Safety and Efficacy of Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (rIX-FP) in Previously Untreated Patients with Hemophilia B.

Introduction Recombinant fusion protein linking coagulation factor IX (FIX) with albumin (rIX-FP) has been shown to be an effective, well-tolerated treatment for patients with severe hemophilia B who had previously received factor replacement therapy. This study investigated the safety and efficacy of rIX-FP in previously untreated patients (PUPs). Methods Patients with moderately severe/severe hemophilia B (≤2% FIX) previously untreated with FIX replacement products received rIX-FP (25-75 IU/kg) prophylaxis weekly or on-demand treatment over ≥50 exposure days (EDs). Primary outcomes were the number of patients who developed FIX inhibitors and mean incremental recovery (IR) following a 50 IU/kg dose of rIX-FP. Secondary outcomes included incidence of adverse events (AEs) and annualized bleeding rates (ABRs). Results In total, 12 PUPs with a median age of 0 years (range, 0-11 years) were treated with rIX-FP for a median of 50 EDs (6/12 prophylaxis; 6/12 on-demand then prophylaxis). Overall, 11/12 patients did not develop FIX inhibitors; one 11-year-old patient developed an inhibitor against FIX after 8 EDs and was ultimately withdrawn. Mean (standard deviation) IR was 1.2 (0.4, n = 8) (IU/dL)/(IU/kg). Of the 137 treatment-emergent AEs recorded, five were attributed to rIX-FP. On the prophylaxis regimen, median ABR was 1.0 (range, 0-3.9, n = 12). No thromboembolic events or deaths occurred during the study. Conclusion This study provides data to support the safety and efficacy of rIX-FP in PUPs requiring on-demand or prophylactic treatment for moderately severe/severe hemophilia B, consistent with results in previously treated patients. Overall, 1/12 patients developed an inhibitor against FIX.

Classification of recombinant factor VIII products and implications for clinical practice: A systematic literature review.

INTRODUCTION: Consensus over the definition of recombinant factor VIII (rFVIII) product classification in haemophilia A is lacking. rFVIII products are often classified as standard half-life (SHL) or extended half-life (EHL); despite this, no universally accepted definition currently exists. One proposed definition includes half-life, area under the curve, and technology designed to extend half-life; however, the International Society on Thrombosis and Haemostasis defines activity over time as the most intuitive information for building treatment regimens and the World Federation of Hemophilia describes rFVIII product classification in terms of infusion frequency. AIM: To summarise published data on the clinical and pharmacokinetic criteria used to define rFVIII product classification. METHODS: PubMed and EMBASE database searches of English-language articles (2002-2022) were conducted using search strings to identify the relevant population, intervention, and outcomes (e.g., clinical and pharmacokinetic parameters). Articles then underwent title/abstract and full-text screens. RESULTS: Among 1147 identified articles, 62 were included. Half-life was the most widely reported outcome with no clear trends or product groupings observed. No clear groupings emerged among other outcomes, including infusion frequency, consumption, and efficacy. As activity over time was reported in few articles, further investigation of its relevance to rFVIII product classification is warranted. CONCLUSION: The findings of this systematic literature review suggest that parameters other than half-life might be important for the development of a comprehensive and clinically relevant rFVIII product classification definition. There seems to be an opportunity to consider parameters that are clinically meaningful and useful for shared decision-making in haemophilia A treatment.

Extended half-life factor IX prophylaxis up to every 21 days in hemophilia B: a longitudinal analysis of the efficacy and safety in selected adult patients.

Background: Extended half-life factor IX (FIX) products have revolutionized prophylactic treatment for patients with hemophilia B as patients maintain protective FIX levels with minimal occurrence of spontaneous bleeding. rIX-FP is an extended half-life FIX product that allows prolonged dosing intervals. Objectives: To assess individualized and prolonged prophylactic dosing interval up to 21 days in adult patients (≥18 years) with hemophilia B in the rIX-FP clinical trial program. Methods: Patients who were included in the PROLONG-9FP phase III study or who received rIX-FP during surgery could continue into an extension study for long-term assessment. Patients began 7-day prophylaxis with rIX-FP, and after 6 months, they could extend dosing intervals to every 14 days. In the extension study, adult patients could switch to a 21-day regimen if well-controlled on a 14-day regimen. Results: Eleven patients transitioned from a 7-day prophylaxis regimen to a 14-day regimen and finally to a 21-day regimen, 5 of whom were treated on demand at enrollment. Patients who switched to the 21-day regimen had a median annualized spontaneous bleeding rate of 0.0 across all regimens. The median observed FIX activity remained >5 IU/dL until day 21 after a single 100-IU/kg dose of rIX-FP. After 6 months on the 21-day regimen, 2 patients switched back to a 14-day regimen. No inhibitors, anaphylactic reactions, or thromboembolic events occurred. Conclusion: Patients who are well controlled on a once-weekly regimen might extend their treatment interval to 14 days, and in adult patients, further extension to up to 21 days (100 IU/kg) may be considered.

Assessment of joint bleeding and target joints in patients with severe or moderately severe hemophilia B (factor IX ≤2%) receiving prophylaxis with rIX-FP in the PROLONG-9FP clinical trial program.

OBJECTIVE: To assess the impact of prophylaxis with rIX-FP, a fusion protein linking recombinant factor IX (FIX) with human albumin, on joint outcomes. METHODS: Joint outcomes were assessed in pediatric (<12 years) and adult/adolescent (≥12 years) patients receiving rIX-FP prophylaxis every 7, 10, or 14 days; patients (>18 years) well-controlled on a 14-day regimen could switch to a 21-day regimen. Target joints were defined as ≥3 spontaneous bleeds into a single joint within a 6-month period. RESULTS: For adult/adolescent (n = 63) and pediatric (n = 27) patients, median (Q1, Q3) annualized joint bleeding rate was 0.39 (0.00, 2.31), 0.80 (0.00, 2.85), 0.20 (0.00, 2.58), and 0.00 (0.00, 1.78) when treated with 7-, 10-, 14-, or 21-day prophylaxis. 50.0%, 38.9%, 45.5%, and 63.6% of adult/adolescent patients had no joint bleeds when treated with 7-, 10-, 14-, or 21-day prophylaxis, respectively, and 40.7%, 37.5%, and 37.5% of pediatric patients had no joint bleeds when treated with 7-, 10-, or 14-day prophylaxis. Ten adult and two pediatric patients developed target joints; all resolved by the end of the study. CONCLUSION: Prophylaxis with rIX-FP produced low joint bleeding rates and provided excellent hemostatic efficacy in the treatment of joint bleeds. All target joints reported resolved with rIX-FP prophylaxis.

IDELVION: A Comprehensive Review of Clinical Trial and Real-World Data.

Hemophilia B is a bleeding disorder caused by a deficiency of coagulation factor IX (FIX). Treatment with FIX replacement products can increase FIX activity levels to minimize or prevent bleeding events. However, frequent dosing with standard-acting FIX products can create a high treatment burden. Long-acting products have been developed to maintain bleed protection with extended dosing intervals. Recombinant factor IX-albumin fusion protein (rIX-FP) is a long-acting product indicated for the treatment and prophylaxis of bleeding events and perioperative management in adult and pediatric patients. This review outlines data from all previously treated patients in the Prophylaxis and On-Demand Treatment using Longer Half-Life rIX-FP (PROLONG-9FP) clinical trial program and summarizes real-world data evaluating the use of rIX-FP in routine clinical practice. In the PROLONG-9FP program, rIX-FP demonstrated effective hemostasis in all patients at dose regimens of up to 21 days in patients aged ≥ 18 years and up to 14 days in patients aged < 12 years. rIX-FP has a favorable pharmacokinetic profile and an excellent safety and tolerability profile. Extended dosing intervals with rIX-FP led to high levels of adherence and reduced consumption compared with other FIX therapies. Data from real-world practice are encouraging and reflect the results of the clinical trials.

Efficacy, Safety and Pharmacokinetic Results of a Phase III, Open-Label, Multicenter Study with a Plasma-Derived Von Willebrand Factor (VWF)/Factor VIII (FVIII) Concentrate in Pediatric Patients <12 Years of Age with Hemophilia A (SWIFTLY-HA Study).

BACKGROUND: Plasma-derived von Willebrand factor/factor VIII (pdVWF/FVIII; VONCENTO®, CSL Behring) is a high-concentration, low-volume, high-purity concentrate, with a high level of VWF high-molecular-weight multimers and a VWF/FVIII ratio of ~2.4:1. METHODS: This study (NCT01229007) investigated the pharmacokinetics (PK), efficacy and safety of pdVWF/FVIII in 35 previously treated (minimum 20 exposure days [EDs]) pediatric patients (<12 years) with severe hemophilia A. PK was evaluated with a single 50 IU FVIII/kg dose of pdVWF/FVIII. Efficacy and safety analyses were performed during on-demand treatment (n=17) or prophylaxis (n=18) for up to 100 EDs with a maximum study duration of 12 months. RESULTS: PK profiles were similar for patients aged <6 years and those aged 6-12 years, and, as expected, the youngest patients had an increased clearance. On-demand patients reported 320 non-surgical bleeding (NSB) events and received a median number of 29.0 infusions (median dose 34.2 IU FVIII/kg). Hemostatic efficacy was assessed by the investigator as excellent/good in all cases (24%/76%). The 18 patients in the prophylaxis arm experienced 173 NSB events (97 NSBs [56%] in three patients). Five patients (28%) had no NSB events. Overall, patients received a median number of 92 infusions (median dose 30.6 IU FVIII/kg). The majority of bleeds (92%) were successfully controlled with only one infusion. Hemostatic efficacy was assessed by the investigator as excellent (86%) or good (14%). Inhibitors occurred in three patients of which two were transient (low titer) and one persisted (high titer). These three patients had known risk factors for inhibitor development. CONCLUSION: This study demonstrated comparable PK profiles for pediatric patients aged <6 years and aged 6-12 years, and an excellent efficacy and safety profile in this population. The adverse events reported were mostly mild to moderate with inhibitor rates within the expected incidence range.

An Open-Label Extension Study to Assess the Long-Term Efficacy and Safety of a Plasma-Derived von Willebrand Factor (VWF)/Factor VIII (FVIII) Concentrate in Patients with von Willebrand Disease (SWIFT-VWDext Study).

OBJECTIVE: Plasma-derived von Willebrand factor/factor VIII (pdVWF/FVIII; VONCENTO®, CSL Behring) is a high-concentration, low-volume, high-purity concentrate, which contains a high level of high-molecular-weight multimers and a VWF/FVIII ratio of ~2.4:1. The SWIFT ("Studies with von Willebrand factor/Factor VIII") program is evaluating pdVWF/FVIII in patients with von Willebrand disease (VWD). The long-term efficacy and safety profile of pdVWF/FVIII was investigated in this multicenter, open-label, extension study. METHODS: Pediatric, adolescent, and adult patients with VWD who required treatment of non-surgical bleeds (NSBs), treatment during surgical events or who were receiving prophylaxis and who had completed one of two previous clinical trials of pdVWF/FVIII were included. Efficacy and safety analyses were performed for on-demand (n=10), prophylaxis (n=8), or on-demand and prophylaxis (n=2) treatment in patients pre-treated with pdVWF/FVIII for ≥12 months. RESULTS: Seven patients experienced a total of 402 NSBs in the on-demand arm, of which 77 required treatment and nine NSB events in three patients were considered major. Nine patients reported 118 NSBs in the prophylaxis arm, with 96 events requiring treatment and seven patients experiencing 12 major NSB events. Excellent or good hemostatic efficacy was reported by the investigator for 98.7% (on-demand) and 97.9% (prophylaxis) of NSB events treated with pdVWF/FVIII, without relevant differences between subgroups by age. pdVWF/FVIII was well tolerated, and the adverse events seen were mild-moderate and consistent with the safety profile for this product seen in other studies. There were no cases of anaphylactic reactions and angioedema, development of VWF/FVIII inhibitors, thromboembolic events, or viral infections. CONCLUSION: This contemporary comprehensive development program evaluating pdVWF/FVIII across all ages demonstrates long-term safety and efficacy for treatment and prevention of bleeds in patients with severe VWD, supporting the benefit-risk profile of pdVWF/FVIII.

Pharmacokinetics, Efficacy and Safety of a Plasma-Derived VWF/FVIII Concentrate (Formulation V) in Pediatric Patients with von Willebrand Disease (SWIFTLY-VWD Study).

PURPOSE: Formulation V (VONCENTO®) is a plasma-derived high-concentration/low-volume, high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate, originally indicated for von Willebrand disease (VWD) in adults and adolescents. This multicenter, open-label study (SWIFTLY-VWD) evaluated the pharmacokinetics (PK), as well as hemostatic efficacy and safety, of Formulation V in pediatric patients (<12 years) with severe VWD requiring treatment or prophylaxis of bleedings. METHODS: PK investigations were performed following one dose of Formulation V at Day 1 and 180. Nonsurgical bleeds were analyzed, while hemostatic efficacy was graded as excellent/good/moderate/none. Safety assessments included adverse events, and presence of VWF and/or FVIII inhibitors. RESULTS: Formulation V was administered as on-demand (N=13) or prophylaxis therapy (N=4) for 12 months (<6 years, N=9; 6 to <12 years, N=8). PK parameters for VWF markers were generally comparable to adults but showed lower VWF:ristocetin cofactor (RCo) exposure. Incidence of major bleeds was lower for prophylaxis (3.3%) than on-demand therapy (27.1%); joint bleeds were also lower (3.3% vs 11.5%, respectively). Investigator-reported excellent/good hemostatic efficacy against nonsurgical bleeds was 100%. No clinically relevant differences in PK, hemostatic efficacy, or safety were observed between age-groups (<6 years and 6 to <12 years). Formulation V was well tolerated. Adverse events were mild-moderate and consistent with the adult safety profile. No cases of anaphylactic reactions or angioedema, development of FVIII/VWF inhibitors, thromboembolic events, or viral infections were reported. CONCLUSION: This study provides evidence for use of Formulation V to treat and prevent bleeding in pediatric patients with severe VWD, and led to the European approval of Formulation V in children.

High adherence to prophylaxis regimens in haemophilia B patients receiving rIX-FP: Evidence from clinical trials and real-world practice.

INTRODUCTION: Adherence to prophylaxis regimens is essential for bleed prevention in haemophilia but remains a challenge due to the need for frequent infusions. AIM: To evaluate patient adherence to prophylaxis regimens with a long-acting recombinant factor IX (rIX-FP; IDELVION® ) in clinical studies and real-world practice. METHODS: In two phase 3 clinical studies, patients with haemophilia B (FIX ≤2%) recorded their dose, dosing frequency and rIX-FP consumption in an e-diary. Adherence to prescribed prophylaxis regimens was assessed in all patients and to prescribed dose in patients ≥12 years only. Additionally, adherence to rIX-FP prophylaxis regimens in real-world practice was captured. RESULTS: In clinical studies, 94.9% (n = 56/59) of patients ≥12 years and 100% (n = 27) of paediatric patients received ≥80% of the expected number of infusions for their assigned prophylaxis schedule. Overall, mean adherence rate was 95.5% across all prophylaxis regimens in patients ≥12 years and 97.9% with a 7-day regimen in paediatric patients. In patients ≥12 years, 85.7% (n = 54/63) were dose adherent, defined as receiving within 10% of their prescribed dose ≥80% of the time. In real-world practice, adherence was observed in 100% (n = 14 and n = 15, respectively) of patients in two haemophilia treatment centres and 57.1% (n = 4/7) of patients in a third centre; non-adherence (n = 3/7) was linked to insurance-related and parental issues. CONCLUSION: In clinical studies, patients with haemophilia B had high adherence rates to rIX-FP prophylaxis regimens with a variety of dosing intervals, enabling them to achieve very low bleeding rates. High adherence may also be achievable in real-world practice.

Long-Term Safety and Efficacy of Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Previously Treated Pediatric Patients with Hemophilia B: Results from a Phase 3b Extension Study.

INTRODUCTION: A phase 3b extension study evaluated the long-term safety and efficacy of a recombinant fusion protein-linking coagulation factor IX (FIX) with albumin (rIX-FP) for the routine prophylaxis and on-demand treatment of bleeding in pediatric hemophilia B patients. METHODS: Previously treated patients aged <12 years with moderate to severe hemophilia B enrolled in a 3-year extension study following a phase 3 pivotal study in which they received weekly rIX-FP prophylaxis. In the extension study, they could maintain or extend their prophylaxis interval to every 10 or 14 days if they were well controlled on the 7-day regimen. RESULTS: Compared with their initial regimen, by the end of the study, dosing intervals were the same, extended, and shortened in 16, 4, and 4 patients, respectively. Very low annualized spontaneous bleeding rates (AsBRs) were observed; median AsBR was 0.0 for the 7- and 10-day regimens, and 1.1 for the 14-day regimen. The 7- and 14-day regimens were comparable in preventing spontaneous bleeds; mean (95% confidence interval) difference in AsBR of -1.2 (-2.6 to 0.3) bleeding episodes/year/subject. Overall, 96% of bleeding episodes were successfully treated with one or two injections of rIX-FP. Patients on a 14-day regimen maintained a mean steady-state trough FIX level of >7.2 IU/dL. No patient developed an inhibitor. CONCLUSION: This extension study demonstrated the long-term safety and efficacy of weekly rIX-FP in pediatric patients. Additionally, it showed that adequate bleed protection can be achieved with 10- or 14-day rIX-FP regimens in selected pediatric patients while maintaining safety.

Simplifying surgery in haemophilia B: Low factor IX consumption and infrequent infusions in surgical procedures with rIX-FP.

INTRODUCTION: Long-acting recombinant factor IX (FIX) products may simplify the surgical treatment of haemophilia B patients. The impact of rIX-FP, a recombinant FIX fused to recombinant albumin, on FIX consumption and surgical management was assessed in patients with haemophilia B. MATERIALS AND METHODS: Male patients, ≤65 years old with severe haemophilia B (FIX activity ≤2%) requiring non-emergency surgery were enrolled in the surgical substudy of PROLONG-9FP. Dosing was based on World Federation of Hemophilia guidelines and patients' pharmacokinetics. Haemostatic efficacy was assessed on a 4-point scale. rIX-FP consumption and safety were monitored throughout the perioperative period. RESULTS: This updated dataset reports on thirty (8 minor and 22 major) surgeries conducted in 21 patients. A single preoperative bolus was used in 96.7% (n = 29) of surgeries. After minor surgery, patients received a median (range) of 0 (0-3) infusions with a median (range) consumption of 0 (0-178.89) IU/kg in the 14-day postoperative period. In patients who underwent major surgery (including 15 patients undergoing joint replacement surgery), the median (range) number of infusions in the 14-day postoperative period was 5 (0-11) and median consumption was 221.7 (0-444.07) IU/kg. Haemostatic efficacy was rated as excellent or good in 87.5% (7/8) of minor surgeries and 95.5% (21/22) of major surgeries. CONCLUSION: Surgical procedures can be performed using a single preoperative bolus of rIX-FP in nearly all patients. During postoperative care, use of rIX-FP necessitated infrequent infusions and low FIX consumption. Overall, data suggest rIX-FP simplifies perioperative care in patients with haemophilia B.

Long-term safety and efficacy of rIX-FP prophylaxis with extended dosing intervals up to 21 days in adults/adolescents with hemophilia B.

BACKGROUND: An international, multicenter extension study evaluated recombinant fusion protein linking recombinant coagulation factor IX (FIX) with recombinant human albumin (rIX-FP) in hemophilia B (FIX ≤ 2%) patients previously enrolled in a phase III study or who initiated rIX-FP prophylaxis following surgery. OBJECTIVES: To investigate the long-term safety and efficacy of rIX-FP prophylaxis in adult previously treated patients (PTPs) with hemophilia B. METHODS: Male PTPs were treated with a 7- (35-50 IU/kg), 10- or 14-day regimen (50-75 IU/kg). Patients ≥18 years who were well-controlled on a 14-day regimen for ≥6 months could switch to a 21-day regimen (100 IU/kg). RESULTS: A total of 59 patients (aged 13-63 years) participated in the study. Following a single dose of 100 IU/kg rIX-FP, in patients eligible for the 21-day regimen, the mean terminal half-life was 143.2 hours. Mean steady-state FIX trough activity levels ranged from 22% with the 7-day regimen to 7.6% with the 21-day regimen. Median (Q1, Q3) annualized spontaneous bleeding rates were 0.00 (0.00, 1.67), 0.28 (0.00, 1.10), 0.37 (0.00, 1.68), and 0.00 (0.00, 0.45) for the 7-, 10-, 14-, and 21-day regimens, respectively. Comparable efficacy was demonstrated for both the 14- and 21-day regimens compared to the 7-day regimen. Overall, 96.5% of bleeding episodes were treated successfully with 1 to 2 rIX-FP infusions. No patients developed an inhibitor and treatment was well tolerated. CONCLUSIONS: rIX-FP extended interval prophylaxis provides dosing flexibility and, in selected patients, a 21-day regimen may provide an alternative option to minimize treatment burden and individualize treatment.

Health-related quality of life in paediatric haemophilia B patients treated with rIX-FP.

INTRODUCTION: Frequent infusions and bleeds can impact on the health-related quality of life (HRQoL) of paediatric haemophilia B patients. rIX-FP (IDELVION® ) is a fusion protein linking recombinant factor IX with recombinant albumin, and is associated with low bleeding rates with a weekly regimen, which could improve HRQoL. AIMS: To measure the effect of rIX-FP prophylaxis on the HRQoL of paediatric patients and treatment satisfaction in their caregivers using the Haemo-QoL and Hemo-SATP questionnaires, respectively. METHODS: At baseline and end-of-study (EOS), patients 4-11 years old participating in the PROLONG-9FP program answered the Haemo-QoL questionnaire and gave information on their socio-demographic data and physical activity. Caregivers completed the Hemo-SatP . Minimal important differences (MID) (|Cohen's d| > 0.5) between baseline and EOS and the number of responders (patients with meaningful subject-level improvements over time) at EOS were calculated. RESULTS: Twenty patients (age group I: 4-7 years old [n = 12]; age group II: 8-12 years old [n = 8]) completed the Haemo-QoL questionnaire at baseline. MIDs were found in age group I representing improvement for "physical health" (d = -0.547) domain; 60% of patients were responders for "physical health." In age group II, MIDs were seen in most domains; 71.4% patients were responders in "total score." In caregivers, improvements were seen for most domains of the Hemo-SatP with a small effect size. Fewer patients missed school when treated with rIX-FP and 94.1% patients maintained their physical activity level. CONCLUSION: Prophylaxis with rIX-FP led to substantial improvements in HRQoL in paediatric patients and treatment satisfaction in caregivers.

Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study).

VONCENTO (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived, high concentration, lower volume [relative to HAEMATE P (CSL Behring)], high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a VWF/FVIII ratio similar to HAEMATE P. This open-label, multicentre study investigated the pharmacokinetic, haemostatic efficacy, and safety profiles of VONCENTO in study participants at least 12 years of age with von Willebrand disease (VWD) who required treatment of nonsurgical bleeding (NSB) events or underwent surgery or prophylaxis. The first 12-month on-demand treatment period comprised a pharmacokinetic investigation and an efficacy analysis. After 12 months, qualifying study participants were switched to prophylactic therapy and included in a further 12-month efficacy analysis. In total, 21 study participants (including three adolescents, and 13 study participants with VWD type 3) received VONCENTO as on-demand treatment for 12 months. 'Excellent'/'good' haemostatic efficacy was achieved in 98.3% of the 407 NSB events assessed by investigators. Following the switch to prophylactic treatment, the total number of NSBs in eight patients markedly decreased from 304 to 10 (with haemostatic efficacy judged to be 'excellent' for all). The annualised bleeding rate also significantly decreased from a median of 26.5 events to one event. Safety assessments showed no inhibitory antibodies to either FVIII or VWF, no transmission of infectious agents, no thromboembolic events and no treatment-related serious adverse events. VONCENTO was shown to be well tolerated and provided excellent haemostatic efficacy in the treatment of bleeds or during prophylaxis in study participants with VWD, including also those with type 3, the severest form of VWD.

Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO®) in subjects with haemophilia A (SWIFT-HA study).

INTRODUCTION: VONCENTO® (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate,which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and aVWF/factor VIII (FVIII) ratio of ~2.4:1, similar to Haemate® P (CSL Behring). METHODS: The pharmacokinetic, efficacy and safety profiles of VONCENTO® were investigated in this multicentre,double-blind, randomised study. Subjects aged ≥ 12 years with haemophilia A who required treatment of nonsurgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO® or BIOSTATE® reference product (Biostate-RP) (Day 1; Day 8 [n= 16], repeated on Day 180 [VONCENTO® only; n=15]). Efficacy and safety analyses were performed either during on-demand treatment (n=52) or prophylaxis (n=29)for ≥ 6 months and ≥ 50 exposure days, respectively. RESULTS: Besides the confirmation of bioequivalence between VONCENTO® and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either 'excellent' or 'good' in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0-34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013).VONCENTO® was well tolerated and no inhibitory antibodies were identified during the study period. CONCLUSIONS: This study demonstrated the bioequivalence of VONCENTO® to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.

Endometrial effects of tibolone in elderly, osteoporotic women.

OBJECTIVE: To investigate endometrial effects of tibolone administered to postmenopausal women for 3 years. METHODS: Postmenopausal women (N=3,519) aged 60-85 years (mean 68 years) with a uterus and with osteoporosis were randomly assigned to receive tibolone orally, 1.25 mg per day, or identical placebo. We evaluated effects on endometrial thickness in all women, and examined endometrial histology in 635 participants considered to be at increased risk for abnormalities (with unexpected vaginal bleeding or endometrial thickness more than 4 mm). RESULTS: During the first year of study, mean endometrial thickness increased 1 mm in women receiving tibolone (P<.001), but no further increases were noted during the next 2 years. Diagnostic biopsies among 499 women receiving tibolone and 136 who were receiving placebo showed cumulative incidences of endometrial hyperplasia less than 1%. Among the 15% of women whose biopsy showed an endometrial polyp (similar rate in tibolone and placebo), those receiving tibolone were more than twice as likely to show hyperplasia within the polyp. A marginal increase in grade 1 endometrioid adenocarcinoma (P=.06 compared with placebo) was found among women receiving tibolone. Prevalences of vaginal bleeding during the study were 10.8% in the tibolone group and 2.8% in the placebo group (P<.001). CONCLUSION: Tibolone treatment during 3 years minimally increased endometrial thickness, hyperplastic polyps, endometrial carcinoma, and vaginal bleeding.

The effects of tibolone in older postmenopausal women.

BACKGROUND: Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. METHODS: In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. RESULTS: During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. CONCLUSIONS: Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)

Fibroblast Growth Factor Enhances Long-term Potentiation in the Hippocampal Slice.

Recently we reported that perfusion of hippocampal slices with epidermal growth factor (EGF) lead to enhancement of potentiated responses after tetanic stimulation. In the present study we report that basic fibroblast growth factor (FGF) can also lead to an enhancement of potentiated responses. FGF is a mitogen for several cell types and exhibits neurotrophic effects on neurons of the central nervous system (CNS). Rat hippocampal slices were perfused with FGF at a concentration of 10-9 M. During extra- and intracellular recordings in the CA1-region, the addition of FGF to the perfusing medium produced no change in evoked responses if single pulse or paired pulse stimulation was used. Furthermore FGF had no influence on the resting membrane potential and input resistance. However, after tetanic stimulation, FGF-treated slices showed an increase in the magnitude of potentiation compared to control slices. Taken together with the EGF data these results support the hypothesis that growth factors like FGF with neurotrophic potential on CNS-neurons can influence synaptic efficacy. Furthermore these results show that factors which are able to modulate developmental plasticity and regenerative plasticity can also modulate synaptic plasticity.