Clinical Research/Clinical Trials

Objective:

As a prospective, longitudinal, observational registry of patients with hemophilia (PWH) A and B, the World Bleeding Disorders Registry (WBDR) aims to collect uniform and standardized patient data and guide clinical practice across the world. The WBDR was established in January 2018 by the World Federation of Hemophilia (WFH), with a five-year target of 10,000 patients at 200 Hemophilia Treatment Centres (HTCs) in at least 50 countries.

Methods:

Data collection occurs at the level of participating HTCs and include data on basic demographics, diagnostics, and clinical variables included in the Minimal Data Set, in addition to an Extended Data Set to obtain more complete patient data. All data entered in the WBDR are quality assessed through the WFH Data Quality Accreditation Program. Additionally, an international data integration component was developed to conduct data transfer from existing patient registries to the WBDR.

Summary:

In the first two years, 80 HTCs from 38 countries have received ethics approval. Over 5200 PWH have been enrolled, including 771 patients imported directly from the Czech National Hemophilia Program Registry via data transfer. Patients registered in the WBDR represent all regions of the world and all World Bank Gross National Income (GNI) categories. Trends in global care around the world are beginning to emerge from this early data: the median age at diagnosis for severe patients, an indicator of the level of care in a country, varies considerably based on GNI: ranging from 45 months in low income countries, to 25, 12 and 10 in lower-middle, upper-middle and high income countries respectively. Bleed rates, treatment regimens and factor use also highlight large discrepancies in care globally.

Conclusions:

The significant progress the WBDR has accomplished in its first two years laid a solid foundation on which the registry will continue to expand. This global network of HTCs and patients has started providing real-world data, on which evidence to improve the quality of care worldwide will be generated. The WFH thanks the many dedicated health care providers and patients who are part of this important initiative.

The WBDR is supported by our Visionary Partners: SOBI and Takeda; and our Collaborating Partners: Bayer, CSL Behring, Grifols, Pfizer, and Roche.

Objective:

Hemophilia A (HA) is an X-linked disorder caused by mutations in the gene encoding Factor VIII protein (FVIII). Gene therapy is increasingly being viewed as a viable treatment option for hemophilia. Herein, long-term clinical safety and efficacy are presented from a Phase 1/2 study of an AAV-mediated gene therapy for severe HA.  
 
Methods:

Valoctocogene roxaparvovec is an adeno-associated virus-mediated gene therapy that delivers a functional, codon-optimized, B domain-deleted, human FVIII gene under the control of a liver-specific promoter (AAV5-hFVIII-SQ). An ongoing Phase 1/2 study continues to evaluate the safety and efficacy of valoctocogene roxaparvovec in thirteen males with severe HA. Study participants received a single intravenous injection of valoctocogene roxaparvovec at one of two dose levels (6×10¹³vg/kg, n=7; 4×10¹³vg/kg, n=6).

Summary:

Participants who received 6×10¹³vg/kg valoctocogene roxaparvovec showed a reduction in annualized bleeding rate (ABR) of 96%, from a pre-treatment median(mean) of 16.5(16.3) to 0.0(0.7) at year three. Participants demonstrated an absence of target joints and target joint bleeds, with 86% experiencing zero bleeds requiring FVIII treatment. ABR diminished by 92% in 4×10¹³vg/kg participants, from a pre-treatment median(mean) of 8(12.2) to 0(1.2) at year two. Sixty-seven percent of 4×10¹³vg/kg participants experienced zero bleeds requiring FVIII treatment.
 
FVIII usage demonstrated a reduction from pre-treatment median(mean) of 139(137) infusions to 0(5.5) at year three in 6×10¹³vg/kg participants, and from 156(147) to 0.5(6.8) at year two in 4×10¹³vg/kg participants.
 
In 6×10¹³vg/kg participants, FVIII levels reported by chromogenic assay reached a median(mean) of 60.3(64.3), 26.2(36.4), and 19.9(32.7) IU/dL at the end of one, two, and three years post-infusion, respectively. In 4×10¹³vg/kg participants, FVIII levels reported by chromogenic assay reached a median(mean) of 22.9(21.0) IU/dL and 13.1(14.7) IU/dL at the end of one and two years post-infusion, respectively. Although FVIII levels were measured and will be presented using both the chromogenic substrate assay and the one-stage assay, chromogenic assay results appear to more accurately represent the true level of circulating FVIII.

The safety profile of valoctocogene roxaparvovec remains favorable and unchanged, with transient, asymptomatic ALT elevations and no FVIII inhibitor development reported to-date.

Conclusions:

Following a single administration of valoctocogene roxaparvovec, participants showed sustained, clinically relevant FVIII activity that reduced self-reported bleeding and exogenous FVIII replacement use at 156 weeks and 104 weeks post-administration in 6×10¹³vg/kg and 4×10¹³vg/kg dose cohorts, respectively.

Objective:

Von Willebrand disease (VWD) is the most common inherited bleeding disorder, however, initial diagnosis and subsequent management of patients after diagnosis remains a challenge. The aim of this study was to characterize the specialists who are treating patients before and after diagnosis of VWD. We also identified the most common bleeding types and the treatments given to these patients.

Methods:

This retrospective study analysed data from a US medical claims insurance database (IQVIA PharMetrics Plus Database) for patients who had made insurance claims for VWD (International Classification of Diseases, ninth edition [ICD-9] code: 286.4). The claims were made from January 01, 2006 to June 30, 2015. Patients with ≥2 medical claims for VWD and who were continuously enrolled for a 2-year period before and after their 1 st VWD claim were included in this study. Descriptive statistics were used to summarize patient demographic and clinical characteristics, which included bleed types, treating physician specialty, and type of VWD treatment, in both the pre- and post-diagnosis periods.

Summary:

A total of 3,756 patients were included: 73% were female, and the median age at VWD diagnosis was 34 years old (age range 2–82 years). Pre-diagnosis, the top 3 treating physician specialties were hospitalists (22%), primary care physicians (14%) and obstetrician-gynecologists (13%). Post-diagnosis, the top 3 treating physician specialties were hospitalists (14%), primary care physicians (8%) and obstetrician- gynecologists (10%). Only 6% of patients saw a specialist hematologist before VWD diagnosis for a bleeding event and this decreased to 3% after diagnosis. The number of claims made by patients for bleeding events decreased from 45% pre-diagnosis to 34% post-diagnosis. In females, heavy menses were the most common bleed type, representing 29% of pre-diagnosis claims and 21% of post-diagnosis claims. In males, epistaxis was the most common bleed type, representing 13% of pre-diagnosis claims and 8% of all post-diagnosis claims. Overall, insurance claims for medical treatments associated with VWD increased from 19% pre-diagnosis to 27% post-diagnosis. The most prescribed treatments in women were oral contraceptives, desmopressin (DDAVP) and aminocaproic acid (ACA) (pre-diagnosis: 18%, 5% and 2%, respectively; post- diagnosis: 20%, 11% and 5%, respectively). In men, the most prescribed treatments were DDAVP, ACA and von Willebrand factor (VWF) concentrates (pre-diagnosis: 5%, 4% and 2%, respectively; post-diagnosis: 9%, 6% and 4%, respectively).

Conclusions:

These data show an overall reduction in the frequency of bleeding event insurance claims after VWD diagnosis. This was coupled with an increase in treatment insurance claims for DDAVP, ACA and VWF after diagnosis. These results highlight the importance of diagnosis of VWD and treatment optimization in these patients. Also, only a minority of patients received care from a hematologist, which may impact treatment and care.

Background:

Congenital afibrinogenemia is an autosomal recessive bleeding disorder referring to the total absence of fibrinogen measured by an antigenic assay. The commonest manifestation of the disease is bleeding from mucosal surfaces, however musculoskeletal bleeding, gynecologic and obstetric complications, spontaneous bleeding, bleeding after minor trauma and during interventional procedures or thromboembolic episodes.

Objective:

We hereby report the only case of this disorder in Slovakia with a successful perioperative management of hemostasis during revision total hip arthroplasty.Method and results: Preoperatively, the patient received fibrinogen concentrate in the dose of 75mg/kg, this dose increased the level of fibrinogen after 2 hours to corresponding 170mg/dL. During surgery, the patient received fibrinogen concentrate in the dose of 25mg/kg. The patient was administered an intraoperative transfusions because of blood loss. Twenty-four hours after surgery, the fibrinogen concentrate was applied in the patient at the dose 37.5 mg/kg every 8 hours. One day after surgery, we administered fibrinogen concentrate at the dose of 37.5 mg/kg every 12 hours with a targeted level of fibrinogen in the interval of 130-150mg/dL. We continued to reduce the dose of fibrinogen concentrate. The patient was discharged safely at 12th day after surgery with level of fibrinogen above 50mg/dL. The administration of fibrinogen concentrate was combined with low molecular weight heparin.

Conclusion:

Our results in this patient with congenital afibrinogenemia who underwent the successful repeated total left hip arthroplasty reaffirm the recommendation to tailor treatment to ensure a hemostasis balance between the replacement of clotting factor (fibrinogen concentrate) and thromboprophylaxis.

Objective:

Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are two modified rFIX compounds with extended half-lives compared with standard FIX products. We report results from two head-to-head, single-dose pharmacokinetic (PK) trials comparing N9-GP with standard FIX and rFIXFc in previously-treated patients (PTPs) with congenital hemophilia B (≤2% FIX).

Methods:

paradigm™1 (NCT00956345) was a first human-dose trial in PTPs investigating the safety and PK of a single N9-GP dose. Sixteen PTPs (21-55 years) received one dose of their previous FIX product, followed by one dose of N9-GP at the same dose level (25, 50, or 100 IU/kg) with ≥7 days between doses. FIX activity was assessed up to 48 hours (standard FIX) or 168 hours (N9-GP) with additional samples at 2 and 4 weeks analyzed by one-stage clotting assay (TriniCLOT™) with product-specific standard as calibrator. paradigm™7 (NCT00956345) was a multicenter, randomized, head-to-head trial where 15 patients (21-65 years) received single injections (50 IU/kg) of N9-GP and rFIXFc with ≥21 days between doses. FIX activity was assessed for up to 240 hours using a one-stage clotting assay (SynthAFax or Actin FSL) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity–time curve from 0 to infinity, dose normalized to 50 IU/kg (AUC0-inf,norm).

Summary:

In paradigm™1, the estimated terminal half-life of N9-GP was 93 hours, 4.8 times longer than for patients’ previous product. For N9-GP, estimated incremental recovery at 30 minutes (IR30min) (1.33 IU/dL per IU/kg) was 94% and 20% higher compared with rFIX and plasma-derived FIX (pdFIX), respectively. AUC0-inf,norm with N9-GP was 10.1 times and 7.7 times higher compared with rFIX and pdFIX, respectively. Time to 3% and 1% FIX activities was 16.2 and 22.5 days, respectively. In paradigm™7, the estimated AUC0-inf,norm measured with one-stage clotting assay was 4.4 times higher for N9-GP compared with rFIXFc (9656 versus 2199 IU*h/dL). IR30min was 2.2 times higher (1.7 versus 0.8 IU/dL per IU/kg), maximum activity, dose normalized to 50 IU/kg, was 2 times higher (91% versus 45%), and FIX activity at 168 hours was 5.8 times higher (19% versus 3%). N9-GP had a longer terminal half-life (103.2 versus 84.9 hours; ratio: 1.22). Results were similar when measuring FIX activity with chromogenic assay. One patient in paradigm™1 developed transient hypersensitivity symptoms during administration of N9-GP and was excluded from PK analyses. No patient developed inhibitors in either trial, and no unexpected safety concerns were identified.

Conclusion:

These two single-dose PK trials show that N9-GP achieves higher FIX activity levels and greater AUC than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. These findings will support clinicians’ understanding of differences in PK between specific FIX products.

Objective:

Recombinant factor IX Fc fusion protein (rFIXFc) is an extended half-life therapy approved for the treatment of children and adults with hemophilia B. B-LONG parent (NCT01027364) and B-YOND extension (NCT01425723) Phase 3 studies evaluated the safety and efficacy of rFIXFc in prevention and treatment of bleeding in previously treated subjects with severe hemophilia B. This analysis evaluated clinical outcomes for over 3 years in a subgroup aged ≥50 years using B-LONG and B-YOND interim data cut 2.

Methods:

Subjects were assigned to one of the following treatment regimens: weekly prophylaxis (WP; 20–100 IU/kg every 7 days), individualized interval prophylaxis (IP; 100 IU/kg every 8–16 days), modified prophylaxis (MP-tailored dosing if IP and WP were suboptimal), and episodic treatment (ET; on-demand dosage dependent on type and severity of bleeding episode). In B-YOND, subjects could change treatment groups at any time and may appear in more than one treatment regimen. For this subgroup analysis outcomes included inhibitor development, the annualized bleeding rate (ABR), ABRs for subjects with target joints and target joint resolution, hemophilia quality of life questionnaire for adults (Hem-A-QoL), cumulative exposure, and factor consumption.

Summary:

Overall, 26 subjects ≥50 years of age (median [range], 56 [50–71] years) in B-LONG and/or B-YOND received rFIXFc (WP, n = 13; IP, n = 7; MP, n = 3; ET, n = 8). Baseline median (interquartile range [IQR]) ABR was 1 (0–5) and 20 (12–27) for subjects who received prophylaxis and on-demand treatment regimens, respectively. No subjects developed inhibitors. On-treatment overall ABRs (median [IQR]; with n ≥5) were 2.13 (1.16–4.35; WP), 1.14 (0.48–2.64; IP), and 12.83 (8.96–20.59; ET). On-treatment target joint ABR (median [IQR]; with n ≥5) was 3.17 (1.16–4.35; WP, n=9). All 19 target joints resolved with prophylactic treatment. Mean (standard deviation) total Hem-A-QoL score changed by –3.9 (10) points from baseline to last visit for 9 subjects always on prophylactic treatment during the parent and extension studies. Subjects had a median (IQR) of 3.42 (0.98–4.31) years of treatment with rFIXFc and 90 (44.0–198) cumulative rFIXFc exposure days. Factor consumption remained stable.

Conclusions:

In subjects ≥50 years of age with severe hemophilia B, these data from over 3 years of rFIXFc prophylaxis demonstrated sustained bleed control and target joint resolution while maintaining consistent factor consumption. Results are consistent with the overall study population, suggesting that rFIXFc treatment provides long-term clinical benefits for individuals with severe hemophilia B, irrespective of age and presence of target joints.

Objective:

BAY 81-8973 (Kovaltry®) is a full-length, unmodified recombinant human factor VIII (FVIII) for prophylaxis and treatment of bleeds in patients with hemophilia A. Safety and efficacy of BAY 81-8973 in children, adolescents, and adults were established in the LEOPOLD clinical trials. This analysis reports interim data from the LEOPOLD Kids extension study for patients with ≥100 exposure days (EDs) to BAY 81-8973 in the main study plus extension study.

Methods:

In LEOPOLD Kids, boys aged ≤12 years with severe hemophilia A and ≥50 EDs to FVIII received BAY 81-8973 (25–50 IU/kg) ≥2 times/wk for ≥50 EDs. Patients completing the main study could enroll in an ongoing extension study for ≥100 EDs.

Summary:

Of 51 patients who completed the main study, 46 (90.2%) entered the extension study (aged <6 years, n=22; aged 6–12 years, n=24). Patients were treated for a median (range) of 1494 (175–1989) days and accumulated 546 (67–1011) EDs in the extension study. Median (quartile [Q]1; Q3) dose per prophylaxis infusion was 37.7 (33.1; 41.8) and 30.9 (29.1; 34.9) IU/kg for younger and older patients, respectively; annual prophylaxis dose was 4984 (3679; 6529) and 4089 (3283; 5555) IU/kg. Median (Q1; Q3) annualized number of total bleeds was 2.0 (0.2; 4.2) and 1.8 (0.5; 3.0) for younger and older patients, respectively; annualized total bleed rate was 3.0 (0; 6.0) and 0 (0; 6.4) for these patients in the main study. Median (Q1; Q3) annualized total bleeds within 48 hours of prophylaxis infusion was 0.8 (0; 1.7) and 1.0 (0.1; 1.6) in younger and older patients in the extension study. Response was excellent/good in 337/405 bleeds (83.2%); data were missing for 22 (5.4%) bleeds. Most bleeds (93.5%) were mild/moderate and were spontaneous (42.4%) or trauma related (53.6%). One patient experienced a mild treatment-related serious adverse event (transient very low FVIII inhibitor titer concurrent with acute infection and positive immunoglobulin G anticardiolipin) and remained in the extension study. No change in treatment was required, and the patient was clinically well.

Conclusions:

Data from the LEOPOLD Kids extension study show that BAY 81-8973 provides safe and effective long-term prophylaxis in children with severe hemophilia A treated for a median of 4.1 years, confirming safety results observed in the main study.

Objective:

As a single gene disorder of Factor VIII (FVIII), hemophilia A (HA) is an ideal candidate for gene therapy. We present results from an ongoing Phase 1/2 study of valoctocogene roxaparvovec (BMN 270; AAV5-FVIII-SQ) gene transfer in patients with severe HA.

Methods:

As of 16 April 2018, 13 subjects (6E13 vg/kg, n=7; 4E13 vg/kg, n=6) received a single intravenous dose of valoctocogene roxaparvovec, an AAV5 vector containing a B-domain-deleted FVIII gene. Safety, efficacy, immunogenicity, and other endpoints are being evaluated.

Summary:

FVIII activity is presented as median levels over 4-week intervals. In the 6E13 cohort, FVIII activity plateaued by Week 20 post-valoctocogene roxaparvovec, with median levels between Weeks 20-104 in the non-hemophilic range ([range] 46-122 IU/dL); Week 104 median FVIII activity was 46 IU/dL ([range] 6-145 IU/dL). In the 4E13 cohort, median [range] FVIII activity increased to just below the normal range (NR) at Week 52 [n=6]: 32 [3-59] IU/dL. Prior FVIII prophylaxis subjects had median [interquartile range, IQR] annualized FVIII infusions decline from 139 [122-157] (6E13) and 156 [126-183] (4E13) to 0 [0-0.4] and 0 [0-1] 4 weeks post-infusion through last follow-up; median [IQR] annualized bleeding rates post-infusion were 0 [0-0] in both cohorts (no bleeding episodes in 5 subjects in each cohort). Mild, grade 1, asymptomatic alanine aminotransferase (ALT) increases were reported in six of seven 6E13 and four of six 4E13 subjects; one 4E13 subject had a grade 2 ALT increase. Peak ALT levels ranged from 44-141 U/L (upper limit of normal=43 U/L). All subjects had a normal ALT level at last follow-up and all subjects were off of corticosteroid therapy. No subjects developed inhibitors to FVIII.

Conclusions:

Gene transfer with valoctocogene roxaparvovec in subjects with severe HA resulted in sustained, clinically relevant FVIII activity that reduced self-reported bleeding and exogenous FVIII use 2 years post-infusion in the 6E13 cohort. FVIII activity in the 4E13 cohort was maintained at the upper range of mild HA 1 year post-infusion. Both doses enabled achievement of long-term therapeutic levels of FVIII activity and prevention of hemophilia-related bleeding with a favorable safety profile.

Background:

Emicizumab was approved by the FDA in 2017 for routine prophylaxis in PwHA with inhibitors. HAVEN 1, a phase III study in adolescent and adult PwHA with inhibitors, demonstrated that emicizumab prophylaxis significantly reduced annualized treated bleed rate by 87% (P<0.001) vs no prophylaxis. In this retrospective, post-hoc analysis, we examined the use of BPAs to treat breakthrough bleeds before and after emicizumab initiation in HAVEN 1.

Methods:

HAVEN 1 patients were included from emicizumab-treated Arms A (previously treated with only episodic BPA) and C (previously treated with prophylactic BPA) and who had participated in the non-interventional study (NIS). In both studies, bleed and treatment data collection were comparable. In the study protocol, no guidance for the treatment of bleeds was provided; and hemostatic efficacy was not measured, thus optimal treatment of bleeds cannot be accurately assessed. Additionally, only data before October 7th, 2016 are included in this analysis to better represent treatment patterns before amended BPA guidance was provided. We describe the total number of patients and bleeds, number of infusions per bleed, and the cumulative dose/kg per bleed before and after emicizumab initiation.

Results:

This analysis (48 total patients) included 24 patients each from Arm A and Arm C who participated in the NIS prior to enrollment in the HAVEN 1 trial. On average, patients received numerically fewer activated prothrombin complex concentration (aPCC) infusions with lower cumulative doses while on emicizumab as compared to prior to emicizumab administration. In Arm A, 11 bleeds were treated with aPCC resulting in an average of 1.2 aPCC infusions/ bleed and an average cumulative aPCC dose/ bleed of 95.9 U/kg while on emicizumab as compared to 136 bleeds resulting in an average of 1.7 infusions/ bleed and cumulative dose 134 U/kg prior to emicizumab. Similar findings were seen in Arm C (bleeds, aPCC infusion/cumulative dose numbers: 14,2.3/166.6 U/kg on emicizumab compared to 205, 2.6/189 U/kg prior to emicizumab.) Fewer bleeds were treated with rFVIIa and no clear trend was seen regarding how rFVIIa was used to treat bleeds. In Arm A, 11 bleeds were treated with rFVIIa resulting in an average of 1.5 infusions/ bleed and cumulative dose 212.2 µg/kg on emicizumab, vs 97 bleeds, 1.4 infusions/ bleed and cumulative dose 181.6 µg/kg prior. In Arm C, 14 bleeds were treated with rFVIIa resulting in 4.4 infusions/ bleed and cumulative dose 555.6 µg/kg on emicizumab vs 58 bleeds, 8.6 infusions/ bleed and cumulative dose 1829 µg/kg prior.

Conclusions:

Treatment of bleeds with aPCC in HAVEN 1 resulted in numerically fewer infusions and lower cumulative doses of aPCC per bleed while on emicizumab when compared to bleeds treated prior to emicizumab initiation. Treatment of bleeds with rFVIIa showed no clear trend.

Advancements in medical care for the hemophilia patients has created the need for an active and intentional process of transition from pediatric oriented health care to adult oriented health care. Instruments to measure transition “readiness” have not been validated in the adolescent and young adult (AYA) hemophilia population. The primary aim of this study was to identify the baseline state of transition readiness of hemophilia males in their ability to take charge of their own care as they transition from pediatrics to adult care using a validated Transition Readiness Assessment Questionnaire (TRAQ). Our secondary objective was: 1) To compare transition readiness between young adults who are transitioned to an adult hemophilia clinic in a separate facility versus those who continue to receive care in the same facility but transitioned to an adult provider.

Methods:

For this purpose, we conducted a cross-sectional study at the Hemophilia study of Western New York (HCWNY), Buffalo (same facility) and at Children’s Hospital of Michigan (CHM), Detroit (separate facility). Inclusion criteria: 1) males who are currently 16-21 years old, 2) diagnosis of hemophilia A and B regardless of severity, 3) ability to read English at a grade 8 level. TRAQ is a 20-item, 5- domain patient-reported assessment of health and health care self-management skills with possible scores ranging from 1 (low) to 5 (optimal). Parents/legal guardians of patients aged 16 to 17 and patients aged 18-21 were mailed a letter explaining the study in detail. The willing participants were directed to the questionnaire link. The responses were anonymous which were directly imported into excel spread sheet without collecting any identifying information of the participants.

Results:

A total of 13 individuals at the two sites participated. Amongst these, there were 5 from the HCWNY site, 1 with mild hemophilia and 1 patient reported unknown severity. The mean overall TRAQ score was 4+0.8. The mean scores for the different subscales were: managing medications (4.2+0.8), appointment keeping (4.1+0.9), tracking health issues (3.6+1.2), talking with providers (4.4+1.2) and managing daily activities (4.1+1.1). No differences in the overall and the subscales scores was noted between the two centers (Wilcoxon rank sum for all p>0.05).

Conclusions:

Our results suggest that the hemophilia youth in our population appear to have good readiness to transition from pediatric to adult care. We did not find a difference between the two different clinical care settings. The tracking health issues portion of TRAQ demonstrated the least readiness. Our study demonstrates that transition readiness assessments can be implemented in the hemophilia treatment centers, which can be used to guide clinical care.

Objectives:

Von Willebrand disease (VWD) is a common inherited bleeding disorder, but awareness among healthcare professionals is low. Timely and proper diagnosis integral for reducing VWD burden, access to proper therapies, and avoidance of improper medication. Hence, we sought to estimate the prevalence of undiagnosed VWD among commercially insured patients in the United States with a recent history of bleeding events.

Methods:

Patients with a VWD diagnosis who were users of or candidates for von Willebrand factor were identified from the IMS PharMetrics Plus Database (2006─2015). We constructed a unary patient-finding model based on 12 prediagnosis variables that best defined this population, and applied to a set of undiagnosed patients with recent bleeding events from the same database. ‘Best fit’ (confidence level 5/6) and ‘good fit’ (confidence level 3/4) patients were identified. Prevalence of symptomatic undiagnosed VWD in the commercially insured population was estimated from the best-fit and good-fit population size (projection factor 10.4).

Summary:

Overall, 507 668 undiagnosed patients with recent bleeding events were identified (86% female, 14% male). Application of the VWD model identified 3318 best-fit and 37 163 good-fit patients; 91% of best-fit patients were females aged <46 years, with heavy menstrual bleeding the most common claim. Projection to the full commercially insured US population provided an estimate of 35 000 - 387 000 symptomatic, undiagnosed patients with VWD.

Conclusion:

There is a high prevalence of symptomatic, undiagnosed VWD (undiagnosed bleeding disorder patients that likely have VWD) in the commercially insured population. This data underscores the importance of improved disease education to both patients and the first line treaters, including OBGYN, emergency room, and pediatricians. Enhanced awareness of VWD symptoms and their impact, and of screening and testing procedures, may improve diagnosis of VWD and reduce the disease burden.

Introduction & Objective:

Standard approaches to prophylaxis may be further improved by taking into account individuals’ pharmacokinetic (PK) profile, thereby increasing the likelihood of therapeutic success [Valentino 2012, Valentino 2014, Lissitckov 2017]. One study demonstrated an association between more time spent above higher FVIII levels (20 and 30%) and lower bleeding rates [Valentino 2016]. Furthermore, a consensus statement proposes to target specific factor levels to tailor treatment for different patient profiles [Iorio 2017]. Additionally, new extended half-life treatments provide physicians with another option to personalize therapy. As more data and therapeutic options become available, it is important to understand physicians’ current perceptions and practice patterns with respect to personalizing haemophilia A care in the US.

Materials & Methods:

Physicians in the US who treat persons with severe hemophilia A and provided informed consent were eligible to complete a cross-sectional, double-blinded web-based survey to evaluate physicians’ perceptions and practice patterns with respect to measuring PK and if/how they personalize FVIII treatment with this information, when and to what extent. This abstract presents results from the first half of the survey which focused on ways in which physicians measure FVIII pharmacokinetics and personalize care.

Results:

Ninety physicians completed the survey. The top three most important considerations for personalizing therapy in general were bleeding history, patient goals, and physical activity. The most commonly cited reason for conducting a PK assessment was product switch (74%) while the most common barrier was patient willingness/availability (60%). Physicians reported using a PK-based approach to personalize treatment in 25% (median) of their severe patients. Of physicians who use PK, trough levels (91%), half-life (58%), peak levels (56%) and Area Under the Curve (22%) were used. While 12% of these physicians reported using all PK parameters, 18% only used trough levels. 23% reported using peak, trough and half-life in combination. Most physicians (89%) indicated using PK data to adjust dose and 50% also used it as a patient education opportunity.

Conclusions:

There was significant variability across respondents as to how PK is assessed and how PK parameters are used in treatment decisions, suggesting an opportunity to increase awareness and use of PK-guided personalization to ultimately improve patient care. Additional education on the definitions and details of PK-guided dosing could help improve overall adoption of this treatment strategy and align the community on what it means to personalize therapy using PK information. More research studying the association between PK-guided prophylaxis and outcomes is encouraged to better understand how best to personalize PK-based prophylaxis for different patient scenarios.

Background:

Congenital FXD is a rare bleeding disorder characterized by spontaneous joint and mucocutaneous bleeding and gastrointestinal or intracranial hemorrhage. pdFX is a US- and EU-approved treatment for congenital FXD, but data in children <12 years have been unavailable.

Aims:

To investigate pdFX efficacy, safety, and pharmacokinetics in children <12 years with moderate to severe congenital FXD.

Methods:

In this 6-month, open-label, multicenter, phase 3, prospective study in children <12 years, all subjects had a confirmed diagnosis of moderate to severe congenital FXD (basal FX:C <5%), severe bleeding history, or an F10 gene mutation causing a documented severe bleeding type. Subjects received routine prophylaxis at recommended 40–50 IU/kg twice weekly to maintain trough FX:C levels ≥5%. Each investigator assessed efficacy based on standardized criteria and presence of breakthrough bleeding. All subjects provided informed consent and the protocol was approved by appropriate independent ethics committees.

Results:

Mean age of the 9 trial completers was 6.8 years. Eight subjects had severe and 1 had moderate FXD. Overall, 537 prophylactic infusions were administered; mean dose/child was 38.6 IU/kg. Ten bleeds in 3 of 9 children were reported: 6 minor, 3 major, 1 unassessed. Investigators rated overall pdFX efficacy as excellent in all subjects. Overall mean incremental recovery was 1.74 IU/dL per IU/kg. FX trough levels were maintained >5% after visit 4 (days 29–42) in all subjects.

A total of 28 treatment-emergent adverse events (TEAEs) were reported in 8 children; none were considered pdFX related. No significant changes were noted in vital signs, physical exams, or laboratory measurements. No evidence of inhibitor development was seen.

Conclusion:

pdFX is efficacious in the prophylaxis of bleeding episodes in subjects <12 years with moderate to severe FXD. Safety profile in this population is consistent with previous results in subjects ≥12 years.

Funding: Bio Products Laboratory

Background:

A high-purity plasma-derived FX concentrate (pdFX) has been developed for treatment of hereditary FX deficiency, an autosomal recessive disorder.

Aim:

This post hoc analysis describes the pharmacokinetics, safety, and efficacy of pdFX in 10 women and girls with hereditary FX deficiency.

Methods:

In this open-label study, subjects (10 women/girls, 6 men/boys) aged ≥12 years with moderate or severe FX deficiency (basal plasma FX activity ≤5 IU/dL) were enrolled and received 25 IU/kg pdFX for on-demand treatment of bleeding episodes or preventative use for up to 2 years. All subjects provided informed consent and the protocol was approved by appropriate independent ethics committees.

Results:

Nine women and girls had severe and 1 had moderate FX deficiency, were aged 25.5 (median; range 14–58) y, and received a total of 267 pdFX infusions (178 for on-demand and 89 for preventative treatment). Men and boys (5 severe and 1 moderate FX deficiency) received a total of 159 pdFX infusions (64 on-demand; 95 preventative). The mean number of infusions per subject per month was higher among women and girls (2.48) than males (1.62). The mean pdFX incremental recovery was similar between women/girls and men/boys (2.05 vs 1.91 IU/dL per IU/kg, respectively), as was mean half-life (29.3 and 29.5 h, respectively). Among women and girls, 132 assessable bleeding episodes (61 heavy menstrual bleeding, 47 joint, 15 muscle, and 9 other) were treated with pdFX. Women and girls reported a treatment success rate (ie, subject rating of “excellent” or “good” response to pdFX) of 98%, comparable to the 100% treatment success rate among men and boys. After study completion, 2 subjects received pdFX for hemostatic cover during obstetric delivery. Additional infusion, bleed, and safety data will be presented.

Conclusion:

These results show that, in women and girls with moderate or severe hereditary FX deficiency, who experience reproductive tract and other bleeding events, pdFX was safe and effective. The pharmacokinetic profile of pdFX in women and girls was similar to that of men and boys.

Funding: Bio Products Laboratory

Background:

Gene transfer for hemophilia offers the potential to convert the disease from a severe to mild phenotype with a single treatment. AMT-060 consists of an AAV5 vector containing a codon-optimized wildtype hFIX gene under control of a liver-specific promoter.

Objective:

This phase 1/2 study investigates the safety and efficacy of AMT-060 at 2 dose levels in adults with moderate-severe or severe hemophilia B.

Methods:

Multi-national, open-label, dose-escalating study in patients with factor IX (FIX) activity ≤2% of normal, and a severe bleeding phenotype (prophylactic exogenous FIX; or ondemand exogenous FIX, plus ≥4 bleeds/year or hemophilic arthropathy). Patients received either 5x1012 gc/kg (n=5) or 2×1013 gc/kg (n=5) of AMT-060 iv. Efficacy assessments include endogenous FIX activity (measured ≥10 days after use of exogenous FIX); reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events, immunological and inflammatory biomarkers.

Summary:

There were no screening failures due to AAV5 neutralizing antibodies. Mean FIX activity in the lower dose cohort was 5.2% (min-max, 3.0-6.8%; n=4; 1 patient remaining on prophylaxis excluded) during 1 year of follow-up, and 6.9% (min-max, 3.1-12.7%; n=5) in the higher dose cohort during 26 weeks follow-up. Eight of 9 patients on FIX prophylaxis discontinued use after AMT-060 infusion. Follow-up to up to 1.5 years will be presented, with annualized reduction of exogenous FIX use and spontaneous bleeding rates. Mild, temporary elevations in ALT were observed in 3 patients with higher mean FIX activity (6.3-12.7%; 1 in the lower and 2 in the higher dose cohort). Each received a tapering course of prednisolone. ALT elevations were not associated with changes in FIX activity or a capsid-specific T-cell response.

Conclusions:

Patients continue to show sustained clinical benefit and endogenous FIX activity with no T-cell activation ≥1 year after a single infusion of AMT-060.

Objective:

This report assesses the changes in bleeding patterns as previously treated severe hemophilia A patients were switched from their pre-study standard factor VIII (FVIII) prophylactic treatment regimen to prophylaxis with BAX 855 - an extended half-life, pegylated, full-length recombinant FVIII built on ADVATE - during their participation in the pivotal trial.

Methods:

Patients’ informed consent and appropriate ethics committee approvals were obtained. At baseline, eligible patients reported their pre-study treatment regimen and average annualized bleeding rate (ABR) for the previous 3-6 months. Patients assigned to the prophylactic arm were to receive 45±5 IU/kg of BAX 855 twice weekly for ≥50 exposure days or approximately 6 months. This per-protocol analysis included 101 treated patients in the prophylactic arm.

Summary:

The overall mean (SD) ABR for these treated patients was 3.7 (4.7), which was lower than the ABR for the 17 patients treated on-demand during the study (40.8 [16.3] - who were all treated on-demand pre-study). Of the 101 subjects in BAX 855 prophylactic arm, 82 were treated on prophylaxis and 19 were treated on-demand during the pre-study period. The BAX 855 prophylactic dosing frequency was reduced by a mean (SD) of 26.7% (27.9) compared to the frequency reported in the pre-study period, which is approximately equivalent to one less prophylactic infusion per week when using BAX 855 for prophylaxis. The mean dose per prophylactic infusion was higher for the BAX 855 treatment regimen compared to pre-study (44.53 vs 38.12 IU/kg), but FVIII consumption per week was lower during the study compared to pre-study (83.96 vs 97.79 IU/kg/week). More patients treated on BAX 855 prophylaxis during the study treatment period had zero bleeding episodes compared to during their pre-study period: 37.8% vs 23.2%. The mean ABR was lower for subjects on BAX 855 prophylaxis compared to pre-study: 4.13 vs 9.74.

As expected, the 19 patients treated on-demand pre-study had a higher mean ABR (31.53) and all experienced bleeding (ie, none had zero hemarthroses during the pre-study period) compared to during their BAX 855 prophylactic treatment period (mean ABR of 1.68 and 47.4% had zero bleeding episodes).

Conclusions:

These results further demonstrate the benefit of BAX 855 prophylaxis (45±5 IU/kg twice weekly) and support its efficacy profile for the prevention of bleeding when used twice weekly, which suggests that fewer infusions may be needed to maintain prophylactic efficacy.

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.

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.

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.

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:

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 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.

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.

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.

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