Research Studies

Background:

A high-purity plasma-derived FX concentrate (pdFX) has been developed for treatment of hereditary FX deficiency, an autosomal recessive disorder.

Aim:

This post hoc analysis describes the pharmacokinetics, safety, and efficacy of pdFX in 10 women and girls with hereditary FX deficiency.

Methods:

In this open-label study, subjects (10 women/girls, 6 men/boys) aged ≥12 years with moderate or severe FX deficiency (basal plasma FX activity ≤5 IU/dL) were enrolled and received 25 IU/kg pdFX for on-demand treatment of bleeding episodes or preventative use for up to 2 years. All subjects provided informed consent and the protocol was approved by appropriate independent ethics committees.

Results:

Nine women and girls had severe and 1 had moderate FX deficiency, were aged 25.5 (median; range 14–58) y, and received a total of 267 pdFX infusions (178 for on-demand and 89 for preventative treatment). Men and boys (5 severe and 1 moderate FX deficiency) received a total of 159 pdFX infusions (64 on-demand; 95 preventative). The mean number of infusions per subject per month was higher among women and girls (2.48) than males (1.62). The mean pdFX incremental recovery was similar between women/girls and men/boys (2.05 vs 1.91 IU/dL per IU/kg, respectively), as was mean half-life (29.3 and 29.5 h, respectively). Among women and girls, 132 assessable bleeding episodes (61 heavy menstrual bleeding, 47 joint, 15 muscle, and 9 other) were treated with pdFX. Women and girls reported a treatment success rate (ie, subject rating of “excellent” or “good” response to pdFX) of 98%, comparable to the 100% treatment success rate among men and boys. After study completion, 2 subjects received pdFX for hemostatic cover during obstetric delivery. Additional infusion, bleed, and safety data will be presented.

Conclusion:

These results show that, in women and girls with moderate or severe hereditary FX deficiency, who experience reproductive tract and other bleeding events, pdFX was safe and effective. The pharmacokinetic profile of pdFX in women and girls was similar to that of men and boys.

Funding: Bio Products Laboratory

Objectives:

Contemporary real-world data on units dispensed and expenditures associated with use of standard half-life (SHL) and extended half-life (EHL) factor VIII replacement products in U.S. patients with hemophilia A are limited. This exploratory analysis of real-world administrative data was conducted to determine units dispensed and factor replacement product-related direct expenditures associated with currently marketed recombinant SHL and EHL FVIII products, and to examine inter-product switches.

Methods:

De-identified claims data from the commercially available Truven Health MarketScan® Research US claims database were used to identify direct expenditures and number of international units (IUs) dispensed for all patients with a diagnosis code of ICD-9 286.0/ICD-10 D66 who used SHL (SHL group) and/or EHL (EHL group) during the study period from Aug 1, 2014 to Jan 31, 2017. Data on switching from an SHL to an EHL factor VIII replacement product were captured in patients with continuous pharmacy enrollment for whom claims data were available for at least 1 calendar quarter and up to 1 year before and after the index date of a product switch. Descriptive statistics were used to analyze results.

Summary:

Cross-sectional analysis.
The SHL group comprised 415 patients, among whom six distinct SHL FVIII products had been dispensed, and the EHL group included 91 patients, among whom two EHL FVIII products had been dispensed. The age distribution of the two groups was similar (p =0.57), although the proportion of patients under 18 years of age was somewhat higher in the SHL group than in the EHL group (46.9% vs 36.2%). The median FVIII product dispensation per calendar quarter was 46,409 IU (IQR, 12,760-87,670 IU) (SHL) versus 67,375 IU (IQR, 50,524-98,264 IU) (EHL). Median expenditures per calendar quarter were substantially higher for EHL ($135,519; IQR, $100,320-186,557) than for SHL ($61,152; IQR, $18,593-115,845).

Switching analysis.
Of the patients in the EHL group, 29 had switched from one of three SHL FVIII products to one of two EHL FVIII products during the study period. The total median IU dispensation per calendar quarter increased following the switch from 58,598 IU (pre-switch, SHL) to 68,036 IU (post-switch, EHL; 16% increase), as did the factor-related expenditure ($76,553, SHL, versus $141,101, EHL; 84% increase).

Conclusion:

Real-world data derived from a large claims database, unadjusted for treatment regimen or hemophilia severity, reveal marked differences in metric units and expenditures among hemophilia A patients to whom SHL and/or EHL products were dispensed. Switching from an SHL to an EHL FVIII replacement product was associated with a substantial increase in units dispensed and factor expenditures. Further analyses, incorporating essential clinical characteristics, should be explored.

Objective:

Through the Annual Global Survey (AGS), the World Federation of Hemophilia (WFH) has been collecting national aggregate data on people with bleeding disorders since 1999. Lack of diagnosis and treatment for women and girls with bleeding disorders remains a challenge in the bleeding disorder community. Highlighting gender data from the AGS can help bring awareness to the issues facing women and girls.

Methods:

The Report on the AGS 2015 includes demographic and treatment-related data from 111 countries, representing 91% of the world population. The AGS began collecting data on gender distribution in 2007. Gender data from 2007 to 2015 is summarized.

Summary:

The Report on the AGS 2015 demonstrates that 65,284 women were identified as having a bleeding disorder. The five types of hereditary bleeding disorders with the largest proportion of women are: platelet disorders (65%), von Willebrand (VWD) Fibrinogen (56%), FXI deficiency (55%), and FV deficiency (Figure 1). A gender breakdown for hemophilia A and B indicates that there are women who are affected by hemophilia (N=3,988 (3%), N=1,328 (5%) for hemophilia A and B, respectively) (Figure 1). The most common bleeding disorder for women and girls is VWD. From 2007 to 2015, the reported number of women with VWD increased by 17,220 (21,710 – year 2007, 38,930 – year 2015). This is a 79% increase in the number of women identified with VWD compared to a 65% increase in men identified with VWD during the same time period.

Conclusions:

AGS data recognizes the women and girls around the world who are affected by bleeding disorders. The WFH Annual Global Survey data is available to the bleeding disorder community as an advocacy tool.

Objective:

To provide genotyping and enrollment into the My Life, Our Future research repository for individuals with Hemophilia and potential carriers by offering a community based outreach program.

Methods:

Utilizing the ATHN dataset, potential participants who had not been previously genotyped were identified. In addition, a recruitment letter was prepared and sent to invitees of the local NHF Chapter Annual Dinner. Interested subjects were instructed to contact the genetic counselor, who discussed the project and scheduled them in 15 minute research timeslots. A hospital mobile unit, stocked with medical supplies and a centrifuge, was obtained to provide a site for registration, phlebotomy and processing of specimens. Staff for the event included the following: three staff to consent participants; four staff providing venipunctures, two staff to process specimens, two staff to assist with registration and a driver for the mobile unit. Funding was secured through NHF to support the genotyping day.

Summary:

Fifteen subjects, including 3 males and 12 females, scheduled appointments for the 4-hour recruitment time period. In addition, three subjects were added the day of the project and a waiting list was started for those wishing to enroll at a future event. In total, 17 subjects were enrolled from 9 families. In several cases, family members from different generations enrolled, including an at-risk carrier female, her mother and grandmother. Ages of participants ranged from 4-91. All participants chose to participate in the research repository. One participant’s specimen had to be destroyed due to a mislabelled MLOF ID (an add-on subject). It took approximately 10 hours to prepare for the event including 2 hours of planning related to the mobile unit (5 staff) and 8 hours to develop the recruitment letter, prepare the IRB amendment, mail letters, schedule participants, prepare consent packets, obtain MLOF ID numbers, and arrange phlebotomy kits (4 staff). It took 5 hours and 12 staff to successfully implement the program on the genotyping day. In comparison, we typically process on average two patients per 4 hour comprehensive clinics held two times per month, with 2 staff involved with other concurrent job assignments.

Conclusions:

The outreach program is an effective way to recruit individuals for genotyping and participation in the MLOF research repository. Participants were excited to participate and inquired about future events. The event provided a relaxed atmosphere with extended family members present, allowing for multi-generational and diverse recruitment. When considering a genotyping day versus scheduled clinic time, additional preparation time is needed to arrange logistics and avoid error, but the number of participants is significantly increased.

Dr. Tine Wyseure obtained her Master’s degree in Drug Discovery and Development, and earned her Ph.D. in Pharmaceutical Sciences at the University of Leuven, Belgium. Since 2015, she has been a research associate in the lab of Dr. Laurent Mosnier at The Scripps Research Institute in San Diego. Dr. Wyseure’s 2016 JGP research fellowship award project is focused on investigating the effects of impaired TAFI activation in hemophilia on the progression of hemophilic joint disease. The lack of active TAFI worsens joint bleeding and chronic inflammation and drives the striking development of fragile blood vessels in diseased joints. In search of the missing link, Dr. Wyseure has discovered a novel paradigm on how the formation of new blood vessels is controlled by TAFI and suggests that patients with hemophilia may lack this control switch, causing the formation of unstable and leaky blood vessels.

Objective:

The aim of this study was to determine if the young boys with hemophilia at our clinic have gross motor delays that may have been missed during the annual physical therapy evaluation. By identifying delays, our clinic can improve the standard of care and promote gross motor development in our patients to enhance their ability to be physically active and protect their joints and muscles from injury.

Method:

Over a one year period, boys with hemophilia A or B between the ages of 4 to 14 were tested by the physical therapist at our clinic using the Bruinink’s-Oseretsky Test of Motor Proficiency, Second Addition, BOT2. The BOT2 is a valid and reliable gross motor test for 4 to 21 year olds and is widely used to detect mild to moderate motor delays. The five gross motor subtests used in this study included upper extremity (UE) coordination, bilateral coordination, balance, strength, running speed and agility (run/agility). A total of 42 boys completed the study with scores distributed between three age groups: Group 1=4-7 year olds; Group 2=8- 11 year olds; and Group 3=12-14 year olds. Exclusion criteria included a bleed within the last week that was unresolved or other physical limitation preventing participation. All severities of hemophilia were included in the study, but were not separately analysed in the results.

Results:

Each age group mean scores for the subtests were within the normal mean range of 15±4 except for strength in Group 2. Group 1 had some participants score above average for four of the subtests, while Group 2 and 3 only scored above average on one subtest. Group 1 had 6-18% score below average on four of the subtests while Group 2 had 27-47% and Group 3 had 30-50% score below average on all 5 subtests. No adverse events or bleeds occurred during or as a result of the gross motor testing.

Conclusion:

At our Hemophilia Treatment Center, more than 50% of the boys tested had gross motor dels. The percentage of boys showing deficits increased and persisted after age 7. This reinforces the need to include some standardized gross motor testing during the annual physical therapy evaluation of our patients with hemophilia to identify boys with scores below average and make referrals at an early age to prevent persisting gross motor delays.

Dr. Christopher Ng was a pediatric hematology/oncology fellow at the University of Colorado - Anschutz Medical Campus. Dr. Ng attended medical school at the Keck School of Medicine at the University of Southern California and completed his pediatrics residency at the University of Washington/Seattle Children's Hospital. Dr. Ng received the NHF-Baxalta Clinical Fellowship in 2013. Dr. Ng's 2015 JGP research fellowship award project focused on a multi-system evaluation of von Willebrand factor function in Type 1 von Willebrand Disease mutations.