Research Studies

Objective:

Joint status and health-related quality of life (HRQoL) were assessed as part of the 3-year SPINART study, which compared routine prophylaxis versus on-demand treatment in adults with severe hemophilia A. We report SPINART joint outcome results obtained using the Colorado Adult Joint Assessment Scale (CAJAS) and HRQoL data from Haemo-QoL-A assessments.

Methods:

The open-label, randomized, controlled, parallel-group, multinational SPINART study enrolled male patients aged 12–50 years with severe hemophilia A who had ≥150 exposure days to any factor VIII (FVIII) product, no inhibitors, no prophylaxis for >12 consecutive months in the past 5 years, and 6–24 documented bleeding events or treatments in the previous 6 months. All patients were treated with Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS), either on demand or as prophylaxis (25 IU/kg 3 times weekly, with dose escalation of 5 IU/kg permitted once per year). CAJAS assessments were performed at baseline and years 1, 2, and 3. The physiotherapists performing CAJAS assessments were blinded to patient treatment assignment, bleeding history, and previous joint assessment data. Change from baseline to year 3 in CAJAS total score was prespecified as the second of 2 secondary endpoints; higher CAJAS scores indicate worse joint function. Haemo-QoL-A was completed at baseline, month 6, and years 1, 2, and 3; higher Haemo- QoL-A scores indicate better HRQoL. Between-group comparison was made using constrained longitudinal data analysis. Data are presented for the intent-to-treat (ITT) population.

Summary:

84 patients (42 prophylaxis, 42 on demand) comprised the ITT population; Haemo-QoL-A data were available for 41 and 42 patients, respectively. For CAJAS total score, least squares (LS) mean change from baseline to year 3 was 0.63 for on demand and –0.31 for prophylaxis (LS mean difference, –0.94; 95% CI, –1.61 to –0.26; P=0.0072). LS mean change in CAJAS total score for the on-demand and prophylaxis groups was 0.19 and –0.46 at year 1 and 0.34 and –0.57 at year 2, respectively. For Haemo-QoL-A total score, LS mean change from baseline to year 3 was –6.00 for on demand and 3.98 for prophylaxis (LS mean difference, 9.98; 95% CI, 3.42 to 16.54).

Conclusions:

In adults with severe hemophilia A, joint function and HRQoL improved continuously over 3 years with prophylaxis compared with on-demand use.

Objectives:

Biopharmaceuticals are an emerging branch of therapeutic agents. Their short half-life, rapid elimination and ability to induce a specific immune response, however, may impair their applicability. These disadvantages have been overcome by chemical modification with polyethylene glycol (PEG), which has enhanced the PK and safety of several marketed proteins since the 1990s. PEGylation uses metabolically stable PEG polymers, often with a molecular size of 5-60 kDa.

PEGylated rFVIII candidates include PEG-protein-conjugates with a minimal amount of PEG attached to the protein. Baxter and Nektar are developing BAX 855, a PEGylated full-length recombinant (r) FVIII based on the FVIII molecule used for Baxter’s licensed rFVIII (ADVATE). Due to the high potency of FVIII, the absolute amount of conjugated PEG applied with PEG-FVIII is within the range of μg per kg body weight and week. PEGylation was optimized to retain functionality of the FVIII molecule and improve its pharmacokinetic properties.

PEGs ≤20 kDa are rapidly cleared mainly via the kidneys and excreted into urine. Over time, the protein portion of the PEG-FVIII conjugate is degraded by proteolysis leaving a PEG portion which is rapidly eliminated.

Methods:

Preclinical safety, toxicokinetics and formation of anti-product antibodies were assessed in rats dosed intravenously at 350 or 700U/kg BAX 855 every other day, and in macaques receiving 150, 350 or 700U/kg BAX 855 every five days, for 28 days.

Like other non- degradable entities, physiological clearance mechanisms of PEG may include liver macrophage uptake. Clearance by macrophages in mammals has been reported to cause vacuolization at high cumulative doses. Generally, vacuoles were shown to consistently resolve over time, with no cellular damage, inflammation at the vacuolization site or functional deficits of affected tissues, and are therefore regarded to not affect the safety of PEGylated therapeutics.

Summary:

No systemic adverse effects or vacuolizations were observed after 28-day intravenous administration with BAX 855. Therefore, 700 U/kg was considered the no observed adverse effect level in these studies.

Conclusions:

This favorable safety profile provides the basis for proceeding with human trials.

Objective:

Prevalence of clinical depression in persons with hemophilia (PWH) has been reported to be from 0%–50%. Most papers studied fairly small numbers of PWH; many had no controls and used instruments not validated for depression. One recent paper, using the Patient Health Questionnaire-9, a validated instrument for depression, reported a prevalence of 37% in 41 adult PWH. Our objective was to determine the prevalence of depression in PWH in the United States.

Methods:

Using the MarketScan® Commercial and Medical Research databases, we compared depression prevalence in 2506 PWH and 7518 controls. Male patients with hemophilia A were identified using an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code (ICD-9-CM 286.0) and were matched (based on age, eligibility months in the study, region, and health plan type) in a 1:3 ratio with controls (no hemophilia diagnosis). Evidence of depression was determined using ICD-9-CM 296.20– 296.26, 296.30–296.36, and 311 codes. Chi-square tests were used to compare frequencies.

Summary:

PWH had a statistically significant increase in depression prevalence overall and in age groups 50–59 years and 60–69 years and a numerical increase in all other age groups except 18–29 years (Table). The delta between PWH and controls steadily increased between ages 30 and 69 years.

Table. Patients with Major Depressive Disorder

Conclusions:

Commercial claims databases have limitations, including coding errors and inability to verify accuracy of diagnoses. However, in PWH versus a 3:1 control group in a US commercially insured sample that may not be representative of the overall population, depression prevalence was greater in PWH, reaching a peak of 16% in those aged 60–69 years. Awareness of this comorbidity is important as the hemophilia population ages in an era of declining healthcare-delivery resources.

Background:

Bleeding risk during physical activities for persons with hemophilia has been shown to be reduced with adequate factor levels (Broderick 2012). With extended half-life Factor VIII and IX products offering opportunities for longer intervals between infusions, it is important to understand the bleeding risk for patients who have an active lifestyle.

Objective:

To evaluate the relative risk of bleeding between prophylaxis schedules using recombinant Factor VIII (rFVIII) vs. rFVIII-Fc among different patient physical activity profiles

Methods:

A mathematical model based on the literature was developed. Factor levels were estimated using a one-compartment pharmacokinetic model (Collins 2010). Half-life and incremental recovery values were taken from a crossover study of rFVIII and rFVIII-Fc (Mahlangu 2014). Five prophylaxis regimens were evaluated: two common to rFVIII (30IU/kg every other day (EOD); 35IU/kg 3x/week) and three studied in the rFVIII-Fc pivotal trial (2x/ week: 25IU/kg covering 3 days and 50IU/kg covering 4 days per week; 50IU/kg every 5 days; 65IU/kg 1x/week). Activities such as swimming, running and wrestling were classified as Type 1, Type 2, and Type 3 in Broderick 2012, derived from the NHF “Playing It Safe Brochure” (Anderson 2005). Risk of bleeding by activity category and factor level at time of activity was calculated using the odds ratio values from Broderick 2012. Three hypothetical patient activity profiles were evaluated: Consistently Active (M-Sun: Type 2 activities), Regular Exerciser (M-F: Type 2 activities, Sat-Sun: Type 1 activities), and Weekend Warrior (TThSun: Type 1 activities, MWF: Type 2 activities, Sat: Type 3 activities). For each regimen, the infusion schedule with the lowest bleeding risk for each patient activity profile was selected. The relative bleeding risk vs. the best prophylaxis regimen was estimated and compared for the activity profiles.

Results:

rFVIII 30IU/kg EOD and 35IU/kg 3x/week achieved the two lowest bleeding risk for all three patient activity profiles. Compared to rFVIII every other day, bleeding risk was increased by 20%, 25% and 46% for the Consistently Active patient prescribed rFVIII-Fc twice per week, every 5 days, and 1x/week, respectively. Compared to rFVIII 3x/week, bleeding risk was increased by 20%, 30% and 44% for the Regular Exerciser and by 21%, 32% and 45% for the Weekend Warrior prescribed rFVIII-Fc 2x/week, every 5 days, and 1x/ week, respectively.

Conclusion:

This model suggests that active patients characterized with the above profiles may have reduced bleeding risk with rFVIII compared to extended half-life FVIII dosing regimens evaluated in this analysis.

Hemophilia is a rare lifelong condition which can be potentially life-threatening. Parents bare a significant responsibility for delivery of medical care because the treatment for hemophilia begins early in life for children within the home setting. As a result, parents frequently exhibit a heightened level of stress, anxiety, and subsequent trauma around the acceptance of the illness and the administration of medication management. To address the multifaceted nature of chronic illness for patients and their families, the ideal treatment utilizes a multidisciplinary team. Our proposed 3P Patient Parent Power Program aims to standardize care for families with patients of hemophilia using a tiered approach of psychosocial support. The necessary level of support will be provided to parents in order for them to successfully provide in-home prophylactic factor treatment. The goal of the program is to reduce parental stress and anxiety related to this chronic illness and increase feelings of empowerment for the parent and child.

Children with severe Hemophilia (CWH) suffer pain and inconvenience due to the required IV factor concentrates' injections and mostly exhibit poor quality of life. These children don't have any hope that their life will improve in the future. Most of them keep the Hemophilia a secret; therefore they are unable to get any emotional support from their peer group. These parameters are known stressors and triggers leading to depression, especially among children and adolescents (due to their lack of mature psychological defense mechanisms). The consequences of depression might be hazardous, since such children may neglect their medical treatment, leading to further deterioration of their medical state.

Objective:

We compared the depression level of children with Hemophilia to healthy children of the same age and background.

Methods:

Depression was evaluated using a standard validated questionnaire of depression that was developed by A.Beck - the CDI. We compared 20 children with severe Hemophilia with 25 non-Hemophiliac children.

Summary:

The calculated score for degree of depression was 7.6 for CWH vs age matched controls with a score of 12.32. The mean of normal populations is around 9. Parametrical T test for Equality of Means = 0.013.

This is the first reported study objectively addressing the issue of depression in CWH.

Conclusions:

We found the opposite of what we had expected: The children with Hemophilia were rated significantly much less depressed then the children without Hemophilia. This finding merits further validation in future larger studies and

must be examined very carefully, due to the complexity of the psychological defense mechanisms.

Objectives:

PAIR is an ongoing, global, non-interventional, post-authorization safety surveillance designed to collect information on ADVATE safety and effectiveness in immune tolerance induction (ITI) therapy in routine practice.

Methods:

From July, 2007 to April, 2011, individuals with hemophilia A and inhibitors were enrolled in 10 countries. The primary objective is to assess the incidence of adverse events (AEs) related to ADVATE during ITI therapy. Secondary objectives are incidence of central venous access device (CVAD)-related complications, and success rates of ITI therapy. Maximum observation period for ITI is 33 months plus a 12 month follow-up.

Summary:

As of April 1, 2014, 36 of 44 subjects (81.8%) completed ITI therapy, 28 (63.6%) of which completed the 12 month follow-up. Six subjects withdrew prior to completing ITI therapy. Dosing regimens were: ≥200 IU/kg/day (n=4, 9.1%); 131-199 IU/kg/day (n=3, 6.8%); 90-130 IU/kg/day (n=26, 59.1%) and <90 IU/kg/day (n= 11, 25.0%). During the observation period, 337 bleeding episodes and 273 AEs were reported for all enrolled subjects (N=44). Of these AEs, 52 (19.0%) were serious and none were considered related, while 15 (5.5%) were non-serious and related. CVAD complications were common; 32 subjects experienced one or more CVAD-related AE such as hospitalization, line infection, line malfunction, line removal, and pain following port-a-cath bleed. Of the subjects that completed ITI, 21 achieved negative titer levels, two experienced a high to low titer conversion, seven failed to achieve negative titer, and six were un-assessable per protocol. After 18 months therapy, Kaplan Meier estimates of success for achievement of first negative titer was 65.4% (asymptotic 95% CI: 48.7-81.5%, n=36) for the completer group. Rates were higher for the per protocol analysis set (72.2%, CI: 54.6-87.5%, n=30), and slightly lower for the full analysis set (63.5%, CI: 48.0- 78.7%, n=44).

Conclusions:

These interim outcome results are consistent with previous reports from PAIR and other published data on ADVATE in ITI. No new ADVATE related safety issues have been seen. The last two participating subjects will end observation within the next year.

Objectives:

This prospective clinical trial was conducted to assess the safety, hemostatic efficacy and pharmacokinetic (PK) profile of a recently developed recombinant factor IX (BAX326*) in pediatric previously-treated patients (PTPs) with severe or moderately severe hemophilia B.

Methods:

PTPs aged <12 years with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B were eligible for enrollment. BAX326 was administered as prophylaxis twice a week over 6-months, and on demand for treatment of bleeds. Efficacy was evaluated by treatment response rating (excellent, good, fair, none) and annualized bleeding rate (ABR). PK assessments after one 75 ± 5 IU/kg infusion of BAX326 were assessed using a non-linear mixed model (population PK) approach. IR was measured as part of the PK evaluation 30 minutes after the initial PK infusion and at 5, 13 and 26 weeks after the initial infusion.

Summary:

Nine subjects (39.1%) had no bleeds during the study. A total of 26 bleeds occurred (mean ABR 2.7 ±3.14, median 2.0), of which 2 were spontaneous. Fewer bleeds occurred in joints than in non-joint sites (19 non joint vs. 7 joint bleeds). Hemostatic efficacy was excellent or good in >96% of bleeds, and the majority (88.5%) resolved after 1-2 infusions. The median IR (IU/dl)/(IU/kg) at the initial PK assessment was 0.685 (range: 0.31- 1.00). As expected, a higher IR was observed in association with increased patient age; IR was slightly lower in subjects < 6 years (median 0.591; range: 0.31-0.75), than in subjects aged 6 to <12 years (median 0.714; range: 0.51-1.00). IR was consistent over time. There were no adverse reactions, no thrombotic events and no hypersensitivity reactions. None of the subjects treated (N=23) developed inhibitory or specific binding antibodies against FIX.

Conclusions:

BAX326 is efficacious and safe as prophylactic treatment as well as for bleed control in pediatric hemophilia B patients.

*Licensed in the USA and Australia (Rixubis®; Baxter Healthcare Corp., USA).

Objective:

To assess impact of hemophilia on relationships and employment during the transition to adulthood in young adult (YA) patients with hemophilia (PWH).

Methods:

Analysis of US YA-PWH respondents (aged 18-30 years) in the HERO study.

Summary:

Of 189 US adult PWH HERO respondents, 66 were aged 18-30 years (median: 26). Most lived in large cities (52%) or suburban areas (29%); 73% reported household income of <$60,000/year. Some (32%) were married or in long-term relationships; 20% lived alone. Negative impact on relationships was reported by 32%; 62% predicted an impact in the future, 62% cited difficulty understanding issues, and 52% worry about supporting a family. Only 9% had children; 77% wanted to have children. Only 45% received genetic counseling from the HTC; of those, 60% felt it was helpful. Most were very/quite satisfied with support of partners/spouses (95%), family (92%), and friends (86%). Negative reactions telling friends were reported by 41%; 59% reported most/all of their friends knew about their hemophilia. Most (78%) were employed with 57% reporting office work. One fifth (20%) reported being disabled, and 14% received disability benefits. The majority (74%) reported negative impact on employment; 39% reported moderate/very large impact. Many (43%) reported current treatment allows them to work in most situations, 37% selected a job based on their needs, 29% were helped to obtain a job, 24% had to leave a job, 20% were not hired, and 18% lost a job due to hemophilia. Only 36% received advice from the HTC on work/employment, mostly on what to do if a bleed occurs at work (71%), suitable jobs (67%), when (63%) and what (33%) to tell an employer, and workplace precautions (46%). Fifty-eight percent found the advice helpful. Only 37% reported most/all of their colleagues know about their hemophilia; 38% reported a select few or 1-2 and 26% none. Most were very/quite satisfied with the support of colleagues at work/school (82%). Most YA-PWH (62%) were members of an organization or online (48%) or other (35%) support group.

Conclusions:

During the transition to independent adults, YA-PWH are likely planning for family and careers. Many reported negative impacts on relationships and employment, highlighting a need for career counseling. YA-PWH are supported by friends and colleagues, but this may be a limited group. HTCs are an underutilized resource for addressing these issues, with perhaps online peer-support networks playing a larger role during this transition to adulthood and independence.

Objective:

Hemophilia A and B are X-linked bleeding disorders caused by the deficiency of clotting factor VIII or IX, respectively. Mutations in the F8 gene can result in hemophilia A while mutations in the F9 gene can lead to hemophilia B. The objective of this analysis was to evaluate the F8 and F9 genotypes of subjects screened for enrollment in the phase III clinical trials of rFVIIIFc in hemophilia A (A-LONG) and of rFIXFc in hemophilia B (B-LONG).

Methods:

The F8 and F9 genotypes of 170 subjects with severe hemophilia A and 114 subjects with severe hemophilia B, respectively, were compared with several genotype databases (HAMSTeRS, [Hemophilia A Mutation, Structure, Test and Resource Site], CHAMP [CDC Hemophilia A Mutation Project], and King’s College London Hemophilia B database), as well as with the NCBI human F8 and F9 sequences.

Summary:

Among 170 subjects with hemophilia A, inversions in intron 22 (Int22inv) were identified in 36%, nucleotide substitutions in 39%, frameshift mutations in 21%, Int1inv in 3%, and an in-frame duplication in 1 subject. Previously unreported mutations (frameshift, missense, nonsense, and splice site changes) were found in 24 subjects, with 2 unrelated subjects having the same mutation, resulting in 23 novel mutations being identified. Among 114 subjects with hemophilia B, the majority (86%) had some form of substitution mutation (missense, nonsense, splice-site change), consistent with previous reports. Thirteen previously unreported mutations were identified, including 10 substitutions (7 missense, 2 nonsense and 1 splice-site change), 1 deletion, and 2 insertions.

Conclusions:

In this analysis, 23 previously unreported mutations in the F8 gene of subjects with severe hemophilia A and 13 in the F9 gene of subjects with severe hemophilia B were identified. Identifying mutations allows for prenatal diagnosis and identification of carrier status. These results will lead to further enhancement of databases for hemophilia A and B mutations and may assist in clarifying the relationship between genotype, phenotype, and pathophysiology in individuals with hemophilia.

Objective:

To evaluate changes in healthcare resource utilization and haemophilia related events among patients diagnosed with haemophilia A between 2008 and 2012.

Methods:

This retrospective study analyzed data from the Humedica de-identified electronic medical record database between January 2008 and December 2012. Male patients diagnosed with hemophilia A (ICD-9-CM 286.0) receiving treatment with a clotting factor were eligible if they 1) were ≥18 years of age 2) did not receive Factor IX therapy and 3) did not have a diagnosis of Von Willebrand while receiving factor VIII therapy containing von Willebrand factor. All patient level resource utilization was converted to utilization per patient year. Resource utilization was then compared across time periods using repeated measures analysis of variance (ANOVA). The annualized number of haemophilia related events (haemophilic arthropathy or other joint related events) was calculated for each year. McNemar’s chi-square test was used to compare the frequencies across years.

Summary:

136 patients contributing 375 patient-years were included in this study. Office/clinic visits accounted for the majority of healthcare encounters annually; 7.5 all-cause visits per year and 2.2 haemophilia related visits per year. The number of annual all-cause office/clinic visits for Haemophilia A patients decreased significantly over time from 12.5 visits in 2008 to 5.9 visits in 2012 (p=0.0404), while haemophilia A-specific annual visits decreased from 4.0 to 1.5 (p=0.1991) during the same period. On average haemophilia A patients had less than 1 inpatient and emergency room visits per year, which did not change significantly over time (p=0.6371 and p=0.4845, respectively). Over the 5-year period, haemophilic events occurred in 30.93% of patient years, changed from 23.81% in 2009 to 34.09% in 2011 (p=0.6658).

Conclusions:

Office/clinic outpatient visits among patients diagnosed with haemophilia A has decreased overtime. However, the rate of haemophilia related arthropathies and other associated events have remained high. Further analysis is needed to understand how to best manage patients diagnosed with haemophilia A and reduce the proportion of patients who develop reduced joint mobility due to bleeding into joints.

Objective:

To analyse real-world FIX dosing and treatment interval patterns. A secondary objective was to compare the observed dosing patterns with the dosing regimens for FIX products evaluated in clinical studies.

Methods:

A retrospective analysis was conducted using aggregate Specialty Pharmacy Provider (SPP) records from 2012 through Q12014. 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 a shipment of any FIX product. Patients were excluded from the analysis if they were being treated episodically, for immune tolerance induction, or their pharmacy records did not specify a prescribed infusion dose. Patients with missing or extremely abnormal weights were also excluded. The patient’s weekly consumption was calculated for each shipment record by multiplying the prescribed infusion dose by the dose frequency and dividing the product by the patient’s weight, resulting in the patient’s average weekly prescribed dose (IU/kg/week). Patients were also categorized according to dosing interval.

Summary:

The analysis included 118 hemophilia B patients with a median age of 20 (range: 2-63) and median weight of 55.4 kg (range: 9.5-129 kg). Pharmacy dispensing records represented 78 distinct prescribers across 29 states. FIX therapies evaluated included Benefix®, Alphanine®, Mononine®, and Rixubis®. The average weekly consumption across all therapies was 139.0 IU/kg/week (95% CI, 128.7-150.3). Dosing frequency ranged from every other day to once weekly. Twice weekly was the most common dosing interval, representing 56.8% of patient records. According to clinical trial data and FDA labelled dosing for FIX therapies, lower weekly consumption may be expected. For BeneFIX the mean weekly consumption was 80.6 IU/kg, 40.3 IU/kg administered twice-weekly. For Rixubis the mean weekly consumption was 88.9 IU/kg, 49.4 IU/kg administered 1.8 times/week and a US dosing recommendation of 40-60 IU/kg dosed twice-weekly. Two prophylactic regimens have been evaluated for AlprolixTM. In the last 3 months of B-LONG, in the weekly prophylaxis arm, the overall median dose on study was 40.5 IU/kg. The individualized interval prophylaxis arm had a median weekly dose of 50.0 IU/kg, 100 IU/kg administered every 14 days. No real world dosing is available for Alprolix due to its recent approval.

Conclusions:

Dosing regimens evaluated in the real world for conventional FIX products indicate greater consumption than reported in clinical trials. This may result in unpredictability for payers who are responsible for healthcare budgets.

Objective:

To investigate the prevalence of comorbidities among adults with hemophilia in the Hemophilia Utilization Group Studies (HUGS)

Methods:

Standardized interviews were conducted for two prospective cohort studies HUGS- Va (hemophilia A) and HUGS-Vb (hemophilia B) at six and ten US Hemophilia Treatment Centers, respectively, between 2005 and 2011. Clinical records were reviewed. Information captured included self-reported comorbidities, sociodemographics, treatment patterns and other clinical characteristics. Overweight and obesity were defined as body mass index (BMI) 25-29 kg/m2 and BMI ≥30 kg/m2, respectively. The prevalence of comorbidities was calculated. The association of comorbidities with hemophilic severity, age and type of hemophilia were assessed using appropriate statistical methods for categorical or continuous variables.

Summary:

The analyses included a total of 213 adults (HUGS-Va: n=147, HUGS-Vb: n=66) aged 20 to 65 years (mean±standard deviation: 36.6±12.9). Approximately, 64% of hemophilia A and 44% of hemophilia B individuals had severe hemophilia. The five most prevalent self-reported comorbidities were liver disease/hepatitis (66%), overweight/obesity (60%), arthritis (51%), human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) (24%), and hypertension (23%). The individuals in the hemophilia A sample were more likely to report liver disease/hepatitis (71% vs. 53%) and HIV/AIDS (30% vs. 9%) than those in the hemophilia B sample (all p<0.009). The prevalence of overweight/obesity (59% vs. 60%), arthritis (55% vs. 42%), and hypertension (22% vs. 24%) were not significantly different between hemophilia A and hemophilia B samples (all p>0.05). Prevalence of comorbidities was greater among individuals with severe than mild/moderate hemophilia for most conditions: liver disease/hepatitis (79% vs. 48%), arthritis (61% vs. 38%), HIV/AIDS (37% vs. 6%), and stroke/brain haemorrhage (11% vs. 2%) (all p<0.02), the exception being overweight/obesity (52% vs. 70%, p=0.007). The individuals with hemophilia A had a significantly greater number of comorbidities than those with hemophilia B (mean±standard deviation: 2.5±1.9 vs. 1.0±1.1; p<0.0001); 85% of the hemophilia A sample reported having more than one comorbidity compared to 61% of those with hemophilia B (p<0.0001). The number of comorbidities increased significantly with advancing age (p<0.0001).

Conclusions:

As one of the largest prospective studies of persons with hemophilia, the HUGS sample is representative of the US hemophilia A and B populations. Except for overweight/obesity, the most prevalent comorbidities reported in HUGS related to their hemophilia complications, and were significantly associated with hemophilic severity. As the life expectancy of persons with hemophilia increases, the need for studies focusing on the health care needs of individuals with hemophilia and comorbid conditions will increase.

Objectives:

Factor VIII (FVIII) prophylaxis regimens for severe hemophilia A that allow more flexible dosing than the standard 3-times-weekly regimen while maintaining efficacy may improve adherence. This analysis compared the clinical efficacy of once- or twice-weekly versus ≥3-times-weekly prophylaxis dosing of Bayer’s sucrose-formulated recombinant FVIII (rFVIII-FS) in patients with severe hemophilia A.

Methods:

Data from 3 postmarketing studies were pooled. Patients with severe hemophilia A and no history of inhibitors who were receiving ≥1 prophylaxis infusion/wk of rFVIII-FS for ≥80% of a prophylaxis observation period (≥5 months) were included. Patients were categorized based on age (<18 and ≥18 years) and physician-assigned treatment regimens of 1–2 prophylaxis injections/wk (n=63) or ≥3 prophylaxis injections/wk (n=76). Descriptive statistics were determined for annualized bleeding rates (ABRs) by dosing group and age subgroups.

Summary:

Median (quartile 1; quartile 3) ABR for all bleeds was 2.0 (0; 4.0) in the group receiving 1–2 prophylaxis injections/wk and 3.9 (1.5; 9.3) in the group with ≥3 prophylaxis injections/wk. Similarly, median ABRs for joint, spontaneous, and trauma-related bleeds were numerically lower in the group receiving 1–2 prophylaxis injections/wk. The trend toward lower ABRs in the group with 1–2 prophylaxis injections/wk was observed in both age subgroups, although ABRs were somewhat higher in patients ≥18 vs <18 years. Zero annualized bleeds were reported by 30% and 7% of patients in the groups with 1–2 prophylaxis injections/wk and ≥3 prophylaxis injections/wk, respectively.

Conclusions:

These data demonstrate that bleeding control can be achieved in some patients with severe hemophilia A using a <3-times-weekly prophylaxis dosing regimen and that physicians’ judgment based on bleeding phenotype can successfully direct the frequency of prophylactic dosing.

Objective:

Baxter has developed BAX 855, a PEGylated form of Baxter’s recombinant full length FVIII (rFVIII) product based on the ADVATETM manufacturing process. Here we describe it ́s manufacturing and structural and functional characterization.

Methods:

A rFVIII intermediate of the ADVATETM manufacturing process is the starting material for the conjugation process for preparing BAX 855 by proprietary PEGylation technology from Nektar Therapeutics. Similar technology has been successfully employed for marketed and licensed PEGylated drug products and drugs in clinical use. The manufacturing process for BAX 855 comprises several steps, including controlled PEGylation followed by cation exchange chromatography. Final formulation uses the same excipients as ADVATETM. BAX 855 was characterized by a number of analytical methods, focusing on the elucidation of the primary structure, posttranslational modifications, PEGylation site distribution and three- dimensional structure. The overall hemostatic potency of BAX 855 in FVIII-deficient plasma was assessed by conventional FVIII 1-stage clotting and chromogenic assays and with a thrombin generation assay. The tenase cofactor activity of FVIII was determined by measuring the kinetics of FXa generation. Binding of BAX 855 in comparison to ADVATETM was determined to its ligands VWF and low-density lipoprotein-receptor-related protein (LRP).

Summary and Conclusions:

BAX 855 is a full-length rFVIII with extended half-life. PK studies in different animal species and humans with hemophilia A display longer survival of BAX 855 compared to ADVATETM. The product is based on the original, native FVIII protein utilized in the production of ADVATETM. Our analyses show that BAX 855 can be manufactured reproducibly without changes to the protein structure characteristic for a fully functional full-length rFVIII molecule. The process is suited to manufacture BAX 855 in large scale and showed a good batch to batch consistency, ensuring an equivalent product quality for each batch. BAX 855 has a specific activity similar to that of rFVIII in ADVATETM and PEGylation degrees in the range of 2 to 3 mol PEG / mol rFVIII. SDS-PAGE and Western blot analysis of BAX 855 confirm PEGylation and demonstrate an increase in the molecular weight of the various FVIII domains.

In comparison to ADVATETM the functional properties of BAX 855 were fully retained except for binding to LRP, indicating that PEGylation did not have an impact on the functional properties of rFVIII. The latter might explain why BAX 855 shows prolonged survival in the circulation of hemophilic species and patients with hemophilia A than ADVATETM.