Objective:
Report results of an open-label international study that collected retrospective data on compassionate use of high-purity plasma-derived FX concentrate (pdFX) in subjects with hereditary factor X (FX) deficiency (FXD).
Methods:
This study included subjects with hereditary FXD (irrespective of severity) who received compassionate use pdFX as routine prophylaxis (RP), on-demand (OD) treatment, short-term prevention, and/or perisurgical hemostatic cover. Dosing was at the investigator’s discretion and tailored to each patient. Data from date of first compassionate use dose until data cutoff (31 December 2015) were collected retrospectively.
Summary:
All 15 enrolled subjects from 12 study centers received ≥1 pdFX dose for compassionate use. Of these, 13 subjects were aged ≥12 years (mean, 22.8 years) and 2 were aged <12 years, 8 (53.3%) were female, 12 (80.0%) were white, 3 (20.0%) were Asian. All subjects had moderate or severe FXD (FX activity [FX:C] <5 IU/dL).Of the 15 patients, 7 received only RP, 7 received only OD, and 1 alternated between OD and RP. The 8 subjects on RP received a total of 1239 RP infusions (mean, 154.9 infusions/subject, range 39–492), with a mean dose/infusion/subject of 32.5 IU/kg. The 2 subjects aged <12 years received larger RP doses than the 6 older subjects (mean doses/infusion/subject of 51.1 vs 26.3 IU/kg).Twelve subjects (8 OD, 4 RP; all aged ≥12 years) reported 88 bleeds (34 minor, 7 major, and 47 not rated); 37 bleeds were menorrhagic, 28 were traumatic, 17 were spontaneous, 4 were other, and 2 had unknown cause. pdFX efficacy was rated as effective for the 79 bleeds (including 1 subdural hematoma) treated with OD pdFX. Mean pdFX dose was 22.2 IU/kg/infusion/subject, with a mean of 9.5 infusions/subject to treat a bleed. More bleeds occurred in the OD than in the RP population.Two subjects underwent 1 dental procedure each, with only 1 presurgical pdFX dose required per patient; a third surgery, a portacath insertion, required 6 infusions to prevent postoperative bleeding. Two successful pregnancies/childbirths were also reported, with no abnormal bleeding complications or efficacy/safety concerns reported.The mean duration of compassionate use was 87.6 weeks for the 15 subjects, with a range of 15–211 weeks (0.3–4.0 years). Over the 1373 infusions administered across 25.2 subject-years, investigators rated overall pdFX efficacy as excellent in 14 (93.3%) subjects and good in 1 (6.7%) subject. No adverse drug reactions, safety concerns, infusion site reactions, tolerability issues, or inhibitor development were reported during pdFX compassionate use.
Conclusions:
The higher bleed rate in OD versus RP use and the treatment duration (up to 4 years) support the efficacy and safety of pdFX demonstrated in prospective clinical studies and its continued use in the treatment of subjects with hereditary FXD.
Objective:
To examine whether a difference exists in factor consumption and cost after a person with factor VIII or factor IV switches from a standard half-life (SHL) factor product to an extended half-life (EHL) factor product managed by a single specialty pharmacy.
Methods:
All electronic medical records of patients with factor VIII or IX deficiencies who filled factor prescriptions with a single specialty pharmacy were reviewed. Data, including regimen, dosing and label instructions for fills of all recombinant and plasma-derived factor VIII and factor IX products between September 2013 and December 2017 were examined retrospectively. Adult patients (age ≥ 18 years) who switched from an SHL to an EHL product with 6 months of fill data available, for both periods before and after the initial EHL prescription was dispensed, were eligible for inclusion. Total cost was calculated using average wholesale price (AWP) using MediSpan (accessed June 1, 2018).
Summary:
Sixty-three (63) people with factor VIII deficiency and 29 people with factor IX deficiency met study criteria by having a prescription for factor and switching from an SHL product to an EHL product, as well as 6 months of dispensing prior to and after the change. The mean cost of therapy with an SHL factor VIII product for 6 months was $272,192 versus $455,260 for 6 months after switching to an EHL factor VIII product, an increase of 67%. The mean number of units of an SHL factor VIII product dispensed was 141,934 units compared to 181,688 units of an EHL factor VIII product per person, which is an increase of 28%. The mean cost of therapy with an SHL factor IX product for 6 months was $234,146 versus $474,858 for the 6 months after switching to an EHL factor IX product, an increase of 100%. The mean number of units of an EHL factor IX product dispensed was 147,730 units compared to 124,509 of an EHL factor IX product, a decrease of 16%.
Conclusion:
EHL products have several reported advantages over SHL products including longer interval between infusions, less frequent troughs (that may lead to decreased risk of bleeding episodes) and improved adherence. This analysis of dispensing data from a single specialty pharmacy indicates that change of prescription from SHL products to EHL products is associated with a higher cost of treatment. There are many more elements in factor prescribing that could contribute to future discussion.
This study will evaluate hemophilia treatment center (HTC) services provided to women with hemophilia A or B (Factor VIII or Factor IX level [ 50%). The American Thrombosis and Hemostasis Network (ATHN) maintains a confidential national database for patients with bleeding and clotting disorders. Utilizing this existing ATHNdataset, the study will analyze the effect of gender on the delivery of comprehensive care in patients with hemophilia A and B. The project will focus on how gender impacts three specific components of care: identification of patients with factor VIII or IX deficiency, inclusion of patients in the comprehensive care model, and monitoring of joint bleeding as a key component of comprehensive care provided by HTCs. Demonstrating gender-based disparities in comprehensive care would provide evidence for making changes to improve the clinical care provided to women with hemophilia. This study will add to the knowledge regarding the care of women with hemophilia, helping to inform future studies of this under-researched population.
Objective:
Repeated joint bleeding in patients with hemophilia leads to hemophilic arthropathy (HA), which cannot be entirely prevented by clotting factor replacement. Vascular remodeling and permeability are associated with hemarthrosis and may contribute to HA progression; however, the underlying mechanisms and effects of FVIII replacement are poorly understood. Here, we explored vascular changes and synovial gene expression profiles in FVIII-deficient mice after induced hemarthrosis +/- FVIII replacement.
Methods:
Hemarthrosis was induced in FVIII-deficient mice by sub-patellar needle puncture +/- 100-200 IU/kg recombinant human FVIII (rhFVIII) intravenously 2 hours before and 6 hours after injury. Vascularity and gene expression were analyzed at baseline and 2 weeks post-injury. Vascularity was assessed by histology with Safranin-O-Fast Green and α-smooth muscle actin (αSMA) staining, and by musculoskeletal ultrasound with Power Doppler to detect microvascular flow. The permeability of synovial vessels was determined by quantification of extravasated albumin-bound Evans blue dye in knee joints at near-infrared fluorescence. For gene expression studies, RNA was extracted from synovial tissue and cDNA libraries were prepared using the NEBNext Ultra II DNA Library Prep Kit and sequenced on an Illumina NextSeq500 platform (single-end; 75bp reads). The R BioConductor packages tximport, edgeR and limma were used to read Salmon transcript files and implement the limma-voom method for differential expression analyses. Functional enrichment was performed using Signaling Pathway Impact Analysis.
Results:
Knee injury caused profound hemarthrosis in vehicle-treated mice that was largely prevented with rhFVIII prophylaxis (day 2 hematocrit: 26.4% and 46.3%, respectively). Soft tissue proliferation increased to a similar extent in both groups, as did various vascular parameters: microvascular flow (vehicle: 1.8-fold; rhFVIII: 1.5-fold), vessel number (vehicle: 2.2-fold, p=0.0005; rhFVIII: 2.0-fold, p=0.004), vessels with diameter ≥ 20 µm (vehicle: 2.9-fold, p=0.02; rhFVIII: 2.7-fold, p=0.02), and αSMA area per vessel (vehicle: 2.3-fold, p>0.05; rhFVIII: 3.6-fold, p=0.0006). Vascular permeability also increased significantly after joint bleeding (1.7-fold, p=0.0007) and was only partially rescued by rhFVIII prophylaxis (1.3-fold, p>0.05). RNA sequencing revealed a strong transcriptional response (1527 differentially expressed genes (DEG), 13 perturbed pathways), that was not substantially dampened in rhFVIII-treated mice (891 DEG, 20 perturbed pathways). Notably, perturbation of extracellular matrix (ECM)-receptor interactions was highly significant with vehicle (pGFWER=1.7x10-11) and rhFVIII prophylaxis (pGFWER=1.4x10-10). STRING analysis of the top 20 DEG revealed enrichment of ECM components and organization, and numerous genes encoding ECM constituents, including collagens and MMPs, were significantly upregulated. Changes in ECM gene expression may facilitate the observed synovial tissue and vascular remodeling after hemarthrosis.
Conclusions:
Hemarthrosis in FVIII-deficient mice triggers profound changes in synovial gene expression that may drive associated tissue and vascular remodeling processes. These changes are incompletely mitigated by rhFVIII prophylaxis. Further exploration will enable identification of disease markers and targeted drug discovery to intercept the progression of HA.
Background:
Inherited factor X deficiency is an autosomal recessive bleeding disorder with an estimated occurrence rate of 1:1,000,000¹. Historically, bleeding symptoms have been treated with topical therapies, antifibrinolytic agents, fresh frozen plasma (FFP) or plasma-derived FIX concentrates (PCCs). In 2015, the first factor X (FX) concentrate was approved in the U.S.
Objective:
This organization was interested in reviewing clinical outcomes such as perceived pain and unplanned hospitalizations of adults and children with FX disease currently being treated in the home with Coagadex®. METHODS: This organization conducted a retrospective review of a population of seven adult and pediatric patients. Patients were surveyed for pain, bleeding episodes, hospitalizations/ ER visits, dosing parameters and administration methods pre/post initiation of FX therapy. There were 3 children, 12 years old and under and four adults. Ages ranged from 5-60 years old with the average age of 27.9. There were five males and two females. The average length of treatment was 6.4 months. One patient was naïve, six converted from other therapies. Dose ranges administered by caregivers or self-infusion were 750 -2800 IU (26-61 IU/Kg). One patient was on-demand and six were administering prophylaxis therapy.
Results:
There were two converted prophylaxis patients reported pain with PCC’s and none with FX; one on-demand naïve patient stated his pain was markedly improved with prn administration of FX; four converted prophylaxis patients with no prior pain history reported no changes in pain on FX therapy. For on-demand patients treating bleeding episodes, three reported a decrease in the number of bleeding episodes, three were unchanged and one reported one additional bleeding episode. A total of ten hospitalizations or emergency room visits were reported during the six months prior to initiation of FX treatment and only one in the six months following initiation of treatment.
Conclusion:
Early recognition and home treatment with FX concentrate allows for prompt resolution of bleeding symptoms, decreased pain and decreased hospitalization or emergency room visits. Further investigation is needed to determine cost-savings for decreased hospitalization/ ER visits.References:Brown, D.L. & Kouides, P.A. (2008). Diagnosis and treatment of Inherited Factor X deficiency. Haemophilia. (14). 1176-1182. Retrieved from: https://www.hemophilia.org/sites/default/files/document/files/DiagnosisAndTreatmentOfInheritedFact…
Klaus Bonazza received his Ph.D. in chemistry from Vienna University of Technology. He is currently a postdoctoral researcher at Boston Children's Hospital and appointed at Harvard Medical School, mentored by Dr. Timothy Springer. His field of interest is the ultra-large concatemeric protein von Willebrand factor (VWF), which accounts for the adaptability of hemostasis to different flow conditions in the blood vessels.
At moderate, physiological flow VWF has a packed, "bird nest's" shape whereas strong elongational flow conditions, occurring downstream of vascular restrictions or injuries, induce a transition to a threat-like, elongated state. On top of this overall unpacking, tensile forces, which are exerted on the chain and transmitted by its A1 domain, cause local conformational changes which activate binding of thrombocyte receptor Glycoprotein Ib (GPIbα) to initiate coagulation. With his JGP fellowship award, Dr. Bonazza will pioneer a new method to obtain structural insights into force dependent VWF unpacking, A1 deformation and GPIbα binding based on hydrogendeuterium exchange under elongational flow conditions.
