Research Studies

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.

Objective:

TFPI is a potent inhibitor of the tissue factor (TF)-induced extrinsic pathway of coagulation. Inhibition of TFPI with antibodies, aptamers, or peptide inhibitors improves hemostasis and may become an option for non-i.v. treatment of patients with hemophilia including those with inhibitors.

Method:

We developed a TFPI inhibitory fusion peptide (FP) consisting of a linear and a cyclic peptide connected by an optimized linker. The two peptides bind to different epitopes on TFPI and synergistically inhibit TFPI. The FP was further improved by half-life extending (HL) non-covalent albumin binding. HL-FP was characterized for in vitro inhibition of TFPI, pharmacokinetics, and improvement of coagulation in animal models of hemophilia.

Results:

HL-FP bound to and efficiently inhibited TFPI in several in vitro test systems. The binding affinity of < 1nM correlated well with inhibition of TFPI in model assays, resulting in IC50s of ~0.7nM. HL-FP efficiently inhibited plasma TFPI, which improved all thrombin generation (TG) parameters in hemophilia A and B patient plasma (EC50s of 6 to 20nM). HL-FP increased peak thrombin levels of hemophilia plasma to a range established for individual normal plasma. Assays were also carried out at flTFPI concentrations up to 10nM, which is 40- to 50- fold above normal. Increased TFPI levels may occur locally upon platelet activation. HL-FP efficiently neutralized elevated TFPI, raising TG to levels observed for inhibition of physiologic TFPI concentrations. Non-covalent binding to albumin substantially increased the half-life to ~4 h with ~50% s.c. bioavailability in mice. The ex vivo procoagulant activity determined by TG correlated well with HL-FP plasma concentrations. In a repeated dose study, the HL-FP was well tolerated and did not accumulate TFPI, indicating that HL-FP did not interfere with TFPI clearance. HL-FP significantly reduced bleeding in the hemophilia mouse tail cut model at a dose as low as 40 nmol/kg. In marmoset monkeys, HL-FP efficiently improved ex vivo plasma TG, even at low peptide plasma concentrations (25-55nM).

Conclusion:

To summarize, we developed a TFPI inhibitor composed of two TFPI antagonistic peptides that completely inhibits TFPI. Introduction of an entity non-covalently binding to albumin provides intermediate half-life extension and s.c. bioavailability. This HL-FP improved coagulation and hemostasis in animal models of hemophilia, did not interfere with TFPI clearance receptor interactions, and efficiently neutralized elevated TFPI. Our HL-FP appears to be useful in preventing bleeding in hemophilia, and provides a FVIII and FIX independent approach for non-i.v. treatment.

Objective:

To assess the pharmacokinetics (PK), safety, and efficacy of the first high- purity, plasma-derived factor X concentrate (pdFX) for on-demand treatment of bleeding episodes in a prospective, open-label, multicenter, nonrandomized phase 3 study in subjects with hereditary moderate or severe factor X (FX) deficiency (basal plasma FX activity <5 IU/dL).

Methods:

Included subjects were aged ≥12 years who required treatment with replacement therapy for ≥1 spontaneous or menorrhagic bleed in the past 12 months. Subjects received 25 IU/kg of pdFX on-demand for specific bleeds or as preventative use for 6 months to 2 years. PK was assessed following a single dose at baseline and after ≥6 months. Each bleed was categorized as major or minor, and subjects assessed efficacy for each bleed as “excellent,” “good,” “poor,” or “unassessable”; hospital- treated bleeds were also assessed by investigators. At study end, each investigator assessed the overall efficacy of pdFX. Safety assessments were adverse events (AEs), inhibitor development, viral seroconversions, and changes in laboratory parameters.

Summary:

The study enrolled 16 subjects (aged 12-58 years [mean 27.1 years], 62.5% female) with moderate (n=2) and severe (n=14) FX deficiency. PK parameters did not differ between baseline and repeat assessment visits, with overall mean (median, interquartile range [IQR]) incremental recovery of 2.00 (2.12, 1.79-2.37) IU/dL per IU/kg and half-life of 29.4 (28.6, 25.8-33.1) hours. In total, 468 pdFX infusions were administered; 187 bleeds treated with pdFX were analyzed for efficacy (98 major and 88 minor), of which 155 (82.9%) were treated with one pdFX infusion. A mean (standard deviation) of 1.2 (0.5) infusions per bleed were administered, with a median (IQR) dose of 25.0 (24.4-26.7) IU/kg. Efficacy of pdFX was rated as excellent in 90.9% of bleeds, good in 7.5%, and poor in 1.1%. For the 15 subjects who completed the study, investigators rated overall pdFX efficacy as excellent in 12 (80%) and good in 3 subjects (20%). Six mild/moderate AEs were observed, no serious AEs were considered by investigators to be possibly related to study drug, and no hypersensitivity reactions or clinically significant trends in any laboratory safety parameters were observed.

Conclusions:

In this study, pdFX was safe and efficacious in on-demand treatment of bleeds and short-term preventative therapy in subjects with moderate or severe FX deficiency at a nominal dose of 25 IU/kg. PK results supported these observed hemostatic effects.

Objective:

Patient satisfaction with healthcare services enhances patient experience, improves outcomes, and is increasingly mandated by public and private payers. While many US Hemophilia Treatment Centers (HTC) periodically assess patient satisfaction, the lack of a uniform survey hampered national measurement. To remedy this knowledge gap, the US HTC Network implemented a national patient satisfaction survey in 2015.

Methods:

A Regional HTC Coordinator workgroup devised, piloted, and finalized a two-page survey for self-administration online, at clinic, or at home, in English or Spanish and mailed to households. Survey content and format were based on national health surveys to enhance comparability and scientific robustness, informed by legacy regional HTC surveys. Questions assessed patient demographics; satisfaction with services, team members, and care processes; and Healthy People 2020 adolescent transition objectives. Surveys included open ended questions to obtain qualitative data. Respondents were anonymous but identified with their respective HTCs. Participation was voluntary. Persons with genetic bleeding disorders who had HTC contact in 2014 were eligible. During February 2015, 124/130 HTCs sent surveys to 27,563 households. Parents completed surveys for children under age 15. No reminders were sent. Data were entered and analyzed at a central site and aggregated at national, regional and HTC levels.

Results:

Over 4800 households (17.4%) returned surveys by April 30, 2015. National analyses on 4332 surveys reveal that 96.6% were ‘always’ or ‘usually’ satisfied with HTC care. Over 80% were ‘always’ satisfied with the core HTC team members. Three quarters of 12-17 year olds were ‘always’ satisfied with HTC encouragement regarding becoming more independent, and how the HTC discussed caring for a bleeding disorder upon reaching adulthood. Eighty– 90% were ‘always’ or ‘usually’ satisfied with care processes, e.g. shared decision making, care coordination, ease of obtaining timely information and services, and being treated respectfully. Insurance and language were ‘always’ a problem for 20%. 29.0% of respondents were female and 10.3% Hispanic. 83.4% were Caucasian, 5.8 African- American, 3.1% Asian/Pacific Islander or Native Hawaiian, 4.3% Multiple races, and 4% Other. Over half had severe or moderate FVIII or FIX deficiency or VWD Type 3. Ages ranged from newborns to 96 years: 38% under 18, 20% age 18 – 34, and 42% over age 35.

Conclusions:

Implementing a National Patient Satisfaction Survey for the US HTCN is feasible, and provides valuable information. Satisfaction with HTC services is high, but insurance and language ‘always’ pose problems for one fifth. Further analyses will examine regional differences.

The study will characterize the skeletal health of factor VIII deficient mice with and without exercise and compare these two groups to each other and to historic results from wild-type mice. We hypothesize that exercise will improve the skeletal health of factor VIII deficient (KO) mice. Outcome measures include measurement of bone mineral density (BMD), cortical thickness, stiffness, resistance to fracture and resistance to stress.

Social workers have been active members of the multidisciplinary teams of hemophilia treatment centers for many years, but the roles of these social workers may differ greatly from center to center. Social workers are often the advocate for patients and a primary source of assistance, information and referral. In many HTCs, they also provide counseling and therapy services to patients and consultation to staff. Indeed, these social workers appear to provide a wide variety of psychosocial and case management services to patients with bleeding disorders and their families. This research project will attempt to describe the various role tasks of hemophilia treatment center social workers, describe these tasks and identify the influences of the role in each HTC. An online survey will be developed and emailed to the approximately 135 HTC social workers across the nation. Data will be analyzed and shared with the social worker community through sessions and posters and the NHF annual meeting.

Background:

BAY 1093884 is a fully human monoclonal antibody against tissue factor pathway inhibitor (TFPI) developed as a bypass agent for hemophilia patients with inhibitors. It restores thrombin burst for stable clot formation in hemophilic conditions in vitro.

Aims:

The goal of this study was to elucidate the in vivo prophylactic hemostatic potency of BAY 1093884.

Methods:

The hemophilia A mouse tail vein transection model was used for this study to mimic the venous bleeding characteristics of severe hemophilia. Male hemophilia A mice (n=12/group) were treated prophylactically with escalating doses of BAY 1093884. All treatments were administered as single intravenous (IV) bolus at 4 different time courses prior to injury (1, 3, 5, and 7 days). Bleeding was induced by a 1.2-mm deep incision across the left lateral vein. Following injury, the animals were monitored hourly for moribundity for up to 9 hours and after 24 hours followed by euthanasia.

Results:

Efficacious doses of BAY 1093884 providing 50% protection for survival (ED50) for up to 6 days after IV bolus ranged from 0.6–2 mg/kg. In comparison, only 25% protection was achieved 6 days after the treatment with a very high dose of 1000 IU/kg of recombinant factor VIII (rFVIII). The effect of a single IV dose of 18 mg/kg BAY 1093884 providing 80%–90% survival was maintained over 8 days (ED50 6 mg/kg), whereas a single IV dose of rFVIII failed to provide protection over an 8-day period.

Conclusions:

These studies demonstrate that BAY1093884 prevents bleeding and increases long-term survival to a greater degree than rFVIII in hemophilia A mice and may offer a convenient prophylactic treatment option for hemophilia patients with inhibitors.

Background:

Activity limiting joint disease has greatly decreased with the introduction of prophylactic treatment for people with severe bleeding disorders. Previous research using the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2TM), a standardized, normative, age and sex matched test of motor development, suggested motor development of males aged 4-21 years with bleeding disorders may be lower than age-matched peers.

Objective:

The primary purpose of this study was to compare the gross motor proficiency of boys with hemophilia ages 4-21 years followed at the Hemophilia Center at Oregon Health & Science University utilizing the BOT-2. Secondarily, we examined the relationship between joint health and gross motor proficiency.

Methods:

1. a)  Participants and setting: Thirty-four subjects with either hemophilia A or B were recruited

   from our center. Data collection occurred during clinic visits or at the patients’ homes.

2. b)  Design and Procedures: A prospective, cross-sectional study design was used. The Upper Limb Coordination, Bilateral Coordination, Balance, Running Speed and Agility, and Strength subtests of the BOT-2 were administered. Body composition, range of motion, presence of an inhibitor, and use of prophylaxis were collected at the time of testing or from chart review.

3. c)  Analyses: Analysis of variance (ANOVA) modeling was used to compare BOT-2 scores of PWH with baseline BOT-2 scores estimated from the general population of comparable age.

Summary:

Mean Running Speed & Agility scores were greater among boys with hemophilia compared to the control population (p=0.0026). Agility scores were similar between boys with hemophilia A and B (p>0.60), and significantly greater compared to the control group (p=0.0153). No other significant differences were found comparing boys with hemophilia to the control group. Within the boys with hemophilia cohort, age-adjusted ANOVA found no significant differences in BOT-2 scores between subjects of different severities, treatment regimen (prophylaxis or episodic), or diagnoses (Hemophilia A or B).

Conclusion:

Boys with hemophilia have the same or better gross motor proficiency as age matched peers.

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 analyze real world rFVIIIFc patient characteristics and treatment interval patterns in patients with hemophilia A based on specialty pharmacy dispensing records.

Methods:

A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from July 2014 through Mar 2015. SPP data included 63 different attributes for each prescription, including trade name, NDC, quantity shipped, prescribed infusion dose, days supplied, and dose frequency. Patients were considered eligible for the analysis if they received at least one shipment of rFVIIIFc for a prophylactic treatment regimen. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or pharmacy records did not specify a prescribed infusion dose. Patients were categorized according to their age and dosing interval.

Summary:

The analysis included 405 hemophilia A patients that received at least one shipment of rFVIIIFc with a median age of 23 (range: 2-68) and median weight of 70 kg (range: 10-154kg). Eight percent of dispensing records were for patients less than 6 years of age, 29% were between 6 and 17 years of age, and 63% were 18 years or greater. Pharmacy dispensing records represented 179 distinct prescribers across 40 states. Dosing frequency ranged from four times weekly to beyond once-weekly, with every four days as the most common dosing interval, representing 33% of patient records. The median infusion frequency was every four days. Fifty percent of all patients had a dosing frequency of four days or greater. Of the patients receiving rFVIIIFc that had previous rFVIII dispensing records, the most common rFVIII dosing frequency was three times per week. The majority of patients previously on prophylaxis regimen with a rFVIII dosing frequency of three times per week had a decreased number of prophylactic infusions per week on rFVIIIFc; 4% of patients reduced infusion frequency to every 3 days, 44% of patients reduced infusion frequency to twice weekly, 30% of patients reduced infusion frequency to every 4 days, 10% of patients reduced infusion frequency to every 5 days.

Conclusions:

Current SPP dispensing records demonstrate that rFVIIIFc is being used in a broad patient population based on age range and geographical distribution. Patients with hemophilia A in the US may experience reductions in FVIII infusion frequency when they switch to rFVIIIFc, with conversion to an infusion frequency every four days as the most common treatment regimen and the recommended prophylaxis starting dose according to the US Prescribing Information.