Research Studies

Objective:

To assess the pharmacokinetics (PK) and efficacy of prophylactic treatment with BAX 855 - a novel polyethylene glycol (peg)ylated full-length recombinant factor VIII, built on the rAHF-PFM (ADVATE) protein - by age group in previously-treated male patients with severe hemophilia A.

Methods:

Adolescent (12 to <18 years) and adult (18 to 65 years) subjects received 45 ± 5 IU/kg BAX 855 twice weekly as prophylaxis for approximately 6 months. PK was assessed in a subgroup (n=25 planned, including ≥6 adolescents) for one ADVATE infusion, then for BAX 855 at the initial infusion and after ≥50 exposure days (EDs). Efficacy was assessed in all subjects.

Summary:

Twenty-six subjects (8 adolescents, 18 adults) were included in the PK evaluation, and 121 (23 adolescents, 98 adults) were included in the efficacy analysis (all subjects assigned to treatment, i.e. full analysis set). The extended half-life (T1/2) and mean residence time (MRT) of BAX 855 (initial dose) compared to ADVATE were demonstrated by fold increases in the means of 1.4 and 1.5, respectively in both adolescents and in adults, using the one-stage clotting assay. The initial and repeat PK assessments of BAX 855 showed similar results. Consistent trends were observed when PK was determined using the chromogenic assay. The arithmetic mean (SD) annualized bleeding rate (ABR) during prophylaxis with BAX 855 was higher in adolescents than in adults (6.2 [6.1] versus 3.2 [4.2]). ABRs for injury-related bleeding episodes (BEs) were higher in adolescents (arithmetic mean [SD]:2.3 [3.2] versus 1.7 [3.1] in adults), thus contributing to the overall higher ABR in this group. Joint ABRs were lower in adolescents (arithmetic mean [SD]: 1.8 [2.5] versus 3.2 [8.8] in adults) with an inverse relationship for non-joint ABRs. Six adolescents (26.1%) and 39 adults (40.2%) had zero BEs. A total of 48 BEs occurred in adolescents (20 minor; 26 moderate; 2 severe); 182 occurred in adults (69 minor; 103 moderate; 10 severe). The hemostatic efficacy of BAX 855 was rated excellent or good at resolution for the majority of BEs in both age groups (93.8% in adolescents; 92.9% in adults).

Conclusions:

Although fewer adolescents than adults were included in the study, the data suggest that BAX 855 is efficacious in both age groups for twice-weekly prophylaxis and control of BEs. As expected, joint ABR was higher in the adult group.

Attainment of self-management skills, disease knowledge, and a documented transition plan are key elements for smooth transfer from pediatric to adult care for patients with chronic disease. Our hemophilia center had no standardized approach for assessing key patient competencies or independence readiness. In the last quarter of 2014, our team undertook a quality improvement project; we developed a transition tool with the goals of consistently assessing self-efficacy skills at a sustained rate of 90% during annual comprehensive visits; and developing patient-centric skill-building plans based on these assessments.

We previously reported that after four PDSA ramps of tool utilization, 31 patients, age 2-21 years, had been seen in hemophilia comprehensive clinic during the 3 month period studied. Utilizing the newly developed tool, 97% had a global assessment of competency with respect to their current age group; 93% had transition or progress plans documented. This demonstrated significant improvement compared with retrospective data from the three month period prior to implementation of the tool.

Since this previous report, we have continued to utilize the tool during hemophilia comprehensive clinic. In the proposed poster, we will demonstrate sustainability of the tool through analysis and presentation of Hemo-milestone data from the first half of 2015. Further, based on these results we will propose additional areas of study inspired by the transition tool, with the aim of continued improvement of the skill-building and transition process. These include improved utilization of educational materials based on identified learning needs; evaluation of documented, planned interventions; the development of collaborative educational events with our partner adult HTC; and retrospective, patient- centered evaluation of the transition process after the transition to adult hemophilia care.

Objective:

Clinical knowledge gaps of hemophilia can affect patient outcomes through delayed diagnosis/referral as well as improper monitoring and interventions. A study was undertaken to identify and characterize clinical practice gaps and confidence levels in the management of hemophilia specific to pediatricians.

Methods:

Building upon a previous assessment developed in 2014, an updated global, hemophilia-specific continuing medical education-accredited clinical practice assessment survey was developed utilizing current evidence-based consensus guidelines and best practices, including guidelines from the National Hemophilia Foundation and the World Federation of Hemophilia. The assessment included both knowledge- and case -based, multiple-choice questions that healthcare providers completed confidentially on-line between March 23, 2015 and April 9, 2015. Areas such as appropriate triggers for initiating prophylaxis and use of physical therapy were assessed. Responses from pediatric providers were de- identified and aggregated prior to analysis.

Summary:

660 pediatricians (30% of total respondents) completed the survey, from the following locales: North America (36%), Asia (23%), Europe (15%), Middle East (10%), Africa (7%), Central/South America (6%), and Australia (4%). Academic (31%), private practice (27%), community hospital (19%), community clinic (12%), and hemophilia treatment center (3%) practice settings were identified. Analysis of pediatricians who indicated professional interaction with hemophilia patients (87% of pediatrician respondents) demonstrated knowledge gaps including (% incorrect responses): classification of severity of hemophilia (37%); optimal use of prophylactic therapy, e.g., when to initiate (31%), at what dose (53%), prophylaxis in active patients (26%); likelihood of inhibitors (75%); using bypassing therapy (58%); comprehensive care model (61%); supporting overall joint health and quality of life (70%); and adherence (60%). A low level of confidence in the ability to identify when to use prophylaxis was reported among 31% of pediatricians. The top barriers to the administration of prophylaxis identified by the pediatric providers included lack of availability of FVIII or FIX concentrates, lack of venous access, and insurance coverage (29%, 22%, and 21% for respondents, respectively).

Conclusions:

This study demonstrated gaps in knowledge and confidence about the assessment and optimal care of hemophilia for pediatricians, suggesting that further education specific to the needs of these providers is warranted.

Objectives:

This trial evaluated the hemostatic efficacy, pharmacokinetics, and safety of a recombinant VWF (rVWF) in adults with severe von Willebrand disease (VWD) (type 3 [VWF:Ag ≤ 3 IU/dL], severe type 1 [VWF:RCo< 20 IU/dL], 2A [VWF:RCo< 20 IU/dL], 2N [FVIII:C<10% ], 2B, or 2M).

Methods:

Bleeds were to be treated initially with rVWF and rFVIII (1.3:1 ratio), followed by rVWF alone (as long as FVIII:C >40%). Hemostatic efficacy was evaluated using a pre- defined 4-point rating scale (none=4, moderate=3, good=2, excellent=1). PK parameters for rVWF vs. rVWF:rFVIII were assessed in a randomized crossover design, and a 6-month repeated PK evaluation for rVWF alone.

Summary:

Of 31 subjects assigned to bleed treatment, 22 (17 type 3, 4 type 2A and 1 type 2N) experienced 192 bleeding episodes (several in multiple locations) that were treated with rVWF: 106 occurred in mucosal tissue (including 32 menorrhagic, 42 nasopharyngeal, 26 mouth/oral bleeds), 59 joint bleeds, 6 gastrointestinal bleeds, and 37 in other locations. Treatment success (mean efficacy rating <2.5) was achieved in all 22 subjects (100%; Clopper-Pearson exact 90% confidence interval: 87.3 to 100.0). ‘Excellent’ ratings were given for 186/192 (96.9%) bleeds (119/122 minor, 59/61 moderate, 6/7 severe, 2/2 unknown severity) and the remaining 3.1% were ‘good’. One infusion was effective in 81.8% of bleeds (median [range]: 1 [1-4] overall; 2 [1-3] for severe bleeds). The subject’s own assessment of treatment efficacy (an exploratory endpoint), was ‘excellent’ within 8 hours after the first infusion for 125/134 (93.3%), ‘good’ for 8/134 (6.0%) and ‘moderate’ for 1/134 (0.7%) bleeding episodes. A substantial increase in FVIII:C and sustained stabilization (> 40% by 6 hours, rising to >80% 24 hours post-infusion) was observed after infusion with rVWF. PK parameters for VWF Ristocetin cofactor (VWF:RCo, a surrogate for the platelet-dependent function of rVWF) were similar when rVWF was infused alone (mean T1/2 21.9 h vs. 19.6 h with rVWF:rFVIII). Eight adverse events (tachycardia, infusion site paraesthesia, ECG t wave inversion, dysgeusia, generalized pruritis, hot flush, chest discomfort and increased heart rate) in 5 subjects were assessed as related to rVWF. No inhibitor or anti-VWF binding antibody development was observed, and there were no thrombotic events or severe allergic reactions.

Conclusions:

rVWF was safe, well-tolerated and effective in the treatment of a variety of bleeding presentations in severe VWD. The sustained stabilization in FVIII:C after the initial infusion enables subsequent infusion of rVWF without rFVIII, when multiple infusions are required.

Objective:

Promote awareness of and an opportunity for dialogue regarding variability among prescribed regimens to enhance care for hemophilia A patients with inhibitors undergoing immune tolerance.

Methods:

Retrospective chart review of all severe hemophilia A patients receiving interdisciplinary inhibitor management home infusion support between March of 2013 and March of 2015. Excluded mild patients developing inhibitors postoperatively and those for which insufficient titer information was provided/available from prescribers. 14 patients met the inclusion criteria. We attempted to further categorize these regimens in to low and high dosing regimens as outlined in the International Immune Tolerance Study.

Summary:

We identified 14 patients on 7 different ITI regimens, none of whom expressly followed the “low or high dose regimens” of 50 units per kg 3 times a week or 200 units per kg daily. They were on either recombinant FVIII products (11) or vWF containing products (3). The reviewed population was followed by 11 different HTC’s which included 13 different prescribers. We noted time to tolerization (when information available), bleed rate, as well as the interventions and support offered patients by the homecare inhibitor team. Although the sample was small, a notable increase in bleeds was seen in those patients on regimens below100 units/kg/day. Time to tolerization was unavailable for 3 of the 14. Of the remaining 11, time to tolerization ranged from 1-45 months and there was no significant difference seen amongst regimens.

Conclusions:

Seven different regimens for ITI were prescribed for 14 unique patients across the country. All achieved successful immune tolerance, but there was variability in the frequency of spontaneous bleeds and time to tolerance. Exact time to tolerance was limited by both the inability to obtain lab values (titers) from the prescriber or long periods between titer levels. Immune tolerance induction dosing regimens have been long debated and several studies continue to attempt to provide clarity and guidance. A missing component of the research published to date is the importance of patient adherence and the benefit of prescriber/pharmacist/payer collaboration. Economic influences further complicate this as many HTC’s perceive pharmacies as competitors, rather than collaborators in care. Additionally, payers may limit networks or implement other barriers to refills. The authors wish to work collaboratively to remove these barriers and enhance outcomes.

Objective:

To evaluate efficacy of IB1001 for perioperative management of bleeding under surgical circumstances in hemophilia B patients.

Methods:

The efficacy of IB1001 for perioperative management has been evaluated in a prospective, open-label, multicenter international study where 17 subjects (16 male PTPs and one female hemophilia B carrier) underwent 20 major surgical procedures. The PTPs were defined as patients with a minimum of 150 exposures to another factor IX preparation. The subjects had severe or moderately severe (factor IX level ≤ 2 IU/dL) hemophilia B without inhibitors, with exception of one mild hemophilia B female carrier. Efficacy of IB1001 was based on the surgeon’s assessment including estimation of blood loss as ‘less than expected’, ‘expected’, or ‘more than expected’ at the time of surgery and assessment of hemostasis at 12 and 24 hours post-surgery as ‘superior’, ‘adequate’, or ‘poorly controlled’. Transfusion requirements were also monitored.

Summary:

Thirteen major procedures in 12 male subjects were managed by bolus regimen, and 6 major procedures in 4 male subjects were managed by continuous infusion regimen. Mean loading dose for 13 major procedures managed by bolus regimen was 120 ± 11.4 IU/kg and mean maintenance bolus dose (given every 12 hours) was 59.7 ± 12.2 IU/kg. During the 24 hours following surgery, factor IX levels were successfully maintained over 60%, as intended. Factor IX levels at pre-infusion were 59.7% ± 15.9% at 12 hours after surgery and 54.4% ± 16.5% at 24 hours after surgery. For a major procedure in one female carrier, the bolus dose was 110 IU/kg, while the mean maintenance dose was 44.9 ± 7.0 IU/kg. Mean loading dose for 6 major procedures managed by continuous infusion regimen was 95.4 ± 14.5 IU/kg and the mean maintenance infusions were 7.1 ± 4.0 IU/kg/hr. In all major procedures, blood loss at the time of surgery was ‘expected’ or ‘less than expected’ as assessed by the surgeon. IB1001 was rated by the surgeon as ‘superior’ or ‘adequate’ in controlling hemostasis post-surgery, including 8 knee arthroplasties, two elbow arthroplasties, one knee amputation, one percutaneous Achilles tendon lengthening, one open inguinal hernia repair, one tibiotalar fusion, two arthroscopic synovectomies, three debridements and one total hysterectomy/bilateral oopherectomy. There were no transfusions required perioperatively.

Conclusions:

At the time of surgery, blood loss was expected or less than expected after IB1001 treatment, while post-surgery effective hemostasis control was achieved following IB1001 treatment in hemophilia B patients.

Dr. Noh's research will utilize induced pluripotent stem cells (iPSC) and manipulate them in vitro to expand production of megakaryocytes and platelets that express therapeutic proteins, including FVIII. The project will further determine whether this system of autologous platelets which overexpress FVIII can be delivered directly to the site of injury and hemorrhage, thereby circumventing and evading neutralization by alloantibody inhibitors in hemophilia A. Dr. Noh received her Ph.D. in Preventive Pharmacology from Seoul National University in South Korea. She has been a postdoctoral fellow in Dr. Mitchell Weiss' lab at The Children's Hospital of Philadelphia since 2012. Dr. Noh is currently being mentored in this JGP project by Dr. Mortimer Poncz at CHOP.

Introduction:

BAY 81-8973 is Bayer’s new full-length recombinant factor VIII product in development for the treatment of hemophilia A, with no human- or animal-derived raw materials added to the cell culture, purification, or formulation process. The pharmacokinetic (PK) properties of BAY 81-8973 were investigated in 3 studies in previously treated adults, adolescents, and children.

Methods:

For all PK evaluations, a single dose of 50 IU/kg BAY 81-8973 was injected. Serial blood samples were collected over 48 hours in adults and 24 hours in children <12 years of age. PK samples in adolescents and adults were analyzed using one-stage and chromogenic assays. Limited samples were collected in children and were analyzed using only the chromogenic assay. Ethnic subgroups included Chinese, Japanese, and non-Asian patients.

Results:

PK parameters using the chromogenic assay for children (aged <12 years), adolescents (aged 12–17 years), and adults (aged ≥18 years) are shown in Table 1.

Table 1. Pharmacokinetic Parameters Based on the Chromogenic Assay

Conclusions:

Analysis of PK across the different age groups showed that the values for maximum concentration (Cmax) and area under the curve (AUC) for adolescents were within the range of those seen for adults. PK values were slightly lower in children than in adults. There were no significant differences among the ethnic groups studied.

Background:

BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor developed as a bypass agent for hemophilia patients with inhibitors. It restores thrombin burst, leading to stable clot formation in hemophilic conditions in vitro and effectively stops bleeding in vivo.

Aims:

Efficacy and thrombogenic potential of BAY 1093884 were evaluated in bleeding models in acquired hemophilia A rabbits and the Wessler venous stasis model, respectively.

Methods:

The efficacy of BAY 1093884 was tested in rabbit bleeding models. Anti-factor VIII antibodies rendered rabbits hemophilic, increasing bleeding time by ~3-fold (median 120–390 seconds) in an ear bleeding model and >7-fold (median 240–1800 seconds) in a saphenous vein bleeding model. In the Wessler model, thrombosis was induced by complete ligation of the jugular vein after administration of BAY 1093884, recombinant FVIIa (rFVIIa), or activated prothrombin complex concentrate (aPCC) to measure in vivo hypercoagulability.

Results:

In both bleeding models, BAY 1093884 corrected bleeding time close to normal in a dose-dependent manner. A statistically significant reduction in saphenous vein bleeding was reached at 1 and 3 mg/kg BAY 1093884, reducing bleeding time to 330 and 240 seconds, respectively. In contrast, 1 mg/kg rFVIIa only slightly reduced bleeding time to a median of 1200 seconds. In the Wessler model, 1 mg/kg rFVIIa and 40 IU/kg aPCC resulted in thrombus formation, reaching full occlusion in rabbits with normal coagulation system. In contrast, BAY 1093884 up to 100 mg/kg did not fully occlude, and only showed a slight increase in localized clot formation over baseline, which could be completely prevented by an anticoagulant. In addition, no stasis-triggered thrombi were seen in hemophilia A rabbits treated with BAY 1093884, indicating reduced thrombogenicity risk for BAY 1093884 in patients with hemophilia.

Conclusions:

These studies showed that BAY 1093884 potently controls bleeding in hemophilic rabbits while showing reduced thrombogenic risk compared with the current standard of care.

Objective:

To assess pain and functional impairment through 5 patient-reported outcome (PRO) instruments in non-bleeding adults with hemophilia.

Methods:

Adult men with hemophilia (mild-severe) with history of joint pain/bleeding completed a hemophilia/pain history and 5 PROs (EQ-5D-5L with visual analog scale [VAS], Brief Pain Inventory v2 [BPI-SF], International Physical Activity Questionnaire [IPAQ-SF], SF- 36v2, and Hemophilia Activities List [HAL]) during routine visits. Initial patients were asked to complete the PROs again after their estimated 3-4 hour visit (retest population). PRO scores were calculated from published algorithms. Generally, higher scores indicate better health- related quality of life (HRQoL) and functional status, and greater pain severity/interference.

Summary:

381 Patients were enrolled between October 2013 and October 2014; 164 of the initial 187 completed the retest and are reported here. Median time for completion of the initial survey/PROs was 36.0 minutes and 21.0 minutes for the PRO retest. Most retest subjects had hemophilia A (74.4%) and were white-non-Hispanic (72.6%). Median (Q1, Q3) age was 33.9 (26.9, 46.0), 48.7% were married, 62.6% had some college or graduate education, 80.7% were employed, and 61.0% were overweight or obese. HCV (49.4%) was more common than HIV (16.5%); 61.0% self-reported arthritis/bone/joint problems. Median EQ-5D- 5L VAS was 80.0 (0-100 scale), and EQ-5D-5L health index 0.80 (-0.11-1 scale); 61.6% reported any problems with mobility (29.3% reported moderate/severe problems), 55.8% with usual activities (18.4% moderate/severe), and 22.0% with self-care (4.3% moderate/severe). 73.2% reported pain-discomfort (43.3% moderate/severe), and 41.1% anxiety-depression (14.7% moderate/severe). For BPI, median pain severity was 3.0 (0-10 scale) and pain interference 2.9 (0-10 scale); median worst pain was 6.0, least pain 2.0, average pain 3.0, and current pain 2.0. Pain most impacted general activity, mood, walking ability, and normal work, and least impacted relations with other people. Ankles were the most frequently reported site of pain. Median IPAQ total activity was 693.0 MET/min/week; 49.3% reported no activity in the prior week. Median SF-36v2 scores (0-100 scale) were lower for physical health (39.6) than for mental health (51.6). Median overall HAL score was 76.1 (0-100 scale); complex lower extremity activities were the most impacted activity domain.

Conclusions:

These 5 PRO instruments provide different levels of detail describing the impact of hemophilia on pain and function, and consequently, have varied burdens of administration. PRO data from the retest population demonstrate that most adults with hemophilia experience pain and functional impairment that impacts HRQoL, highlighting the importance of assessments and patient dialogue.

Objective:

To assess the safety and efficacy of treatment with the first high-purity plasma-derived factor X concentrate (pdFX) in 2 prospective, multicenter, open-label, nonrandomized phase 3 studies in subjects with hereditary mild to severe mild factor X (FX) deficiency (basal plasma FX activity [FX:C] <20 IU/dL) undergoing surgery.

Methods:

Subjects aged ≥12 years received pdFX preoperatively to raise plasma FX:C to 70-90 IU/dL and postoperatively as necessary to maintain levels at ≥50 IU/dL until they were no longer at risk of bleeding due to surgery. Efficacy assessments included blood loss during surgery, requirement for blood transfusion, postoperative bleeding, and changes in hemoglobin levels. Following treatment, efficacy of pdFX in the control of bleeding was assessed as “excellent,” “good,” “poor,” or “unassessable.” Safety outcomes included adverse events (AEs), inhibitor development, viral seroconversions, and other clinically significant changes in laboratory parameters.

Summary:

Five subjects (aged 14-59 years) underwent 7 surgical procedures (major procedures: 2 knee replacements, 1 coronary artery bypass graft, and 1 extraction of 6 teeth; minor procedures: 2 extractions of 1 tooth each and 1 extraction of 2 teeth). Median pdFX exposure was 181 IU/kg (over 13 infusions) for major procedures and 89 IU/kg (over 2.5 infusions) for minor procedures. A median dose of 48.85 (range, 30.88– 54.41) IU/kg was administered preoperatively, resulting in plasma FX:C levels of 0.77- 1.32 IU/mL, and a median FX incremental recovery of 2.21 (range, 1.67-2.34) IU/dL per IU/kg was observed. For all procedures, bleeding control was rated by investigators as “excellent,” no blood transfusions were required, and no clinically significant changes in hemoglobin levels were observed. Blood loss was rated as “as expected” in 5 procedures and “less than expected” in 2 procedures compared with a similar patient without a coagulation disorder undergoing the same surgery. The most common AEs were constipation and dyspepsia (3 cases each). No treatment-related AEs, thrombotic events or evidence of thrombogenicity, viral seroconversions, or inhibitor development were observed.

Conclusions:

These results show that pdFX was safe and efficacious as replacement therapy for 5 subjects with mild to severe FX deficiency undergoing a variety of surgical procedures on 7 occasions. Based on these findings, dosing should be tailored to the severity of the surgical procedure and the patient’s concomitant medical issues, and continual assessment of plasma FX levels in the perioperative period is recommended.

Introduction and Objectives:

In the phase 3 B-LONG and Kids B-LONG studies, subjects with severe hemophilia B receiving rFIXFc prophylaxis had low annualized bleeding rates (ABRs), with decreased weekly factor consumption and fewer infusions compared with pre- study FIX treatment. This report evaluated the effect of rFIXFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.

Methods:

Eligible subjects for B-LONG (≥12 y) and Kids B-LONG (<12 y) were previously treated males with severe hemophilia B (≤2 IU/dL endogenous FIX activity). Subjects in B- LONG were enrolled into 1 of 4 treatment arms: Arm 1, weekly prophylaxis; Arm 2, individualized interval prophylaxis; Arm 3, episodic treatment; or Arm 4, perioperative management (not included in this analysis). All subjects in Kids B-LONG started on weekly prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 4, 16, 26, 39, 52, and end of study (B-LONG) and Weeks 3, 12, 24, 36, 50, and end of study (Kids B-LONG). At each visit after their first rFIXFc dose, subjects were asked to rate their activity level relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of physical activities. To summarize each subject’s change in physical activity over the course of the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.

Results:

Overall, 123 and 30 subjects enrolled in B-LONG and Kids B-LONG, respectively. The majority of subjects in B-LONG reported more or the same amount of physical activity, and few subjects reported less physical activity during the study (less, the same, more, undetermined in Arm 1 [n=60], 7%, 42%, 35%, 17%; Arm 2 [n=25], 16%, 28%, 48%, 8%; Arm 3 [n=27], 15%, 26%, 30%, 30%, respectively). Results were generally similar for subjects in Kids B-LONG (for subjects aged <6 y [n=15], 13%, 27%, 47%, 13%; for subjects aged 6 to <12 y [n=15], 7%, 13%, 67%, 13%).

Conclusions:

ABRs were low in B-LONG and Kids B-LONG despite similar or increased physical activity levels reported by the majority of subjects. These results suggest that people with severe hemophilia B across a variety of age groups may maintain or increase their physical activity levels with rFIXFc, while also reducing infusion frequency and weekly factor consumption, without compromising efficacy.