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.
Objectives:
Emicizumab, a novel bispecific humanized monoclonal antibody promotes coagulation by bridging FIXa and FX to replace the function of missing activated FVIII, and has potential to address unmet medical needs in pediatric persons with hemophilia A (PwHA) with inhibitors. This study assessed efficacy, safety and pharmacokinetics of once-weekly subcutaneous emicizumab prophylaxis in pediatric PwHA with inhibitors.
Methods:
The study (NCT02795767) enrolled PwHA with inhibitors aged <12 years (or 12–17 years if <40 kg) previously treated with bypassing agents to receive emicizumab prophylaxis for ≥52 weeks. Emicizumab was administered subcutaneously at 3 mg/kg/week for 4 weeks, followed by 1.5 mg/kg/week thereafter. Efficacy objectives included bleed rate, and comparison of the bleed rate on emicizumab prophylaxis vs historical bleed rate obtained from a prospective, non-interventional study (NIS; NCT02476942). The NIS collected detailed, high-quality real- world data on bleeds and safety outcomes from a cohort of pediatric PwHA with inhibitors treated according to local, routine clinical practice. Participants from the NIS could subsequently enter the HAVEN 2 study, which permitted intra-individual comparisons.
Summary:
This interim analysis included 20 PwHA with inhibitors aged 3–12 years (median 8.5); 19 aged <12 years were included in the efficacy analyses. The median observation time was 12.1 weeks (range 7–14). In total, 18/19 (94.7%) participants had zero treated bleeds and 12/19 (63.2%) did not bleed while on study. Overall, 14 bleeds were reported in 7 participants, with none occurring in a joint or muscle. No participants have required up- titration of emicizumab. A substantial reduction in ABR on study vs ABR on prior treatment with bypassing agents (non-interventional study) was observed in 8 participants included in the intra-individual comparison; all 8 participants reported zero bleeds with emicizumab prophylaxis (efficacy period 85–99 days). Emicizumab was well tolerated; most common AEs were mild injection-site reactions (15%) and nasopharyngitis (15%). Three unrelated serious AEs were observed (mouth hemorrhage, appendicitis, catheter site infection). No thromboembolic or thrombotic microangiopathy events were reported. No anti-drug antibodies were detected. Mean trough emicizumab concentrations of >50 μg/mL were achieved after 4 loading doses of 3 mg/kg/week and sustained with maintenance doses of 1.5 mg/kg/week, and were consistent across age groups and body weight.
Conclusion:
Emicizumab prophylaxis was well tolerated and prevented/reduced bleeds in pediatric PwHA with inhibitors. Clinically meaningful reductions in ABR were observed compared with ABR on prior treatment with bypassing agents. The pharmacokinetic profile of emicizumab was similar to that seen in adolescent/adult PwHA with inhibitors. These interim data show the potential for emicizumab to reduce the disease and treatment burden for pediatric PwHA with inhibitors.
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.
Background:
The impact of family history on mothers of sons with hemophilia is unknown. The primary purpose of this study was to determine whether differences exist in perceived vulnerability of sons, protective behaviors toward sons and reported stress when comparing mothers of sons with hemophilia who have a known family history of hemophilia with mothers who have an unknown family history of hemophilia.
Methods:
We performed a prospective, single visit study of mothers who have a son with hemophilia. Following informed consent, participants answered demographic and family history questions and completed three surveys: the Parent Protection Scale, the Child Vulnerability Scale and the Parenting Stress Index.
Results:
A total of 39 participants completed the study, including 21 mothers with a known family history of hemophilia and 18 mothers with an unknown family history of hemophilia. No significant differences were found in perceived vulnerability, protective behavior and reported stress in mothers with a known family history of hemophilia compared to those without a known family history of hemophilia. However, the total Parent Protection Scale scores were significantly higher among mothers of sons with hemophilia with a history of inhibitor, compared to those without a history of inhibitor. Mothers of sons with hemophilia without siblings scored significantly higher on the Parent Protection Scale, Supervision and Control sub-scores, as well as the Parent Stress Index, Difficult Child sub-score. Child Vulnerability Scale scores increased along with the Parent Protection Scale, Dependence sub-scores and Separation sub-scores. Child Vulnerability Scale scores increased along with the total Parent Stress Index scores, as well as with increasing Parent Stress Index, Difficult Child sub-scores and Parent-child dysfunctional Interaction sub-scores.
Discussion:
Historically, social workers in hemophilia programs have observed psychosocial differences between mothers of sons with hemophilia who have a known versus unknown family history. We did not find differences in the measures we utilized between groups. Instead, the results of this study demonstrated the complex system of behaviors exhibited by all mothers of sons with hemophilia, enriching the understanding of the impact of family history of hemophilia when providing comprehensive care services to mothers of sons with hemophilia and families.
Implications/Next Steps:
The results of this study will lead to the improvement of hemophilia center clinical social work assessment of family functioning, specifically the mother-son relationship. Further research needs to be initiated to explore the complex psychosocial differences in individual mothers of sons with hemophilia, individual sons with hemophilia, family systems and social systems impacted by hemophilia.
