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.
Background:
Until recently, the hemophilia B community has only had standard Factor IX (FIX-Fc) products as treatment choices. With the availability of additional standard rFIX products and extended half-life (EHL) rFIX-Fc, there has been much debate (1-4) regarding clinical and cost expectations, balanced with optimizing use in patients. To level the debate, an understanding of real-world prescription costs of patients who switch to EHL FIX-Fc products is warranted.
Objectives:
1) To characterize patients who switch from rFIX to EHL rFIX-Fc, and 2) to understand their change in factor costs.
Methods:
Retrospective analysis using national US specialty pharmacy dispensing databases from Jan 1, 2013-Apr 25, 2015 of Hemophilia B (ICD-9 code 286.1) individuals who switched from rFIX to rFIX-Fc. Descriptive statistics summarized patient characteristics. Patients who had at least 90 days of prescription coverage on both products were included. Utilization was averaged on a monthly basis pre and post switch. Costs were calculated by multiplying the units by the wholesale acquisition prices for each product (Red Book) and the percentage change in cost from rFIX to EHL-rFIX was compared. This analysis studied patients who switched but stayed on similar regimens. Cohorts were characterized as prophylaxis to prophylaxis (P to P), or on-demand to on-demand (OD to OD).
Results:
Sixteen switchers were included in the study. Hemophilia severity was reported as 62.5% severe, 12.5% moderate, 6.25% mild, and 18.75% of unknown severity. The P to P cohort comprised of the majority of patients at 87.5% (n=14) while OD to OD were smaller at 11% (n=2). The median ages for these cohorts were similar. The P to P median age was 15 (range: 5-51) and OD to OD was 14 (range: 13-15) years old. Median prescription costs increased in the P to P cohort by 40% (range: -56% to 181%), while OD to OD increased by 173% (range: 1% to 348%).
Conclusion:
While the availability of EHL rFIX-Fc allows hemophilia B patients an option with less frequent infusions, our findings demonstrate that for those who initially switched from prophylaxis to prophylaxis or from on-demand to on-demand regimens, costs increased for the majority of patients. This analysis provides initial real-world cost data for those who have switched to EHL and may be helpful in decision makers’ understanding of the value of EHL rFIX-Fc in hemophilia B.
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.
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.
