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:

PUPs B-LONG aimed to evaluate the safety and efficacy of recombinant factor IX Fc fusion protein (rFIXFc) for prevention and treatment of bleeds in previously untreated patients (PUPs) with hemophilia B.

Methods:

In this open-label, multicenter, multinational, Phase 3 study (NCT02234310), male PUPs aged <18 years with hemophilia B (≤2 IU/dL endogenous FIX) were to receive prophylaxis with rFIXFc. Investigators could treat patients episodically before initiating prophylaxis. Primary endpoint was occurrence of inhibitor development. Secondary endpoints included annualized bleed rate (ABR) and assessment of response to treatment of bleeding episodes with rFIXFc.

Summary:

Of 33 patients enrolled, 26 (79%) were <1 year old, 6 (18.2%) had a known family history of inhibitors, 28 (84.8%) received prophylaxis (17 [51.5%] switched from episodic treatment), and 5 (15.2%) received episodic treatment only. Twenty-seven (81.8%) patients completed the study. Twenty-one (63.6%), 26 (78.8%), and 28 (84.8%) patients had ≥50, ≥20, and ≥10 exposure days (EDs) to rFIXFc during the study, respectively. One patient on prophylaxis developed a low-titer inhibitor (<5.00 BU/mL) after 11 EDs; rate of inhibitor development was 3.0% (1/33 patients). Twenty-three (69.7%) patients had 58 treatment-emergent serious adverse events (TESAEs); 2 were assessed as treatment related (FIX inhibition and hypersensitivity in 1 patient, resulting in withdrawal). Median ABR (prophylaxis) was 1.2 (Table 1). Median number of rFIXFc infusions required to resolve a bleeding episode was 1 (Table 1). For infusions with an evaluation, subjects’ assessment of response to bleeding episode treatment was rated as excellent/good for 22/22 (100%) infusions in the episodic treatment group and 50/57 (87.7%) infusions in the prophylaxis treatment group.

Conclusions:

The study population was representative of PUPs with hemophilia B. Prophylaxis and treatment of bleeding episodes with rFIXFc were effective and generally well tolerated, without unanticipated safety findings. Type and incidence of TESAEs were similar to those expected for the pediatric hemophilia population.

Objective:

The adolescent/adult pivotal phase 3 pathfinder 2 trial assessed N8-GP (turoctocog alfa pegol, ESPEROCT^®) use for routine prophylaxis and treatment of bleeds in previously treated patients (PTPs).

Methods:

pathfinder 2 was a multi-center, multi-national, single-arm study evaluating safety, efficacy and pharmacokinetics. Adolescents/adults (aged ≥12 y) with severe hemophilia A were administered prophylaxis (50 IU/kg Q4D) in the main phase with option for eligible patients (0-2 bleeds in prior 6 months) to randomize (2:1) to 75 IU/kg Q7D or 50 IU/kg Q4D during extension 1 (24 weeks) and continue treatment into extension 2. An on-demand group was included throughout. Current analysis covers January 2012 through December 2018.

Summary:

Of the 186 PTPs (including 46 [25%] from the US) enrolled in the main phase, 150 (81%) started extension 1, 139 (75%) completed extension 1, and 128 (69%) completed the study. Mean age was 31.1 years, weight 75 kg and BMI 24.3.

The complete trial covers 785 patient-years of treatment (66,577 exposure days [ED]) during which there were 2,758 bleeds, including 1,807 (66%) spontaneous bleeds and 1,735 (63%) joint bleeds. Twelve patients treated on-demand for a mean 3.1 years reported nearly half of all bleeds (1,270, 46%), including 971 (54%) spontaneous bleeds and 627 (36%) joint bleeds. Hemostatic efficacy was rated excellent/good in 2,470 (90%) episodes; 2,614 bleeds (95%) were treated with 1-2 injections.

Of 175 patients on prophylaxis, 55 of 110 eligible were randomized in extension 1. For 177 patients treated with 50 IU/kg Q4D prophylaxis for 613 years (57,723 ED), 126 (71%) experienced 1,312 bleeds. For 61 low-bleed patients with 134 years (7,255 ED) on 75 IU/kg Q7D prophylaxis, 53 (87%) experienced 176 bleeds. Median ABRs are shown in the TABLE.

N8-GP mean trough levels were 3.1 IU/dL on 50 IU/kg Q4D and 1.0 IU/dL on 75 IU/kg Q7D.

A total of 1,827 adverse events were reported over 785 exposure years, including 63 serious adverse events. One patient with an intron 22 inversion developed a low-titer inhibitor at 93 ED and was withdrawn when it progressed to >5 BU. Non-neutralizing anti-PEG antibodies were seen at baseline in 12 patients (6.5%) prior to first N8-GP exposure and 11 (5.9%), who had negative anti-PEG at baseline, had positive antibodies after exposure.

Conclusion:

These data support the safety and efficacy of N8-GP in a controlled phase 3 trial setting in adolescents/adults. Prophylaxis with N8-GP with a consistent dose/interval (50 IU/kg Q4D) was effective in preventing bleeds; extended dosing was evaluated as successful for a subgroup of low-bleed patients. No significant safety issues were identified. 

Objective:

The completed pediatric phase 3 pathfinder 5 trial assessed the safety and efficacy of N8-GP (turoctocog alfa pegol, ESPEROCT^®) use for routine prophylaxis and treatment of breakthrough bleeds in previously treated children.

Methods:

pathfinder 5 was a multicenter, multinational, single-arm study evaluating safety, efficacy, and pharmacokinetics. Children (aged <12) with severe hemophilia A were administered prophylaxis (target 60 [50-75] IU/kg twice weekly) in the main phase (26 weeks) followed by an extension phase. Current analysis covers study initiation (February 2013) through completion (September 2018).

Summary:

Of the 68 children (34 aged 0-5, 34 aged 6-11) enrolled, 63 completed the main phase and 62 completed the extension. Most (95%) were previously on prophylaxis. The total study period amounted to 306 patient-years (32,138 exposure days); median (mean) patient exposure was 4.9 (4.5) years.

Overall, 838 adverse events (AEs) were reported; 18 serious AEs included 2 possibly/probably related to N8-GP (severe allergic reaction [1] and increasing bleeding symptoms [1]). No inhibitor development was observed in the trial. Two AEs resulted in withdrawal; a third patient with severe allergic reactions (after 4 doses) that resolved after 2 hours without any treatment met preestablished withdrawal criteria. There were no anti-PEG antibodies of clinical significance; however, 21 (31%) patients had anti-PEG antibodies at baseline (prior to exposure), and 1 patient had a single positive measurement after exposure at a titer <1.

Overall, 55 patients (81%) reported 330 bleeds during the study; most were traumatic (67%). The success rate for hemostasis was 84% (excellent/good); 71% were treated with 1 injection, and 88% of patients were successfully treated with 1-2 injections. Median (mean) utilization for bleeds was 68 (95) IU/kg.

Median ABRs are shown below; estimated mean ABR was 1.1. Forty-seven percent of children had no spontaneous bleeds throughout the trial. Of 13 children with 17 target joints at baseline, 77% (main phase) and 46% (complete trial) reported no bleeds in their target joints. For those previously on prophylaxis, the mean observed ABR was 2.3 compared with the historical ABR of 6.4. The mean prophylaxis dose was 64.7 IU/kg with an interval of 3.5 days.

N8-GP prolonged single dose half-life by 1.9x compared with the child’s prior FVIII product. The mean trough levels on twice-weekly dosing were 0.019 IU/mL (0.016 ages 0-5, 0.024 ages 6-11).

Conclusion:

These data support the safety and efficacy of N8-GP in a controlled phase 3 trial setting in children. Prophylaxis with N8-GP using a consistent dose/interval (65 IU/kg twice weekly) was effective in preventing bleeds. No unexpected safety issues were identified. 

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:

Inhibitor development is the most serious complication of hemophilia A therapy. Immune tolerance induction (ITI) is the gold standard for inhibitor eradication, restoring factor VIII (FVIII) responsiveness. Retrospective data on ITI therapy using rFVIIIFc have been reported (Carcao et al. Haemophilia. 2018). The ReITIrate study (NCT03103542) was designed to prospectively evaluate success of rescue ITI with rFVIIIFc.

Methods:

ReITIrate, a prospective, interventional, multicenter, open-label study, enrolled patients with severe hemophilia A and inhibitors, who failed previous ITI attempts. The primary purpose is to describe the outcome of ITI performed with rFVIIIFc (200 IU/kg/day) within a maximum of 60 weeks. Here, patient baseline characteristics are reported using descriptive statistics and listings.

Summary:

Sixteen subjects were included in the study between November 2017 and December 2018. The median (range) age at study enrollment was 7.5 (2–46) years. Seven subjects had a known family history of inhibitors. The median (range) number of prior ITI attempts was 1 (1–3) and the median (range) total ITI duration was 51.5 (12–155) months. All subjects had previously received high-dose ITI, with 3 subjects receiving plasma products, 6 subjects receiving recombinant products, and 7 subjects receiving both recombinant and plasma products for previous courses of ITI. Four subjects received prior immunomodulatory therapy. The median (range) inhibitor titer at screening and historical peak were 11 (0.9–635) BU/mL and 127 (8–3000) BU/mL, respectively. During the 12 months prior to enrollment, the median (range) number of bleeds was 5 (0–24); 11 subjects used activated prothrombin complex concentrate (aPCC) for treatment of bleeds, 5 subjects received recombinant factor VIIa (rFVIIa), and 1 subject each received FVIII/von Willebrand factor, recombinant FVIII, and tranexamic acid. Twelve subjects received prophylaxis with bypassing agents during this period (10 aPCC, 1 rFVIIa, and 1 both products).

Conclusions:

This is the first prospective study describing rescue ITI with an extended half-life recombinant FVIII product. Enrolled subjects had multiple risk factors for poor ITI outcomes and a long duration of previous ITI. There is an unmet need for successful tolerization in such patients, allowing regular FVIII prophylaxis and potentially leading to improved clinical outcomes and quality of life.

Objectives:

This study has a primary objective to determine the efficacy of VWF/FVIIII concentrate (Wilate) in the prophylactic treatment of previously treated patients with type 3, type 2 (except 2N), or severe type 1 VWD.

Secondary objectives of this study will be to collect data to 1) Assess the VWF:Ac and VWF:Ag incremental IVR of VWF/FVIIII concentrate over time, 2) Assess the safety and tolerability of VWF/FVIIII concentrate in this indication.

Also the study will examine, the efficacy of VWF/FVIIII concentrate in the treatment of breakthrough bleeding episodes (BEs), and in surgical prophylaxis, as well as the quality of life (QoL) during prophylaxis with VWF/FVIIII concentrate.

Methods:

The study is planned to enrol 28 PTPs aged ≥6 years and with VWD type 1, 2A, 2B, 2M, or 3. Eligible patients must be receiving on-demand treatment with a VWF-containing product, with at least 1, and an average of ≥2, documented spontaneous BEs per month in the preceding 6 months requiring treatment with a VWF-containing product. This will be assessed as part of a run in observational study to collect bleeding rate prior to the start of prophylaxis.

From the beginning of the study, patients will receive prophylactic treatment with VWF/FVIIII concentrate for 12 months and record all BEs in a patient diary. Based on these data, the frequency of BEs and the annualized bleeding rate (ABR) under prophylactic treatment will be calculated.

Treatment efficacy of BEs will be assessed by the patient (together with the investigator in case of on-site treatment) using a 4-point scale (excellent, good, moderate, none)
In case patients undergo surgeries, efficacy of VWF/FVIIII concentrate will be assessed at the end of surgery by the surgeon and at the end of the postoperative period by the haematologist. In both cases, predefined assessment criteria will be used. In addition, an overall assessment of efficacy will be made at the end of the postoperative period by the investigator.

Summary/conclusions:

Prophylactic treatment in other congenital bleeding disorders is widely accepted as the standard of care to prevent bleeding and preserve quality of life in patients. This form of treatment in VWD is not well characterized prospectively as yet. This study will provide data on the efficacy of prophylactic treatment in reducing the rate of bleeding and on the impact of prophylaxis on the quality of life in VWD patients.
 

Background:

Recombinant adeno-associated viruses (rAAV) are replication-deficient, non-integrating viruses commonly used as vectors for gene therapies currently in clinical development. Systemic administration of gene therapy raises the possibility of vertical germline transmission of the vector DNA.

Aim:

Here, we investigated the possibility of germline transmission following IV administration of an AAV serotype 5 vector designed for the liver-directed expression of human Factor IX which is being studied in clinical trials for hemophilia B.

Methods:

Since hemophilia B predominantly occurs in male patients, paternal germline transmission was investigated in mice in a GLP compliant study, according to current gene therapy guidelines (EMEA/273974/2005). Male C57Bl/6 mice (n=15) each received a single intravenous infusion of 2x1014 gc/kg AAV5-hFIX and were mated 6 days later with untreated female mice (n=30). On day 20 post-treatment, males were sacrificed and the seminal vesicle, epididymis, testes and a sperm sample were collected. Successfully mated females were necropsied on day 17 of gestation and the uterus, placenta and fetuses collected for each female. Each fetus was examined for viability and externally visible abnormalities. All samples were analyzed for vector DNA by QPCR.

Results:

No effect of treatment was observed on male mating performance, fertility indices, maternal body weight, food consumption, pregnancy performance, external fetal abnormalities, or fetal weights. Vector DNA levels of up to 2x106 gc/μg gDNA were detected in male reproductive tissues (epididymis, seminal vesicle, sperm, and testes), but not in female uterus, placenta and offspring. Although vector DNA was detected in the reproductive tissues of males, there was no evidence of transmission of vector DNA to female reproductive tissues or to the fetuses.

Conclusion:

The risk of paternal germline transmission following AAV5-based vector administration is therefore considered to be low.

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:

The Evolving Treatment of Hemophilia’s Impact on Neurodevelopment, Intelligence and Other Cognitive Functions (eTHINK) study aims to evaluate the impact of hemophilia on neurodevelopment and cognitive function through the use of validated instruments and to identify covariates that drive differences in neuropsychological performance.

Methods:

A sample of at least 510 males aged 1-21 years (~25 per age) with hemophilia A or B (any severity, with or without inhibitors) will be enrolled in a cross-sectional, non-interventional study. Following ethics review and informed consent, data collected will include a structured developmental and hemophilia history interview, a standardized neurologic examination, and a comprehensive neuropsychological assessment of cognitive/motor development (Bayley-III), intelligence (WPPSI-IV/WASI-II), attention/processing speed (CogState™), executive function (BRIEF-P/BRIEF2/BRIEF-A), mood and behavior (BASC-3), and adaptive behavior (ABAS-3). Assessments will include objective tests as well as parent and patient self-report rating scales. Z scores will be derived from published general population norms for each instrument and analyzed to develop hemophilia population specific norms. Secondary analysis for predictors of outcome will include regression modeling and chi-square tests of top vs bottom quartile responses.

Summary:

Initiated in the early 1990s under Centers for Disease Control, Maternal and Child Health Bureau, and National Institutes of Health, the Hemophilia Growth and Development Study (HGDS) evaluated the impact of hemophilia on neurodevelopment, executive function, and intelligence. The 4-year observational study enrolled 333 patients from 14 US centers, aged 6-18 years at baseline (62% HIV+), who underwent annual/semi-annual comprehensive assessments including neurologic examination, neuroimaging (MRI), and neuropsychological assessment. Results suggested that hemophilia and HIV had independent effects at baseline and follow-up. Baseline neurologic examination findings were common, as were progressive abnormalities of gait/coordination. Imaging showed baseline CNS bleeds in 12% of patients and new CNS bleeds (2% per year), which often occurred in the absence of reported head trauma. HIV+ children were more likely to show lower scores on neuropsychological assessments. Academic/adaptive skills were lower than expected based on mean IQ, and more behavioral/emotional problems were seen, including attention abnormalities related to known/silent CNS bleeds. There was a large shift in mean scores in IQ and achievement for the children with more severe hemophilia. Six small studies published between 1996 and 2009 reported impacts on academic achievement, attention, and behavior.

Conclusions:

HGDS established 25 years ago that hemophilia and HIV have independent effects on cognitive and behavioral function in children with hemophilia. Since then, standards of care in hemophilia treatment have changed significantly, but no follow-up studies have investigated whether these changes have affected the profile of neurocognitive outcomes in hemophilia. We therefore designed the eTHINK study to provide valuable insights into whether subgroups of children and young adults with hemophilia remain at risk for impaired neuropsychological outcomes.

Objective:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. In the PROTECT VIII study, BAY 94-9027 provided effective protection against bleeds and was well tolerated with twice-weekly, every-5-day, and every-7-day prophylaxis in patients with severe hemophilia A. We report interim safety data from the PROTECT VIII extension study evaluating long-term outcomes in patients using BAY 94-9027 prophylaxis for >5 years .

Methods:

Previously treated patients aged 12 to 65 years with severe hemophilia A were enrolled in PROTECT VIII, in which they received BAY 94-9027 for 36 weeks on demand or as twice-weekly (30–40 IU/kg), every-5-day (45–60 IU/kg), or every-7-day (60 IU/kg) prophylaxis. Patients could subsequently participate in an extension study with the same or a different regimen. Adverse events (AEs), anti-PEG antibodies, inhibitor development, renal safety, and plasma PEG levels were evaluated during the extension phase.

Summary:

One hundred twenty-one of 134 patients from PROTECT VIII continued in the extension study receiving BAY 94-9027 either on demand (n=14) or as prophylaxis (n=107). At data cutoff (January 2018), patients aged 15 to 67 years at time of analysis (median age, 40 y) had a median (range) of 1420 (297–1965) days in the trial since enrollment and a median (range) of 223 (23–563) exposure days . Prophylaxis patients were treated either twice weekly (n=23), every 5 days (n=33), every 7 days (n=23), or switched frequency during the extension (n=28) . Overall, 9 patients (7.4%) experienced treatment-related AEs during the extension classified as either mild (n=4), moderate (n=4), or severe (n=1) . Two patients (1.7%) experienced 3 SAEs considered to be treatment-related (elevated liver function tests in a patient with hepatitis C ; 2 incidences of back pain); these 2 patients discontinued the study. Transient low-titer anti-PEG antibodies were detected at a single visit in 8 patients but were not associated with clinical events. No patients developed FVIII inhibitors or had sustained levels of detectable PEG in plasma . No specific changes in renal parameters were observed.

Conclusions:

During the ongoing PROTECT VIII extension, BAY 94-9027 prophylaxis was well tolerated for >5 years, and no patients developed FVIII inhibitors.

Objective:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. In the PROTECT VIII Kids trial, BAY 94-9027 was efficacious for the prevention and treatment of bleeding episodes in previously treated children with severe hemophilia A. We report interim long-term efficacy and safety data from the PROTECT VIII Kids extension study.

Methods:

In PROTECT VIII Kids, previously treated patients (PTPs) aged <12 years with severe hemophilia A received BAY 94-9027 prophylaxis twice weekly (25‒60 IU/kg), every 5 days (45‒60 IU/kg), or every 7 days (60 IU/kg). Patients completing ≥50 exposure days (EDs) and ≥6 months in the main study or a 12-week safety substudy (part 2) that enrolled PTPs aged <6 years could continue in the optional extension for an additional ≥50 EDs.

Summary:

Fifty-nine of 73 patients treated with BAY 94-9027 in PROTECT VIII Kids (main study or part 2) continued in the extension (median [range] age at enrollment in the main study, 5.0 [2–11] years). At data cutoff (January 2018), patients had a median (range) of 1456 (351–1665) days in the trial (main study or part 2 plus extension). Patients in the extension received prophylaxis twice weekly (n=20), every 5 days (n=20), every 7 days (n=8), or switched prophylaxis frequency during the extension (variable frequency; n=11). Median (range) dose/infusion was 52.1 (19–62) IU/kg. Median annualized bleeding rate (ABR) for total bleeds was 1.8 for all patients and 0.8, 1.1, 2.1, and 3.2 for those treated twice weekly, every 5 days, every 7 days, or with varying frequency, respectively. Median ABR for joint bleeds in all patients was 0.7. During the extension, 3 patients (5.1%) experienced treatment-related adverse events (AEs) classified as mild (n=1), moderate (n=1), or severe (n=1). One patient discontinued because of a serious AE that was not related to treatment. No confirmed FVIII inhibitors or anti-PEG antibodies were observed; no patients had sustained levels of detectable PEG in plasma.

Conclusions:

Long-term treatment (up to ~4.5 years) with BAY 94-9027 prophylaxis was efficacious and well tolerated in previously treated pediatric patients with severe hemophilia A.

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:

In the PROTECT VIII phase 2/3 trial, the extended–half-life recombinant factor VIII product BAY 94-9027 provided effective bleed protection with twice-weekly, every-5th-day, and every-7th-day prophylaxis for 36 weeks. Herein, we report interim efficacy data from the PROTECT VIII extension study in patients receiving BAY 94-9027 prophylaxis for up to 5.4 years.

Methods:

In the PROTECT VIII trial, previously treated males aged 12 to 65 years with severe hemophilia A received BAY 94-9027 for 36 weeks on demand or for prophylaxis either twice weekly (30–40 IU/kg), every 5 days (45–60 IU/kg), or every 7 days (60 IU/kg). Patients could continue in the extension study using the same or a different regimen. Bleeds were recorded in electronic patient diaries, and annualized bleeding rates (ABRs) were calculated.

Summary:

Of 134 patients enrolled in PROTECT VIII, 121 patients aged 15 to 67 years (median age, 40 years) at the data cutoff (January 2018) continued in the extension with either on-demand treatment (n=14) or prophylaxis (n=107). At the time of analysis, patients had spent a median of 3.9 years (range, 297–1965 days) in the study since enrollment, with a median of 223 (range, 23–563) exposure days. Median (quartile [Q] 1; Q3) ABR for total bleeds during the extension study was 34.1 (20.3; 36.6) for on-demand patients and 1.6 (0.3; 4.6) for prophylaxis patients. Median (Q1; Q3) ABR for joint bleeds was 0.9 (0; 3.3) for prophylaxis patients during the extension. Median (Q1; Q3) ABR for total bleeds during the extension was similar for patients receiving prophylaxis twice weekly (1.7 [0.8; 3.6]; n=23), every 5 days (1.2 [0; 4.6]; n=33), and every 7 days (0.7 [0; 1.6]; n=23); among patients who switched prophylaxis frequency during the extension (n=28), total ABR was 3.1 (1.2; 6.2). Compared with the main study, ABR during the extension was further reduced in patients who remained in their treatment arm, including patients receiving prophylaxis every 7 days (median [Q1; Q3] main study ABR for total bleeds, 0.96 [0; 4.3]) . Of patients receiving prophylaxis, 20.6% had zero bleeds during the extension. No safety issues were identified.

Conclusions:

Good bleeding control was maintained with BAY 94-9027 prophylaxis with extended intervals of every 5 days and every 7 days throughout the PROTECT VIII extension study for up to >5 years.

Objective:

BAY 94-9027 is an extended–half-life recombinant factor VIII (FVIII) product. Efficacy in maintaining hemostasis during major surgery was evaluated in a subset of patients with severe hemophilia A in the phase 2/3 PROTECT VIII study.

Methods:

Patients aged 12–65 years requiring major surgery during PROTECT VIII or its ongoing extension were included in the analysis. Patients with severe hemophilia A undergoing major surgery who were not enrolled in PROTECT VIII but met all study inclusion and exclusion criteria also were eligible to participate. BAY 94-9027 dosing during the perioperative period was based on preoperative pharmacokinetic measurements and adjusted at the physician’s discretion. Types of procedures and duration of surgeries, BAY 94-9027 consumption on the day of surgery, intraoperative blood loss, surgeon assessment of hemostasis during surgery, and need for blood transfusion were evaluated.

Summary:

17 patients (median [range] age, 37 [13–61] years) underwent 20 major surgeries, including 15 orthopedic surgeries (9 joint replacements [hip, n=1; knee, n=6; ankle, n=2], 2 open synovectomies, 3 arthroscopies, and 1 thigh hematoma evacuation), 3 complex dental extractions, 1 penile prosthesis, and 1 inguinal hernia repair at data cutoff (January 2015). Median (range) surgical duration was 102 (17‒217) minutes, and median (range) total dose used on day of surgery, including preoperative, intraoperative, and postoperative infusions on that day, was 72.4 (43‒136) IU/kg. Median (range) number of FVIII infusions on the day of surgery was 2 (1–3), with 40% of procedures requiring only 1 infusion (preoperative) on that day. Following a median (range) presurgical dose of 52.1 (41–64) IU/kg, the median (range) FVIII level (chromogenic assay; measured in a central laboratory) immediately before the second infusion was 71.6 (44–140) IU/dL; median (range) time between the presurgical and second infusions was 12.3 (3.6–50.0) hours. Hemostasis during surgery was good (13/20; 65%) or excellent (7/20; 35%) for all procedures. Intraoperative blood loss was within expected ranges for all surgeries (median [range], 50 [0–1000] mL), and blood transfusions were required in 4 patients undergoing knee surgeries.

Conclusions:

BAY 94-9027 is efficacious in maintaining hemostasis during major surgeries in adolescents and adults with severe hemophilia A. Excellent or good hemostasis with blood loss as expected was achieved in all surgical procedures, which included major orthopedic surgeries (75% of all procedures), with 40% of patients requiring only a single infusion of BAY 94-9027 on the day of surgery.

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.

Objective:

Hepatitis C virus (HCV) infection is a significant health problem for patients with bleeding disorders due to the absence of highly effective HCV screening of blood products prior to the early 1990s. The aim of this analysis was to evaluate the safety and efficacy of the ribavirin-free regimen of glecaprevir/pibrentasvir (G/P) among patients with a history of bleeding disorders.

Methods:

Data from 11 Phase 2 and 3 registrational studies conducted across 18 countries worldwide were included. HCV genotype (GT) 1–6-infected patients with compensated liver disease received G/P for 8, 12 or 16 weeks. The sustained virologic response 12 weeks after end of treatment (SVR12) rate and safety are reported.

Results:

Sixty-two patients with history of bleeding disorders were identified, the most common disorder being hemophilia (37%, [23/62]). The remaining 63% (39/62) of patients had other disorders, including Von Willebrand disease. The cohort was 76% (47/62) male and 89% (54/62) white race with a mean age of 50.5 years (standard deviation ± 12.1). Additionally, 23% (14/62) had compensated cirrhosis. The HCV genotype breakdown among the patients was: GT1, 39%; GT2, 18%; GT3, 21%; GT4, 13%, GT5, 8%; GT6, 2%. In addition to bleeding disorders, a medical history of anemia was reported in 16% (10/62) of patients. SVR12 was achieved in 100% (62/62) of patients. Adverse events (AEs) were reported in 68% (42/62) of patients, and 37% (23/62) of patients experienced an AE assessed as possibly related to study drugs. Serious AEs (SAE) were reported in 3 (5%) patients, none being assessed as related to the study drugs; 2 of these SAEs (1 per patient) were associated with the underlying bleeding disorder. There was 1 (2%) AE leading to discontinuation of study drug (dyspepsia); the patient went on to achieve SVR12. There was 1 (2%) non-treatment emergent death reported, occurring 60 days after the last dose of study drug. Post-baseline grade ≥3 laboratory abnormalities occurred in 3 patients: one each in hemoglobin, aspartate aminotransferase and bilirubin (all n = 1; 2%), without concurrent elevations in alanine aminotransferase.

Conclusions:

G/P achieved a 100% SVR12 rate in patients with a history of bleeding disorders and demonstrated a favorable safety profile, thus providing support for treatment of chronic HCV infection with the G/P regimen in this patient population.

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:

Emicizumab, a novel bispecific humanized monoclonal antibody promotes coagulation by bridging FIXa and FX to replace the function of missing activated FVIII, and has potential to address unmet medical needs in pediatric persons with hemophilia A (PwHA) with inhibitors. This study assessed efficacy, safety and pharmacokinetics of once-weekly subcutaneous emicizumab prophylaxis in pediatric PwHA with inhibitors.

Methods:

The study (NCT02795767) enrolled PwHA with inhibitors aged <12 years (or 12–17 years if <40 kg) previously treated with bypassing agents to receive emicizumab prophylaxis for ≥52 weeks. Emicizumab was administered subcutaneously at 3 mg/kg/week for 4 weeks, followed by 1.5 mg/kg/week thereafter. Efficacy objectives included bleed rate, and comparison of the bleed rate on emicizumab prophylaxis vs historical bleed rate obtained from a prospective, non-interventional study (NIS; NCT02476942). The NIS collected detailed, high-quality real- world data on bleeds and safety outcomes from a cohort of pediatric PwHA with inhibitors treated according to local, routine clinical practice. Participants from the NIS could subsequently enter the HAVEN 2 study, which permitted intra-individual comparisons.

Summary:

This interim analysis included 20 PwHA with inhibitors aged 3–12 years (median 8.5); 19 aged <12 years were included in the efficacy analyses. The median observation time was 12.1 weeks (range 7–14). In total, 18/19 (94.7%) participants had zero treated bleeds and 12/19 (63.2%) did not bleed while on study. Overall, 14 bleeds were reported in 7 participants, with none occurring in a joint or muscle. No participants have required up- titration of emicizumab. A substantial reduction in ABR on study vs ABR on prior treatment with bypassing agents (non-interventional study) was observed in 8 participants included in the intra-individual comparison; all 8 participants reported zero bleeds with emicizumab prophylaxis (efficacy period 85–99 days). Emicizumab was well tolerated; most common AEs were mild injection-site reactions (15%) and nasopharyngitis (15%). Three unrelated serious AEs were observed (mouth hemorrhage, appendicitis, catheter site infection). No thromboembolic or thrombotic microangiopathy events were reported. No anti-drug antibodies were detected. Mean trough emicizumab concentrations of >50 μg/mL were achieved after 4 loading doses of 3 mg/kg/week and sustained with maintenance doses of 1.5 mg/kg/week, and were consistent across age groups and body weight.

Conclusion:

Emicizumab prophylaxis was well tolerated and prevented/reduced bleeds in pediatric PwHA with inhibitors. Clinically meaningful reductions in ABR were observed compared with ABR on prior treatment with bypassing agents. The pharmacokinetic profile of emicizumab was similar to that seen in adolescent/adult PwHA with inhibitors. These interim data show the potential for emicizumab to reduce the disease and treatment burden for pediatric PwHA with inhibitors.

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.

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.

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.

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 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:

Efficacy and safety of routine prophylaxis vs on-demand treatment with Bayer’s sucrose-formulated recombinant factor VIII (rFVIII-FS) in patients with severe hemophilia A were evaluated in the randomized, controlled SPINART study.

Aim:

Patient- and joint-level changes at year 3 in magnetic resonance imaging (MRI) and Colorado Adult Joint Assessment Scale (CAJAS) scores were compared to investigate if individual joint data revealed results that may have been obscured in previously reported patient-level analyses.

Methods:

SPINART included males aged 12–50 years with severe hemophilia A, ≥150 exposure days to FVIII, no inhibitors, and no prophylaxis for >12 months in the past 5 years. Patients were randomized 1:1 to rFVIII-FS on demand or prophylaxis (25 IU/kg 3x/wk). Changes from baseline to year 3 were evaluated for 6 index joints (knees, ankles, elbows) using the Extended MRI (eMRI) scale and CAJAS. Percentages of patients or joints with improved, unchanged, or worsened scores were evaluated.

Summary:

Of the 84 patients in SPINART, eMRI and CAJAS change from baseline data were available for 62 (prophylaxis, n=32; on demand, n=30) and 76 patients (n=39; n=37) and for 386 (n=197; n=189) and 446 joints (n=224; n=222), respectively. Categoric analysis of CAJAS data at year 3 showed a higher percentage of patients treated prophylactically vs on demand with improved scores (64.1% vs 43.2%) and a lower percentage with worsened scores (28.2% vs 51.4%); with eMRI, the percentage improved was smaller (12.5% vs 6.7% improved; 75.0% vs 73.3% worsened). At individual joints, improved, unchanged, and worsened CAJAS scores in patients treated with prophylaxis vs on demand were 46.0% vs 33.3%, 22.3% vs 24.3%, and 31.7% vs 42.3%; eMRI values were 8.1% vs 3.7%, 61.9% vs 69.8%, and 29.9% vs 26.5%.

Conclusions:

These data suggest that in adults and adolescents with severe hemophilia A, joint function as measured by CAJAS is more likely to improve after 3 years of routine prophylaxis with rFVIII-FS than joint structure as measured by MRI.