Research Studies

It is unknown if there are differences in attitudes and behaviors between mothers of sons with hemophilia who have a known family history of hemophilia compared to mothers without a known family history. To capture these differences, this study will measure mothers' perceived vulnerability of their sons, protective behaviors toward their sons and reported stress in the mother-son relationship. Sixty mothers will complete the following surveys: Parent Protection Scale, Child Vulnerability Scale and Parenting Stress Index/Short Form. The results of this data will influence clinic social work practice in the comprehensive care model at hemophilia treatment centers.

Dr. von Drygalski's research focuses on better understanding the mechanisms operating the anti-fibrinolytic system and how this process works in patients with hemophilia and specifically with joint bleeding. Accelerated fibrinolysis and clot instability are becoming increasingly recognized as contributing factors to bleeding in hemophilia. One important molecule that prevents fibrinolysis is called TAFI (Thrombin Activatable Fibrinolysis Inhibitor). Dr. von Drygalski will be studying the dual anti-fibrinolytic and anti-inflammatory functions of TAFI in hemophilia arthropathy and develop a therapeutic TAFI-based approach to improving the efficacy of FVIIa based bypassing strategies for acute bleeding and joint protection. Her mentors and collaborators are John H. Griffin, PhD, Laurent O. Mosnier, PhD and Martin Lotz, MD, distinguished researchers at UCSD -The Scripps Research Institute. Dr. von Drygalski received her M.D. from the Universities of Erlangen/Nurnberg and Munich in 1995 and her Pharm.D. from the University of Munich in 1988. She joined the faculty in July 2011 as Assistant Clinical Professor at UCSD and Director of the Adult Hemophilia and Thrombosis Treatment Center, Division of Hematology/Oncology, Department of Medicine. She also has an appointment as Adjunct Assistant Professor at the Scripps Research Institute (TSRI). The funding for this award is made possible thanks to a generous grant from Novo Nordisk.

Dr. Stacy Croteau received her B.S. and M.S. in Neuroscience, and her M.D. at Brown University, where she was awarded AOA. She was resident and chief resident in pediatrics at Boston's Children's Hospital and received the Sydney Farber Award. At the time of her application, she was a third year Pediatric Hematology-Oncology fellow at Boston Children's Hospital and was accepted on faculty at Harvard as an instructor in pediatrics. Her research during fellowship was on a clinical review of Kaposi form Angioendotheliomas which resulted in 2 publications in the Journal of Pediatrics (2013, and 2014) as well as an ASH Trainee Research Award. She was the first fellow to complete the BCH-Novartis Clinical Fellowship in Early Oncology Drug Discovery. While a NHF-Baxalta Clinical Fellow, Dr. Croteau will be mentored by Dr. Ellis Neufeld, Medical Director of the Boston Hemophilia Center. She also has plans to pursue clinical research in “rationally designed personalized prophylaxis regimens”.

Dr. Maissaa Janbain was born in Lebanon and received her M.D. degree from the Lebanese University in 1999. After completing her internship and residency in Internal Medicine in Lebanon, she came to the U.S., where she completed a second internship and residency in internal medicine at Case Western Reserve University in Ohio. She then entered the Hematology/Oncology Fellowship program at Tulane University, which she is scheduled to complete in 2015. Dr. Janbain has developed a strong interest in coagulation medicine and has spent much time receiving guidance from her mentor Dr. Cindy Leissinger, Director of the Louisiana Comprehensive Hemophilia Center. In conjunction with Dr. Leissinger, she has worked on clinical research projects for porcine rFVIII and FXIII. Dr. Janbain has not only had several research abstracts accepted but also presented at several professional meetings. She is interested in global assays and thromboelastometry. She has been applying this technique to assess FVIII and VWF in pregnant women.

The project's ultimate goal is to expand nursing knowledge of hemarthrosis/soft-tissue bleeding detection by presenting our HTC's experience with how MSKUS improves accurate diagnosis and guides treatment of bleeding and other pain etiologies. By completing the retrospective data review, we hope that the experience of a large center HTC spanning both adults and pediatrics will be made available. We believe that the current restraints of MSKUS implementation include cost of equipment, operator certification, and quality of interpretation to guide interventions. Therefore, partnering with radiology experts may be helpful for other HTCs around the country when using this modality in the future. Our center's experience will show that collaboration with radiologists for real-time imaging is successful with nursing evaluation and coordination.

Dr. Lindsey George is a pediatric hematology/oncology fellow at The Children's Hospital of Philadelphia. As a NHF-Baxalta Fellow, Dr. George will receive clinical training under the mentorship of Dr. Leslie Raffini, Director of the Hemophilia Treatment Center at The Children's Hospital of Philadelphia. She will also be pursuing training in translational science in coagulation molecular biology and gene transfer in the laboratory of Dr. Katherine High. Dr. George graduated from Cornell University and received her M.D. from the State University of New York at Buffalo School of Medicine. She did her pediatric residency and chief residency training at Weill Cornell Medical School, where she had the fortunate opportunity to interact with Dr. Donna DiMichele. Dr. George has a longstanding interest in the intricacies of coagulation physiology and the incorporation of that understanding to the clinical care of patients with coagulation disorders. Dr. George hopes to contribute to the improvement of treatment for patients with bleeding and thrombotic disorders through a career in translational research.

Background:

BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor (TFPI) developed as a bypass agent for hemophilia patients with inhibitors. It restores thrombin burst for stable clot formation in hemophilic conditions in vitro.

Aims:

The goal of this study was to elucidate the in vivo prophylactic hemostatic potency of BAY 1093884.

Methods:

The hemophilia A mouse tail vein transection model was used for this study to mimic the venous bleeding characteristics of severe hemophilia. Male hemophilia A mice (n=12/group) were treated prophylactically with escalating doses of BAY 1093884. All treatments were administered as single intravenous (IV) bolus at 4 different time courses prior to injury (1, 3, 5, and 7 days). Bleeding was induced by a 1.2-mm deep incision across the left lateral vein. Following injury, the animals were monitored hourly for moribundity for up to 9 hours and after 24 hours followed by euthanasia.

Results:

Efficacious doses of BAY 1093884 providing 50% protection for survival (ED50) for up to 6 days after IV bolus ranged from 0.6–2 mg/kg. In comparison, only 25% protection was achieved 6 days after the treatment with a very high dose of 1000 IU/kg of recombinant factor VIII (rFVIII). The effect of a single IV dose of 18 mg/kg BAY 1093884 providing 80%–90% survival was maintained over 8 days (ED50 6 mg/kg), whereas a single IV dose of rFVIII failed to provide protection over an 8-day period.

Conclusions:

These studies demonstrate that BAY1093884 prevents bleeding and increases long-term survival to a greater degree than rFVIII in hemophilia A mice and may offer a convenient prophylactic treatment option for hemophilia patients with inhibitors.

Background:

Activity limiting joint disease has greatly decreased with the introduction of prophylactic treatment for people with severe bleeding disorders. Previous research using the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2TM), a standardized, normative, age and sex matched test of motor development, suggested motor development of males aged 4-21 years with bleeding disorders may be lower than age-matched peers.

Objective:

The primary purpose of this study was to compare the gross motor proficiency of boys with hemophilia ages 4-21 years followed at the Hemophilia Center at Oregon Health & Science University utilizing the BOT-2. Secondarily, we examined the relationship between joint health and gross motor proficiency.

Methods:

1. a)  Participants and setting: Thirty-four subjects with either hemophilia A or B were recruited

   from our center. Data collection occurred during clinic visits or at the patients’ homes.

2. b)  Design and Procedures: A prospective, cross-sectional study design was used. The Upper Limb Coordination, Bilateral Coordination, Balance, Running Speed and Agility, and Strength subtests of the BOT-2 were administered. Body composition, range of motion, presence of an inhibitor, and use of prophylaxis were collected at the time of testing or from chart review.

3. c)  Analyses: Analysis of variance (ANOVA) modeling was used to compare BOT-2 scores of PWH with baseline BOT-2 scores estimated from the general population of comparable age.

Summary:

Mean Running Speed & Agility scores were greater among boys with hemophilia compared to the control population (p=0.0026). Agility scores were similar between boys with hemophilia A and B (p>0.60), and significantly greater compared to the control group (p=0.0153). No other significant differences were found comparing boys with hemophilia to the control group. Within the boys with hemophilia cohort, age-adjusted ANOVA found no significant differences in BOT-2 scores between subjects of different severities, treatment regimen (prophylaxis or episodic), or diagnoses (Hemophilia A or B).

Conclusion:

Boys with hemophilia have the same or better gross motor proficiency as age matched peers.

Objective:

Kids B-LONG was an open-label phase 3 study that evaluated the safety, efficacy, and pharmacokinetics (PK) of rFIXFc in previously treated children (aged <12 years; ≥50 prior exposure days [EDs] to FIX) with severe hemophilia B (≤2 IU/dL endogenous FIX) and no history of FIX inhibitors.

Methods:

Participants initiated prophylactic treatment with 50–60 IU/kg rFIXFc once-weekly; dose and interval adjustments were based upon PK data and bleeding frequency. The primary endpoint was development of inhibitors (neutralizing antibodies). Key secondary outcomes included PK and annualized bleeding rate (ABR).

Summary:

The study enrolled 30 participants (<6 years of age, n=15; 6 to <12 years of age, n=15); 90% completed the study. Prestudy, all participants received FIX prophylaxis (23/30 were dosing ≥2x/week). The median time on study was 49.4 weeks; 24 participants had ≥50 rFIXFc EDs. No participant developed inhibitors to rFIXFc. The pattern of adverse events reported was typical of the population studied. There were no serious allergic reactions and no thrombotic events. No serious adverse events were assessed by the investigator as related to rFIXFc. The terminal half-life (geometric mean [95% CI]) of rFIXFc was 66.5 (55.9, 79.1) hours in the <6 years cohort (n=11) and 70.3 (61.0, 81.2) hours in the 6 to <12 years cohort (n=13). The geometric mean (95% CI) half-life of prestudy BeneFIX was 18.2 (15.5– 21.3) hours in the <6 years cohort (n=11) and 19.2 (17.6–20.9) hours in the 6 to <12 years cohort (n=9). Median (IQR) ABR was 1.97 (0.00, 3.13) overall, and 0.00 (0.00, 1.16) for spontaneous bleeds; 33.3% of participants reported no bleeds on study. At study end, 97% of participants were dosing once weekly. The median (IQR) total weekly prophylactic dose with rFIXFc was 59.4 (53.0, 64.8) IU/kg and 57.8 (51. 7, 65.0) IU/kg, in the <6 years and 6 to <12 years cohorts, respectively. The prestudy FIX median (IQR) total weekly prophylactic dose was 110.0 (58.0, 188.0) IU/kg and 100.0 (58.0, 120.0) IU/kg in the <6 years and 6 to <12 years cohorts, respectively. 75.0% of bleeding episodes were controlled with 1 infusion; 91.7% with 1 or 2 infusions (median average dose per infusion: 68.22 IU/kg).

Conclusions:

rFIXFc was safe and effective for the prevention and treatment of bleeding in children with severe hemophilia B. Study participants achieved low bleeding rates with extended-interval rFIXFc prophylaxis, while reducing their weekly prophylactic factor consumption compared with their prior FIX regimen.

Objective:

To analyze real world rFVIIIFc patient characteristics and treatment interval patterns in patients with hemophilia A based on specialty pharmacy dispensing records.

Methods:

A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from July 2014 through Mar 2015. SPP data included 63 different attributes for each prescription, including trade name, NDC, quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received at least one shipment of rFVIIIFc for a prophylactic treatment regimen. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or pharmacy records did not specify a prescribed infusion dose. Patients were categorized according to their age and dosing interval.

Summary:

The analysis included 405 hemophilia A patients that received at least one shipment of rFVIIIFc with a median age of 23 (range: 2-68) and median weight of 70 kg (range: 10-154kg). Eight percent of dispensing records were for patients less than 6 years of age, 29% were between 6 and 17 years of age, and 63% were 18 years or greater. Pharmacy dispensing records represented 179 distinct prescribers across 40 states. Dosing frequency ranged from four times weekly to beyond once-weekly, with every four days as the most common dosing interval, representing 33% of patient records. The median infusion frequency was every four days. Fifty percent of all patients had a dosing frequency of four days or greater. Of the patients receiving rFVIIIFc that had previous rFVIII dispensing records, the most common rFVIII dosing frequency was three times per week. The majority of patients previously on prophylaxis regimen with a rFVIII dosing frequency of three times per week had a decreased number of prophylactic infusions per week on rFVIIIFc; 4% of patients reduced infusion frequency to every 3 days, 44% of patients reduced infusion frequency to twice weekly, 30% of patients reduced infusion frequency to every 4 days, 10% of patients reduced infusion frequency to every 5 days.

Conclusions:

Current SPP dispensing records demonstrate that rFVIIIFc is being used in a broad patient population based on age range and geographical distribution. Patients with hemophilia A in the US may experience reductions in FVIII infusion frequency when they switch to rFVIIIFc, with conversion to an infusion frequency every four days as the most common treatment regimen and the recommended prophylaxis starting dose according to the US Prescribing Information.

Background:

Arthropathy is one of the major complications in hemophilia, leading to functional limitations and poor quality of life. Exercise is recommended as being beneficial for people with hemophilia, yet a lack of exercise-related evidence using exercise and control groups exists in this population, compared to other joint pathologies (i.e. osteoarthritis).

Objective:

To evaluate effects of post-hemarthrosis exercise on: pain; swelling; bone density and joint damage, using an animal model.

Methods:

Twelve Wistar rats were divided into an Exercise Group (EG; n=6) and Control Group (CG; n=6). All rats received eight weekly intraarticular injections in their right knees with 0.1 mL autologous blood, and left knees with 0.1 mL saline solution. The EG performed an 8 wk swimming protocol (during the period of intraarticular injections) of 60 min (5x week) with 5% body weight attached on their tails. Pain status was assessed weekly with a static weight-bearing incapacitance test (SWIT). Joint diameters were measured post-protocol with a digital microcaliper. Bone mineral density was assessed using dual-energy X-ray absorptiometry (whole-body, tibia, femur and knee joint) pre and post-study. Following sacrifice, bilateral knee X-rays were taken and scored with Pettersson’s score. Resting heart rate and heart weight were registered post-study, as markers of physical training.

Results:

CG manifested decreased weight-bearing with SWIT, compared to EG (p<0.001). EG presented reduced joint swelling, compared to CG (p=0.034). Significant increase in bone mineral density variation (BMD∆) was observed at the tibia (p=0.016), and knee (p=0.018) of the EF compared to CG. The EG also showed a tendency of an increase in femoral BMD∆ compared to CG (p=0.09). Pettersson scores demonstrated increased bone destruction in the CG compared to EG (p=0.05).

Conclusion:

This is the first time that beneficial effects of a swimming exercise protocol on pain, swelling, bone density and radiologic changes have been shown in a blood-induced, joint damage animal model. Hopefully this data will provide clues for future study designs in this area.

Objective:

To evaluate efficacy of IB1001 with respect to breakthrough bleeding during prophylaxis and with respect to control of hemorrhaging in prophylaxis and on-demand treatment regimens in previously treated patients (PTPs) with hemophilia B.

Methods:

The efficacy of IB1001 has been evaluated in a prospective, open-label, uncontrolled multicenter international study in which a total of 68 male PTPs between 7 and 64 years of age received IB1001 either as prophylaxis or on-demand treatment. All subjects had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B without inhibitors. There were 61 subjects who received prophylaxis [predominantly secondary or tertiary prophylaxis as defined by World Federation of Hemophilia (WFH) guidelines] and 12 were treated on-demand during the study conduct. Both, the subjects and the study investigators rated the efficacy of IB1001 in management of bleeding episodes.

Summary:

The mean number of exposure days (ED) was 138.2 (median: 127.5 ED), including 55 subjects with ≥ 50 ED and 45 subjects with ≥ 100 ED. Subjects on prophylaxis received a mean intravenous dose of 55.0 ± 12.8 IU/kg IB1001 twice weekly, while subjects in the on- demand regimen received a mean dose of 60.0 ± 18.2 IU/kg IB1001. In the prophylaxis group, median annualized bleed rate (ABR) was 1.52, and in the on-demand group, median ABR was 16.39. There were 19/61 (31.1%) subjects on IB1001 prophylaxis who reported no bleeding episodes. A total of 508 bleeding episodes were treated with IB1001; 286 bleeds were recorded for patients on prophylaxis and 222 in the on-demand regimen. Majority of the bleeds (70.9%) resolved after a single IB1001 infusion, while 13% of the bleeds required two infusions. A minority of the bleeds (4.7%) required 5 or more infusions; these bleeds were predominantly related to trauma, target joints and/or muscle bleeds. Subjects rated efficacy of IB1001 as ‘excellent’ or ‘good’ in 84% of all treated bleeding episodes. Of 414 subject visits where the efficacy of IB1001 was evaluated by the study investigators, 92% were rated as ‘effective’ in prevention and treatment of bleeding by IB1001.

Conclusions:

IB1001 is effective for the treatment of hemophilia B either as secondary or tertiary prophylaxis or on an episodic (on-demand) basis. Based on clinical trial data, IB1001 is effective in controlling breakthrough or episodic bleeding episodes.

Introduction:

Since the emergence of community-acquired methicillin-resistant S. aureus (MRSA), severe manifestations of infection are encountered more frequently. Venous thrombosis (VT) has been previously reported in children with S. aureus infections. This study reviews our institutional experience and outcomes of children with VT and staphylococcal infections.

Methods:

A retrospective analysis of 15 pediatric patients (≤ 18 years) treated for VT and staphylococcal infections at Children’s Memorial Hermann Hospital between January 1, 2010 and December 31, 2014 was performed.

Results:

Fifteen patients were included (10 males, 5 females) with a median age at diagnosis of 8 years (range 2 mo-17yrs). Underlying infections included: osteomyelitis (n=7), soft tissue infection (n=3), aortitis (n=1), meningitis (n=1), septic arthritis (n=1), central line infection (n=1), septicemia (n=1). Primary presentation included: swelling (n=12), pain (n=11), tenderness (n= 8), and color changes (n=3). One patient had prior history of VT. Family history was positive for VT in one patient. Isolated organisms included: MRSA (n=9), MSSA (n=3), polymicrobial (n=2), and Staphylococcus non- aureus (n=1). Eight patients had central venous catheters (CVC) and 5 of them had thrombosis at the CVC site. VT sites identified by Doppler US (DUS) included: upper extremity (n= 5), lower extremity (n= 8), and neck (n=2). All thrombophilia work up was negative. The median D-dimer at diagnosis was 3 ug/ml (range: 0.31- 6.54 ug/ml). Median time elapsed between infection and VT diagnosis was 5.5 days (range: 0-35 days). All patients received anticoagulation using LMWH (1mg/kg/dose) except one who had superficial thrombophlebitis and was managed conservatively. Median time to achieve therapeutic anti- factor Xa level was 2.5 days (range 1- 6 days). Median duration of anticoagulation was 3 months. Three out of 13 patients (23%) had resolution of thrombosis within one week of anticoagulation. Four other patients had thrombus resolution by DUS at 3-6 months. Five patients did not have DUS at 3-6 months. None of the 15 patients required hospital re- admission for bleeding or thrombotic complications.

Discussion:

Staphylococcal infections may increase the risk of VT in children. Nine out of 15 patients (60%) with VT had a documented MRSA infection, which appears to confer an even higher risk for development of VT. Over half of the patients responded favorably to anticoagulation with resolution of VT within 6 months.

Conclusions:

A high index of suspicion for VT is warranted in children with Staphyloccoccal infections (particularly MRSA) to promptly diagnose and treat. This approach may improve outcomes and minimize complications including septic emboli and post-thrombotic syndrome. Prophylactic anticoagulation in presence of MRSA infection could be considered in future studies.

Keywords: Children, staphylococcal infection, venous thrombosis

Objective:

Hemophilia is marked by frequent joint bleeding, resulting in acute and chronic pain and functional impairment. Surveys in US adults with hemophilia demonstrate suboptimal pain management and quality of life (QoL). The objective of P-FiQ was to methodologically assess QoL parameters, including functional impairment and pain, and pain management strategies.

Methods:

Adult men with mild-severe hemophilia with a history of joint pain and/or bleeding completed a hemophilia/pain history and various patient-reported outcome assessments (completed twice in “retest” population of initially enrolled patients).

Summary:

Of 164 adults with hemophilia (median age 34) in the “retest” population, more had hemophilia A (74%) than B (26%); 6% had inhibitors. Most had some college-or-above education (63%), 81% were employed, 61% were overweight/obese, and 61% self-reported arthritis/bone/joint problems. Current patient-reported treatment regimens were prophylaxis (42%), on-demand (39%), or mostly on-demand (19%; 25/31 using infusions ahead of activity). One-third (32.9%) reported unrestricted school/work/recreational activities in the prior 6 months; 6.2% reported needing assistance for school/work/self-care, or did not participate in recreational activities because of pain, loss of motion, and weakness. Some patients (31.3%) reported using a cane/crutches/walker (3.8% always) and 7.6% a wheelchair (1.3% always), and 47.0% reported a history of joint surgery (41 knee, 37 ankle, 29 elbow). Patients reported losing an average of 3.7 and 1.8 school/work days in the previous 6 months due to lower and upper extremity problems, respectively. Patients reported that during the prior 6 months they had experienced acute pain only (24%), chronic pain only (33%), or both (29%); 15% reported no pain. Acute pain was most frequently described as sharp (77%), aching (66%), shooting (57%), and throbbing (55%), and chronic pain as aching (74%), nagging (49%), throbbing (44%), and sharp (40%). Most common analgesics in the past 6 months for acute/chronic pain were acetaminophen (69%/58%), NSAIDs (40%/52%), hydrocodone-acetaminophen (29%/33%), oxycodone (12%/11%), and oxycodone- acetaminophen (9%/8%). Most common nonanalgesic treatment strategies reported for acute/chronic pain in the past 6 months were ice (73%/37%), rest (48%/34%), factor or bypassing agent (48%/24%), elevation (34%/28%), relaxation (31%/23%), compression (27%/21%), and heat (25%/15%); other reported strategies include medical marijuana (17%/9%), physical therapy (12%/9%), prayer (11%/8%), faith (9%/8%), alcohol (8%/7%), aquatherapy (5%/6%), illicit drugs (4%/2%), acupuncture (2%/1%), hypnosis (2%/1%), and biofeedback (1%/1%).

Conclusions:

Initial data corroborate the high prevalence of pain and functional disability in adults with hemophilia and highlight opportunities to address clinical assessment, patient dialogue, and management strategies to improve outcomes.

Objective:

The ongoing rFIXFc extension study, B-YOND (clinicaltrials.gov #NCT01425723), evaluates the long-term safety and efficacy of rFIXFc for the treatment of severe hemophilia B. Here we report interim safety and efficacy data for adults and adolescents enrolled in B- YOND.

Methods:

Upon completing B-LONG, eligible subjects could enroll in one of 4 treatment groups in B-YOND: weekly prophylaxis (20 to 100 IU/kg every 7 days), individualized prophylaxis (100 IU/kg every 8 to 16 days, or twice monthly), modified prophylaxis (a prophylaxis regimen different from weekly or individualized prophylaxis), or episodic treatment. Subjects could change treatment groups at any point in the study. The primary endpoint was development of inhibitors. Secondary outcomes included annualized bleeding rate (ABR) and rFIXFc exposure days (EDs).

Summary:

93/115 subjects (80.9%) who completed B-LONG enrolled in B-YOND. As of the interim data cut (17 October 2014), 18 subjects had completed, 7 had discontinued, and 68 remained on study (median time on study, 119.9 weeks). From the start of B-LONG to the B- YOND interim data cut, the median time on rFIXFc was 171.6 weeks and 68 subjects (73%) had ≥100 cumulative rFIXFc EDs. 29/90 subjects (32%) from Arms 1-3 of B-LONG changed treatment groups at the start of or during B-YOND, including 9/19 subjects who changed from episodic to prophylactic treatment (1 subject changed back to episodic treatment before the interim data cut). In the weekly prophylaxis group, the median (IQR) average weekly prophylactic dose was 49.5 (21.0, 105.6) IU/kg. The median (IQR) average dosing intervals in the individualized and modified prophylaxis groups were 13.7 (10.1, 14.0) days and 6.9 (4.9, 7.0) days, respectively (a reduction in annual infusions of ~75% and ~50%, respectively, compared with twice-weekly administration of a standard half-life FIX product). As of the B- YOND interim data cut, no inhibitors were observed, and there were no reports of anaphylaxis or serious hypersensitivity reactions associated with rFIXFc, and no thrombotic events. Adverse events were generally typical of the hemophilia B population; no subject discontinued due to an adverse event. Median ABRs were low with rFIXFc prophylaxis (Table). 97.2% of bleeding episodes were controlled with 1 or 2 infusions.

Conclusions:

Interim data from B- YOND confirm the long-term safety of rFIXFc and the maintenance of a low ABR with prophylactic dosing every 1 to 2 weeks.

Introduction and Objectives:

The phase 3 A-LONG and Kids A-LONG studies demonstrated the safety and efficacy of rFVIIIFc for the control and prevention of bleeding episodes in subjects with severe hemophilia A. This subgroup analysis of A-LONG and Kids A-LONG examined bleeding frequency with rFVIIIFc prophylaxis in subjects with target joints at baseline.

Methods:

A-LONG (≥12 y) and Kids A-LONG (<12 y) subjects with a history of target joints (a major joint with ≥3 bleeding episodes in a 6-month period) who were previously treated with FVIII and received on-study rFVIIIFc prophylaxis were identified. Self-reported pre-study 12- month bleeding history and on-study annualized bleeding rate (ABR) for all bleeds were evaluated.

Results:

93/141 subjects in A-LONG and 13/69 subjects in Kids A-LONG had target joints at baseline. The most prevalent locations of pre-study target joints identified at baseline among subjects in A-LONG were the elbow (61.7%) and ankle (59.6%). Similarly, in Kids A-LONG, these were the ankle (69.2%) and elbow (30.8%). A total of 59.7% and 52.4% of subjects receiving individualized (Arm 1) and weekly (Arm 2) rFVIIIFc prophylaxis in A-LONG, respectively, and 53.8% of subjects receiving rFVIIIFc prophylaxis in Kids A-LONG with target joints at baseline had no target joint bleeding episodes on-study. Median on-study ABRs with rFVIIIFc prophylaxis tended to be lower than pre-study bleeding rates in subjects with target joints at baseline (Table).

Conclusions:

For subjects with severe hemophilia A who had target joints at baseline, rFVIIIFc prophylaxis lowered bleeding rates across age groups compared with pre-study FVIII treatment.

 

Introduction:

BAY 81-8973 is Bayer’s new full-length recombinant factor VIII (FVIII) product for the treatment of hemophilia A, with no human- or animal-derived raw materials added to the cell culture, purification, or formulation process.

Methods:

The safety and efficacy of BAY 81-8973 for routine prophylaxis in patients with severe hemophilia A (<1% FVIII) was evaluated in 3 clinical studies: 2 in adolescent and adult previously treated patients (PTPs; aged 12–65 years [Study 1 and Study 2]) and 1 in children aged ≤12 years (PTPs: completed [Study 3]; previously untreated patients: ongoing), enrolling a total of 204 patients. In Study 1, the prophylaxis regimen was 20–50 IU/kg 2x–3x/wk as determined by the investigator. In Study 2, patients were randomized to prophylaxis (20–30 IU/kg 2x/wk or 30–40 IU/kg 3x/wk) or on-demand treatment. In both 12-month studies, the primary efficacy variable was the annualized bleeding rate (ABR). In Study 3, the prophylaxis regimen was 20–50 IU/kg 2x–3x/wk or every other day, as determined by the investigator, for ≥50 exposure days (approximately 6–8 months). The primary efficacy variable was the ABR for total bleeds occurring within 48 hours of previous prophylaxis treatment; ABR was also analyzed independent of time of injection.

Results:

A total of 193 patients treated with BAY 81-8973 were included in the analysis (Table 1). Sixteen (25.8%), 16 (27.1%), and 23 (45.1%) patients treated prophylactically had 0 bleeding episodes in Studies 1, 2, and 3, respectively.

Table 1. Annualized Bleeding Rates

Conclusions:

Study 1 and Study 2 demonstrated the efficacy and safety of routine prophylaxis treatment with BAY 81-8973 in adolescents and adults. Study 2 also demonstrated the superiority of prophylaxis over on-demand treatment during a one-year treatment period. An additional study in children aged ≤12 years showed low annualized rates for all bleeds, joint bleeds, and spontaneous bleeds within 48 hours after injection or later during routine prophylaxis.