Prospective Data Collection on Patients with Fibrinogen and Factor XIII Deficiencies: Prelimary Results of the PRO-RBDD Project

Abstract The PRO-RBDD is a prospective study of fibrinogen and FXIII deficiency designed to collect data on demographics, laboratory phenotype, genotype, clinical manifestations, obstetric data, surgery, treatment type and its efficacy and safety. Central laboratory testing is also available for diagnosis confirmation and genotyping. The aims of the study are to evaluate the prevalence of bleeding episodes, establish the minimum coagulant activity level to prevent bleeding (spontaneous or post-traumatic), and to monitor patients’ therapeutic regimens (efficacy and complications). The PRO-RBDD network involved 52 Hemophilia Treatment Centers (HTCs) worldwide for a predicted 380 and 573 patients with fibrinogen and FXIII deficiency, respectively. Data collection started in February 2013 and will continue for 3 years (baseline and 6 follow-up visits are planned). Clinical bleeding episodes were classified into four categories of severity relying on the location and potential clinical impact as well as spontaneity of bleeding. Statistical analysis was performed using chi-square. Linear regression analysis was used to explore the association between coagulation factor activity level and clinical bleeding severity, with the relationship between the two variables defined through the coefficient β. Currently, 26 HTCs have obtained local ethical committee approval and 15 have started data entry for 89 and 109 fibrinogen and FXIII deficient patients, respectively. Demographic data showed a similar distribution between males and females with a median age of 21 years (range: 1-84) and 19 years (range: 3-71) for fibrinogen and FXIII deficiency respectively; 38% and 22% of fibrinogen and FXIII deficient patients, respectively, were children (<12 years). The Table reports the association between residual coagulant level (laboratory severity) and clinical bleeding severity for both patient groups (p<0.01). Linear regression confirmed this association (fibrinogen: β=-0.29, p<0.01; FXIII: β=-12.94, p<0.01). Patient age at diagnosis and the type of treatments utilized are also reported (Table). In 33 women with fibrinogen deficiency and 21 with FXIII deficiency, 10 (30%) and 2 (10%), respectively, had menorrhagia; 5 out of 27 pregnancies (18%) in women with fibrinogen deficiency, and 16 out of 26 pregnancies (61%) in women with FXIII deficiency, resulted in spontaneous abortion; bleeding during pregnancy was observed in only 3/21 (14%) FXIII deficient women (only 1 of whom was on prophylaxis). Follow-up data are available for up to 500 days for 51 and 28 patients with fibrinogen and FXIII deficiencies, respectively. Three out of 6 patients with fibrinogen deficiency (50%) on prophylaxis (30-45 mg/kg/month fibrinogen concentrate), experienced bleeding, while no bleeding was observed for 39 of the 45 fibrinogen deficient patients treated on-demand. Of the 14 patients with FXIII deficiency not on prophylaxis, 2 (14%) had spontaneous bleeds. No bleeding was reported for patients with FXIII deficiency on prophylaxis. No thrombotic events were recorded for any patients. Preliminary data from the PRO-RBDD study of patients with fibrinogen and FXIII deficiency confirmed a strong association between coagulant activity levels and clinical severity in both deficiencies, and the efficacy of prophylaxis in patients with FXIII deficiency. For fibrinogen deficiency, the optimal prophylactic treatment regimen requires further study. Abstract 2838. Table Fibrinogen patients FXIII patients Laboratory severity Severe undetectable Moderate 0.1-1 g/L Mild >1 g/L Severe undetectable Moderate 5-30% Mild >30% Bleeding severity Asymptomatic (no documented bleeding episodes) 1 (1%) 16 (19%) 12 (14%) 0 0 9 (10%) Grade I (bleeding after trauma or drug ingestion) 1 (1%) 7 (8%) 4 (5%) 2 (2%) 3 (3%) 2 (2%) Grade II (spontaneous minor bleeding) 4 (5%) 4 (5%) 5 (6%) 1 (1%) 1 (1%) 1 (1%) Grade III (spontaneous major bleeding) 22 (26%) 9 (10%) 0 70 (74%) 6 (6%) 0 Age at diagnosis median (min,max) 1.5 (0,24) 9 (0,84) 29 (0,64) 5 (0,54) 7 (0,36) 30 (2,46) Treatment type On demand 17 (20%) 38 (43%) 21 (24%) 8 (8%) 8 (8%) 7 (7%) Prophylaxis 11 (13%) 0 0 67 (71%) 2 (2%) 4 (4%) Disclosures Peyvandi: Biotest: Research Funding; Baxter: speaker's fee Other; Bayer: speaker's fee Other; Grifols: speaker's fee, speaker's fee Other; LFB: speker's fee, speker's fee Other; CSL Behring: speaker's fee, speaker's fee Other; NovoNordisk: Research Funding, speaker's fee Other; Kedrion biopharma: Research Funding. Mumford:NovoNordisk: Consultancy, speaker fee Other.

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Prospective Evaluation of Bleeding Incidence in Fibrinogen Deficiency (PRO-RBDD Study)

Blood ◽

10.1182/blood.v128.22.207.207 ◽

2016 ◽

Vol 128 (22) ◽

pp. 207-207

Author(s):

Roberta Palla ◽

Marzia Menegatti ◽

Marco Boscarino ◽

Jan Blatny ◽

Ondrej Zapletal ◽

...

Keyword(s):

Replacement Therapy ◽

Cumulative Incidence ◽

Research Funding ◽

Severe Bleeding ◽

Bleeding Events ◽

On Demand ◽

Number Of Patients ◽

Wide Range ◽

Bleeding Episodes

Abstract BACKGROUND: Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenaemia) or both (hypodysfibrinogenaemia) of fibrinogen. Afibrinogenemia is associated with mild-to-severe bleeding, whereas hypofibrinogenemia is most often asymptomatic. Previously, our group (Peyvandi et al, JTH 2006) showed that in a group of 100 patients with afibrinogenemia and hypofibrinogenemia, the mean annual incidence of bleeding episodes was 0.7 on on-demand therapy (range 0-16.5) and 0.5 on prophylactic replacement therapy (range 0-2.6). Dys- and hypodysfibrinogenemia are commonly associated with bleeding, thrombosis, or both; however, most individuals are asymptomatic. Treatment of fibrinogen deficiency is challenging because the minimum amount of fibrinogen to prevent bleeding is unknown and because thromboembolism may occur in association with fibrinogen substitution therapy. Therefore a guideline for optimal treatment is not available yet. AIMS: The 3-year observational prospective study on rare bleeding disorders (PRO-RBDD) aimed at evaluating the incidence of bleeding episodes in patients with fibrinogen deficiency and the benefits and complication of current treatment regimens. METHODS: 17 Hemophilia Treatment Centers worldwide collected data in a web-based database at baseline (patient history) and at pre-specified time-points (every 6 months, follow up study); 146 patients (86 females/60 males) were recorded. Analysis was carried out on patients with available data on both antigen and activity levels. Bleeding incidence was calculated to evaluate number of bleeding episodes in patients on on-demand therapy. A survival analysis was also made to evaluate the cumulative incidence of the first bleeding requiring replacement therapy. Analysis was done using R v.3.3.1 (R Foundation for Statistical Computing, Vienna, Austria). RESULTS: Data on activity and antigen level were available on 96 patients (54 females/42 males), of whom 81 are currently on follow up. Twenty-one (26%) patients were afibrinogenemic, 17 (21%) hypofibrinogenemic, 36 (44%) dysfibrinogenemic and 7 hypodysfibrinogenemic (9%), according to standard classification. Patients were followed up for a median of 810 days (IQR: 728-916, min-max: 221-1215). In on-demand therapy, the bleeding incidence was 0.86 patient-year-1 (95%CI 0.57-1.15) in afibrinogenemia, 0.30 (95%CI 0.15-0.52) in hypofibrinogenemia, 0.14 (95%CI 0.06-0.25) in dysfibrinogenemia and 0.06 (95%CI 0.-0.27) in hypodysfibrinogenemia. At 1200 days of follow up, the bleeding cumulative incidence of the first bleeding treated with replacement therapy was 0.43 (95%CI 0.11-0.64) in afibrinogenemia, 0.30 (95%CI 0.05-0.49) in hypofibrinogenemia, 0.06 (95%CI 0.0-0.14) in dysfibrinogenemia and 0.14 (95%CI 0.0-0.37) in hypodysfibrinogenemia. Prophylaxis regimen (dosage range 50 - 666 mg/Kg/month) with fibrinogen concentrate was used only in one third of patients (6/21) with afibrinogenemia and it seems to reduce the median number of bleeding events per year [from 1 (min-max: 1-3/year) to 0.4 (min-max: 0-1.25)]. Only one allergic reaction and no thrombotic events were reported. CONCLUSION: The results of this prospective observational study on patients with fibrinogen deficiency showed that the bleeding incidence decreased accordingly to plasmatic fibrinogen levels. Preliminary data on a limited number of patients with afibrinogenemia showed a reduction of bleeding episodes even if a wide range of prophylaxis dosage has been used. A larger group of patients and a longer follow up period are required to evaluate the efficacy of prophylaxis and to find the optimal target level to prevent spontaneous major bleeding in afibrinogenemic patients. Disclosures Palla: Pfizer: Other: travel support . Menegatti:Pfizer: Other: travel support . Blatny:CSL Behring: Speakers Bureau. Halimeh:Bayer Healthcare GmbH: Research Funding, Speakers Bureau; Baxalta Innovations GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; CSL Behring GmbH: Research Funding, Speakers Bureau; Novartis Pharma GmbH: Speakers Bureau; Novo Nordisk Pharma GmbH: Research Funding, Speakers Bureau; Octapharma GmbH: Research Funding, Speakers Bureau; LFB GmbH: Speakers Bureau; Pfizer Pharma GmbH: Research Funding, Speakers Bureau. Siboni:LFB: Speakers Bureau; Bayer: Speakers Bureau. Laros-Van Gorkom:Baxter: Research Funding; CSL Behring: Research Funding; Sanquin: Speakers Bureau. Schutgens:CSL Behring: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta: Research Funding; Novonordisk: Research Funding. De Moerloose:Bayer: Consultancy, Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding, Speakers Bureau; LFB: Speakers Bureau; Stago: Speakers Bureau; Novonordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Research Funding. Casini:CSL Berhing: Speakers Bureau; Bayer: Other: Travel support. Makris:CSL Behring: Consultancy; Novo Nordisk: Consultancy; Freeline Therapeutics: Consultancy; Bayer: Speakers Bureau; Biogen: Speakers Bureau; Grifols: Speakers Bureau. Chapin:Baxalta: Consultancy; CSL Behring: Consultancy; Novo Nordirsk: Consultancy; Alexion Pharmaceuticals: Consultancy; Apopharma: Consultancy; Bayer: Consultancy. Peyvandi:CSL Behring: Speakers Bureau; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; Grifols: Speakers Bureau; SOBI: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Bayer: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau.

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Improvement of Efficacy Outcomes in Patients Who Switched from Sucrose-Formulated rFVIII to BAY 81-8973 Prophylaxis in the LEOPOLD Clinical Trials

Blood ◽

10.1182/blood-2020-137532 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 20-21

Author(s):

Gili Kenet ◽

Thomas Moulton ◽

Erika Soltes Rak ◽

Brian M. Wicklund ◽

Sanjay P Ahuja

Keyword(s):

Research Funding ◽

Hemophilia A ◽

Study Drug ◽

Study Cohort ◽

Efficacy And Safety ◽

Old Patients ◽

On Demand ◽

Adults And Children ◽

Previously Treated ◽

Bleeding Episodes

Background BAY 81-8973 (Kovaltry®) is a full-length, unmodified, recombinant factor VIII (FVIII), indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding and routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia A. It has the same amino acid sequence as sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). Pharmacokinetic comparisons confirmed BAY 81-8973 to have a longer half-life and lower clearance than FVIII-FS. The objective of this analysis was to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS prior to enrolling into the LEOPOLD clinical studies receiving BAY 81-8973. Methods LEOPOLD I (NCT01029340) Part B and LEOPOLD Kids (NCT01311648) were Phase 3, multinational, open-label studies that included male patients with severe hemophilia A receiving on-demand or prophylactic therapy, with ≥50 exposure days to any FVIII product and no history of FVIII inhibitors. Patients in LEOPOLD I were >12 years old and received 20-50 IU/kg BAY 81-8973 prophylaxis twice-weekly (2×W) or three times a week (3×W) for up to one year. Patients in LEOPOLD Kids were ≤12 years old and received 25-50 IU/kg BAY 81-8973 ≥2×W for six months. Dosing regimens for both studies were assigned by the investigator. In this analysis, efficacy and safety are assessed in the subset of patients in LEOPOLD I Part B and LEOPOLD Kids who were previously treated with FVIII-FS. Results In LEOPOLD I, 22 (35.5%) patients were previously treated with FVIII-FS with a median age of 27.0; in LEOPOLD Kids, 24 (47.1%) patients were previously treated with FVIII-FS with a median age of 5.0 (Table 1). In general, these switch cohorts had similar patient demographics to the whole study cohort (Table 1) and any differences did not affect the final analysis. Most patients did not change their dosing frequency when starting treatment with BAY 81-8973 but most increased their dose (FVIII-FS dose is 25 IU/kg 3×W [adults] or every other day [EOD; children]; BAY 81-8973 dose is 25-40 IU/kg 2×W or 3×W [>12 years] or 25-50 IU/kg 2×W, 3×W or EOD [≤12 years]). Switching from FVIII-FS to BAY 81-8973 resulted in lower median annualized bleeding rates (ABRs) in the LEOPOLD studies. In LEOPOLD I, median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) in the 12 months of FVIII-FS treatment prior to study entry, to 1.0 (0.0; 6.8) (Figure 1). In LEOPOLD Kids, median total ABR decreased from 3.0 (1.0; 12.0) to 2.0 (0.0; 6.0) for 0-<6 year old patients (n = 13) and from 4.0 (0.0; 10) to 0.0 (0.0; 2.1) for 6-12 year old patients (n = 11) after switching from FVIII-FS to BAY 81-8973 (Figure 1). Joint and spontaneous median ABRs were zero for <12 year old patients treated with BAY 81-8973. There were no study-drug-related adverse events (AEs) or serious AEs (SAEs) reported in patients switching from FVIII-FS to BAY 81-8973 in either LEOPOLD I Part B or LEOPOLD Kids (Table 2). One patient in the LEOPOLD Kids main study discontinued BAY 81-8973 due to a central venous catheter-related infection after six months of treatment, which was not considered study-drug-related. No FVIII inhibitors developed in any patients in either study. Conclusions Switching from FVIII-FS to BAY 81-8973 resulted in improved bleeding control in adults and children with hemophilia A and was well-tolerated. Disclosures Kenet: PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Wicklund:Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire (Takeda): Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding.

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Safety of Exposure to Recombinant Activated FVII (rFVIIa) Doses In Patients with Hemophilia and Inhibitors (CHwI) to Factors VIII or IX.

Blood ◽

10.1182/blood.v116.21.3675.3675 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3675-3675 ◽

Cited By ~ 1

Author(s):

Amy D. Shapiro ◽

Ellis J. Neufeld ◽

David L. Cooper

Keyword(s):

Clinical Trials ◽

Single Dose ◽

Research Funding ◽

Prophylactic Treatment ◽

Data Sources ◽

On Demand ◽

Frequency Of Use ◽

The Us ◽

Bleeding Episodes ◽

Higher Doses

Abstract Abstract 3675 Background: The FDA-approved label for recombinant FVIIa (rFVIIa), for treatment of bleeding episodes and prevention of bleeding in surgical or invasive procedures in CHwI patients, recommends initial dosing with 90 mcg/kg as a bolus injection. Patients typically require 2–3 injections for bleed resolution. Based upon three clinical trials comparing a single dose of 270 mcg/kg to 3 doses of 90 mcg/kg, the single-dose 270 mcg/kg rFVIIa regimen was approved by the EMA in March 2007 for treatment of mild-to-moderate bleeds in hemophilic inhibitor patients. Published reports indicate that rFVIIa dosing utilized in clinical practice varies widely. Furthermore, the broad adoption of home treatment makes it difficult to estimate how frequently higher doses (doses > 90 mcg/kg) are used, particularly in the US, and whether or not higher doses pose safety concerns, namely development of thromboembolism. Objectives: To report the frequency of use of higher doses of rFVIIa for on-demand or prophylactic treatment in clinical trials and registries that included safety monitoring, particularly for occurrence of thromboembolic events (TEs). Methods: Data for on-demand treatment of bleeds with rFVIIa in patients with CHwI, were obtained from two published, prospective, randomized studies, one prospective, observational diary study in the US, and the ongoing US-based Hemophilia and Thrombosis Research Society (HTRS) registry database. Data on prophylactic use of rFVIIa in patients with CHwI were obtained from a published, prospective, randomized trial. Information on demographics, rFVIIa dosing, and frequency of TEs were collected and reported using descriptive statistics. Results: A total of 232 CHwI patients reported 20,496 rFVIIa doses administered either for on-demand treatment of 2,286 bleeding episodes or prophylactic treatment for 1,885 days. The majority (81%) of patients were diagnosed with hemophilia A and reported an inhibitor titer range of 0.5 – 20,000 BU, and 9% of patients were diagnosed with hemophilia B. Whites comprised 72% of patients for whom race information was available. Patient age ranged from < 1 year to 62 years, and adults (>18 years old) comprised 37% of the patients studied. All five data sources included use of rFVIIa doses > 90 mcg/kg, the dose recommended in the current US label. Doses of rFVIIa > 120 mcg/kg, > 160 mcg/kg and >240 mcg/kg comprised 40.2% (8,232 doses), 25.9% (5,316 doses) and 8.0% (1,644 doses), respectively, of the 20,496 doses administered to all patients, and comprised 30.8% (1,171 doses), 27.3% (1,037) and 12.1% (460), respectively, of the 3,800 doses administered specifically to adults (>18 years old). No TEs were reported across the five data sources irrespective of the dose administered. Conclusions: A comprehensive review of data of over 20,000 rFVIIa doses used for either prophylactic or on-demand treatment of bleeding episodes demonstrates the frequent use and safety of rFVIIa doses above the US FDA-approved dose. The absence of TEs in 8,232 higher doses (i.e. doses > 120 mcg/kg, including 460 doses > 240 mcg/kg in adults) suggests TEs are likely uncommon at doses up to 300 mcg/kg, and reaffirm the low TE incidence (0.2%) reported in CHwI trials at standard doses (≤ 90 mcg/kg). Substitution of fewer high doses in place of more frequent lower doses may provide improved compliance and avoid the need for short interval repetitive dosing. Evaluation of additional data sources such as the ongoing European ONE Registry, the recently completed PRO-PACT study (retrospective global chart review for assessment of prophylactic treatment), UKHCDO, and other global registries in countries where 270 mcg/kg dosing has been approved for clinical use, will enlarge the current data set and provide even better estimates of the frequency of use of higher doses of rFVIIa and occurrence of TEs across a larger, more global population. Disclosures: Shapiro: Novo Nordisk: Consultancy. Off Label Use: rFVIIa dosing for approved indications above the PI recommendations. Neufeld:Novo Nordisk: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Cooper:Novo Nordisk Inc.: Employment.

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Coagulation Factor Activity Level and Clinical Bleeding Severity in Rare Bleeding Disorders: Results From the European Network of Rare Bleeding Disorders (EN-RBD),

Blood ◽

10.1182/blood.v118.21.3312.3312 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3312-3312

Author(s):

Flora Peyvandi ◽

Roberta Palla ◽

Marzia Menegatti ◽

Simona M Siboni ◽

Susan Halimeh ◽

...

Keyword(s):

Research Funding ◽

Linear Regression Analysis ◽

Strong Association ◽

Coagulation Factor ◽

Activity Level ◽

Clotting Factor ◽

Bleeding Disorders ◽

Factor Activity ◽

European Network ◽

Bleeding Severity

Abstract Abstract 3312 The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practice in the care of patients with RBDs (rare bleeding disorders frequency <1/0.5-2M). The aim of this first report was to explore the relationship between the coagulation factor activity levels and clinical bleeding severity in patients with RBDs. A total of 592 records on patients with RBDs were cross-sectionally collected over a period of three years. Data on clinical bleeding episodes were available for 495 patients and were classified into four categories according to severity. The mean age of patients was 31 years (range, 7 months-95 years), with 51% being females. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F)FX, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. It is of clinical relevance to identify levels that are not associated with spontaneous major bleeding, which was done by constructing receiver operating characteristic curves. These levels were highest for FXIII deficiency (25 U/dl), followed by FV+VII (15 U/dl), FVII (15 U/dl), FX (5 U/dl), and FV (1 U/dl) deficiencies. For fibrinogen deficiency, a factor activity level of 20 mg/dl is needed to ensure absence of major spontaneous bleeding. There is a clear relation between coagulation factor activity level and clinical bleeding severity in RBDs, which is different for the missing clotting factor. Disclosures: Peyvandi: NovoNordisk, CSL Behring: Honoraria. Bidlingmaier:CSL Behring, Bayer Schering: Research Funding; CSL Behring, NovoNordisk, Pfizer, Bayer Schering: Membership on an entity's Board of Directors or advisory committees; Baxter, Biotest, CSL Behring, NovoNordisk, Pfizer, Bayer Schering: Honoraria. Schved:LFB, CSL Behring, Novonordisk, Bayer Schering: Research Funding.

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Pharmacokinetics, Efficacy and Safety of BAX326, a Novel Recombinant Factor IX: A Prospective, Controlled, Multicenter Study in Previously Treated Patients with Severe (FIX Level < 1%) or Moderately Severe (FIX Level ≤ 2%) Hemophilia B.

Blood ◽

10.1182/blood.v120.21.2222.2222 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2222-2222

Author(s):

Jerzy Windyga ◽

Toshko Lissitchkov ◽

Oleksandra Stasyshyn ◽

Vasily Mamonov ◽

Luminita Rusen ◽

...

Keyword(s):

Research Funding ◽

Prophylactic Treatment ◽

Hemophilia B ◽

Control Group ◽

On Demand ◽

Previously Treated ◽

Bleeding Episodes ◽

The Mean ◽

Hemostatic Efficacy ◽

Level 2

Abstract Abstract 2222 Hemophilia B is a congenital X-linked bleeding disorder whose severity is associated with diminished or absent levels of circulating FIX. Treatment with regular prophylactic FIX infusions has significant medical and quality of life benefits by maintaining adequate plasma levels of FIX for hemostasis approximating a non-diseased state. BAX326 nonacog gamma is a novel recombinant FIX (rFIX) that is manufactured without the addition of any materials of human or animal origin, and viral inactivation/reduction is achieved through solvent/detergent (S/D) treatment as well as 15nm nanofiltration. Pharmacokinetics, hemostatic efficacy and safety of BAX326 were assessed in a prospective clinical trial in patients aged 12 to 65 years with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B, previously treated with plasma-derived and/or recombinant FIX concentrates. PK parameters were compared with a commercially-available rFIX used as an active control in a crossover design. Hemostatic efficacy of BAX326 administered twice weekly as prophylaxis was compared with a historical control group treated on-demand. A total of 86 patients were enrolled and 73 were treated with BAX326. All subjects treated had previous exposure to a FIX concentrate for ≥ 150 days prior to entry into the study. Subjects included in the PK analysis (n=28) received one 75 ± 5 IU/kg infusion with BAX326 and one infusion with commercial rFIX in random order prior to receiving prophylactic treatment at a dose range from 40 to 60 IU/kg two times a week with BAX326. An additional 31 subjects also received prophylactic treatment (21–67 exposure days), and 14 subjects received BAX326 on-demand (5–25 exposure days). More than 70% of subjects had 50 or more exposure days to BAX326 during the study. PK equivalence between BAX326 and the comparator rFIX was confirmed as the 90% confidence intervals of the ratio (BAX326/comparator rFIX) of the geometric mean of AUC 0–72 h/dose (1.063 [1.03; 1.09]) was fully contained in the margins for equivalence (0.8 to 1.25). The mean half-life (T1/2) of BAX326 was 26.70h ± 9.55, and incremental recovery (IR) was 0.87 ± 0.22 IU/dL: IU/kg. Repeated PK analysis after 6 months of prophylactic treatment confirmed the results of the initial values. Twice weekly prophylactic treatment with BAX326 was effective in preventing bleeding episodes, with a significantly lower (79%, p<0.001) annualized bleed rate (ABR) during prophylaxis (mean ABR 4.20) compared to an on-demand treatment in a historical control group (mean ABR 20.0). Among the 56 subjects on prophylaxis, 24 subjects (43%) did not bleed; the mean ABR for joint bleeds was 2.79, and 1.70 for spontaneous bleeds. Of 238 total acute bleeds, 201 (84.4%) were controlled with 1–2 infusions of BAX326. Hemostatic efficacy at resolution of bleed was rated excellent or good in 95.4% of all treated bleeding episodes. The efficacy as related to degree of severity of bleeding episodes was excellent or good in 96.8 % of minor bleeds, 95 % of moderate bleeds and 92.9 % of major bleeding episodes. BAX326 was safe and well-tolerated, with similar adverse reaction rates to the comparator rFIX. The safety assessments demonstrate the safety and tolerability of BAX326 in patients with moderately severe or severe hemophilia B. There were no product related SAEs, no inhibitory or binding FIX antibodies, no antibodies to CHO, and no allergic reactions or thrombotic events; AEs considered related to BAX326 (dysgeusia and pain in extremity) were transient and mild, and occurred with an overall incidence of 2.7%. There were no treatment-related AEs within 24 hours after infusion. Elevated pre- and post-infusion values for thrombogenic markers (TAT, F1.2 and D-dimer) in some subjects did not reveal any pattern indicative of clinically relevant thrombogenicity with either BAX326 or the comparator rFIX, and were not associated with AEs. These data indicate that BAX326 is safe and efficacious in treating bleeding episodes and in routine prophylaxis in patients aged 12 years and older with hemophilia B. None of the historical risk factors, such as hypersensitivity reactions, inhibitor formation or thrombotic events were observed and few related adverse events occurred. Disclosures: Windyga: Baxter: Research Funding. Lissitchkov:Baxter: Research Funding. Stasyshyn:Baxter: Research Funding. Mamonov:Baxter: Research Funding. Rusen:Baxter: Research Funding. Lamas:Baxter: Research Funding. Oh:Baxter: Employment. Chapman:Baxter: Employment. Fritsch:Baxter: Employment. Pavlova:Baxter: Employment. Wong:Baxter: Employment. Abbuehl:Baxter: Employment.

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Natural History Of Hemophilic Joint Disease Using Sensitive Imaging With Magnetic Resonance Imaging (MRI)

Blood ◽

10.1182/blood.v122.21.209.209 ◽

2013 ◽

Vol 122 (21) ◽

pp. 209-209

Author(s):

Thomas J Glorioso ◽

John M Kittelson ◽

Michael L Manco-Johnson ◽

Bjorn Lundin ◽

Walter Hong ◽

...

Keyword(s):

Natural History ◽

Board Of Directors ◽

Research Funding ◽

Healthcare Research ◽

Rate Of Change ◽

Advisory Committees ◽

On Demand ◽

Age Related ◽

History Of ◽

Bleeding Episodes

Abstract Introduction Arthropathy, the most costly chronic complication of severe hemophilia A (HemA) can be prevented by routine replacement of factor VIII (FVIII) when initiated prior to joint bleeding (primary prophylaxis) [NEJM;357:535]. However, the efficacy of prophylaxis initiated after the onset of recurrent hemarthroses or with established arthropathy (secondary or tertiary prophylaxis) is unknown. This individual patient meta-analysis was performed to derive the natural history of arthropathy in HemA patients treated only in response to acute bleeding (on demand therapy) as a baseline for future work to estimate the amelioration of arthropathy attributable to secondary or tertiary prophylaxis. Methods Data from individual participants in 3 studies who received on demand therapy were aggregated into a single database. Eligibility for this analysis included FVIII ≤ 2%, negative history for inhibitor, bleeding history for 12 months prior to study data acquisition and assessment of both ankles, knees and elbows; joints were assessed using physical examination (PE) and T2* gradient echo MRI scored as previously described using the World Federation of Hemophilia Gilbert score and the 45 point extended MRI scales [Haemophilia;6:649; ISTH OP Mon 7/1/13, 9 am]. MRI data were divided into soft tissue and osteochondral changes. Bleeding and Gilbert data for all 6 joints and MRI data for knees and ankles were analyzed using standard descriptive statistics and regression methods to quantify the rate of change in scores of joint damage with age. Results The 3 studies included the Joint Outcome Study [NEJM;357:535] and the JOS Continuation Study (JOSc), the Spinart Study baseline results [JTH;11:1119] and a Cross-Sectional MRI study [Haemophilia;189 Suppl3:117]. The 3 studies provide data on 275 individuals aged 1 to 50 years. Clinical, Gilbert and MRI data were extracted and analyzed from multiple joints in each of 157 individuals who were receiving on-demand treatment only. The median age was 21 (range 1 – 50), and across all studies the median number of bleeding episodes in the prior 12 months was 18 (range 0 to 82). The rate of change in outcomes as a function of age is shown in Table 1 and Figure 1. The number of bleeding episodes was approximately constant at 20 bleeding episodes per year regardless of age (Figure 1a; p = 0.72 for relationship with age). Gilbert scores showed a steeper rise in young patients but did not increase after the late teens (Figure 1b; change of 0.34 Gilbert points/year of life, p=0.07). MRI scores, in contrast to bleeding rates and Gilbert scores, showed continued age-related deterioration (Figure 1c; change of 2 MRI points/year of life, p < 0.0001). Age-related total and osteochondral deterioration on MRI increased steadily with age (on average 2 MRI-points/year of age, p < 0.0001 for each), whereas soft tissue scores increased rapidly to approximately 9 by age 20, and then plateaued at a score of approximately 10 for ages 20-50 (0.08 MRI points/year, p =0.28). Conclusions Individual patient meta-analysis of bleeding frequency, joint PE and MRI joint structure was useful to determine the natural history of hemophilic arthropathy in patients treated with on-demand therapy, and showed a continuous increase in joint bone and cartilage abnormalities across the age span despite an early leveling in bleeding rate and joint physical function. These data will be critical to determine the quantitative effects of prophylaxis on mitigation of joint deterioration when initiated at various ages following the onset of joint bleeding. Disclosures: Manco-Johnson: Bayer HealthCare: Research Funding. Lundin:Bayer HealthCare: Research Funding. Hong:Bayer HealthCare: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Manco-Johnson:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding; NovoNordisk: Membership on an entity’s Board of Directors or advisory committees; Eisai: Research Funding.

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Characteristics of Patients without Bleeding in a Pivotal Trial of Extended Half-Life, Pegylated, Full-length Recombinant Factor VIII (BAX 855) in the Treatment of Hemophilia A

Blood ◽

10.1182/blood.v126.23.1105.1105 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1105-1105

Author(s):

Alice D. Ma ◽

Robert Klamroth ◽

Marilyn J. Manco-Johnson ◽

Werner Engl ◽

Jacqueline A Dyck-Jones ◽

...

Keyword(s):

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Prophylactic Treatment ◽

Employment Equity ◽

Advisory Committees ◽

On Demand ◽

Bleeding Episodes ◽

Equity Ownership ◽

The One

Abstract BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE (rFVIII) with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In the pivotal trial, previously treated patients (PTPs) received BAX 855 prophylaxis with a twice-weekly 45 IU/kg dosing regimen. Of 101 patients in the per protocol analysis set, 40 (39.6%) patients achieved zero bleeding during 6 months of prophylactic treatment with BAX 855, compared with the on-demand treatment arm in which every patient (n=17) experienced at least 1 bleeding episode. Pharmacokinetic parameters were assessed in a subset of patients with zero bleeding (n=9). Assessments were performed for rFVIII, for an initial infusion of BAX 855 and for a repeat infusion of BAX 855 after 6 months of treatment. Using the one-stage clotting assay, BAX 855 demonstrated an extended circulation time compared to rFVIII with a mean (standard deviation [SD]) half-life (T1/2) of 16.13 (3.827) hours vs 11.44 (2.250) hours (ratio BAX 855/rFVIII: 1.4). Over time, the 6 month assessment of BAX 855 T1/2 remained stable at 16.30 (3.137) hours (ratio repeat/initial BAX 855: 1.0), based on the one-stage clotting assay. Incremental recovery (IR) measurements were comparable with 2.41 (0.454) IU/dL for rFVIII and 2.62 (0.684) IU/dL for BAX 855. As expected, clearance (CL) was higher for rFVIII compared to BAX 855: 0.0380 (0.009) vs 0.0205 (0.007) dL/(kg*h). Historical annualized bleeding rates (ABRs) in the 40 patients without bleeding during prophylactic treatment were calculated based on the previous 3-6 months of each patient's diary or recall. Historical ABRs ranged from 0-80 with a median ABR of 7. However, patients may have either been receiving on demand or prophylactic FVIII treatment prior to entering the prophylactic arm of the trial, accounting for the range in ABRs. The median pre-trial ABR of patients in the on-demand arm, all of whom experienced bleeding, was much higher at 41.5 (range: 12.9-67.9). Of the 40 patients without bleeding who were in the prophylaxis arm of the trial, 31 received prophylaxis in their previous pre-trial regimen, while 9 had received on-demand treatment prior to enrolling in the trial. A target joint was defined as a single joint (ankles, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period. At screening, 30% of patients without bleeding on the study had 0 target joints, while 37.5% had 1-2 and 32.5% had ≥3 target joints. Of the patients who had >3 target joints at screening, there were 4 (10%) patients with 4 and 1 (2.5%) patient with 6 target joints at screening. In contrast, patients in the on-demand group (who had all been treated on-demand prior to the trial) had a higher incidence of target joints at screening: 11.8% of patients had 0 target joints, while 52.9% had 1-2 and 28.3% had ≥3 target joints. The presence or absence of preexisting arthropathy did not seem to influence the likelihood of having zero bleeding during the trial. In 65% of the patients without bleeding, arthropathy was present at screening. This is higher than was found in the patients treated on-demand (47.1%) who all experienced bleeding. A patient was considered to have arthropathy if it was indicated in the medical history or if the patient had joint surgery. Blood group types were collected on the patients without bleeding. The results showed: A-50%; B-12.5%; AB-7.5%; O-15%; unknown 15%. This is rather different than the blood types of the 17 on demand patients who all experienced joint bleeding: A-35.3%; B-5.9%; AB-17.6%; O-35.3%; unknown 5.9%. There were fewer blood group O patients among the patients without bleeding. While some of the characteristics of patients on prophylaxis without bleeding episodes were similar to those of patients treated on-demand who all experienced bleeding, patients without bleeding had fewer target joints at screening, lower median historical ABR, and lower incidence of blood type O. Disclosures Ma: Kedrion: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Klamroth:Biogen and SOBI: Honoraria, Speakers Bureau; Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau. Manco-Johnson:Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Engl:Baxalta: Employment, Equity Ownership. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

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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

Blood ◽

10.1182/blood-2020-139910 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 40-41

Author(s):

Amy D Shapiro ◽

Giancarlo Castaman ◽

Katarina Cepo ◽

Sidsel Marie Tønder ◽

Tadashi Matsushita ◽

...

Keyword(s):

Board Of Directors ◽

Dose Level ◽

Research Funding ◽

Main Part ◽

Prophylactic Treatment ◽

Phase 2 ◽

Advisory Committees ◽

On Demand ◽

Term Efficacy ◽

Bleeding Episodes

Introduction Concizumab is a high-affinity, anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody currently in clinical investigation for the once-daily subcutaneous prophylactic treatment of patients with hemophilia. We present results from the combined main and extension parts (at least 76 weeks) of the phase 2 explorer4 trial (NCT03196284), which aimed to assess the safety and longer-term efficacy of concizumab in patients with hemophilia A with inhibitors (HAwI) and hemophilia B with inhibitors (HBwI). Methods explorer4 comprised a main part, which lasted at least 24 weeks for all patients, and an extension part, which lasted at least 52 weeks. The primary objective of the main part of explorer4 was to assess the efficacy of concizumab in preventing bleeds in patients with HAwI/HBwI, evaluated as annualized bleeding rate (ABR) at the last dose level after at least 24 weeks. This objective has been addressed in previous reporting of the main part of the trial (Shapiro A, et al. Blood 2019; 134[22]:1973-1982). During the main part of the trial, patients were randomized 2:1 to receive either concizumab prophylaxis or on-demand treatment with recombinant activated factor VII (rFVIIa). At the end of the main part, patients in the rFVIIa on-demand arm were switched to 0.15 mg/kg concizumab for the extension part. Concizumab dose was escalated to 0.20 and 0.25 mg/kg in both the main and extension parts if a patient experienced ≥3 treated spontaneous bleeding episodes within 12 weeks and if deemed safe by the investigator. The objective of the extension part of the trial was to assess safety and longer-term efficacy of concizumab. Endpoints included ABR after at least 76 weeks of treatment, concizumab and free TFPI concentrations prior to last dose administration at 76 weeks, number of adverse events (AEs) and occurrence of anti-drug antibodies (ADAs) during 76 weeks of treatment. ABR was estimated using LS-means estimates, based on a negative binomial regression with log of exposure time to concizumab in main and extension part as offset. Results Twenty-five patients with inhibitors were exposed to concizumab during the explorer4 trial; 15 with HAwI and 10 with HBwI. Eight of these patients received on-demand treatment with rFVIIa during the main part of the trial before receiving their first concizumab dose in the extension phase. The estimated ABR at the last dose level for all patients treated with concizumab during the main and extension parts was 4.8 (95% CI: 3.2-7.2), while during the trial this was 5.7 (95% CI: 4.2−7.8) (Table 1). During the main and extension parts, 4 (16%) patients had zero treated bleeding episodes on their last dose level. Plasma concentrations of concizumab were variable during the extension part of the trial (Table 2). Increased concizumab concentration was observed in patients who received concizumab 0.20 mg/kg; these patients also had lower concentrations of free TFPI (Table 2). There were no AEs leading to withdrawal, no thromboembolic events and no deaths during the main and extension parts of the trial. ADAs developed in 6 patients. Elevated prothrombin fragment 1+2 and D-dimer levels were observed in some patients treated with concizumab. Conclusions Results from the combined main and extension parts of the phase 2 explorer4 trial were in line with the clinical proof of concept established in the main part of the trial and provided further details of the safety and longer-term efficacy of subcutaneous prophylactic treatment with concizumab for at least 76 weeks in patients with HAwI and HBwI. Disclosures Shapiro: BioMarin: Research Funding; Agios: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Catalyst BioSciences: Membership on an entity's Board of Directors or advisory committees; Sangamo: Research Funding; OPKO: Research Funding; Daiichi Sankyo: Research Funding; Sigilon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion Biopharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk Hemophilia Foundation: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Glover Blood Therapeutics: Research Funding; Octapharma: Research Funding; Pfizer: Research Funding; ProMetic Bio Therapeutics: Consultancy, Research Funding. Castaman:Uniqure: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ablynx: Honoraria; Alexion: Honoraria; Bayer: Honoraria; Baxalta/Shire: Honoraria; Sobi: Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Speakers Bureau; Werfen: Speakers Bureau; Kedrion: Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau. Cepo:Novo Nordisk: Current Employment. Marie Tønder:Novo Nordisk: Current Employment. Matsushita:Sysmex: Honoraria; Octapharm: Honoraria; Bayer: Consultancy, Honoraria; Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Shire/Takeda: Honoraria; Bioverative/Sanofi: Honoraria; CSL: Honoraria; JB: Honoraria; KMB: Honoraria; Kirin: Honoraria; Nichiyaku: Honoraria. Young:Bayer, CSL Behring, Freeline, UniQure: Consultancy; BioMarin, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Sanofi Genzyme, Spark, Takeda, and UniQure: Honoraria; Genentech/Roche, Grifols, and Takeda: Research Funding. Zupancic-Šalek:NovoNordisk Health Care AG: Honoraria, Speakers Bureau; Baxter: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Octapharma: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Sobi: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau. Jimenez Yuste:NovoNordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Honoraria; Sobi: Consultancy, Honoraria, Research Funding; CSL: Honoraria; Octapharma: Honoraria.

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Modelling FVIII Levels for Prediction of Zero Spontaneous-Joint Bleeding in a Cohort of Severe Hemophilia a Subjects with Target Joints Initiated on Tertiary Prophylaxis

Blood ◽

10.1182/blood.v128.22.2576.2576 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2576-2576 ◽

Cited By ~ 2

Author(s):

Kathelijn Fischer ◽

Pratima Chowdary ◽

Peter Collins ◽

Amy Cotterill ◽

Barbara Konkle ◽

...

Keyword(s):

Research Funding ◽

Median Number ◽

Activity Level ◽

Severe Hemophilia ◽

On Demand ◽

Kaplan Meier ◽

Fviii Activity ◽

Equity Ownership ◽

Post Hoc ◽

Trough Levels

Abstract Background Prophylaxis is increasingly the standard of care for adults with severe hemophilia A (SHA), however the optimal dose and treatment regimen when initiating tertiary prophylaxis is unknown. The relationship between factor level and risk of bleeding is not established, particularly in patients with joint disease. A post hoc analysis was conducted on a cohort of adult SHA patients who switched to prophylaxis from on demand therapy. Methods The cohort included 63 subjects with measured factor VIII (FVIII) levels of <1 IU/dL, aged 7 to 59 years, receiving on-demand treatment and with a minimum of eight joint hemorrhages in the 12 months prior to enrollment. After 6 months observation of on demand treatment and a full pharmacokinetic (PK) analysis, subjects were randomized to 12 months of either standard prophylaxis (20-40 IU kg−1 every 2nd day) or PK-tailored prophylaxis (20-80 IU kg−1 every 3rd day) targeting FVIII trough levels ≥1 IU/dL. Subjects had a median age of 28 years, and median weight of 71Kg. At study start, 95.2% of subjects had ≥1 target joints (median 3). During on demand treatment before randomization, the median number of spontaneous-joint bleeds was 29.9/year (range: 0 to 91.3). During prophylaxis, the median number of spontaneous-joint bleeds was 0/year (range: 0 to 10.2) in the combined prophylaxis groups. A PK model was fitted to the FVIII activity levels collected during the PK analysis for each subject independently. These individual models were used to predict the FVIII activity level at the time of bleed on the assumption of linear pharmacokinetics and no inter-occasion variability. For each subject the highest FVIII activity level associated with a spontaneous-joint bleeding event was considered as the minimally effective level to prevent spontaneous-joint bleeds. A Kaplan-Meier estimate for the proportion of subjects with no spontaneous-joint bleeds above FVIII activity level was carried out. For subjects who had no spontaneous-joint bleeding events an assumption was made that they would have bled only at 0 IU/dL, even in situations where the trough levels may have been higher. Results The Kaplan-Meier curve for proportion of the cohort without spontaneous-joint bleeds as function of predicted FVIII level is presented in Figure 1. The corresponding estimates are presented in Table 1. Based on this analysis in this cohort, the majority of patients (63%) would not be expected to have spontaneous-joint bleeds while maintaining a trough level of 1 IU/dL with more marginal improvements in response to higher FVIII levels. These results indicate that, in subjects with multiple target joints starting tertiary prophylaxis, most experience no spontaneous-joint bleeds for a predicted FVIII level ≥1 IU/dL, however, bleeds occurred at much higher predicted FVIII levels in some subjects. This is within the range of FVIII levels associated with hemophilia (0-40%) (White GC, et al. Thromb Haemost. 2001 Mar; 85(3):560). Conclusion The results of the model and the present post-hoc analysis support current trends to personalize prophylaxis based on individual variations in bleeding phenotypes, despite similar FVIII levels. To prevent all spontaneous-joint bleeds, some patients may require higher levels, findings which are congruent with those published on the natural history of joint bleeding in mild, moderate, and severe hemophilia patients (Den Uijl IE et al. Haemophilia. 2011;17(6):849-853). Disclosures Fischer: Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Chowdary:Sobi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Biogen Idec: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria; Bayer: Honoraria. Collins:NovoNordisk: Consultancy; Sobi: Consultancy; CSL Behring: Consultancy, Research Funding; Shire: Consultancy, Speakers Bureau. Cotterill:Shire: Employment. Pipe:UniQure: Consultancy; Pfizer: Consultancy; Genentech/Roche: Consultancy; Biogen: Consultancy; CSL Behring: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy, Other: Grant funding. Wolfsegger:Shire: Employment, Equity Ownership. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Goldstine:Shire: Employment. Valentino:Shire: Employment. Spotts:Shire: Employment.

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On-Demand Treatment of Bleeding Episodes in Patients with Hereditary Factor X Deficiency Using a High-Purity Factor X Concentrate: Data from 2 Clinical Trials and a Data-Collection Study

Blood ◽

10.1182/blood-2018-99-111397 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1215-1215

Author(s):

James N. Huang ◽

Chioma Akanezi ◽

Amy Shapiro

Keyword(s):

Data Collection ◽

Board Of Directors ◽

Research Funding ◽

Perioperative Management ◽

Factor X ◽

Open Label ◽

Phase 3 ◽

Advisory Committees ◽

On Demand ◽

Bleeding Episodes

Abstract Introduction: Hereditary factor X (FX) deficiency is a rare bleeding disorder characterized by spontaneous joint, mucosal, and muscle bleeds as well as intracranial hemorrhage. Women and girls may also experience menorrhagia. In the past, hereditary FX deficiency has been treated with fresh frozen plasma or a prothrombin complex concentrate, both of which contain variable amounts of FX. Plasma-derived FX (pdFX) is a high-purity FX concentrate approved in the United States for on-demand treatment of patients with hereditary FX deficiency aged 12 years and older and for perioperative management of bleeding in patients with mild hereditary FX deficiency. pdFX is approved in the European Union for treatment and prophylaxis of bleeding episodes as well as perioperative management in patients with hereditary FX deficiency. Objectives: To present efficacy and safety data from 2 phase 3 clinical studies and 1 data-collection study evaluating pdFX for on-demand treatment of bleeds in patients with hereditary FX deficiency. Methods: Results from 2 phase 3 clinical studies and 1 data-collection study of patients with severe (FX activity [FX:C] <1 IU/dL) or moderate (FX:C 1-5 IU/dL) FX deficiency are included. TEN01 was a prospective, open-label, multicenter, nonrandomized study of subjects aged ≥12 years. Bleeds were treated with an initial dose of 25 IU/kg pdFX followed by additional doses as needed. TEN02 was a prospective, open-label, multicenter, nonrandomized study in children less than 12 years old. In TEN01 and TEN02, pdFX efficacy was assessed as excellent, good, poor, or unassessable. TEN05 was a retrospective, multicenter data-collection study in patients of any age who received ≥1 dose of pdFX on a compassionate-use basis. Investigators retrospectively rated pdFX treatment of bleeds as effective (with hemostasis achieved with the expected number of doses for the severity of the bleed), not effective, or unknown. In TEN05, dosing was at the discretion of the investigator. All protocols were approved by each center's local or national independent ethics committee. All subjects provided written informed consent prior to enrollment. Results: A total of 19 subjects were analyzed from the 2 prospective clinical trials; 12 of these subjects were also included in the retrospective data-collection study. Ages ranged from 1 to 58; 16 of 19 patients were aged ≥12 years. FX deficiency was severe in 17 patients and moderate in 2 patients. During the studies, 326 bleeds were reported, with a median of 12 (range 1-59) bleeds per patient in TEN01, 4 (1-5) bleeds per patient in TEN02, and 5.5 (2-26) bleeds per patient in TEN05. Of these 326 bleeds, 270 bleeds in 18 subjects were treated with pdFX and evaluated. Severity was major for 108 bleeds, minor for 116 bleeds, and not rated for 46 bleeds. Reported bleed causes were menorrhagia (n=97), spontaneous (n=93), trauma or injury (n=75), other (n=3), and unknown (n=2). Bleed locations were mucosal (n=117), joint (n=79), muscle (n=38), other (n=30), and unknown (n=6). Most bleeds (n=230, 85.5%) were treated with a single pdFX infusion (the maximum number of infusions for a single bleed was 12). The total factor dose per bleed per subject ranged from 7.92 to 82.0 IU/kg, with a median of 25.0 IU/kg in TEN01, 31.7 IU/kg in TEN02, and 23.8 IU/kg in TEN05. Treatment effectiveness was assessed by investigators as excellent or good in 43 of 44 rated bleeds (97.7%) in TEN01 and TEN02. One was rated poor in TEN01. In TEN05 pdFX was reported as effective in all 79 rated bleeds (100%). In TEN01, 6 adverse events in 2 patients were reported as related or possibly related to pdFX treatment; all were mild or moderate. No adverse events in TEN02 were considered related or possibly related to pdFX treatment, and no adverse drug reactions or safety concerns were reported in TEN05. No thromboembolic events, inhibitor development, or hypersensitivity reactions were reported in the 3 studies. Conclusions: Across 3 studies, pdFX was rated as effective at treating a variety of bleeds in patients with FX deficiency. Only one dose of pdFX was needed to treat most (85.5%) bleeds. At the doses used in these studies, on-demand pdFX treatment was well tolerated in pediatric and adult subjects. Disclosures Huang: Baxter: Research Funding; Biogen: Research Funding; Pfizer: Research Funding; Novartis: Other: support to attend meeting; Bio Products Laboratory: Other: Study Investigator. Akanezi:Bio Products Laboratory: Employment. Shapiro:BioMarin: Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; OPKO: Research Funding.

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