Research Studies

Introduction and Objectives:

In the phase 3 A-LONG and Kids A-LONG studies, subjects with severe hemophilia A receiving rFVIIIFc prophylaxis 1-2 times/week had low annualized bleeding rates (ABRs), with comparable pre-study and on-study weekly factor consumption for subjects previously on FVIII prophylaxis. This report evaluated the effect of rFVIIIFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.

Methods:

Subjects eligible for A-LONG (≥12 y) and Kids A-LONG (<12 y) were previously treated males with severe hemophilia A (<1 IU/dL endogenous FVIII activity). Subjects in A- LONG were enrolled into 1 of 3 arms: Arm 1, individualized prophylaxis; Arm 2, weekly prophylaxis; or Arm 3, episodic treatment. All subjects in Kids A-LONG received rFVIIIFc prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 7, 14, 28, 38, 52, and end of study (A-LONG) and Weeks 2, 7, 12, 17, 22, 26, and end of study (Kids A-LONG). At each visit after their first rFVIIIFc dose, subjects were asked to report any changes in their activity levels 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 during the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.

Results:

A total of 165 and 71 subjects enrolled in A-LONG and Kids A-LONG, respectively. Overall, the majority of subjects in A-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=117], 8%, 36%, 51%, 5%; Arm 2 [n=23], 9%, 48%, 39%, 4%; Arm 3 [n=23], 9%, 52%, 26%, 13%, respectively). Results were generally similar for subjects in Kids A-LONG (for subjects aged <6 y [n=35], 3%, 26%, 66%, 6%; for subjects aged 6 to <12 y [n=34], 9%, 26%, 56%, 9%).

Conclusions:

The majority of subjects in A-LONG and Kids A-LONG reported similar or increased physical activity levels during the studies, while maintaining low ABRs. These self- reported data suggest that subjects across a variety of age groups with severe hemophilia A who are transitioning to rFVIIIFc may maintain or increase physical activity levels, while reducing infusion frequency and maintaining similar weekly factor consumption, without compromising efficacy.

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.

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:

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.

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.