Research Studies

Objective:

To assess the safety and efficacy of treatment with the first high-purity plasma-derived factor X concentrate (pdFX) in 2 prospective, multicenter, open-label, nonrandomized phase 3 studies in subjects with hereditary mild to severe mild factor X (FX) deficiency (basal plasma FX activity [FX:C] <20 IU/dL) undergoing surgery.

Methods:

Subjects aged ≥12 years received pdFX preoperatively to raise plasma FX:C to 70-90 IU/dL and postoperatively as necessary to maintain levels at ≥50 IU/dL until they were no longer at risk of bleeding due to surgery. Efficacy assessments included blood loss during surgery, requirement for blood transfusion, postoperative bleeding, and changes in hemoglobin levels. Following treatment, efficacy of pdFX in the control of bleeding was assessed as “excellent,” “good,” “poor,” or “unassessable.” Safety outcomes included adverse events (AEs), inhibitor development, viral seroconversions, and other clinically significant changes in laboratory parameters.

Summary:

Five subjects (aged 14-59 years) underwent 7 surgical procedures (major procedures: 2 knee replacements, 1 coronary artery bypass graft, and 1 extraction of 6 teeth; minor procedures: 2 extractions of 1 tooth each and 1 extraction of 2 teeth). Median pdFX exposure was 181 IU/kg (over 13 infusions) for major procedures and 89 IU/kg (over 2.5 infusions) for minor procedures. A median dose of 48.85 (range, 30.88– 54.41) IU/kg was administered preoperatively, resulting in plasma FX:C levels of 0.77- 1.32 IU/mL, and a median FX incremental recovery of 2.21 (range, 1.67-2.34) IU/dL per IU/kg was observed. For all procedures, bleeding control was rated by investigators as “excellent,” no blood transfusions were required, and no clinically significant changes in hemoglobin levels were observed. Blood loss was rated as “as expected” in 5 procedures and “less than expected” in 2 procedures compared with a similar patient without a coagulation disorder undergoing the same surgery. The most common AEs were constipation and dyspepsia (3 cases each). No treatment-related AEs, thrombotic events or evidence of thrombogenicity, viral seroconversions, or inhibitor development were observed.

Conclusions:

These results show that pdFX was safe and efficacious as replacement therapy for 5 subjects with mild to severe FX deficiency undergoing a variety of surgical procedures on 7 occasions. Based on these findings, dosing should be tailored to the severity of the surgical procedure and the patient’s concomitant medical issues, and continual assessment of plasma FX levels in the perioperative period is recommended.

Introduction and Objectives:

In the phase 3 B-LONG and Kids B-LONG studies, subjects with severe hemophilia B receiving rFIXFc prophylaxis had low annualized bleeding rates (ABRs), with decreased weekly factor consumption and fewer infusions compared with pre- study FIX treatment. This report evaluated the effect of rFIXFc on subjects’ physical activity across a variety of age groups using a subject-reported assessment.

Methods:

Eligible subjects for B-LONG (≥12 y) and Kids B-LONG (<12 y) were previously treated males with severe hemophilia B (≤2 IU/dL endogenous FIX activity). Subjects in B- LONG were enrolled into 1 of 4 treatment arms: Arm 1, weekly prophylaxis; Arm 2, individualized interval prophylaxis; Arm 3, episodic treatment; or Arm 4, perioperative management (not included in this analysis). All subjects in Kids B-LONG started on weekly prophylaxis. There were no restrictions regarding physical activity. Physical activity assessments were conducted at Weeks 4, 16, 26, 39, 52, and end of study (B-LONG) and Weeks 3, 12, 24, 36, 50, and end of study (Kids B-LONG). At each visit after their first rFIXFc dose, subjects were asked to rate their activity level relative to their prior study visit as: more (or more intensive), fewer (or less intensive), or about the same amount of physical activities. To summarize each subject’s change in physical activity over the course of the study compared to baseline, subjects’ reports were classified into four groups: less, the same, more, or undetermined.

Results:

Overall, 123 and 30 subjects enrolled in B-LONG and Kids B-LONG, respectively. The majority of subjects in B-LONG reported more or the same amount of physical activity, and few subjects reported less physical activity during the study (less, the same, more, undetermined in Arm 1 [n=60], 7%, 42%, 35%, 17%; Arm 2 [n=25], 16%, 28%, 48%, 8%; Arm 3 [n=27], 15%, 26%, 30%, 30%, respectively). Results were generally similar for subjects in Kids B-LONG (for subjects aged <6 y [n=15], 13%, 27%, 47%, 13%; for subjects aged 6 to <12 y [n=15], 7%, 13%, 67%, 13%).

Conclusions:

ABRs were low in B-LONG and Kids B-LONG despite similar or increased physical activity levels reported by the majority of subjects. These results suggest that people with severe hemophilia B across a variety of age groups may maintain or increase their physical activity levels with rFIXFc, while also reducing infusion frequency and weekly factor consumption, without compromising efficacy.

Objective:

This report assesses the changes in bleeding patterns as previously treated severe hemophilia A patients were switched from their pre-study standard factor VIII (FVIII) prophylactic treatment regimen to prophylaxis with BAX 855 - an extended half-life, pegylated, full-length recombinant FVIII built on ADVATE - during their participation in the pivotal trial.

Methods:

Patients’ informed consent and appropriate ethics committee approvals were obtained. At baseline, eligible patients reported their pre-study treatment regimen and average annualized bleeding rate (ABR) for the previous 3-6 months. Patients assigned to the prophylactic arm were to receive 45±5 IU/kg of BAX 855 twice weekly for ≥50 exposure days or approximately 6 months. This per-protocol analysis included 101 treated patients in the prophylactic arm.

Summary:

The overall mean (SD) ABR for these treated patients was 3.7 (4.7), which was lower than the ABR for the 17 patients treated on-demand during the study (40.8 [16.3] - who were all treated on-demand pre-study). Of the 101 subjects in BAX 855 prophylactic arm, 82 were treated on prophylaxis and 19 were treated on-demand during the pre-study period. The BAX 855 prophylactic dosing frequency was reduced by a mean (SD) of 26.7% (27.9) compared to the frequency reported in the pre-study period, which is approximately equivalent to one less prophylactic infusion per week when using BAX 855 for prophylaxis. The mean dose per prophylactic infusion was higher for the BAX 855 treatment regimen compared to pre-study (44.53 vs 38.12 IU/kg), but FVIII consumption per week was lower during the study compared to pre-study (83.96 vs 97.79 IU/kg/week). More patients treated on BAX 855 prophylaxis during the study treatment period had zero bleeding episodes compared to during their pre-study period: 37.8% vs 23.2%. The mean ABR was lower for subjects on BAX 855 prophylaxis compared to pre-study: 4.13 vs 9.74.

As expected, the 19 patients treated on-demand pre-study had a higher mean ABR (31.53) and all experienced bleeding (ie, none had zero hemarthroses during the pre-study period) compared to during their BAX 855 prophylactic treatment period (mean ABR of 1.68 and 47.4% had zero bleeding episodes).

Conclusions:

These results further demonstrate the benefit of BAX 855 prophylaxis (45±5 IU/kg twice weekly) and support its efficacy profile for the prevention of bleeding when used twice weekly, which suggests that fewer infusions may be needed to maintain prophylactic efficacy.

Prophylactic factor VIII (FVIII) replacement therapy in hemophilia A requires frequent administration because of the short half-life of FVIII. Polyethylene glycol (PEG) conjugation is thought to extend FVIII half-life by decreasing hepatic clearance. BAY 94-9027 is a rationally designed B-domain–deleted (BDD) FVIII molecule with a 60-kDa PEG molecule attached to a specific amino acid (1804) to increase circulating half-life and reduce the exposure to epitopes reported to cause immunogenicity in the A3 domain while preserving full biological function. BAY 94-9027 is currently in clinical trials and has prolonged half-life and improved efficacy in animal models and humans.

To determine whether half-life extension with BAY 94-9027 is related to PEG steric hindrance, we first investigated whether PEG impacts BAY 94-9027 binding interactions. Direct binding of hybrid of kidney and B cells (HKB)11-derived FVIII, BAY 94-9027 or BDD-FVIII, was assessed by measuring the ability of a panel of immobilized monoclonal antibodies directed toward different FVIII domains to capture FVIII. Interactions with more physiologic partners were indirectly assessed by thrombin generation assay (TGA) and by an in vitro hepatocyte clearance assay.

Our results indicate that the presence of A3-directed PEG reduced BAY 94-9027 capture by immobilized antibodies directed toward FVIII regions at or near the site of conjugation. Capture by antibodies directed toward the A3 and C2 domains were most impacted, while those directed toward A1 and A2 still bound BAY 94-9027. The A3-specific C7F7 antibody showed ~50% lower capture of BAY 94-9027 vs BDD-FVIII at 20 ng/mL of FVIII. C7F7 capture of PEG-BDD-FVIII was further reduced when a di-PEG conjugate of BDD-FVIII was subjected to the same assay, again confirming that PEG sterically modulates PEG-BDD-FVIII reactivity to the antibody. To determine whether steric effects observed with PEG may impact FVIII function globally, TGA was performed with BAY 94-9027 spiked into FVIII-deficient plasma and subjected to 1 pM tissue factor initiation. By TGA, both BDD-FVIII and BAY 94- 9027 generated comparable peak thrombin levels, with EC50 values of 3.9 and 3.2 nM for BDD-FVIII and BAY 94-9027, respectively. These results indicate that the PEG did not disrupt activated PEG-BDD-FVIII interactions with its partners in the factor Xase enzyme complex, consistent with published PEG-BDD-FVIII efficacy. By hepatocyte clearance assay, PEG- BDD-FVIII clearance was reduced ~30-40% compared with BDD-FVIII, regardless of whether von Willebrand factor was present. This reduction in hepatocyte clearance is likely to contribute to the prolonged plasma half-life reported for BAY 94-9027.

Objective:

To assess the effect of digital monitoring on bleeding rates in patients with hemophilia A using prophylaxis.

Methods:

A total of 294 eligible patients with hemophilia A were included in our observational study. Eligible patients used clotting factor concentrates and had no active inhibitors. Patients used a digital health tool powered by MicroHealth to log bleeds and infusions via smartphone, texting, or online. The study observational period was August 2014 to January 2015. Patients using the tool could choose to invite their care professionals for monitoring. For each patient, Hemophilia Treatment Center (HTC) monitoring was defined as having at least one HTC professional: 1. Linked to the patient and with online access to the infusion logs; 2. Receiving notifications when the patient had bleeds and/or had adherence below a threshold, and; 3. Having two or more patients under monitoring. There were a total of 35 and 259 patients in the monitoring and non-monitoring groups, respectively.

We conducted Bayesian analysis using linear mixed models and a negative binomial distribution to compare the relative risk of bleeding rates for patients with and without HTC monitoring.

Summary:

Patients using HTC monitoring had a relative bleeding rate of 0.60 vs. patients without monitoring, which is equivalent to a 40% reduction in bleeding rates for monitored patients (95% credible interval: 0.38—0.96).

Patients on the monitoring and no monitoring groups were comparable except that the monitoring group had 23% more pediatric patients (p<0.001). However, bleeding rates between pediatric and adults were comparable (p=0.500). Subgroup analysis showed no differences in the reductions of bleeding rates due to monitoring between pediatric-only and adult-only subgroups (p=0.353).

Conclusions:

The use of digital tools for chronic care monitoring is a growing global trend.

A reduction in the annualized bleeding rate of 40% (~2 bleeds a year) is both statistically and clinically significant and may have a cumulative protective impact on patients’ long-term outcomes. Observational studies are subject to sample bias, however, patients in both groups were technologically savvy and motivated enough to track their condition using a digital health tool. Given that this intervention is free, safe, and fits the accountable care model, we encourage clinicians to explore its adoption. Confirmatory studies on this topic are encouraged.

Objective:

Hemophilia is a congenital deficiency in a clotting factor resulting in a propensity for severe and disabling bleeds. Joint bleeds can lead to disabling arthropathy and past contamination of blood products resulted in an epidemic of HIV and hepatitis. We hypothesize that these issues may result in declines in quality of life, psychosocial well-being, and socialization (integration into society) and that socialization correlates with health-related quality of life (HR-QoL).

Methods:

We developed a socialization survey and interview for patients age >20 with hemophilia A (n=14) or B (n=4) and their spouses/significant others (SSOs) (n=9). The interviews were analyzed using PROMIS (patient-reported outcomes measurement information system-29) domains. Patients completed surveys in health-related quality of life measures including both A36 Hemofilia-QoL and WHOQOL-BREF. Patients were also scored according to the Colorado Joint Assessment Scale and Karnofsky Performance Scale. IRB approval and informed consent were obtained.

Results:

19 patients were enrolled (ages 24-78), one withdrew. Nine patients had severe hemophilia, 5 had moderate disease, and 4 were mild. Four patients did not have SSOs (22%, 90% CI: [8%; 44%]); these included two severe and two moderate patients, one with HIV, and three with hepatitis C. Five SSOs declined participation. For the WHOQOL-BREF, patients reported overall quality of life in the physical domain an average score of 60 (range 13-94), 66 (31-100) in the psychological domain, 66 (31-100) in the social relationship domain, and 81 (44-100) in the environmental domain, all standardized 0-100. For the A36 Hemofilia-QOL, the median score was 94 (range 43-132) out of 144 (totaling physical health, daily activities, joint damage, pain, treatment satisfaction, treatment difficulties, emotional functioning, mental health, and relationships and social activities). Colorado Joint Assessment Scale-QOL provided scores of 6.1 out of 19 for ankles without gait and 8.3 out of 21 with gait, 4.2 for knees without gait, 6.3 with gait, and 3.6 for elbows. Analysis of interviews reflects social roles and social support as common domains in patients, whereas anxiety and anger predominated for SSOs.

Conclusions:

This study employed established instruments as well as novel questionnaires and interview structures, although the latter have not been validated. Analysis points toward patient concerns regarding their social roles while SSOs expressed higher levels of anxiety and anger compared to patients. Both health-related-QoL and disease severity appear to be associated with social support domains of socialization. Patients with more severe disease may be less likely to have SSOs.

Hemophilia is a rare bleeding disorder in which the blood doesn't clot normally. (National Heart, Lung, and Blood Institute, 2013). It mostly affects males.(Raabe, 2008).

For parents hearing that their new baby has hemophilia can be stressful and worrying. Babies do not realize what is happening around therefore parents often tend to be overprotective. As the boys grow up, they are capable of seeing the cause and effect of situations on their own and they realize that they cannot do the same things like their friends. When the adolescence come, teenagers worry about what society thinks, so having hemophilia may make them feel different. (Hemophilia Federation of America, 2015). Hemophilia is not an illness, it ́s just a “life style” which people have to live with.

Within psychological intervention is important to address the emotional aspect of patients and family ́s support patient handling of his illness, personal life and surroundings.

Objective:

Describe intervention strategies in the summer camp “Ceiba” of “Tabasqueña de Hemofilia A.C.” in order to promote the social integration in patients with hemophilia.

Materials:

Intervention programs carried out in the camp were used to realize an analysis of the strategies, which were provided by "Tabasqueña de Hemofilia A.C."

During the last eight years, eight camps were realized, the average of assistants every year was 80, 60 patients (between 6 and 24 years old) and 20 additional people in medical field. The objective of the camps is to learn, enjoy, bring all their everyday life experiences and have a better quality of life. (Tabasqueña de Hemofilia, 2007).

The interventions were directed to: accept and make awareness of patient ́s life ́style, learn about hemophilia, live in cooperation, socialize and integrate, improve communication, express himself, team work, experience the freedom, become independent, self-esteem and have a better quality of life.

Each intervention was related to a specific activity; 3 workshops (Psychologist, hematology and nursing), parents and relatives letters, hydrokinesitherapy, talent show, treasure hunt and visits to entertainment and cultural places.

Camps have a great significant learning in their lives and teach children and teenagers valuable life skills through education, activities and games; socialization is achieved, independence, and sense of individual responsibility and group.

Having this camps around the world and taking this interventions will be excellent, because its an interactive way to achieve self- realization and learn to live with the disease, knowing others with the same "life ́s style".

Objective:

People with hemophilia (PWH) commonly self-infuse at home, and can provide valuable insights into device attributes. While Novo Nordisk initially launched recombinant activated FVII (NovoSeven® RT) with vial adaptors, these were replaced with prefilled diluent syringe (MixPro®) in 2013; rFVIII (NovoEight®) launched with MixPro® in the US in 2015. This market research study assessed PWH and caregiver perceptions and preferences between MixPro® and vial adaptors (original device).

Methods:

A market research study was conducted in Fall 2014, comprising 30-minute face- to-face interviews. In total, 38 PWH (≥18 years) and 29 caregivers of children with hemophilia participated in the study, from Italy (n=20), Spain (n=20) and the US (n=27). Participants were eligible if they regularly home-infused replacement factor, and were excluded if they had ever used rFVIIa or were already familiar with MixPro®.

Summary:

The mean age of participants was 27 years. Most had hemophilia A (84%) with the remainder having hemophilia B (16%), more received prophylaxis (73%) than on demand (27%), and most received rFVIII (73%). Other participants were treated with FIX or plasma- derived FVIII. One PWH had inhibitors and was treated with activated prothrombin complex concentrate. MixPro® was clearly and consistently preferred over vial adaptors, both overall and based on key criteria. Overall, 96% were confident that they could use the system correctly, 73% thought it was intuitive to use, and 93% thought it was easy to learn. When asked to rank 18 defined benefits in order of importance, ‘low contamination risk’ was deemed the most important; the only criteria where MixPro® was not superior were related to verifying mixed factor had been drawn into the syringe. MixPro® was most associated with being: quick, easy, and convenient to use; portable; and overall user friendly. Caregivers placed more emphasis on a device being suitable for a person with less strength, while PWH were more interested in portability and convenience. Results were generally consistent across sub- populations: PWH vs caregivers, and those treated on demand vs prophylaxis.

Conclusions:

MixPro® demonstrated clear advantages over vial adaptors, based on feedback from PWH and caregivers, with respondents reporting it easy to learn and use, and confident they could use it correctly. The results affirm the importance of continuing to innovate on devices in collaboration with the hemophilia community.

Objective:

Highlight the importance of collaboration in addition to dose, frequency, and PK data to personalize regimens in order to minimize bleed rates in Hemophilia A patients on prophylaxis.

Methods:

Dose and bleed data was collected and reviewed from January 1, 2015 through March 31, 2015 for all moderate to severe hemophilia A patients on prophylaxis regimens with traditional acting products in 2 regional bleeding disorder hubs. Units per kilogram per dose, units per kilogram per week, and spontaneous bleed rate were calculated from data. If reporter was unsure of bleed origin, it was counted as a spontaneous bleed.

Results:

Region X had 34 and Region Y had 40 patients that met the inclusion criteria for review. The average dispensed dose for Region X was 43.89 units per kg per dose. For Region Y, it was 35.47 units per kg per dose; a difference of 8.42 units per kg per dose. Due to varying frequency orders, regimens were further calculated in units per kg per week. Region X’s average was 121.38 units per kg per week and Region Y’s was 96.98; a difference of 24.4 units per kg per week. Patients in Region X reported zero spontaneous bleeds during the study period. Patients in Region Y reported 16 spontaneous bleeds from 12 unique patients. Of these patients, target joints were cited as contributing factors with 8 of the 16 bleeds. When appropriate, prescribers were notified and collaboration on regimen adjustments was made. Pharmacokinetic data was inconsistently available.

Conclusion:

Zero spontaneous bleeds should be the goal for hemophilia A patients on prophylaxis. Small changes in dose or frequency can make significant changes in outcomes. Many variables impact bleed rates and doses vary widely. There is the potential for refining dosing algorithms based on a more personalized approach that includes close and careful monitoring of trough levels, patients activity level, bleed pattern and response to changes in treatment plans. This individualized approach would require collaboration between patients, prescribers, and pharmacies. Such an approach can have huge and long-term beneficial effects on pharmacoeconomic, clinical, and quality of life outcomes. Data collected from this study may further assist pharmacists with influencing prescribers to consider pharmacist obtained bleed data and/or obtain and provide PK data so they can assist with regimen adjustment recommendations based on their assessments. With increasing payer pressure and the introduction of longer acting products, this collaboration will become even more imperative.

Background:

Current available factor replacement therapy (FRT) for von Willebrand Disease (vWD) contains FVIII. Thromboembolic events (TEE) are a small but serious risk in patients with elevated FVIII levels as a result of accumulation from repeated doses of FRT (Manucci, 2004).

Aim:

To assess the total medical cost incurred in one year of treating TEEs in vWD.

Methods:

This retrospective database analysis utilized the Marketscan®Database, a US medical claims database, from Jan 2006 to Mar 2014. Patients with inpatient diagnosis for a TEE (ICD-9 code for venous thromboembolism [VTE], myocardial infarction [MI], ischemic stroke [IS], etc.) were identified, with the first inpatient TEE visit defined as the index date (ID). VWD diagnosis (286.4) was required prior to ID and ≥12 month continuous enrollment both prior and post ID. Direct medical costs of TEE management in the first year were estimated for inpatient and outpatient settings. The subset of VWD patients prescribed FRT prior to ID was also described. Costs were adjusted to 2013USD using the medical consumer price index.

Results:

One hundred fifty-three vWD subjects were identified with an inpatient TEE. Mean age at the ID was 56 years (2–94 yrs) and 69.9% were female. Median annual cost and range associated with treatment of TEEs was $21,166 ($1,300–$867,710). VTE and IS were the most common TEEs (36.0% ≥1 VTE, $24,338 ($1,063–$235,090) and 32.7% ≥1 IS, $11,326 ($1,300–$368,550), respectively). Patients prescribed FRT (n=12) had a median annual cost of $64,648 ($4,690–$137,705) for TEE treatment.

Conclusion:

This is the first study to estimate the total cost associated with management of TEEs in vWD. TEEs are a burden to the healthcare system and are potentially life- threatening. A vWD treatment option that can avoid the risk of FVIII accumulation may benefit vWD patients at risk for TEEs.

Dr. Chappell's research project will develop a model for characterizing bleeding in hemophilia and particularly in joints. Using mouse models of hematoma formation and knee joint bleeding, Dr. Chappell will use 3D fluorescent imaging technology in "living" hemophilia B mice to better trace bleeding over time- from induction of a bleed to its resolution. This project will provide additional insights on the basic science underlying hemophilic bleeds, not to mention the optimal interventions and timing of treatment to potentially prevent damage caused by bleeds. Dr. Chappell earned her Ph.D. in Pharmaceutical Sciences from UNC Chapel Hill in 2013. She will pursue her research under the mentorship of Dr. Dougald Monroe, Professor in the Division of Hematology/Oncology, UNC School of Medicine and the UNC McAllister Heart Institute.

 Objective:

The ongoing rFIXFc extension study, B-YOND (clinicaltrials.gov #NCT01425723) , evaluates the long-term safety and efficacy of rFIXFc for the treatment of severe hemophilia B. Here we report interim safety and efficacy data for children aged <12 yrs enrolled in B- YOND.

Methods:

Upon completing Kids B-LONG, eligible subjects could enroll in one of the 3 prophylactic treatment groups in B-YOND: weekly (20 to 100 IU/kg every 7 days), individualized (100 IU/kg every 8 to 16 days, or twice monthly), or modified (a prophylaxis regimen different from weekly or individualized prophylaxis). Subjects could change treatment groups at any point in the study. The primary endpoint was development of inhibitors. Secondary outcomes included annualized bleeding rate (ABR) and rFIXFc exposure days (EDs).

Summary:

At the time of the interim data cut (17 October 2014), 23 subjects had completed Kids B-LONG; all enrolled in B-YOND (<6 yrs of age cohort, n=9; 6 to <12 yrs of age cohort, n=14). As of the interim data cut, 2 subjects had completed and 21 subjects continued in B-YOND (median time on study: 47.7 weeks). From the start of Kids B-LONG to the B-YOND interim data cut, the median time on rFIXFc was 95.3 weeks, with a median of 94 cumulative rFIXFc EDs. All subjects were on weekly prophylaxis in Kids B-LONG; 5 subjects changed treatment groups at the start of or during B-YOND. In the weekly prophylaxis group, the median (IQR) average weekly prophylactic dose was 64 (52, 66) IU/kg and 63 (59, 64) IU/kg in the <6 yrs and 6 to <12 yrs of age cohorts, respectively. The median (IQR) dosing interval among subjects on individualized prophylaxis was 10 (10, 11) days. As of the interim data cut, no inhibitors were observed, there were no reports of anaphylaxis or serious hypersensitivity reactions associated with rFIXFc, and no thrombotic events. Adverse events were typical of the pediatric hemophilia B population; no subject discontinued the study due to an adverse event. Median ABRs were low in both age cohorts (Table). Overall, 95% of bleeding episodes were controlled with 1 or 2 infusions.

Conclusions:

Interim data in children with severe hemophilia B participating in B-YOND confirm the long-term safety of rFIXFc and the maintenance of a low ABR with extended-interval prophylactic dosing.

Introduction:

Efficacy and safety of routine prophylaxis vs on-demand treatment with Bayer’s sucrose-formulated recombinant factor VIII (rFVIII-FS) in patients with severe hemophilia A were evaluated in the randomized, controlled SPINART study.

Aim:

Patient- and joint-level changes at year 3 in magnetic resonance imaging (MRI) and Colorado Adult Joint Assessment Scale (CAJAS) scores were compared to investigate if individual joint data revealed results that may have been obscured in previously reported patient-level analyses.

Methods:

SPINART included males aged 12–50 years with severe hemophilia A, ≥150 exposure days to FVIII, no inhibitors, and no prophylaxis for >12 months in the past 5 years. Patients were randomized 1:1 to rFVIII-FS on demand or prophylaxis (25 IU/kg 3x/wk). Changes from baseline to year 3 were evaluated for 6 index joints (knees, ankles, elbows) using the Extended MRI (eMRI) scale and CAJAS. Percentages of patients or joints with improved, unchanged, or worsened scores were evaluated.

Summary:

Of the 84 patients in SPINART, eMRI and CAJAS change from baseline data were available for 62 (prophylaxis, n=32; on demand, n=30) and 76 patients (n=39; n=37) and for 386 (n=197; n=189) and 446 joints (n=224; n=222), respectively. Categoric analysis of CAJAS data at year 3 showed a higher percentage of patients treated prophylactically vs on demand with improved scores (64.1% vs 43.2%) and a lower percentage with worsened scores (28.2% vs 51.4%); with eMRI, the percentage improved was smaller (12.5% vs 6.7% improved; 75.0% vs 73.3% worsened). At individual joints, improved, unchanged, and worsened CAJAS scores in patients treated with prophylaxis vs on demand were 46.0% vs 33.3%, 22.3% vs 24.3%, and 31.7% vs 42.3%; eMRI values were 8.1% vs 3.7%, 61.9% vs 69.8%, and 29.9% vs 26.5%.

Conclusions:

These data suggest that in adults and adolescents with severe hemophilia A, joint function as measured by CAJAS is more likely to improve after 3 years of routine prophylaxis with rFVIII-FS than joint structure as measured by MRI.

Objective:

To assess the pharmacokinetics (PK), safety, and efficacy of the first high- purity, plasma-derived factor X concentrate (pdFX) for on-demand treatment of bleeding episodes in a prospective, open-label, multicenter, nonrandomized phase 3 study in subjects with hereditary moderate or severe factor X (FX) deficiency (basal plasma FX activity <5 IU/dL).

Methods:

Included subjects were aged ≥12 years who required treatment with replacement therapy for ≥1 spontaneous or menorrhagic bleed in the past 12 months. Subjects received 25 IU/kg of pdFX on-demand for specific bleeds or as preventative use for 6 months to 2 years. PK was assessed following a single dose at baseline and after ≥6 months. Each bleed was categorized as major or minor, and subjects assessed efficacy for each bleed as “excellent,” “good,” “poor,” or “unassessable”; hospital- treated bleeds were also assessed by investigators. At study end, each investigator assessed the overall efficacy of pdFX. Safety assessments were adverse events (AEs), inhibitor development, viral seroconversions, and changes in laboratory parameters.

Summary:

The study enrolled 16 subjects (aged 12-58 years [mean 27.1 years], 62.5% female) with moderate (n=2) and severe (n=14) FX deficiency. PK parameters did not differ between baseline and repeat assessment visits, with overall mean (median, interquartile range [IQR]) incremental recovery of 2.00 (2.12, 1.79-2.37) IU/dL per IU/kg and half-life of 29.4 (28.6, 25.8-33.1) hours. In total, 468 pdFX infusions were administered; 187 bleeds treated with pdFX were analyzed for efficacy (98 major and 88 minor), of which 155 (82.9%) were treated with one pdFX infusion. A mean (standard deviation) of 1.2 (0.5) infusions per bleed were administered, with a median (IQR) dose of 25.0 (24.4-26.7) IU/kg. Efficacy of pdFX was rated as excellent in 90.9% of bleeds, good in 7.5%, and poor in 1.1%. For the 15 subjects who completed the study, investigators rated overall pdFX efficacy as excellent in 12 (80%) and good in 3 subjects (20%). Six mild/moderate AEs were observed, no serious AEs were considered by investigators to be possibly related to study drug, and no hypersensitivity reactions or clinically significant trends in any laboratory safety parameters were observed.

Conclusions:

In this study, pdFX was safe and efficacious in on-demand treatment of bleeds and short-term preventative therapy in subjects with moderate or severe FX deficiency at a nominal dose of 25 IU/kg. PK results supported these observed hemostatic effects.