Research Studies

Objective:

The B-HERO-S study evaluated the impact of mild-severe hemophilia B on the lives of affected adults and children. Here we assess the impact of hemophilia B on relationships.

Methods:

US adults with hemophilia B and caregivers of affected children completed separate 1-hour online surveys that included questions regarding impact on interpersonal relationships.

Summary:

Most (88%) of the 299 adults completing the survey had mild-moderate hemophilia B. Of those, 54% were married or in a long-term relationship, and 44% were single. Most adults (87%) reported that hemophilia impacted their ability to form close relationships with partners or prospective partners; 35% were very/quite dissatisfied with the support received from a previous partner. Ninety percent reported that their experiences in a prior relationship, including satisfaction with support from their previous partner, impacted their decision to enter a relationship with their current partner. Nearly all participants (98%) were very/quite satisfied with the support received from their current partner. The top reason for satisfaction was “my partner takes the lead in providing financial security” (45%). Most were very/quite satisfied with the support from family (87%) and friends (96%). Most participants reported a negative reaction or experience as a result of disclosing their hemophilia (friend/colleague/employer, 76%/80%/82%); some reported having felt bullied by peers/colleagues (69%/66%). Majorities reported that past experiences impacted which friends/colleagues they told about their hemophilia, and how or when they disclosed their hemophilia status to these individuals (97%/95%). Seventy-four percent of participants indicated that hemophilia has affected the quality of their sex life; only 54% were extremely/moderately satisfied with their overall sexual relationship. Many reported having had a bleed during sex (40%). Of 150 caregivers of children with mostly mild-moderate hemophilia (74%), 89% were married or in a long-term relationship, and most felt very/quite supported by their partner (98%) and family (87%). Impact on unaffected siblings was more often mixed (49%) than negative (18%). Most felt very/quite satisfied with support of teachers (91%), children at school (80%), and other adults in regular contact (72%). Most caregivers reported negative experiences telling a friend (76%) or having their child tell a friend (69%) about the child’s hemophilia; 43% reported that their child was bullied as a result of having hemophilia.

Conclusion:

While the impact of severe hemophilia on relationships has been reported in HERO and other studies, B-HERO-S suggests that mild-moderate hemophilia B also significantly impacts relationships of affected men/women and boys/girls, especially in terms of disclosure, intimacy, and feeling bullied by peers/colleagues. Opportunities may be explored to more proactively counsel individuals with mild-moderate hemophilia B and families in the setting of comprehensive care to better navigate interpersonal relationships and improve quality of life.

Background:

Factor VIII (FVIII) pharmacokinetic (PK) parameters and other patient characteristics may play a role in effectiveness of FVIII prophylaxis. Objective: A post-hoc analysis was conducted to assess the association between PK parameters and BAY 81-8973 (Kovaltry® ) prophylaxis regimen in patients with severe hemophilia A.

Methods:

LEOPOLD I was a randomized, open-label, phase 2/3 trial to investigate use of BAY 81-8973 routine prophylaxis for treatment of bleeds in adolescents and adults with severe hemophilia A. In the efficacy part of the trial (part B), patients received BAY 81-8973 at a dose of 20‒50 IU/kg 2x/week (n=18) or 3x/week (n=44) for 12 months. Prophylaxis regimens were determined by study investigators, independent of BAY 81-8973 PK data. A subset of 20 patients (2x/week, n=7; 3x/week, n=13) had data from an earlier PK study (part A), in which patients received a single 50-IU/kg injection of BAY 81-8973 and had blood samples collected over 48 hours to assess PK parameters, including area under the curve (AUC), half-life (t½), and clearance (CL). Estimates of PK parameters were also derived using a population PK model based on data from all patients. This analysis compared model-based PK parameters, baseline characteristics, total annual dosing, and bleed outcomes between 2x/week and 3x/week prophylaxis groups. A similar analysis was done among the subset of patients in part A who had PK data. Differences between 2x/week and 3x/week dosing were assessed using Wilcoxon rank sum tests for continuous variables, and chi-square or Fisher’s exact tests for categorical variables.

Results:

In the full trial population, model-based AUC [mean (SD): 1957.1 (648.3) vs 2139.1 (875.7), 2x/week and 3x/week, respectively], t½ [15.0 (3.7) vs 15.9 (6.6)], and CL [0.028 (0.009) vs 0.027 (0.011)] were comparable between groups. The proportion of patients with ≥3 bleeds at 12 months was 33% for 2x/week and 48% for 3x/week. The 3x/week group had more bleeds in the past 12 months, higher baseline Gilbert bleeding scores, were more likely to have target joints at baseline, and received higher doses of BAY 81-8973 during the 12- month treatment period. In the part A subset analysis, observed and model-based AUC, t½, and CL were similar in both groups. The proportion of patients with ≥3 bleeds at 12 months was 0% for 2x/week and 46.2% for 3x/week (P=0.052).

Conclusions:

The similarity of PK parameters in patients successfully treated with 2x/week and 3x/week regimens suggests that clinical factors other than t½, AUC, and CL are important in predicting success of prophylaxis with BAY 81-8973. Physician decisions, taking into consideration clinical factors to identify appropriate patients for specific prophylaxis regimens, appear to be an important factor for 2x/week or 3x/week dosing with BAY 81-8973. These factors should be considered when individualizing BAY 81-8973 prophylaxis frequency.

Objective:

The B-HERO-S study assessed the impact of hemophilia on US adults with hemophilia B, including affected females. Here we describe the symptoms, management, and impact on education, employment, and engagement in recreational activities in women.

Methods:

Adults aged ≥18 years with hemophilia B (factor IX <40%) completed a survey including questions about bleeding, treatment, and psychosocial impact.

Summary:

Of 299 respondents, 86 were women (median age, 29 years; 6% were aged >45 years) with mild (29%), moderate (65%), or severe (6%) hemophilia. The majority reported arthritis (66%) and anxiety/depression (57%); 19% reported acute and/or chronic pain. Most (86%) were treated with some form of “routine infusions to prevent bleeding”; 16% reported self-infusing, 31%/17% by partners/family. Self-infusion was initiated at median age of 18, and learned from HTCs (86%), camps (71%), or parents (57%). Most reported difficulty with access to factor due to affordability/availability in the past 5 years (72%) or expected in the next 5 years (85%). Women reported a median (mean) of 4 (3.86) bleeds in prior year; 83% bled within the last 4 weeks with most recent bleeding in joints (73%) or muscles (21%). Twenty-five percent reported one specific “bad” joint, most commonly the knee (69%). Nearly all were seen in HTCs (85%) with a median (mean) of 3 (3.5) HTC visits per year. Most (88%) went past high school with 55% completing 4-year college and 24% graduate degrees. Most (94%) reported some negative impact on completing their education (7% very large/69% moderate/19% small impact), most commonly due to difficulties concentrating at school due to bleeds or pain (81%). Most were employed full-time (71%) or part-time (10%), commonly in office work (71%). Most (94%) reported a negative impact on their working life (3% very large/71% moderate/20% small impact); 36% reported leaving a job because of their hemophilia. Nearly all (99%) indicated some negative impact on their ability to engage in recreational activities (3% large/83% moderate/13% small impact). From a list of predetermined activities, dancing (50%) and walking (48%) were the most common current activities; bicycling (20%), dancing (17%), and swimming (16%) were the most common discontinued activities. Most reported treatment changes around activities (21% started prophylaxis, 52% revised time of doses, 38% added doses, 34% changed amount of doses); 8% reported no change and 3% no moderate/vigorous activities.

Conclusion:

Clinical presentation and treatment in women mirrored that reported by men except for greater anxiety/depression and more issues with access to treatment. Nearly all affected women reported a negative impact on their education, employment, and activities. While these results may be limited by bias in recruitment selecting those most symptomatic, the data reveal opportunities to improve awareness of and guidance around management and counselling of affected women.

Background:

Gene transfer for hemophilia offers the potential to convert the disease from a severe to mild phenotype with a single treatment. AMT-060 consists of an AAV5 vector containing a codon-optimized wildtype hFIX gene under control of a liver-specific promoter.

Objective:

This phase 1/2 study investigates the safety and efficacy of AMT-060 at 2 dose levels in adults with moderate-severe or severe hemophilia B.

Methods:

Multi-national, open-label, dose-escalating study in patients with factor IX (FIX) activity ≤2% of normal, and a severe bleeding phenotype (prophylactic exogenous FIX; or ondemand exogenous FIX, plus ≥4 bleeds/year or hemophilic arthropathy). Patients received either 5x1012 gc/kg (n=5) or 2×1013 gc/kg (n=5) of AMT-060 iv. Efficacy assessments include endogenous FIX activity (measured ≥10 days after use of exogenous FIX); reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events, immunological and inflammatory biomarkers.

Summary:

There were no screening failures due to AAV5 neutralizing antibodies. Mean FIX activity in the lower dose cohort was 5.2% (min-max, 3.0-6.8%; n=4; 1 patient remaining on prophylaxis excluded) during 1 year of follow-up, and 6.9% (min-max, 3.1-12.7%; n=5) in the higher dose cohort during 26 weeks follow-up. Eight of 9 patients on FIX prophylaxis discontinued use after AMT-060 infusion. Follow-up to up to 1.5 years will be presented, with annualized reduction of exogenous FIX use and spontaneous bleeding rates. Mild, temporary elevations in ALT were observed in 3 patients with higher mean FIX activity (6.3-12.7%; 1 in the lower and 2 in the higher dose cohort). Each received a tapering course of prednisolone. ALT elevations were not associated with changes in FIX activity or a capsid-specific T-cell response.

Conclusions:

Patients continue to show sustained clinical benefit and endogenous FIX activity with no T-cell activation ≥1 year after a single infusion of AMT-060.

Objective:

Functional impairment from recurrent joint bleeding in people with hemophilia results in joint pain and reduces quality of life. The P-FiQ study formally evaluated patient- and site-reported functional assessment including responses to generic and hemophilia-specific patient-reported outcomes (PROs) tools. Psychometric analyses were used to evaluate reliability, validity, and consistency of responses.

Methods:

Adult males with hemophilia and a history of joint pain or bleeding completed a hemophilia history and 5 PROs assessing function: EQ-5D-5L, Brief Pain Inventory v2 Short Form (BPI), International Physical Activity Questionnaire (IPAQ), Short Form-36 v2 (SF-36v2), and Hemophilia Activities List (HAL). PROs were assessed for reliability, consistency, and correlation, with factors including patient-reported characteristics.

Summary:

A total of 381 adults (median age, 34 years; range, 18-86 years) were enrolled in P-FiQ. Most participants (66%) and sites (59%) reported functional disability in the past 6 months (CDC-UDC scale). Patients self-reported arthritis/bone/joint problems (65%) and history of joint procedures or surgeries (50%). On EQ-5D-5L, most reported problems “today” with mobility (61%) and usual activities (53%) but fewer with self-care (19%). On BPI, similar median pain interference scores (0- 10 scale, 10 is complete interference) were reported with general activity (3.0), walking ability (3.0), and normal work (3.0). On IPAQ, physical activity was reported by 49% of respondents over the prior week, with more reporting walking (35%) than moderate (16%) or vigorous (16%) activities. On SF-36v2, activities in the past 4 weeks that were most frequently limited were vigorous activities (80%), bending, kneeling, or stooping (67%), walking more than a mile (61%), and climbing several flights of stairs (59%). Physical problems caused participants to limit kinds of work/activities (69%), accomplish less than they would like (66%), have difficulty in performing work/activities (65%), and reduce time spent on work/activities (62%). On HAL, greater difficulties were seen for lower vs upper extremity functions/activities; within the lying/sitting/kneeling/standing domain, the most frequent problems in the previous month were squatting for a long time (74%), kneeling (73%) or standing (72%), and kneeling/squatting (70%). Similar items across different PROs were correlated with one another. Self- reported functional impairment was significantly differentiated by BPI pain interference, IPAQ total activity, SF-36v2 physical functioning, and all HAL domains and summary scores.

Conclusion:

PRO instruments assessing functional status range from simple/generic (EQ-5D-5L) to complex/disease-specific (HAL) and provide varying levels of detail. Greater use of formal PRO instruments in the clinical setting may improve dialogue between health care professionals and patients/caregivers and inform proactive approaches to specifically target patient identified functional limitations (eg, HAL) and identify areas for further targeted management strategies.

Dr. Laura Sommerville graduated cum laude from Messiah College and then obtained her MS and PhD degrees in cellular and molecular biology from Temple University. Her graduate work and doctoral dissertation produced several awards and publications in peer reviewed publications. She has been a postdoctoral fellow in the laboratory of Dr. Maureane Hoffman at Duke University since July 2014. Dr. Sommerville's 2015 JGP research fellowship award project is on understanding the loss of perivascular tissue factor during angiogenesis in hemophilia.

Objectives:

Von Willebrand disease (VWD) is a common inherited bleeding disorder, but awareness among healthcare professionals is low. Timely and proper diagnosis integral for reducing VWD burden, access to proper therapies, and avoidance of improper medication. Hence, we sought to estimate the prevalence of undiagnosed VWD among commercially insured patients in the United States with a recent history of bleeding events.

Methods:

Patients with a VWD diagnosis who were users of or candidates for von Willebrand factor were identified from the IMS PharMetrics Plus Database (2006─2015). We constructed a unary patient-finding model based on 12 prediagnosis variables that best defined this population, and applied to a set of undiagnosed patients with recent bleeding events from the same database. ‘Best fit’ (confidence level 5/6) and ‘good fit’ (confidence level 3/4) patients were identified. Prevalence of symptomatic undiagnosed VWD in the commercially insured population was estimated from the best-fit and good-fit population size (projection factor 10.4).

Summary:

Overall, 507 668 undiagnosed patients with recent bleeding events were identified (86% female, 14% male). Application of the VWD model identified 3318 best-fit and 37 163 good-fit patients; 91% of best-fit patients were females aged <46 years, with heavy menstrual bleeding the most common claim. Projection to the full commercially insured US population provided an estimate of 35 000 - 387 000 symptomatic, undiagnosed patients with VWD.

Conclusion:

There is a high prevalence of symptomatic, undiagnosed VWD (undiagnosed bleeding disorder patients that likely have VWD) in the commercially insured population. This data underscores the importance of improved disease education to both patients and the first line treaters, including OBGYN, emergency room, and pediatricians. Enhanced awareness of VWD symptoms and their impact, and of screening and testing procedures, may improve diagnosis of VWD and reduce the disease burden.

Objectives:

Emicizumab, a bispecific humanized monoclonal antibody in development to address unmet medical needs in persons with hemophilia A with inhibitors (PwHAwI), bridges FIXa and FX to replace the function of missing FVIIIa, needed for effective hemostasis. This study assessed efficacy, safety and PK of emicizumab prophylaxis in PwHAwI.

Methods:

Study NCT02622321 was conducted at 43 centers/sites, and enrolled PwHAwI ≥12 y.o. Participants (pts) receiving prior episodic bypassing agents (BPAs) were randomized (2:1) to emicizumab prophylaxis vs no prophylaxis (Arm A vs B). Primary endpoint compared treated bleed rates in Arm A vs B. PwHAwI receiving prior prophylactic BPA received emicizumab prophylaxis in Arm C. Emicizumab was injected subcutaneously at 3 mg/kg/wk for 4 wks, and 1.5 mg/kg/wk thereafter.

Summary:

109 male PwHAwI were enrolled; median age 28 (range 12–75) yrs. Median (range) emicizumab treatment exposure was 24.0 (3.0–47.9) wk overall and 29.5 (3.3–47.9) wk in Arm A. Statistically significant, clinically meaningful reductions (87%) in treated bleed rates were observed between emicizumab prophylaxis vs no prophylaxis (Arm A vs B) (annualized bleeding rate [95% confidence interval] 2.9 [1.69 to 5.02] versus 23.3 [12.33 to 43.89], P<0.0001), and in all secondary bleed-related endpoints (spontaneous, joint, target joint, and all bleeds). Of note, a 79% reduction in treated bleed rate was seen with emicizumab prophylaxis (Arm C) vs BPA prophylaxis prior to study entry in a non-interventional study (NCT02476942; intra-individual comparison, P=0.0003). Overall, 67.3% of PwHAwI on emicizumab prophylaxis had zero treated bleeds. Statistically significant, clinically meaningful improvements in health-related quality of life (HRQoL) and health status were seen for Arm A vs B. Emicizumab was well tolerated. Total of 198 adverse events (AEs) were reported in 103 pts; most common AEs were injection-site reactions (15%), and 12 serious AEs were reported in 9 (8.7%) pts. Thrombotic microangiopathy and thrombosis (2 pts each in primary analysis) were reported and associated with high cumulative aPCC doses averaging >100 U/kg daily for >24 hr prior to event onset. No events occurred with emicizumab prophylaxis alone. Both TMA events resolved once aPCC treatment was stopped, and the thrombotic events did not require anticoagulation; 2 pts resumed emicizumab without sequelae (1 with TMA, 1 with thrombosis). No antidrug antibodies were detected. Mean trough emicizumab concentrations >50 μg/mL were achieved after 4 loading doses (3 mg/kg/wk) and sustained with maintenance doses of 1.5 mg/kg/wk.

Conclusion:

Emicizumab prophylaxis prevented or substantially reduced bleeds in PwHAwI and meaningfully improved HRQoL. Emicizumab had acceptable safety without excess thrombotic risk in the absence of concomitant aPCC. PK levels were sustained with once- weekly maintenance doses. These promising data could support a paradigm shift in the management and lives of PwHAwI.

Bleeding disorders are a group of conditions that result when the blood cannot clot properly (American Society of Hematology, 2017). The most frequently occurring bleeding disorders include von Willebrand Disease (VWD), Hemophilia A, and Hemophilia B (FDA ́s, 2016).Some studies shows that is important to considered the depression in the psychological approach of patients with a bleeding disorder (Recht, Batt, Witkop, Gut, Cooper, Kempton, 2016 and Osorio, Bazán, Izquierdo, 2016). Beck ́s theory defined depression in cognitive terms. He saw the essential elements of the disorder as the “cognitive triad”: (a) negative view of self, (b) a negative view of the world, and (c) a negative view of the future. The depressed person views the world through an organized set of depressive schemata that distort experience about self, the world, and the future in a negative direction (Beck, A. 1972 in Lynn, P. 2015).

Objective:

Compare depression levels in groups of patients with haemophilia, Von Willebrand (VWD) and apparently healthy people.

Methods:

The study design was quantitative, non-experimental, transactional and correlational in which the difference between three groups of participants was analyzed: 41 patients with hemophilia A or B, 10 patients with VW and 20 apparently healthy people. The sample was obtained from Tabasqueña de Hemofilia A.C. through a non - random sampling of subjects - type. Depression symptoms were obtained by Beck ́s inventory and for control variables a questionnaire was applied. All of the findings were assessed by SPSS 21 for Windows program. Data were analysed using descriptive statistics, comparisons between groups were evaluated with Games-Howell coefficient and post hoc test.

Summary:

71 participants with a mean age of 28.24. Considering the patients who have a bleeding disorder, 74.50% of the sample was deficient of factor VIII, 11.76% of factor von Willebrand, 11.76% of factor VII and 1.96% of factor IX; 82.35% of them have access to treatment while 17.64 have not access. Statistically significant differences were found only in apparently healthy people compared to haemophilia patients (p=0.031). A marginal difference was detected between the group of apparently healthy people and von Willebrand patients (p=0.081).

Conclusions:

The presence of a coagulation disease increase the levels of depression and the severity of the symptoms.

Key Words: Hemophilia, Von Willebrand, Depression.

Camping programs for individuals with chronic illness are increasingly common. Unfortunately, few studies have been conducted to empirically evaluate whether camping programs are meeting their intended goals or having the positive outcomes that are expected of them. The current study was conducted as an evaluation of a bleeding disorder camp for patients with bleeding disorders and their siblings.

Participants in the current study included 77 participants, ages 7-20 (mean 11.58, SD = 3.21). The sample was 62.3% male and 63.6% patients (36.4% siblings). Most of the patients (52.6%) had severe bleeding disorders. Participants were administered the Children’s Hope Scale (CHS; Snyder et al., 1991), which evaluates two dimensions of hope (1. Agency, the ability to identify positive goals and 2. Pathways, the ability to find ways to meet identified goals) and overall hope. Participants demonstrated a significant improvement on the agency subscale of the CHS, t(35) = -2.16, p < .05. Participants reported qualitative aspects of living with bleeding disorders, including differences in their lives, aspects of their lives that are better, aspects about bleeding disorders that are often misunderstood, and advice for others with bleeding disorders. Responses to qualitative were analysed across groups (patients and siblings; severe and mild patients) and were found to be very consistent across these groups. This information has helped to provide information about experiences of youth affected by bleeding disorders and will be used to help inform upcoming camp programming. These findings have also demonstrated positive psychosocial outcomes associated with camp attendance.

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