Dr. Smith's research focuses on better understanding the development of factor VIII inhibitors. Specifically, she will focus on the effects of chemical signals, or cytokines, secreted by helper T cells on the development of inhibitor antibodies. She hypothesizes that certain cells, called Th17 cells, play an important role in the development of these antibodies by stimulating inflammation and driving the immune response toward inhibitor production. Dr. Smith received a BS from the University of Delaware before earning her Ph.D. from Montana State University. Prior to her appointment as an Assistant Professor at the University of Texas Medical School at Houston, she spent four years as a postdoctoral research fellow at the University of Michigan.
Moanaro Biswas, PhD, is currently an Assistant Professor in the Gene and Cell Therapy Program at the Herman B Wells Center for Pediatric Research at Indiana University, Indianapolis. She was appointed to this position in May 2018. She received her Masters and PhD in Biotechnology from India. She joined the University of Florida in 2013 as a Postdoctoral Research Associate and was subsequently appointed a faculty position in the department of Pediatrics at UF in 2017. She is mentored by Dr. Roland W. Herzog, a distinguished professor with extensive expertise in gene therapy for hemophilia. While at the University of FLorida, she received the Henry A. Kokomoor Award for excellence in Pediatric Research in 2017. Dr. Biswas has been the recipient of an early career investigator award from Bayer in 2016. Dr. Biswas is interested in studying cell and gene therapy-based treatments for combating inhibitor formation in hemophilia, As the 2018 recipient of the NHF/Novo Nordisk Career Development Award, which is made possible by a generous gift from Novo Nordisk, Dr. Biswas will be researching engineered Treg therapy for tolerance induction in hemophilia A. Chimeric antigen receptor (CAR) expressing Tregs, made specific for FVIII, will be tested in a murine model of hemophilia A. She will explore at the cellular and molecular level, interactions between antigen-specific CAR-Tregs and immune cell types involved in the development of inhibitors to FVIII.
Dr. Shi is a Professor of Pediatric Hematology at the Medical College of Wisconsin and an Investigator of Blood Research Institute at the BloodCenter of Wisconsin. She earned her MD from Fujian Medical University in China in 1990 and her Ph.D. in 1998. Dr. Shi’s research focus is to formulate innovative therapeutic approaches for the treatment of hemophilia A, a genetic bleeding disorder caused by a lack of the critical blood clotting protein, factor VIII (FVIII). One of her research programs funded by the National Institutes of Health, National Heart, Lung, and Blood Institute, is to develop platelet-specific gene transfer strategies for the treatment of hemophilia A and hemophilia A with neutralizing antibodies. In the project supported by the NHF Bridge Grant, Dr. Shi will investigate the potential effect of the FVIII carrier protein, von Willebrand factor, on FVIII immune responses in hemophilia A. Dr. Shi expects that results from her studies will aid the design of more effective protocols to prevent FVIII immune responses and to induce FVIII immune tolerance in patients with HA.
Objective:
Immune tolerance induction (ITI) is the standard of care for inhibitor eradication and restoration of factor VIII (FVIII) responsiveness in subjects with severe hemophilia who develop high-titer inhibitors. Retrospective data support the use of recombinant FVIII Fc fusion protein (rFVIIIFc) in ITI (Carcao et al. Haemophilia. 2018) but this has yet to be confirmed in prospective studies. This study presents preplanned interim results of verITI-8 (NCT03093480).
Methods:
VerITI-8 is a single-arm, nonrandomized, open‐label, ethics-approved study of rFVIIIFc (200 IU/kg/day) for first-time ITI. Eligible subjects had a history of high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL) and provided informed consent. The primary endpoint is time to tolerization, defined by negative inhibitor titer (<0.6 BU/mL) at two consecutive visits; incremental recovery ≥66% of expected at two consecutive visits; and rFVIIIFc half‐life ≥7 hours. ITI failure is defined as not meeting the above criteria by Week 48. This interim analysis was planned when ≥10 subjects had received ≥6 months of rFVIIIFc ITI.
Summary:
Fifteen subjects were screened as of the December 5, 2018 cutoff, while 14 subjects enrolled and had received ≥1 dose of rFVIIIFc for ITI. The median (range) age at start of ITI was 2.6 (0.8–16.0) years and historical peak inhibitor titer was 29.6 (6.2–256.0) BU/mL. Six subjects have been successfully tolerized, with a median (range) time to first negative titer, normal incremental recovery, and tolerization of 2.3 (1.7–15.6), 6.0 (4.3–28.1), and 11.7 (8.1–32.0) weeks, respectively. Seven subjects continue to receive rFVIIIFc ITI (median [range] time on ITI: 16.0 [0.1–35.6] weeks) and 1 subject has failed. No adverse events related to rFVIIIFc have been reported.
Conclusions:
Early results from this prospective/ongoing study of first-time ITI indicate that rFVIIIFc may offer rapid time to tolerization in some subjects with severe hemophilia A and high-titer inhibitors. Achieving tolerance faster can improve quality of life and reduce costs.
Objective:
Acute bleeds in patients with rare bleeding disorders (RBDs), including congenital hemophilia with inhibitors (CHwI), acquired hemophilia, congenital factor VII deficiency, and Glanzmann’s thrombasthenia (GT) must be treated as quickly as possible. This study evaluated the obstacles and experiences of patients with CHwI, or their caregivers, for the early treatment of acute bleeds in non-hemophilia treatment centers (HTCs).
Methods:
Patients in the United States (aged 18–65 years [or caregivers of patients <18 years]) with CHwI, who currently have or have had inhibitors in the last 3–4 years, and who sought treatment in a non-HTC, underwent an interactive online qualitative discussion over 7 days.
Summary:
The survey was completed by 23 respondents (seven patients and 16 caregivers; all patients with CHwI). Respondents were aware of the need to treat bleeds quickly, which had been taught to them by physicians and learned from experience. Delays in respondents initiating their treatment were typically due to: technical issues (e.g., 7/23 respondents had difficulty gaining access to a vein or port); delay in diagnosis (e.g., 5/23 respondents’ child does not inform caregiver of the bleed); convenience (e.g., 3/23 respondents were unwilling/unable to take treatment out of the home); or financial issues (e.g., one respondent had inadequate insurance). Respondents tended to visit a non-HTC as a last resort, often due to the long distance to an HTC when emergency treatment was needed, unsuccessful pain management, or unsuccessful factor administration at home. Most patients/caregivers (20/23) reported treatment delays in emergency departments (EDs). Delays in EDs were often due to healthcare professional’s (HCP) lack of knowledge (16/23 respondents; 4 hours average wait until treatment) and four reported delays due to lack of available treatment (14 hours average wait for treatment). All patients/caregivers reported that they had dealt with uneducated/unaware HCPs, having to spend significant time educating the ED staff. Three respondents reported not waiting for treatment—partly because they chose hospitals very carefully, and because they had educated their closest hospital prior to needing an emergency service. Patients/caregivers with negative experiences reported that HCPs were unwilling to listen to them, did not seek consultation quickly, dismissed their instructions, and directed care that forced an outcome. When patients had satisfactory experiences, HCPs listened intently, immediately called an HTC/patient’s physician, and provided care in consultation. Respondents highlighted the need for HCPs education on hemophilia.
Conclusions:
Patients/caregivers are aware of the need to treat an acute bleed fast, but sometimes delay their treatment, and experience delays when attending non-HTCs. The lack of experience of HCPs in managing acute bleeds contributes to these delays. Improved education of HCPs at non-HTCs and provision of protocols or guidelines would be beneficial for patients with CHwI.
