Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and is associated with significant morbidity and mortality. BP is an orphan disease with estimates of annual incidence of BP of <40 new cases per million people per year. Because of the rarity of the disease, evidence-based treatments are lacking. Steroids, both topical and systemic, are often used depending on disease severity. Infectious complications and sepsis, as well as cardiovascular events are the major causes of death. Overall 3-year mortality has been estimated at 30%. Thus BP is a rare life-threatening disease with a significant unmet need. BP is caused by IgG auto-antibodies that recognize the hemidesmosomal components of the basement membrane region leading to subepidermal blistering. This knowledge has launched efforts to therapeutically target humoral immunity including with the B cell depleting antibody Rituximab, Therapy with Rituximab has its limitations since it fails to target antibody producing cells and renders patients B cell deficientfor many months after a single treatment. Moreover, Rituxumab fails to target the antibody-mediated inflammatory response, mediated by Fc receptor bearing effector cells. We are pursuing an alternative approach with protein tyrosine kinase inhibitors (PTKis) selective for Syk, the PTK required for signaling of both IgG receptors (FcR) and the B cell receptor (BCR). Portola Pharmaceuticals has developed selective Syk inhibitors (PRT060318 and PRT062607) with improved potency and higher specificity as compared with fostamatinib (R788/406), the other Syk inhibitor currently in clinical development. Thus PRT318 and PRT2607 promise greater on-target efficacy with fewer off- target side effects. Syk inhibitors would be predicted t have two direct therapeutic actions important for BP pathogenesis; 1) reduction of the BCR-triggered production of autoantibodies, and 2) uncoupling of the FcR-mediated triggering of the inflammatory response. We provide preliminary data that Portola's syk inhibitors effectively target both pathways in mouse models of inflammation and in normal human volunteers. This proposal brings together an academic- industry partnership involving Portola and the leaders in their respective fields in Syk/Fc receptor biology (Columbia) and bullous skin diseases (Lubeck) to overcome the barriers to translation in this orphan skin disease. In this Phase I program we will provide proof-of- concept for Syk inhibitors in BP using both animal models and relevant ex vivo human biospecimens. Moreover this will lay the groundwork for larger Phase II initiatives using both oral and topical delivery.
Public Health Relevance: This proposal brings together an academic-industry partnership involving Portola Pharmaceuticals and the leaders in their respective fields in Syk/Fc receptor biology (Columbia) and bullous skin diseases (Lubeck) to overcome the barriers to translation in Bullous Pemphigoid, an orphan skin disease. In this Phase I program we will provide proof-of-concept for Syk inhibitors in BP using both animal models and relevant ex vivo human biospecimens.
Public Health Relevance Statement: This proposal brings together an academic-industry partnership involving Portola Pharmaceuticals and the leaders in their respective fields in Syk/Fc receptor biology (Columbia) and bullous skin diseases (Lubeck) to overcome the barriers to translation in Bullous Pemphigoid, an orphan skin disease. In this Phase I program we will provide proof-of-concept for Syk inhibitors in BP using both animal models and relevant ex vivo human biospecimens.
NIH Spending Category: Autoimmune Disease; Rare Diseases
Project Terms: Adverse effects; Animal Model; Antibodies; Antibody-Producing Cells; Autoantibodies; Autoimmune Process; B-Lymphocytes; base; Basement membrane; Binding (Molecular Function); Biological Markers; Biology; Bulla; Bullous Pemphigoid; Bullous Skin Diseases; Cardiovascular system; Cause of Death; chemokine; Chronic; Cleaved cell; Clinical; Clinical Data; clinical remission; Clinical Trials; Collagen Type XVII; Controlled Study; Cryoultramicrotomy; cytokine; Data; Dermal; Dermis; Development; Disease; drug development; Drug Kinetics; Effector Cell; efficacy testing; Epidermis; Event; Evidence based treatment; experience; Fc Receptor; Human; Human Volunteers; Humoral Immunities; IgG Receptors; Immune response; Immunoglobulin G; Immunosuppressive Agents; improved; In Vitro; in vivo; Incidence; Incubated; Industry; Infection; Inflammation; Inflammatory; Inflammatory Response; inhibitor/antagonist; Knowledge; Lead; Lesion; Leukocytes; Life; Malignant Neoplasms; Mediating; Modeling; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; neutrophil; Oral; Orphan; Orphan Disease; Pathogenesis; Pathway interactions; Patients; Pharmacologic Substance; Phase; pre-clinical; Prevention; Production; programs; Protein Tyrosine Kinase; Receptors, Antigen, B-Cell; Recruitment Activity; Relapse; response; Risk; rituximab; Rodent; Safety; Sepsis; Serum; Severity of illness; Signal Transduction; SJL/J Mouse; Skin; skin disorder; small molecule; Specificity; Steroid Resistance; Steroids; Therapeutic; Therapeutic immunosuppression; Topical application; Translations; treatment response; Tyrosine Kinase Inhibitor
