Efficacy of a Bruton's Tyrosine Kinase Inhibitor (PRN‐473) in the treatment of canine pemphigus foliaceus

Abstract

BackgroundBruton'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 the most common canine autoimmune skin disease.ObjectivesTo determine the safety and efficacy of a BTKi in cPF treatment.AnimalsNine privately owned dogs.Methods and materialsNine dogs diagnosed with PF were administered BTKi PRN473. Initial dosages were ≈15 mg/kg once daily, increased to twice daily if inadequate response was seen. Treatment continued for a maximum of 20 weeks, attempting decrease to every other day. Dogs were monitored with complete blood counts, serum biochemistry panels, urinalyses and evaluated with a modified version of a validated human Pemphigus Disease Activity Index (cPDAI). Anti‐desmocollin‐1 (DSC‐1) and desmoglein‐1 (DSG‐1) immunoglobulin G (IgG) titres were performed before and after the treatment period. Drug bound to target was measured in peripheral blood mononuclear cells.ResultsAll nine dogs showed reduction in lesions and cPDAI score during the first two weeks of treatment. At the end of the study, four responses were considered “good”, two “fair”, two “poor” and one dog withdrawn due to recurrence of a previously excised mast cell tumour. Four dogs continued to improve by Week 4; three sustained near complete remission by study's end. The anti‐DSC‐1 IgG titre decreased in three dogs, increased in two, was undetected in three and was not performed in the withdrawn dog. No dogs had detectable IgG to DSG1. Possible adverse effects occurred in three dogs.Conclusions and clinical importanceBruton's tyrosine kinase inhibitor monotherapy may have beneficial effects in some cases of cPF.

Open trial of Bruton’s tyrosine kinase inhibitor (PRN1008) in the treatment of canine pemphigus foliaceus

“…4,5 Previous reports using BTKi in the treatment of cPF have included two posters, one of which presented findings of Dog 1 in the present study, 6 and our previous report on BTKi PRN473. 7 PRN1008 is an oral, reversible covalent BTKi developed by Principia Biopharma for the treatment of human autoimmune disease including pemphigus foliaceus; it has been given the generic name rilzabrutinib. 5,8 PRN1008 has undergone toxicological testing in healthy beagle dogs, including a 12 week Good Laboratory Practice study by Principia Biopharma.…”

“…The BTK probe PRN933 and BTK detection antibody (Clone 53, BD Biosciences; San Jose, CA, USA) used in this study were used as reported in a similar study of cPF and PRN473. 7 PRN933 was synthesized in-house and validated to show similar binding affinity to those studies. Further details of processing of the dogs' B cells and measuring BTK occupancy [% of the BTK enzyme in peripheral blood mononuclear cells (PBMC) bound by PRN1008] were as described previously.…”

“…Further details of processing of the dogs' B cells and measuring BTK occupancy [% of the BTK enzyme in peripheral blood mononuclear cells (PBMC) bound by PRN1008] were as described previously. 7 Determination of IgG titres to DSC-1 and DSG-1 was performed as described previously, utilizing transfected 293T cells expressing canine DSC-1 or DSG-1 on their surface and nontransfected 293T cells without these recombinant proteins. 4,7 Sera were tested at 1:20, 1:50, 1:100, 1:200, 1:400, 1:800, 1:1,600 and 1:3,200, with the last positive dilution recorded.…”

“…7 Determination of IgG titres to DSC-1 and DSG-1 was performed as described previously, utilizing transfected 293T cells expressing canine DSC-1 or DSG-1 on their surface and nontransfected 293T cells without these recombinant proteins. 4,7 Sera were tested at 1:20, 1:50, 1:100, 1:200, 1:400, 1:800, 1:1,600 and 1:3,200, with the last positive dilution recorded. Desmocollin-1 and DSG-1 (IgG) titres were performed before and at the end of treatment for each dog.…”

“…The medication was given once daily with food. This dose was based on previous studies with PRN473, 7 and pharmacological data (Francis D. Expert Pharmacology/Toxicology Review -PRN1008; v.2.0; dated 21 July 2014. Principia Biopharma, data on file).…”