88%) and age ≤2 years (23%). For prophylaxis triggered by joint bleeding, 38% of haemophilia treatment centres indicated that they would initiate prophylaxis after the first joint bleed and 66% after a history of target joint bleeding, defined most frequently as 2–4 bleeds over a 3–6 consecutive month period. A central venous line was used to ensure easy venous access for full-dose prophylaxis therapy in 80% of boys ≤5 years of age. These data offer a basis for projecting long-term factor concentrate needs for persons with haemophilia living in North America.