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).
