Research Studies

Dr. Meeks is an Associate Professor of Pediatrics in the Department of Pediatrics at the Emory University School of Medicine and the Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. She obtained a Bachelor of Science in Mathematics from Duke University where she was elected to Phi Beta Kappa. After earning her medical degree from the University of Mississippi, she completed her clinical training at the University of Virginia and Emory University. Dr. Meeks has a basic, translational, and clinical research interest in the development of inhibitors in hemophilia A. Her work has focused on the early immune response to factor VIII and the diversity of the B-cell response to factor VIII. She is a former NHF clinical fellow who currently has funding to pursue these projects from the Hemostasis and Thrombosis Research Society and the National Institutes of Health.

Dr. Jill Johnsen is scientist and physician at the Washington Center for Bleeding Disorders in Seattle, WA.  She is an Associate Member at the Bloodworks Research Institute and also an Associate Professor of Medicine in the Division of Hematology at the University of Washington. Her research focuses on the study of hereditary and acquired modifiers of blood traits, with particular emphasis on the genetics and biology of variation in blood group and coagulation factors such as factor VIII, factor IX, and von Willebrand Factor.  Dr. Johnsen is honored by this award and grateful for this support that will further the development of a test to enable patients and providers to determine factor levels much more quickly without needing to send blood to a lab.

Objective:

Hemophilia A (HA) is an X-linked disorder caused by mutations in the gene encoding Factor VIII protein (FVIII). Gene therapy is increasingly being viewed as a viable treatment option for hemophilia. Herein, long-term clinical safety and efficacy are presented from a Phase 1/2 study of an AAV-mediated gene therapy for severe HA.  
 
Methods:

Valoctocogene roxaparvovec is an adeno-associated virus-mediated gene therapy that delivers a functional, codon-optimized, B domain-deleted, human FVIII gene under the control of a liver-specific promoter (AAV5-hFVIII-SQ). An ongoing Phase 1/2 study continues to evaluate the safety and efficacy of valoctocogene roxaparvovec in thirteen males with severe HA. Study participants received a single intravenous injection of valoctocogene roxaparvovec at one of two dose levels (6×10¹³vg/kg, n=7; 4×10¹³vg/kg, n=6).

Summary:

Participants who received 6×10¹³vg/kg valoctocogene roxaparvovec showed a reduction in annualized bleeding rate (ABR) of 96%, from a pre-treatment median(mean) of 16.5(16.3) to 0.0(0.7) at year three. Participants demonstrated an absence of target joints and target joint bleeds, with 86% experiencing zero bleeds requiring FVIII treatment. ABR diminished by 92% in 4×10¹³vg/kg participants, from a pre-treatment median(mean) of 8(12.2) to 0(1.2) at year two. Sixty-seven percent of 4×10¹³vg/kg participants experienced zero bleeds requiring FVIII treatment.
 
FVIII usage demonstrated a reduction from pre-treatment median(mean) of 139(137) infusions to 0(5.5) at year three in 6×10¹³vg/kg participants, and from 156(147) to 0.5(6.8) at year two in 4×10¹³vg/kg participants.
 
In 6×10¹³vg/kg participants, FVIII levels reported by chromogenic assay reached a median(mean) of 60.3(64.3), 26.2(36.4), and 19.9(32.7) IU/dL at the end of one, two, and three years post-infusion, respectively. In 4×10¹³vg/kg participants, FVIII levels reported by chromogenic assay reached a median(mean) of 22.9(21.0) IU/dL and 13.1(14.7) IU/dL at the end of one and two years post-infusion, respectively. Although FVIII levels were measured and will be presented using both the chromogenic substrate assay and the one-stage assay, chromogenic assay results appear to more accurately represent the true level of circulating FVIII.

The safety profile of valoctocogene roxaparvovec remains favorable and unchanged, with transient, asymptomatic ALT elevations and no FVIII inhibitor development reported to-date.

Conclusions:

Following a single administration of valoctocogene roxaparvovec, participants showed sustained, clinically relevant FVIII activity that reduced self-reported bleeding and exogenous FVIII replacement use at 156 weeks and 104 weeks post-administration in 6×10¹³vg/kg and 4×10¹³vg/kg dose cohorts, respectively.

Dr. Esther Cooke received her Ph.D. from the Leeds Institute of Cardiovascular and Metabolic Medicine at the University of Leeds, U.K., where she studied the role of fibrinogen phosphorylation in thrombosis. Dr. Cooke is currently a postdoctoral fellow in the laboratory of Dr. Annette von Drygalski, at the University of California San Diego, and in collaboration with the laboratory of Dr. Laurent Mosnier at the Scripps Research Institute. Dr. Cook's JGP Fellowship project will focus on pathological mechanisms associated with joint bleeding, re-bleeding, and the development of hemophilic arthropathy. Dr. Cooke will perform comprehensive gene expression analyses to explore key molecular markers and pathways that drive soft tissue inflammation and vascular changes in joints after bleeding. In this way, she hopes to identify new therapeutic targets and develop novel treatment strategies to down-regulate these processes, thereby reducing re-bleeding tendency and slowing the progression of hemophilic arthropathy.

Objective:

Demonstrate the success of collaborative efforts between the specialized multidisciplinary Infusion Pharmacy Provider (IPP), the prescriber, patient and payer, in achieving improved outcomes.

Methods:

A Case Study including chart review, cost analysis, and interviews with patient and prescriber.

Summary:

Patient is a 23-year-old male with severe hemophilia A and an inhibitor, followed by a Hemophilia Treatment Center (HTC). Patient developed a high titer inhibitor with a Bethesda Titre of 1000 BU/ml as a child. Several complex treatment plans including: Immune Tolerance Therapy (ITT) utilizing plasma derived and recombinant factor products, immunosuppressive therapy, and prophylaxis with bypassing agents failed. Complications with implanted ports resulted in hospitalizations and replacement of approximately twenty ports. Numerous hospitalizations for uncontrolled bleeding episodes and pain management contributed to a disruptive childhood/adolescence and suboptimal quality of life for the patient and family.

Patient was unable to attend school regularly, develop socially, or participate in normal age-appropriate activities. Repeated uncontrollable bleeding episodes led to the development of target joints and hemarthrosis. The complex nature of the patient’s treatment regimen, his psychosocial issues, bleed history, and cost of therapy resulted in frequent communication and collaboration between all stakeholders to maximize therapy outcomes.

Inhibitors presents a significant management challenge.2 Emicizumab (Hemlibra®) was approved for the treatment of hemophilia A with inhibitors in November 2017. Well in advance of the transition, the IPP and prescriber discussed the benefits with the patient. Although understandably reluctant due to his history of failed therapies, the patient agreed to try Emicizumab. Initial doses were administered at the IPP’s Alternate Infusion Suite (AIS) under clinical observation, per prescriber’s request. The patient and caregiver received extensive education regarding potential adverse events, self- administration, and bleed treatment regimen during these visits.

Conclusion:

The coordination of care, communication, and goal alignment by all stakeholders resulted in positive outcomes for this patient. Following eighteen months of therapy with Emicizumab, the patient reports improved over-all quality of life as evidenced by his ability to maintain employment, attend college, and engage in social events/ activities. Twenty-two hospitalizations in the twelve months prior to changing therapies decreased to one in the eighteen months after transitioning. His bleeding events decreased from six to eight bleeds per month to one bleed in the past eighteen months and this bleed was attributed to a missed dose. Education on the importance of adhering to prescribed dosing schedule was reinforced by both the IPP and HTC. His port has been removed. Along with his significant increase in quality of life, the dramatic decrease in overall cost of care will be highlighted.