Novel Therapeutics for Bleeding Disorders (NoT Bleeding) Program

Leslie J. Raffini, MD

The Novel Therapeutics for Bleeding Disorders (NoT Bleeding) Program is a Children’s Hospital of Philadelphia (CHOP) Frontier Program within the Division of Hematology that aims to provide advanced clinical care of inherited bleeding disorders and develop breakthrough treatments through research.

This program combines our established clinical expertise in hemophilia gene therapy and management of bleeding disorders with our research strengths. The goal is to integrate novel therapies safely and efficiently into care for patients. We offer:

• state-of-the-art clinical care and a gene therapy program for adolescents and young adults with hemophilia
• consultation for novel therapies for hemostatic disorders
• identification and management of unclassified bleeding disorders

Background: Hemophilia has been the focus of intensive gene therapy research and treatment efforts due to its high cost for treatment and severe impact on the quality of life for patients with this inherited bleeding disorder. Hemophilia A (HA) and B (HB) are the most common inherited bleeding disorders occurring in aggregate in 1 in 5 000 males due to decreased coagulation factor VIII (FVIII) or FIX activity, respectively.

The bleeding phenotypes correlate with factor activity. People with severe HA/HB (<1% normal factor activity) have frequent spontaneous bleeds, people with moderate HA/HB (1-5% normal) have occasional spontaneous bleeds and bleed with mild trauma, and people with mild HA/HB (5-40% normal) bleed typically only after trauma. The current standard of care is intravenous (IV) factor replacement multiple times a week, but anti-drug antibodies (inhibitors) develop in 30% and 10% of severe HA and HB patients, respectively.

FDA approval of the first therapeutic gene therapy products for HA and HB that use adeno-associated virus (AAV) vector is anticipated in the upcoming months. In addition, there are many other ongoing hemophilia gene therapy clinical trials using a variety of approaches in various stages of development. Although these products have only been studied in patients >18 yrs of age, upcoming trials (which we will participate in) will include younger patients. One challenge observed in the clinical trials of these early products is an immune-mediated response to the AAV capsid protein that occurs in the first months and can result in loss of expression of the transgene. This immune response can be abrogated if identified early and treated with steroids, highlighting the importance of close monitoring by experienced providers.

About the NoT Bleeding Program: Given CHOPs longstanding leadership in developing gene therapy for hemophilia, expertise in the molecular basis of coagulation, and extensive clinical experience, the NoT Bleeding Program is uniquely positioned to counsel patients on choosing the appropriate treatment strategy for each individual’s case and hemostatic physiology.

The clinic will provide state-of-the-art individualized treatment plans for patients with hemophilia and rare blood disorders to assist patients, families and referring physicians to choose the best available therapy for each patient.

The clinic will bring together clinicians and translational scientists to review each case and recommend an optimal treatment course based upon the patient’s history, response to prior therapies, available trials and understanding of the molecular basis of the disease.

Research: The NoT Bleeding program will also offer basic, translational, and clinical research opportunities to train the next generation of hemostasis scientists and physician-scientists. It will be incorporated into the CHOP Cell and Gene Therapy Collaborative goals of advancing gene therapy research and Clinical Training Program. The five principal investigators for the NoT Bleeding Program: Dr. Lindsey George, Dr. Bhavya Doshi, Dr. Leslie Raffini, Dr. Rodney Camire and Dr. Benjamin Samelson-Jones, span a breadth and depth of expertise in the basic mechanisms of hemostasis and thrombosis as well as basic, translational, and clinical research efforts in hemophilia gene therapy. The program will also support three translational research projects to develop novel methods to treat bleeding disorders: 1.) minimize FVIII inactivation by targeting both mechanisms of FVIII inactivation (Dr. George); 2.) develop factor V specific monoclonal antibodies that will prevent and stop bleeding in hemophilia and other rare bleeding disorders (Dr. Camire); and 3.) repurpose an existing licensed therapy for all ages of hemophilia A that works by mimicking one of FVIII’s functions (Dr. Samelson-Jones).

Long-standing history: Through basic, translational and clinical research efforts, CHOP has led the development of hemophilia gene therapy over the last several decades; a natural extension of this longstanding work is to lead the clinical implementation of commercialized hemophilia vector that could be used to establish a general foundation for the institution to incorporate licensed gene therapy products. Establishing the NoT Bleeding Center will create greater synergy among faculty and advance our Center’s capabilities to offer state-of-the-art care of patients with bleeding disorders.