Research Studies

Objective:

This prospective clinical trial was conducted to assess the safety, efficacy and PK of BAX326 (a novel recombinant FIX [rFIX] manufactured without the addition of any materials of human or animal origin, and with two viral inactivation steps [solvent/detergent treatment and nanofiltration]) in previously-treated patients aged 12 to 65 with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B.

Methods:

Hemostatic efficacy after twice weekly prophylaxis with BAX326 was determined in terms of annualized bleeding rate (ABR) compared with a historical control group treated on- demand. PK equivalence was assessed between BAX326 and a commercial rFIX in a crossover design. Safety was evaluated by the occurrence of adverse events.

Summary:

In subjects on twice weekly prophylaxis with BAX326 over at least 3 months (N=56), 24 (43%) did not bleed throughout the study observation period, and the ABR was substantially lower when compared with a historical control group (79% reduction, p<0.001). Joint bleeds (major joints: wrist, elbow, shoulder, hip, knee, ankle) occurred at a mean ABR of 2.85 ± 4.25 compared with 1.41 ± 2.87 in non-joint bleed sites. Of the 32/56 subjects with bleeds, 90.6% (29/32) had arthropathy at screening and only 28.1% (9/32) did not have target joints, as compared to subjects without bleeds, of whom 79.2% (19/24) had arthropathy and 50% (12/24) did not have target joints at screening. Higher mean ABRs were observed in subjects with arthropathy (N=46) versus without arthropathy (N=8) (4.54 vs. 2.57 for all bleeds, 3.16 vs. 1.02 for joint bleeds, and 1.97 vs. 0.25 for spontaneous bleeds). A similar pattern was observed for the ABRs of joint bleeds and spontaneous bleeds in subjects with target joints (N=35) (mean ABR: 2.41 ± 3.79) and those with no target joints (N=21) (mean ABR: 0.58 ± 1.63). Most bleeds were controlled with 1-2 infusions of BAX326 and with an efficacy rating of “excellent.” BAX326 was equivalent to the comparator rFIX in terms of AUC 0 72 h /dose. BAX326 is safe and well tolerated in hemophilia B patients, with no signs of immunogenicity or thrombotic events.

Conclusions:

BAX326 has a positive safety profile and is efficacious in treating bleeds and in routine prophylaxis in PTPs aged ≥12 years with hemophilia B. The results also demonstrate that subjects with target joints and hemophilic arthropathy receiving secondary prophylaxis tend to have higher ABRs as compared to those without these underlying conditions.

Objective:

With increasing life expectancy of people with hemophilia (PWH) in developed countries, the number of PWH affected with age-related diseases is also increasing. Atrial fibrillation is a common health problem in the general population, but in PWH, evidence-based guidelines for the management of AF are lacking.

The aim of this cross-sectional pan-European study is to analyze the prevalence of AF and risk factors for stroke in our adult hemophilia population and to document current anticoagulation practice.

Methods:

The ADVANCE Working Group consists of members from 14 European hemophilia centers. Each center retrieved data on the number of PWH with AF in their hemophilia population, as well as their total number of adult PWH. For each person with AF, a case report form was completed.

Summary:

In total, 29 PWH with AF were documented. The mean age was 68.2 years (IQR 62-75.5). Hemophilia was severe in 6 (20.6%), moderate in 6 (20.6%) and mild in 17 (58.6%) patients. The prevalence in the total studied hemophilia population was 0.94% (29/3094) and increased with age; in patients >40 years it was 1.7% (29/1723) and in patients >60 years 3.6% (23/635). The mean CHA2DS2-Vasc score was 1.3 (IQR 0-2). Hypertension was reported in 12 patients (41.4%), diabetes in 3 (10.3%), previous stroke or TIA in 1 (3.4%), peripheral vascular disease in 4 (13.8%). In 11 patients (37.9%), anticoagulation was started of whom 9 low dose aspirin and 2 vitamin K antagonists. Of these 11 patients, 9 had mild hemophilia, 1 moderate and 1 severe with FVIII prophylaxis. During follow-up after diagnosis (mean follow-up 52.9 months), there were no thrombotic events reported, nor increases in bleeding severity.

Conclusions:

In this largest cohort of PWH with AF so far, the prevalence of AF in hemophilia increases with age and is predominantly present in mild hemophilia. Based on the population based CHA2DS2-Vasc risk scores, PWH have a low stroke risk that might be even lower considering the hypocoagulable state. Hemophilia doctors prescribe anticoagulation therapy approximately in half of their mild hemophilia patients and very few in moderate and severe.

This study explores perceptions among adolescent aged patients with inherited bleeding disorders regarding religiosity/spirituality and whether their beliefs have an impact on the pain they experience. Subjects participating will be assessed in regards to the type, frequency and intensity of pain experienced and measures used to cope with the pain. Finally, we will measure patient self reports of disease self efficacy. To further assess the impact of religiosity/spirituality on the family system, we will be measuring parental perceptions of religiosity/spirituality with parents of the participating adolescents.

Objective:

A novel recombinant coagulation factor VIII, rVIII-SingleChain, produced without added animal- or human-derived materials, is currently in a clinical phase I/III program (AFFINITY). The present non-clinical studies were conducted to investigate the pharmacokinetic (PK) profile of rVIII-SingleChain in animals to support assessment of its PK/pharmacodynamic properties for future clinical use.

Methods:

The PK behavior of rVIII-SingleChain was explored in hemophilia A mice, rats, and monkeys. Intravenous doses of 50-250 IU/kg for rVIII-SingleChain or a marketed full-length rFVIII concentrate were given. Systemic FVIII activity or antigen levels were recorded in plasma samples after injection. A thrombin generation assay was conducted to assess coagulation parameters ex vivo after treatment of hemophilia A mice with 250 IU/kg of rVIII- SingleChain or full-length rFVIII.

Summary:

In all animal species, treatment resulted in improved PK properties for rVIII- SingleChain compared to full-length rFVIII. Increased systemic availability and mean residence time were observed for rVIII-SingleChain. Correspondingly, the clearance rate was decreased and the terminal half-life was enhanced in comparison with full-length rFVIII. In vivo recovery and volume of distribution of rVIII-SingleChain were equivalent to full-length rFVIII. Consistent with the PK characteristics, rVIII-SingleChain showed a more favorable thrombin generation potential compared to full-length rFVIII between 2-6 days after treatment of FVIII-deficient mice. Results obtained showed that thrombin peak levels were kept between 50-250 nM for an increased period of time by rVIII-SingleChain compared to full-length rFVIII, with an average extension of 20 hours.

Conclusions:

The current investigations demonstrated favorable PK properties of rVIII- SingleChain in animal species. The presented results support the evidence necessary for conducting human trials to explore whether such favorable non-clinical PK characteristics may translate into clinical benefit.

Objective:

Few data sources contain sufficient patient count to study the real-world efficacy of factor VIII (FVIII) therapy in patients with hemophilia A (HA). Health insurance claims databases offer that opportunity. This study sought to identify patients with HA receiving prophylaxis versus on-demand FVIII regimens and describe their characteristics and treatment patterns utilizing data from Medicaid programs.

Methods:

Healthcare claims from Florida, Iowa, Kansas, New Jersey, and Missouri Medicaid programs covering 1996 to 2011 were used. Patients with ≥2 HA diagnoses (ICD-9 286.0), ≥2 dispensings for FVIII after age 2, continuous Medicaid eligibility ≥6 months before (baseline period) and ≥12 months after the first FVIII fill, and no evidence of bypassing agents or desmopressin use were included. Prophylaxis and on-demand regimens were identified using an algorithm calibrated to distinguish the regimens within five age groups based on the annual total units of FVIII dispensed regardless of the severity level: 16,480 IU (2–7 years old); 32,770 IU (8–12); 66,920 IU (12–16); 98,349 IU (17–21); 204,552 IU (≥22). The algorithm was developed using prescription records of 1,311 patients from three U.S. specialty pharmacy databases. FVIII treatment patterns and patient demographic and clinical characteristics were examined.

Summary:

From the approximately 14.8 million covered lives encompassed in the five Medicaid databases, a total of 2,408 (0.016%) patients with ≥2 diagnoses for HA were identified; 448 met the study eligibility criteria with 229 (51.1%) patients receiving prophylaxis FVIII and 219 (48.9%) patients receiving on-demand FVIII. Younger patients were more likely to receive prophylaxis therapy (percent by age group: 61% [2–7]; 70% [8–12]; 63% [12–16]; 51% [17–21]; 20% [22+], mean (SD) age, prophylaxis: 10.8 (9.8) years old; on-demand: 18.7 (14.4) years old). Mean (range) observation period was 5.6 (1.0-15.2) years for prophylaxis patients and 5.6 (1.0-15.2) years for on-demand patients.

Conclusions:

In a population of 448 Medicaid patients with HA, this study found that 51.1% and 48.9% patients received prophylaxis and on-demand FVIII regimens, respectively. With the average observation of patients for more than 5.5 years, this database offers the potential for long-term follow-up to assess the relative efficacy of prophylaxis versus on-demand FVIII regimens in decreasing the incidence of bleeding events. These evidences from claims databases are critical to payers and decision makers as they reflect real-world clinical practice and patterns of FVIII use. Information on HA severity level was not available in the databases used.