Treatment Of Bleeding Episodes Research Articles

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

The safety of activated eptacog beta in the management of bleeding episodes and perioperative haemostasis in adult and paediatric haemophilia patients with inhibitors.

IntroductionHaemophilia 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.AimTo assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care.MethodsUsing 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.ResultsSixty 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.ConclusionResults 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.

PHARMACOKINETIC-GUIDED PROPHYLAXIS FOR PEOPLE WITH HEMOPHILIA A

Pharmacokinetic (PK)-guided prophylaxis for people with hemophilia A (PwHA) treatment has been related to fewer bleeding and cost savings have been reported. myPKFiT®is a populational PK tool available for this purpose, developed for α-octocog (Advate®, Takeda) analysis. We evaluated the impact of myPKFiT®-guided prophylaxis in PwHA on replacement costs and bleeding episodes. Men with severe (FVIII < 1%) or moderate (FVIII 1%-5%) HA without inhibitors and treated with Advate®were invited at two Southern Brazilian Hemophilia Treatment Centers. Inclusion criteria involved ≥ 50 exposure days, age 1-65 years, weight 12-120 kg, bleeding-free for ≥ 2 weeks, and last surgical procedure ≥ 6 months. PwHA who developed inhibitor (> 0.6 BU/mL at two time-points) during the study period were excluded. Anthropometric and hemophilia-related data were obtained using a standardized form. PK analysis was performed according to myPKFiT®recommendations, using one-step test. After PK analysis, PwHA were approached to adjust their regimen according to bleeding phenotype, arthropathy, and physical exercise. Replacement regimen and FVIII disposal (from now called consumption) were assessed before and after treatment adjustment. PwHA younger than 15 years were evaluated for 6 months, while those 15 years or older were evaluated for 12 months. Annualized bleeding rate (ABR) was calculated from the reported treated bleeding episodes. FVIII disposal (from now reported as consumption) was adjusted by weight (kg) and monthly. The cost of 1 IU of Advate®was based on the median date of the evaluated periods, which was July/2019. We converted the price in Real into American Dollar, considering the currency at the date that the Brazilian Ministry of Health purchased the product. A total of 37 PwHA were included. In the younger group (n = 20), 75% were severe, and 65% had no hemophiliac arthropathy. Half of these patients were on primary prophylaxis. Two PwHA had a previous history of successful immune tolerance induction. Among the older group (n = 17), 76% were severe, 1 PwHA was treated exclusively on-demand before adjustment, none were on primary prophylaxis, and 12% had no hemophiliac arthropathy. One participant developed inhibitor during the study. Median [interquartile range, IQR] tranged from 9.5 [8.0-10.0] h, among younger individuals, to 10.5 [9.0-11.0] h, among the older ones. Three PwHA from the older group were excluded from the cost analyses: 1 developed inhibitor during follow-up, 1 was treated exclusively on-demand before PK-analysis, and 1 was prescribed plasma-derived FVIII few months after adjustment. From the remaining 34 PwHA, all individuals were advised about behavior and time of infusion, according to their bleeding phenotype, arthropaties, and physical exercise. Among younger PwHA, monthly total FVIII replacement cost increased after PK-based adjustment (p < 0.0001), while reducing costs of episodic therapy (p = 0.05) and increasing costs of prophylaxis (p < 0.0001). Median [IQR] ABR reduced from 3.0 [0.5-10.0] to 1.0 [0.0-2.0]. Among older PwHA, although monthly total and prophylactic costs did not change between the periods, costs of episodic treatment reduced (p = 0.039). ABR did not change either. PK-adjusted prophylaxis was related to increased treatment costs among PwHA < 15 years, but not among individuals ≥ 15 years. Although ABR reduced after adjustment among younger PwHA, no ABR change was evidenced among older participants.

Symptoms in Infants and Toddlers With von Willebrand Disease

Source: Dupervil B, Abe K, O’Brien SH, et al. Characteristics, complications, and sites of bleeding among infants and toddlers less than 2 years of age with VWD. Blood Adv. 2021;5(8):2079-2086; doi:10.1182/bloodadvances.2020004141Investigators from multiple institutions conducted a retrospective study to describe the diagnosis and bleeding history among infants and toddlers with von Willebrand disease (VWD). For the study, data from the CDC Universal Data Collection (UDC) surveillance system established in the US Hemophilia Treatment Center (HTC) Network were reviewed. Children <24 months old, diagnosed with VWD and treated at one of 135 HTCs from 2003 to 2011 were enrolled. For the UDC, data on demographics, VWD diagnosis, family history of bleeding disorders, and history and treatment of bleeding episodes were collected at enrollment and regularly scheduled visits in a systematic manner. VWD type (1, 2, or 3) was classified based on the diagnosis made by the treating physician at the HTC. Descriptive statistics were used to characterize demographics, age at diagnosis, reason for diagnosis (family history or unusual bleeding), and number and anatomic location of bleeding episodes. Chi-square, Fisher exact, or Wilcoxon rank sum tests were used to assess differences when groups were compared.Data on 105 infant and toddlers were analyzed. The mean age of enrollment was 14 months, and 61 (58%) of the patients were male. Among these infants and toddlers, 63% had VWD type 1, 28% type 2, and 9% type 3. There was a family history of bleeding disorders in 79.1%. A family history of VWD prompted diagnostic testing in 68% of study patients; 93% of children diagnosed with type 2 disease had a family history of VWD, compared to 77% of those with type 1 and 44% of those with type 3 (P = 0.02). The mean age at diagnosis of all study patients was 7 months. Children with type 2 VWD were diagnosed at a significantly younger age than those with types 1 and 3 (mean age, 4.7, 8.0, and 6.8 months, respectively; P = 0.04).Among study participants, 22% experienced a bleeding episode before the diagnosis of VWD, 22% were diagnosed at the time of an episode, and approximately 50% were diagnosed before their first notable bleeding event (with testing done because of a family history). Overall, 274 bleeding events were documented in 73 patients. The most common types of bleeding episodes were oral/nasal bleeds (166 episodes, 60.6%) and soft-tissue hematomas (57 episodes, 20.8%); 9 boys (14.8%) experienced unusual bleeding with circumcision. There were 7 episodes of subdural hemorrhages among the study children, occurring both after trauma and spontaneously.The authors conclude that the majority of infants and toddlers with VWD have a family history of the disease, and bleeding episodes are common.Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Von Willebrand disease affects up to 1% of the U.S. population.1 Von Willedbrand Factor (VWF) is an acute-phase reactive glycoprotein that aggregates and adheres platelets to damaged blood vessel walls.2 Many with Type 1 VWD, a partial VWF deficiency associated with autosomal dominant inheritance, are unaware of their bleeding disorder due to mild gum bleeding, epistaxis, petechiae, bruising, gastrointestinal bleeding, and heavy menses often attributable to co-morbidities, medications, or trauma (See AAP Grand Rounds. 2020;44[5]:54.)3 Those with subtypes of type 2 VWD, due to different qualitative VWF defects, have variable inheritance and bleeding symptoms.4 Those with the rarest, type 3 VWD, due to an autosomal recessive inheritance manifesting with an absence of VWF, have severe bleeding symptoms.4In older children, teens, and adults, screening for bleeding disorders includes family history and symptom scores using the International Society on Thrombosis and Haemostasis Bleeding Assessment Tool.5 Falsely abnormal or normal blood test results for CBC, PT, PTT, VWF antigen, VWF activity, Factor VIII, and multimeric analysis arise due to issues with phlebotomy, specimen handling, and assay variability.6 Interpretation of diagnostic test results are affected by blood type, hormones, and concurrent stressors such as fear, exercise, or infection.2 Currently, complex genetic testing plays a limited role in diagnosis and clinical severity in some type 2 VWD cases.7The current investigators review a large cohort of newborns, infants, and toddlers with VWD and describe bleeding episodes, which occur most often before 1 year of age. Limitations of this study include overrepresentation of non-Hispanic whites and missing data for bleeding characteristics or scores, VWF antigen/activity levels, and vitamin K administration at birth. No control cohort with or without bleeding symptoms was available for comparison.A family history of VWD or personal history of oropharyngeal, circumcision-related, hematomas, or intracranial bleeds in children <2 years of age indicate the need for evaluation for VWD.

Matching-Adjusted Indirect Comparison of Efficacy and Consumption of rVIII-SingleChain Versus Two Recombinant FVIII Products Used for Prophylactic Treatment of Adults/Adolescents with Severe HaemophiliaA.

IntroductionGiven the relatively small number of patients with haemophilia A, head-to-head comparisons between recombinant FVIII (rFVIII) products are difficult to conduct. This study compared the efficacy and consumption of rVIII-SingleChain (lonoctocog alfa, AFSTYLA®) with rAHF-PFM (octocog alfa, Advate®) and rFVIIIFc (efmoroctocog alfa, Elocta®), for the prophylaxis and treatment of bleeding episodes in previously treated adolescents/adults with severe haemophilia A, through a matching-adjusted indirect comparison (MAIC).MethodsA systematic literature review identified published clinical trials for rAHF-PFM and rFVIIIFc. Individual patient data for rVIII-SingleChain were used to match baseline patient characteristics to those from published trials, using an approach similar to propensity score weighting. After matching, annualized bleeding rates (ABR), percentage of patients with zero bleeds, and rFVIII consumption were compared across trial populations.ResultsPublished data were identified from two rAHF-PFM trials and one rFVIIIFc trial. rVIII-SingleChain had similar ABR (risk ratio [RR]: 0.74 [0.16; 3.48]; RR: 1.18 [0.85; 1.65]) and percentage of patients with zero bleeds (odds ratio [OR]: 1.34 [0.56; 3.22]; OR: 0.78 [0.47; 1.31]) versus rAHF-PFM and rFVIIIFc, respectively. Annual rVIII-SingleChain consumption was significantly lower than rAHF-PFM (mean difference: − 1507.66 IU/kg/year [− 2011.71; − 1003.61]) and equivalent to rFVIIIFc (RR: 0.96 [0.62; 1.49]).ConclusionAlthough limited to published information for comparator trials, these results suggest that with an annualized rFVIII consumption comparable to rFVIIIFc, but significantly lower than rAHF-PFM, routine prophylaxis with rVIII-SingleChain is able to maintain a similar ABR and percentage of patients with zero bleeds, attesting to the long-acting nature of rVIII-SingleChain.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01853-0.

Final results of the PUPs B-LONG study: evaluating safety and efficacy of rFIXFc in previously untreated patients with hemophilia B

AbstractPUPs B-LONG evaluated the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) in previously untreated patients (PUPs) with hemophilia B. In this open-label, phase 3 study, male PUPs (age <18 years) with hemophilia B (≤2 IU/dL of endogenous factor IX [FIX]) were to receive treatment with rFIXFc. Primary end point was occurrence of inhibitor development, with a secondary end point of annualized bleed rate (ABR). Of 33 patients who received ≥1 dose of rFIXFc, 26 (79%) were age <1 year at study entry and 6 (18%) had a family history of inhibitors. Twenty-eight patients (85%) received prophylaxis; median dosing interval was 7 days, with an average weekly dose of 58 IU/kg. Twenty-seven patients (82%) completed the study. Twenty-one (64%), 26 (79%), and 28 patients (85%) had ≥50, ≥20, and ≥10 exposure days (EDs) to rFIXFc, respectively. One patient (3.03%; 95% confidence interval, 0.08% to 15.76%) developed a low-titer inhibitor after 11 EDs; no high-titer inhibitors were detected. Twenty-three patients (70%) had 58 treatment-emergent serious adverse events; 2 were assessed as related (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal). Median ABR was 1.24 (interquartile range, 0.00-2.49) for patients receiving prophylaxis. Most (>85%) bleeding episodes required only 1 infusion for bleed resolution. In this first study reporting results with rFIXFc in pediatric PUPs with hemophilia B, rFIXFc was well tolerated, with the adverse event profile as expected in a pediatric hemophilia population. rFIXFc was effective, both as prophylaxis and in the treatment of bleeding episodes. This trial was registered at www.clinicaltrials.gov as #NCT02234310.

Recombinant Fusion Protein Linking Coagulation Factor IX with Albumin (RIX-FP) in Previously Treated Adolescents/Adults with Hemophilia B: Long-Term Efficacy and Safety from an Ongoing Phase 3b Extension Clinical Trial

Introduction: A fusion protein genetically linking recombinant human coagulation FIX with recombinant human albumin (rIX-FP, Idelvion®) has been developed with a >5-fold longer half-life in comparison with standard FIX products, supporting a prophylaxis treatment interval of 7- to 14 days. As part of the PROLONG-9FP clinical trial program, this phase 3b study aims to evaluate the long-term safety and efficacy of rIX-FP for routine prophylaxis and on-demand (OD) treatment of bleeding episodes in subjects ≥ 12 years of age with severe hemophilia B (ie, FIX activity of ≤ 2%) and investigates dosing intervals up to 21-days in selected subjects with successful treatment every 14 days.Methods: Previously treated male patients (PTPs) who have completed the adult study CSL654_3001 received once every 7, 10, or 14 days prophylaxis and OD treatment for bleeding episodes. During study subjects could switch from one prophylaxis regimen to another at the discretion of the investigator. Subjects ≥ 18 years of age also had the option to administer rIX-FP once every 21 days. Primary endpoint was the number of subjects developing inhibitors against FIX. Annualized spontaneous bleeding rates (AsBR) were calculated based on data at the cut-off date 15 March 2017. Treatment efficacy was evaluated by number of injections to achieve hemostasis and Investigator assessment of hemostasis.Results: A total of 59 PTPs ≥ 12 years of age were enrolled into the extension study; 58 (93.8%) subjects achieved ≥50 exposure days (EDs) and 54 (91.5%) ≥100 EDs. A total of 11 subjects have switched to a prophylaxis treatment interval of once every 21 days. The median (Q1, Q3) AsBR was 0.33 (0.00, 2.39), 0.00 (0.00, 0.68), 0.00 (0.00, 1.54), and 0.00 (0.00, 0.45) for once every 7, 10, 14 or 21 days prophylaxis, respectively. A total of 9 (42.9%), 11 (64.7%), 20 (50.0%) and 7 (63.6%) subjects on 7, 10, 14 and 21 days regimens experienced 0 spontaneous bleeding episodes, respectively. A total of 98.1% of bleeds were successfully treated with 1 or 2 injections of rIX-FP (95% CI: 92.9% to 99.5%) to achieve hemostasis. There were 3 related adverse events reported by 3 subjects, all of mild intensity (pain, gamma GTP increased, dizziness). No subjects developed inhibitors to FIX or antibodies to rIX-FP.Conclusion: These Phase 3b interim results demonstrated a favorable long-term safety and tolerability profile of rIX-FP and its clinical efficacy for 7-, 10-, 14- or 21 days prophylaxis and treatment of bleeding episodes. None of the subjects developed inhibitors to FIX. DisclosuresPabinger:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Honoraria; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Santagostino:Bayer, Shire, Pfizer, Novo Nordisk, Kedrion, Roche, Sobi, Bioverativ: Other: Advisory board; : Bayer, Shire, Pfizer, Novo Nordisk, Kedrion, Roche, Sobi, Bioverativ, CSL Behring, Grifols, Octapharma: Speakers Bureau. Brainsky:CSL Behring: Employment. Powell:CSL Behring: Employment. Li:CSL Behring: Employment. Seifert:CSL Behring: Employment.

Genetic Fusion to Factor XIII B-Subunit Improves the Pharmacokinetic Properties of Factor IX

Background: Hemophilia B is a X-linked recessive bleeding disorder characterized by coagulation factor IX (FIX) deficiency. FIX concentrates are used in the prevention and treatment of bleeding episodes in patients with hemophilia B. Prophylaxis is currently considered as the optimal care for severe hemophilia. For patients and their families one of the major problems with prophylaxis is the need for frequent venepunctures. The half-life of standard FIX concentrates is approximately 18 h, which requires 2 or 3 intravenous infusions per week to achieve bleeding prevention. Prolonging the half-life of FIX can therefore reduce the frequency of infusions. Recently, extended half-life FIX concentrates have been developed using two major strategies: i) (glyco) PEGylation(1), ii) genetic fusion to immunoglobulin Fc fragments(2), or to albumin(3). These technologies may have some potential disadvantages such as reduced specific activity, unknown long-term adverse effects of PEG exposure and immunological reactivity which are currently under investigation.The aim of the present study was to develop a new strategy to prolong half-life of recombinant human FIX molecule (rFIX) using an innovative approach of fusion.Factor XIII (FXIII) is a protransglutaminase that circulates in plasma as a heterotetramer composed of two catalytic A subunits and two B subunits (FXIIIB). FXIIIB subunits act as a carrier protein that stabilizes the structure of the A subunits and protects FXIII from proteolysis. It has been reported that a primary deficiency of FXIIIB resulted in the secondary rapid loss of A subunit from the plasma (4). Thus, FXIII-B is responsible for the long half-life of the FXIII molecule (10 to 12 days).We designed a new rFIX molecule fused to coagulation FXIII subunit B (FXIIIB) and separated by a short linker sequence containing an activated Factor X-cleavable site (rFIX-LXa-FXIIIB). Thus, we expected that the carrier protein will be removed as soon as traces of (activated factor X) FXa will be generated, leaving rFIX free to perform its enzymatic role in the tenase complex.Methods: Recombinant FIX-LXa-FXIIIB molecules were expressed in human hepatic Huh-7 cell line and purified via a two-step protocol prior to in vitro and in vivo biochemical and pharmacokinetic characterizations.Results: rFIX-LXa-FXIIIB was correctly expressed by Huh-7 cells at the expected molecular weight of 150 kDa and presented similar procoagulant activity compared to rFIX-WT (106.5 UI/dL ; p> 0.05). We showed that the LXa linker was cleavable by FXa, releasing free rFIX molecule before its activation. After cleavage, rFIX was fully activable by activated FXI. Both rFIX-WT and rFIX-LXa-FXIIIB showed similar thrombin generation capacity both in vitro and in vivo after injection in FIX-deficient mice (Area under the thrombin generation curve =300nM.min ; p>0.05).The half-life (T1/2) of rFIX-LXa-FXIIIB molecule was determined in wild-type mice and rats. In mice, as commercially available extended half-life FIX products, the improvement of the half-life was very limited and in rats, it was 2.5 fold longer compared to rFIX-WT (T1/2 10h vs 4h ; p<0.05).A potential advantage of this new molecule is its capacity to bind to fibrinogen via FXIIIB. It has been recently reported that excess plasma FXIIIB2 is not free, but rather circulates bound to fibrinogen (5). We can hypothesize that the rFIX-LXa-FXIIIB fusion protein can circulate bound to fibrinogen and might therefore enhance/accelerate the transformation of fibrinogen into fibrin. In vivo experiments using mice saphenous vein bleeding model are currently conducted in our laboratory to test this hypothesis.Conclusion: We report here a new fusion protein strategy using FXIIIB. The fusion protein has normal specific activity and normal thrombin generating capacity, associated with improved pharmacokinetics in small animal models. These encouraging results suggest that genetic fusion of rFIX to FXIIIB might be a valuable concept to improve the half-life of FIX molecules. The binding capacity of this novel fusion protein to fibrinogen might be an additional advantage that may improve haemostatic capacity of the molecule.1. Negrier C et al. Blood. 2011;118:2695-701.2. Peters RT et al. Blood. 2010;115:2057-64.3. Metzner HJ et al. Thromb Haemost. 2009;102:634-44.4. Miloszewski K et al. Br J Haematol. 1970;19:685-90.5. Byrnes JR et al. Blood. 2016 Oct 13;128:1969-1978 DisclosuresLe Quellec:LFB: Honoraria; Novo Nordisk: Honoraria; Shire: Honoraria. Negrier:Baxter: Research Funding; Alnylam: Research Funding; Bayer: Honoraria, Research Funding, Speakers Bureau; Biogen/SOBI: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Inspiration: Research Funding; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Octapharma: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau; LFB: Honoraria, Speakers Bureau. Dargaud:BMS: Honoraria, Research Funding; Baxalta/Shire: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; LFB: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Stago: Honoraria; Octapharma: Honoraria, Research Funding; Alnylam: Research Funding.

Incidence of von Willebrand disease in Denmark, 1995-2016: A cohort study.

Information about temporal development of von Willebrand disease (VWD) incidence at a population level is scarce. To our knowledge, no study has described the incidence of VWD at a population level. To estimate overall and annual incidence rates of hospital diagnosed VWD in Denmark between 1995 and 2016 as well as the frequency of hospital treated bleeding episodes before and after VWD diagnosis. A registry-based cohort study that included all Danish patients with a first diagnosis of VWD in Denmark, identified in the Danish National Patient Registry through 1995-2016. We identified 1,035 patients with a diagnosis of VWD. The overall incidence rate of VWD in 1995-2016 was 8.6 (95% CI: 8.1-9.2). The annual age-standardized incidence rate per 100000 person-years varied between 4.1 (95% CI: 2.4-5.9) in 1998 and 16.7 (95% CI: 13.1-20.3) in 2005. A prominent peak in rates appeared from 2002 to 2008. One and five years before VWD diagnosis, 6% and 11.5% of the patients had at least one hospital treated bleeding episode. One and five years after diagnosis, the corresponding percentages were 7.9% and 13.4%. These results are the first population-based estimates of VWD incidence. The incidence may be underestimated because asymptomatic individuals may not be diagnosed. The observed peak in incidence from 2002-2008 may be explained by increased medical attention, leading to more patients being diagnosed, rather than an actual increase in VWD incidence. However, overall, we observed no systematic changes in VWD incidence over the study period.

Design of an international investigator-initiated study on MOdern Treatment of Inhibitor-positiVe pATiEnts with haemophilia A (MOTIVATE).

Background:Inhibitor development is the most serious treatment-related complication of replacement coagulation factor VIII (FVIII) therapy for patients with haemophilia A. Immune tolerance induction (ITI), which involves intensive and prolonged treatment with plasma-derived or recombinant FVIII, is the only clinically proven strategy for eradication of inhibitors. The bispecific antibody emicizumab is approved for use in patients with and without inhibitors to prevent bleeding but does not eliminate inhibitors. MOTIVATE (www.motivate-study.com) aims to capture different approaches to the treatment and management of patients with haemophilia A and inhibitors, document current ITI approaches from real-world clinical experience, and evaluate the efficacy and safety of ITI, emicizumab prophylaxis and ITI with emicizumab prophylaxis.Methods:The investigator-initiated MOTIVATE study [ClinicalTrials.gov identifier: NCT04023019; EudraCT 2019-003427-38] will investigate in real-life clinical practice the management of patients with haemophilia A of any severity who have developed inhibitors to FVIII. All treatment is at the investigator’s discretion. The following treatment approaches will be evaluated: Group 1 – ITI with Nuwiq®, octanate® or wilate® and aPCC/rFVIIa if needed to treat bleeding episodes (BEs) or during surgery or for prophylaxis; Group 2 – ITI with Nuwiq®, octanate® or wilate® and emicizumab prophylaxis and aPCC/rFVIIa if needed to treat BEs or during surgery; Group 3 – routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI and aPCC/rFVIIa if needed to treat BEs or during surgery. Patients will not be randomised to a treatment group and may change groups during the study.Conclusions:It is planned to enrol 120 patients who will be followed for up to 5 years. Optional sub-studies will explore factors that may influence ITI results as well as the impact of different treatment approaches on important aspects of patient health, including joint and bone health and the risk of thrombotic events.

The use of rIX-FP in patients with haemophilia B: a nurse's perspective

Abstract The management of patients with haemophilia is complex and requires lifelong care to be delivered by a specialist multidisciplinary team. Haemophilia B results from a deficiency or absence in coagulation factor IX (FIX), leading to easy bruising, and musculoskeletal and internal bleeding. For patients with severe or moderate haemophilia B, prophylaxis with standard half-life (SHL) coagulation FIX products requires frequent intravenous administration, which may negatively impact treatment adherence and increase burden of care. A recombinant fusion protein linking recombinant FIX (rFIX) with recombinant human albumin, rIX-FP, has an extended half-life compared with SHL rFIX, and has demonstrated a favourable safety and efficacy profile for the prevention and treatment of bleeding episodes in phase III and real-world studies of patients with severe haemophilia B. rIX-FP enables treatment to be tailored to the needs of individual patients, with dosing flexibility allowing selected patients to be treated with prophylaxis dosing intervals of 7, 10, 14 or 21 days. Patients switching to rIX-FP can reduce their annualised bleeding rate and some have successfully reduced their prophylactic dosing frequency while maintaining low bleeding rates and consistent factor consumption. This may ultimately minimise the occurrence of haemophilic arthropathy and improve patient quality of life. Educating patients and caregivers on the sustained use of rIX-FP prophylaxis is essential. The lifelong support and guidance provided by healthcare professionals at haemophilia treatment centres (HTCs) are critical for providing an optimal treatment approach that can increase adherence to treatment. This article reviews the pharmacokinetics, efficacy, and safety of rIX-FP demonstrated in clinical trials and clinical practice, and discusses haemophilia nurses’ clinical experiences with rIX-FP in patients in their HTCs.

Efficacy and Safety of Human Fibrinogen Concentrate for the Treatment of Patients with Congenital Fibrinogen Deficiency: Combined Results of the FORMA-02 and FORMA-04 Clinical Trials

Introduction: Congenital fibrinogen deficiency (CFD) is a rare disorder which results from a complete lack (afibrinogenemia) or low levels (hypofibrinogenemia) of functional fibrinogen. Treatment with human fibrinogen concentrate (HFC) can treat bleeding episodes and prevent blood loss in surgical treatment in patients with CFD. Herein we report combined data from two clinical studies on the efficacy and safety of HFC for the treatment of bleeding episodes (BEs) and surgical prophylaxis in adult, adolescent and pediatric patients. Methods: Both FORMA-02 and FORMA-04 were multinational, multicenter, prospective, open-label, uncontrolled Phase 3 studies for the use of HFC in adult and pediatric patients with CFD. They reported the hemostatic efficacy and safety of human fibrinogen concentrate (HFC: Fibryga® Octapharma) for on-demand treatment of BEs and surgical prophylaxis using objective criteria. Efficacy was assessed by the trial investigators and adjudicated by an independent data monitoring and end-point adjudication committee (IDMEAC). All adverse events (AEs) and serious AEs were recorded. Results: The two studies included a total of 39 patients who received HFC. The median (range) age across both studies was 17 (1-54) years, with 14 pediatric (aged 0-11), 6 adolescent (aged 12-18) and 19 adult patients (aged &amp;gt;18). Treatment of Bleeding Events 32 patients received HFC for the treatment of 99 bleeding events (BEs), 97 minor and 4 major. Of these, 72 were spontaneous, and 27 were due to trauma. 10 BEs occurred in pediatric patients (8 minor, 2 major), and 89 in adult/adolescents (87 minor, 2 major). The mean (±SD) total dose per BE was 65.51 mg/kg (±26.47) for adult/adolescent patients (ages 12-54) and 93.78 (±64.60) for pediatric patients (ages 0-11). Investigator-assessed and IDMEAC rated hemostatic efficacy are shown in Table 1. Overall hemostatic efficacy was rated as success (rating of excellent or good) for 99.0% of BEs by the IDMEAC. Treatment efficacy results were comparable when analyzed by age subgroup of adult (≥18 years), adolescent (&amp;gt;12-&amp;lt;18 years) and in two groups of pediatric patients (&amp;lt;6 years and 6-12 years). Surgical prophylaxis A total of 12 patients received HFC across 15 surgeries (13 minor and 2 major), 3 in pediatric patients (major: splenectomy; minor: circumcision and pulpectomy), and 12 in adults/adolescents (major: eye enucleation with socket reconstruction; minor: knee radioisotope synovectomy [n=2], dental extraction [n=3], circumcision [n=2], excision of circumcision scar bud, root canal operation, skin biopsy, and debridement of superficial necrosis). Mean (±SD) loading dose administered prior to surgery was 77.39 (±20.22) in adult/adolescent patients and 78.50 mg/kg (±27.96) for pediatric patients. Seven surgeries required multiple infusions, with the two major surgeries requiring 5 and 7 maintenance infusions, and the five minor surgeries requiring median (range) 3 (1-4) maintenance infusions. Intra- and post-operative hemostatic efficacy for all surgeries is shown in Table 1. Overall hemostatic efficacy of all the procedures was rated 100% successful by both the investigator and IDMEAC assessment. Safety A total of 101 AEs occurred in 23 patients (59.0%), including 16 serious AEs in 6 patients. Of these, 5 AEs in 4 patients were considered to be possibly related to treatment. These included a mild skin reaction (itchiness and redness), ischemia due to digital microthrombi, peripheral phlebitis of the upper limbs, and a portal vein thrombosis following splenectomy. No allergic/hypersensitivity reactions or deaths were observed during either of the studies. Conclusions: HFC treatment was shown to be efficacious for on-demand treatment of BEs and perioperative prophylaxis in this rare CFD population, across two Phase 3 clinical trials. Efficacy was comparable for adult, adolescent and pediatric patients. A favorable safety profile was seen for the treatment of patients with congenital afibrinogenemia with HFC. Disclosures Djambas Khayat: Octapharma: Research Funding. Kruzhkova:Octapharma: Current Employment. Solomon:Octapharma: Current Employment. Schwartz:Octapharma: Current Employment. Peyvandi:Octapharma: Research Funding. OffLabel Disclosure: On label use: Fibryga for treatment of bleeding episodes Off label use: Use of Fibryga as surgical prophylaxis in the US

Safety and Longer-Term Efficacy of Concizumab Prophylaxis in Patients with Hemophilia a or b with Inhibitors: Results from the Extension Part of the Phase 2 explorer4 Trial

Safety and Longer-Term Efficacy of Concizumab Prophylaxis in Patients with Hemophilia a or b with Inhibitors: Results from the Extension Part of the Phase 2 explorer4 Trial

Optimizing the management of patients with haemophilia A and inhibitors in the era of emicizumab: Recommendations from a German expert panel.

Standard treatment of haemophilia A is based on replacing the missing coagulation factor VIII (FVIII) to treat and prevent bleeding episodes. The most challenging complication of FVIII therapy is the development of neutralizing antibodies (inhibitors) that can render treatment ineffective. Eradication of the inhibitor through immune tolerance induction (ITI) remains the most effective strategy for managing these patients. Bypassing agents can be used to help restore haemostasis in inhibitor patients. Several novel agents have recently been developed, such as the FVIII mimetic agent emicizumab, which has been effective in reducing the annualized bleeding rate in haemophilia A patients with inhibitors. When coadministered with repetitive high doses of activated prothrombin complex concentrate (ie >100U/kg/d for ≥24hours), emicizumab was associated with thrombotic microangiopathy and thrombosis events. As a consequence the United Kingdom Haemophilia Centres Doctors' Organisation (UKHCDO) issued the first guidance on the treatment of bleeding episodes in patients receiving emicizumab. To build on and extend this work, a panel of German haemophilia specialists met to discuss the UK guidance, review current evidence and provide additional guidance for German healthcare professionals on how to optimize the management of patients with haemophilia A receiving emicizumab. Recommendations are provided on the use of bypassing and other agents to manage breakthrough bleeding, ITI in the emicizumab era, haemostatic support during surgery and issues relating to laboratory monitoring.

Safety and Efficacy of Turoctocog Alfa in the Prevention and Treatment of Bleeding Episodes in Previously Treated Patients from China with Severe Hemophilia A: Results from the Guardian 7 Trial.

PurposeHemophilia care in China is characterized by widespread use of on-demand regimens and low-dose prophylaxis. With a limited number of approved recombinant factor VIII (FVIII) products, the incidence of arthropathy and disability in hemophilia patients remains high in China. The purpose of this trial was to evaluate the safety and efficacy of turoctocog alfa for prophylaxis and treatment of bleeding episodes in patients from China with severe hemophilia A across all age groups.Patients and MethodsIn this Phase 3, open-label trial, previously treated males of all ages with severe hemophilia A from China received turoctocog alfa for prophylaxis or on-demand treatment of bleeds. The primary endpoint was hemostatic effect for the treatment of bleeds during the main phase of the trial. Secondary endpoints included annualized bleeding rate during prophylaxis and the frequency of FVIII inhibitor development.ResultsOverall, 42 pediatric patients (age <12 years) and 26 adolescent/adult patients (≥12 years) were dosed with turoctocog alfa; 51 patients initiated treatment with prophylaxis, while 17 patients initiated on-demand treatment. During the main phase of the trial (6 months), hemostatic success was 95.1%. During the full trial (up to 24 months), hemostatic success was 95.4%; the overall median ABR was 1.18 bleeds/patient/year for prophylaxis patients; and 25 (51.0%) of 49 patients with target joints at baseline had all target joints resolved. No FVIII inhibitors (≥0.6 BU) were reported.ConclusionTuroctocog alfa was safe and effective for prophylaxis and treatment of bleeding episodes and for surgery in patients from China with severe hemophilia A across all ages.

Knowledge, attitude and practice of health care providers toward prescribing factor replacement at federally funded haemophilia treatment centres in the United States

Abstract Factor replacement is currently the standard of care to prevent or treat bleeding episodes in haemophilia patients. This study examined current prescribing practices of factor therapy for patients at haemophilia treatment centres (HTCs) in the United States. Aims The aims were to evaluate the driving forces for prescribing factor products, to evaluate current attitudes and knowledge toward factor product and industry, and to discuss the implications for health care providers in practice. Methods An anonymous electronic survey was distributed to 744 HTC health care providers (HCPs); 118 responses were analysed. Results The most common driving force for HCPs to change a patient's factor product was poor response to current therapy, while the most common perception of patients’ motivation to switch products was the potential for fewer infusions. HCPs with strong influence over the prescribed therapy identified inadequate pharmacokinetic (PK) studies as an important driving force; patients/caregivers perceived as having a strong influence over which therapy is prescribed selected less frequent dosing as an important motivator. HCPs who allow patients/caregivers to have a strong influence over which factor is prescribed were more likely to cite patient/caregiver request as a significant driving force for change in therapy. Conclusion The haemophilia treatment landscape continues to evolve and is becoming increasingly complex. The multitude of treatment options available now offer choices, presenting a need to focus on patient-centric prophylaxis.

Laboratory Monitoring of Factor VIII and Factor IX in Hemophilia Patients

Objective: This review describes and discusses the different types of factors assays used in the clinical laboratory for the diagnosis, as well as during therapeutic management, of hemophilia patients. Background: After diagnosis, infusion of factor replacement concentrates is the standard of treatment for patients with hemophilia to prevent or treat bleeding episodes. Monitoring of the factor activity is necessary to assure proper treatment. Method: This review describes several assays used to assess the factor activity at the time of diagnosis and during therapeutic management. The pros and cons of each assay are discussed in detail. Conclusion: With the introduction of many new replacement products it is important the clinical laboratory understands the advantages and disadvantages of each assay with respects to each of the replacement products available.

Damoctocog Alfa Pegol: A Review in Haemophilia A

Damoctocog alfa pegol (Jivi®) is approved in the USA, EU, Japan and Canada for the treatment and prophylaxis of previously treated patients aged ≥ 12 years with haemophilia A. Formulated with a 60 kDa polyethylene glycol (PEG) moiety, damoctocog alfa pegol is an intravenously (IV) administered recombinant factor VIII (rFVIII) product with a longer terminal half-life than non-PEGylated FVIII and rFVIII products. In the multinational phase II/III PROTECT VIII trial, prophylaxis with damoctocog alfa pegol reduced the likelihood of bleeding in previously treated patients aged ≥ 12 years with severe haemophilia A, with dosing schedules ranging from twice weekly to once every 7 days. Interim data from the ongoing extension phase indicated that the reduced annualized bleeding rates (ABRs) were maintained for up to 5.2 years of prophylaxis with damoctocog alfa pegol. Damoctocog alfa pegol was also effective in treating bleeding episodes and in providing haemostatic control during surgery. Damoctocog alfa pegol was generally well tolerated in adult and adolescent patients with severe haemophilia A, with most adverse events considered to be unrelated to treatment. There were no new or confirmed cases of FVIII inhibitor development and anti-PEG antibodies, observed in some patients, were of low titre and transient. Damoctocog alfa pegol extends the available treatment options in previously treated adults and adolescents with haemophilia A, offering the possibility of up to once-weekly administration for suitable patients.

Eptacog beta: a novel recombinant human factor VIIa for the treatment of hemophilia A and B with inhibitors

ABSTRACTIntroduction: Hemophilia A and B are X-linked recessive disorders caused by the deficiency of factor VIII or factor IX, respectively. Bleeding episodes are treated with factor replacement therapy. The most serious complication of this treatment is the development of inhibitors. In such patients, bypassing agents, such as activated recombinant human factor VII (rhFVIIa) or plasma-derived activated prothrombin complex concentrates, are administered to prevent or treat bleeding episodes. The high cost of the current bypassing agents limits their availability in emerging countries.Areas covered: Authors reviewed the published data on the development and clinical testing of eptacog beta, a new second-generation rhFVIIa produced in the milk of transgenic rabbits. The available data indicate that activated eptacog beta exhibits structural (N- and O- glycosylation), pharmacodynamic and pharmacokinetic characteristics similar to activated eptacog alfa, its main competitor, but binds slightly better to platelets and HUVEC, and it is safe and effective.Expert commentary: This critical review of available data on activated eptacog beta shows that it represents an alternative source of rhFVIIa at potentially lower cost with easily expandable manufacturing capacity that could contribute to cover the future patient needs.

Laboratory Monitoring of Factor VIII and Factor IX in Hemophilia Patients

<h3>ABSTRACT</h3> This review describes and discusses the different types of factor assays used in the clinical laboratory for the diagnosis, as well as during therapeutic management, of hemophilia patients. After diagnosis, infusion of factor replacement concentrates is the standard of treatment for patients with hemophilia to prevent or treat bleeding episodes. Monitoring of the factor activity is necessary to assure proper treatment. Several assays are used to assess the factor activity at the time of diagnosis and during therapeutic management. The pros and cons of each assay are discussed in detail. With the introduction of many new replacement products, it is important the clinical laboratory understands the advantages and disadvantages of each assay with respect to each of the replacement products available.