Research Studies

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.

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.