Research Studies

Introduction and Objective:

Limited information exists in the recent literature capturing real- world utilization and cost of bypassing agents among hemophiliac patients with inhibitors in the US. The present study compared the cost of on-demand and prophylaxis treatment between aPCC and rFVIIa among inhibitor patients with severe hemophilia.

Methods:

A retrospective analysis of two large US specialty pharmacy databases was conducted using dispensing data over a 28-month period (Jan. 2012 to April 2014). Subjects were included if they had a diagnosis of hemophilia A or B (ICD-9 code 286.0 or 286.1) that was classified as severe and ≥12 months of consecutive prescription claims for only bypassing agents. For patients who switched between bypassing agents or between on- demand (OD) and prophylaxis (P) during the observation period, observations of ≥6 months with consistent prescriptions were selected and analyzed independently. Bypassing agent utilization was annualized and normalized by patient weight (kg). Cost was calculated using 2013 Redbook® US wholesale acquisition costs (aPCC=$1.81/U and rFVIIa=$1.77/μg) and compared by product and regimen using non-parametric statistics.

Results:

A total of 78 subjects with 84 observations met the inclusion criteria. Median age was 20 years old (range 2-64) and median time between the first and last prescription filled was 20.5 months. Approximately 34.5% of the subjects were on aPCC (44.8% [OD] and 55.2% [P]) and 40.5% were on rFVIIa (85.3% [OD] and 14.7% [P]). The remaining subjects (25%) were on various combinations of aPCC and rFVIIa. Median annualized utilization for aPCC and rFVIIa was 7,183U/kg (2,186U/kg [OD] and 9,612U/kg [P]) and 13,838μg/kg (9,493μg/kg [OD] and 27,245μg/kg [P]), respectively. Median annualized cost/kg was significantly lower (p=0.0071) among patients treated on-demand with aPCC ($3,956/kg) compared to rFVIIa ($16,801/kg). Similarly, median annualized cost/kg was also significantly lower (p=0.0093) among patients treated prophylactically with aPCC ($17,399/kg) compared to rFVIIa ($48,223/kg). Overall, median annualized cost/kg for on-demand and prophylaxis treatments was 76.5% and 63.9% lower, respectively, with aPCC compared to rFVIIa. Furthermore, there was no significant difference (p=0.6438) in median annualized cost/kg between aPCC prophylaxis and rFVIIa on-demand.

Conclusion:

Overall, these data suggest that the annualized treatment cost with aPCC is significantly lower compared to that of rFVIIa for both on-demand and prophylaxis regimens. For each patient treated on-demand or prophylactically with rFVIIa, approximately 3-4 patients could be treated with aPCC at comparable cost. Additionally, the median rFVIIa on- demand patient could be prescribed aPCC prophylactically to reduce bleeding episodes without significant cost implications.

Objective:

To assess treatment of young adult (YA) patients with hemophilia (PWH) and issues around access to and use of factor and comprehensive care.

Methods:

Analysis of US respondents aged 18-30 years in the international HERO study conducted in 2010-2011.

Summary:

Of 189 adult PWH HERO respondents in the United States, 66 were aged 18-30 years. More YA-PWH were on prophylaxis (50%) than on-demand alone (24%) or with occasional short-term prophylaxis (24%). Only 27% used treatment medication exactly as prescribed, with 27% a little less, and 21% varying (sometimes more/less). Twenty-six percent reported issues with access to factor in the prior 5 years due to availability or affordability, with 82% citing financial issues. YA-PWH reported a median of 2 bleeds in the prior month and median (IQR) annual bleed rate of 9.5 (12-22) bleeds. Similar to older adults, 80% of YA-PWH reported that a single joint suffers more bleeds than others; the most common joints reported were the ankle (77%), elbow (26%), and knee (21%). YA-PWH rated perceived disease control (1-10 scale, 10=most control) as median (IQR) 8 (7-9). HTC visit frequency was median (mean) 1 (1.66) per year. Similar to older adults (aged >40 years), 21% of YA-PWH reported difficulty in visiting the HTC. Accessibility was the most common reason (79%)—distance to travel (57%) or time to travel (29%); time constraints were more commonly reported by YA-PWH (57%), including being unable to get time off work (50%). When identifying health care professionals (HCPs) involved in management of their hemophilia, YA-PWH named hematologists (83%), nurses (67%), social workers (48%), counselors/psychologists (30%), and physical therapists (26%). The majority were satisfied with care provided by HCPs. YA-PWH reported being very/somewhat knowledgeable about hemophilia (91%). When looking to the future (pessimistic=1 to optimistic=7), YA-PWH were generally optimistic, with median (IQR) 5 (5-7).

Conclusions:

YA-PWH in the United States are more likely to be on prophylaxis than older adults, but less likely to use medication exactly as prescribed. Additional research is warranted to better understand why prescribed regimens are not followed. Despite 50% prophylaxis use, bleeding occurred ~1-2 times/month and YA-PWH reported high perceived disease control. During this period of transition to independence, it is important to note one quarter reported issues around access to treatment and one fifth reported difficulty in visiting the HTC. YA-PWH were satisfied with care, but infrequently reported social workers and physical therapists as part of management.

Objective:

Joint status was assessed in the 3-year SPINART study, which compared routine prophylaxis versus on-demand treatment in adults with severe hemophilia A. We report joint outcomes at year 3 obtained using magnetic resonance imaging (MRI).

Methods:

The open-label, randomized, controlled, parallel-group, multinational SPINART study enrolled males aged 12–50 years with severe hemophilia A who had ≥150 exposure days with 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. 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 by 5 IU/kg permitted once per year). MRI was performed at baseline and year 3 to evaluate the structure of 6 index joints. Each MRI was read by 3 radiologists blinded to treatment assignment who independently completed the extended MRI (eMRI) scale; higher eMRI scores indicate greater joint structure damage. The score for each joint was based on the readers’ median change score for each of the 45 eMRI scale items when comparing MRIs from different timepoints. Total patient score was derived; change from baseline in total patient score was prespecified as the first in a hierarchy of 2 secondary endpoints. Between- group comparison was made using constrained longitudinal data analysis. Data are presented for the intent-to-treat population.

Summary:

Of 84 patients enrolled (42 per treatment group), MRI data were available for 38 on-demand and 41 prophylaxis patients. Least squares (LS) mean change from baseline to year 3 on the eMRI scale total score was 0.96 for on demand and 0.79 for prophylaxis (LS mean difference, –0.17; 95% CI, –0.92 to 0.59; P=0.66). LS mean change from baseline to year 3 for on demand and prophylaxis was 0.06 and 0.01 for the eMRI soft-tissue domain (LS mean difference, –0.04; 95% CI, –0.18 to 0.10; P=0.53) and 0.90 and 0.78 for the eMRI osteochondral domain (LS mean difference, –0.12; 95% CI, –0.82 to 0.58; P=0.74).

Conclusions:

In adults with severe hemophilia A, progression of structural joint damage was not significantly different between patients using rFVIII prophylactically or on demand over a 3-year follow-up period, although less progression was seen with prophylaxis.

Objective:

To describe the rates of falls, injurious falls, and activity restriction due to fear of falling in a population of patients with hemophilia.

Methods:

As part of a study on identifying fall risk in patients with hemophilia, subjects completed a self-administered questionnaire inquiring about fall history over the previous 12 months.

Summary:

75 patients with hemophilia between the ages of 18 and 85 completed the questionnaire. 59 (79%) of these patients had hemophilia A, and 16 (21%) had hemophilia B. 34 (45%) had severe disease, 17 (23%) had moderate disease, and 24 (32%) had mild disease.

25 (33%) of the subjects reported a fall within the last 12 months. The average and median ages of the subjects who fell were 46 and 45 respectively, while the average and median ages of the non-fallers were 41 and 39.5 respectively. Of the 25 patients who fell, 11 (44% of fallers or 15% of total sample) reported an injury caused by the fall. 12 patients (16%) reported restricting activity due to fear of falling. The majority of subjects who reported a fall or injurious fall had mild disease (55 %.), with an average age of 45 and median age of 46.5. The majority of subjects who restricted activity due to fear of falling had mild disease (50%), with most subjects who restricted activity reporting a fall in the previous 12 months (58%)

Conclusions:

Fall rates in hemophilia patients in this study (33%) are similar to or higher than the fall rates found in community dwelling adults 65 years and older (22-33%), although the subjects in this study were younger. Injurious fall rates found in the study (15%) are higher than non-fatal injurious fall rates described in adults age 65 and up (5-11.5%), and similar to those found in adults with arthritis age 45 and up (16.2%). Subjects in this study with mild disease were more likely to fall and to be injured. Activity restriction due to fear of falling (16%) was lower than that found in older adults in other populations (20-60%).

This study suggests that fall risk screening may be an important component of the comprehensive evaluation of patients with hemophilia, including those with mild disease. These results should be confirmed in a larger population of patients and across different treatment centres. Further research into optimal fall risk screening, in-depth assessment and treatment in this population is warranted.

The purpose of this project is to determine if children with hemophilia have gross motor delays. Gross motor skills include, but are not limited to walking, running, jumping, climbing, crawling, balancing, kicking, catching and throwing activities. The large muscles of the body are responsible for performing these types of activities. Strength, balance and coordination are needed to demonstrate and improve these skills. Children with hemophilia may experience internal bleeding in their joints or muscles, which limits their activity. Some children with hemophilia may be restricted from active play or sports for fear of getting an injury that could cause internal bleeding. When activity is restricted, there can be decrease in strength, balance and endurance. If a child has gross motor delays, it puts him at risk for injury when playing with his peers. Physical Therapy evaluations in the Hemophilia Treatment Center help determine changes caused by bleeding episodes. There are specific motor skills children master as they grow, which represent strength, balance and coordination. The comprehensive clinic visits do not allow time to complete an intensive gross motor assessment. Physical Therapists use Manual Muscle Testing, MMT, to grade the strength of each muscle group. MMT strength testing is not appropriate for young children and does not represent strength during functional activities. To accurately determine children's muscle strengths, a standardized gross motor test should be used. The PT at the Comprehensive Care Center for Inherited Blood Disorders will conduct gross motor evaluations in conjunction with the annual visit. The scores will be evaluated to determine which patients have gross motor delays, so they can be referred for therapy services. The BOT 2 is the standardized gross motor test that will be used to determine gross motor levels. The gross motor skills that will be evaluated include bilateral coordination, balance, running speed and agility, upper limb coordination and strength. All patients with hemophilia between the ages of 4 and 12 years will be eligible to be evaluated in the upcoming year with additional PT testing with their annual visit. Patients may be referred to therapy or given a home exercise program depending on the deficits noted during the assessments. The goal is to improve our standard of care at the HTC, by adding gross motor screening for our patients to ensure appropriate referrals are made for therapy services.

Objective:

Kids A-LONG was a global, multi-center, open-label phase 3 study that evaluated the safety, efficacy, and pharmacokinetics (PK) of rFVIIIFc in previously treated patients aged <12 years with severe hemophilia A (<1 IU/dL FVIII activity).

Methods:

All participants had ≥50 prior exposure days (EDs) to FVIII, and no history of FVIII inhibitors. Participants were to be treated with twice-weekly rFVIIIFc prophylactic infusions (Day 1, 25 IU/kg; Day 4, 50 IU/kg), with adjustments to dose (≤80 IU/kg) and dosing interval (≥ every 2 days) as needed by the investigator. A subset of participants (<6 years of age, n=25; 6 to <12 years of age, n=35) underwent sequential PK evaluations with FVIII (50 IU/kg), followed by rFVIIIFc (50 IU/kg). The primary endpoint was development of inhibitors (neutralizing antibodies). Secondary endpoints included PK, annualized bleeding rate (ABR) and number of infusions required to control a bleed.

Summary:

The study enrolled 71 participants from 23 centers (<6 years, n=36; 6 to <12 years, n=35); 94.4% of participants completed the study. Prestudy, 89% of participants received FVIII prophylaxis, the majority (74.6%) of whom required ≥3 infusions per week. The median time on study for treated subjects (n=69) was 26 weeks; 61 participants had ≥50 EDs to rFVIIIFc. No participant developed inhibitors to rFVIIIFc. Overall, the pattern of adverse events reported on rFVIIIFc treatment was typical of the population studied; no serious adverse events were assessed as treatment-related by the investigator. The terminal half-life (arithmetic mean [95% CI]) in participants aged <6 years and 6 to <12 years was 12.67 (11.23, 14.11) hours and 14.88 (11.98, 17.77) hours, respectively. The relative increase in half-life over prior FVIII therapy was ~1.5-fold, consistent with the increase in half-life seen in the A-LONG study of adults and adolescents. Median (IQR) ABR was 1.96 (0.00, 3.96) overall, and 0.00 (0.00, 0.00) for spontaneous bleeds. Median total weekly dose and dosing interval were 88.1 IU/kg and 3.5 days, respectively. 83.7% and 93.0% of bleeding episodes were controlled with 1 or 1–2 infusions, respectively (median dose per bleeding episode: 54.9 IU/kg).

Conclusions:

rFVIIIFc was well-tolerated, efficacious for prophylaxis and treatment of bleeding, and resulted in low bleeding rates. The extended half-life compared to FVIII and the safety profile were generally consistent with that observed in the Phase 3 study in adults and adolescents. rFVIIIFc offers the potential of prolonged dosing intervals and fewer infusions for children with severe hemophilia A.