Elizabeth C Goodale1, Stephen D White1, Petra Bizikova2, Dori Borjesson3, Dedee F Murrell4, Angelina Bisconte5, Michelle Francesco5, Ronald J Hill5, Mohammad Masjedizadeh5, Philip Nunn5, Steven G Gourlay5, Tyler J M Jordan1, Carolyn B Emery6, Catherine A Outerbridge1. 1. Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA. 2. Department of Clinical Sciences, College of Veterinary Medicine, NC State University, 1060 William Moore Drive, Raleigh, NC, 27607, USA. 3. Departments of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA. 4. Department of Dermatology, St George Hospital, University of New South Wales, Sydney, NSW, 2217, Australia. 5. Principia Biopharma Inc., 400 E Jamie Ct, South San Francisco, CA, 94080, USA. 6. William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA, 95616, USA.
Abstract
BACKGROUND: Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is one of the most common canine autoimmune skin diseases. OBJECTIVES: To determine the safety and efficacy of the BTKi PRN1008 in the treatment of cPF. ANIMALS: Four privately owned dogs. METHODS AND MATERIALS: Four dogs diagnosed with PF were administered BTKi PRN1008. Initial dosages approximated to 15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for 20 weeks, attempting to decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels and urinalyses, and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Serum anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin (Ig)G titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells (PBMC). RESULTS: All four dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. Three dogs continued to improve and sustained near complete remission by 20 weeks, at which point three responses were considered "good" and one "fair". Final daily dosages were in the range 17-33 mg/kg. Anti-DSC-1 IgG titre decreased dramatically in one dog, was undetectable in two and was uninterpretable in one dog. No dogs had detectable IgG to DSG1. A possible adverse event occurred in one dog. CONCLUSIONS AND CLINICAL IMPORTANCE: BTKi PRN1008 monotherapy may have some beneficial effects in some cases of cPF.
BACKGROUND: Bruton's tyrosine kinase (BTK) is important in B-cell signalling. Efficacy has been reported for BTK inhibitors (BTKi) in human autoimmune diseases. Canine pemphigus foliaceus (cPF) is one of the most common canine autoimmune skin diseases. OBJECTIVES: To determine the safety and efficacy of the BTKi PRN1008 in the treatment of cPF. ANIMALS: Four privately owned dogs. METHODS AND MATERIALS: Four dogs diagnosed with PF were administered BTKi PRN1008. Initial dosages approximated to 15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for 20 weeks, attempting to decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels and urinalyses, and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Serum anti-desmocollin-1 (DSC-1) and desmoglein-1 (DSG-1) immunoglobulin (Ig)G titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells (PBMC). RESULTS: All four dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. Three dogs continued to improve and sustained near complete remission by 20 weeks, at which point three responses were considered "good" and one "fair". Final daily dosages were in the range 17-33 mg/kg. Anti-DSC-1 IgG titre decreased dramatically in one dog, was undetectable in two and was uninterpretable in one dog. No dogs had detectable IgG to DSG1. A possible adverse event occurred in one dog. CONCLUSIONS AND CLINICAL IMPORTANCE: BTKi PRN1008 monotherapy may have some beneficial effects in some cases of cPF.
Authors: Claire L Langrish; J Michael Bradshaw; Michelle R Francesco; Timothy D Owens; Yan Xing; Jin Shu; Jacob LaStant; Angelina Bisconte; Catherine Outerbridge; Stephen D White; Ronald J Hill; Ken A Brameld; David M Goldstein; Philip A Nunn Journal: J Immunol Date: 2021-03-05 Impact factor: 5.422
Authors: Sibel Ucpinar; Borje Darpo; Ann Neale; Philip Nunn; Jin Shu; Katherine A Chu; Marianne Kavanagh; Hongqi Xue; Pasit Phiasivongsa; Dolca Thomas; Patrick F Smith Journal: Clin Transl Sci Date: 2022-04-03 Impact factor: 4.438
Authors: D F Murrell; A Patsatsi; P Stavropoulos; S Baum; T Zeeli; J S Kern; A-V Roussaki-Schulze; R Sinclair; I D Bassukas; D Thomas; A Neale; P Arora; F Caux; V P Werth; S G Gourlay; P Joly Journal: Br J Dermatol Date: 2021-06-15 Impact factor: 9.302