A new treatment for autoimmune blistering diseases- the efficacy of Bruton's tyrosinase kinase inhibitor PRN473 in canine pemphigus foliaceus

DF Murrell, SG Gourlay, RJ Hill, Bisconte A, Smith P, D Karr, C Outerbridge, Katarina Varjonen, Goodale E, D Borjesson, VP Werth, PA Nunn, SD White

Research output: Contribution to conferencePoster

Abstract

Background/Purpose:
Bruton’s Tyrosine Kinase (BTK) is a target for the treatment of multiple autoimmune diseases. Principia is developing a potent, selective, reversible, covalent inhibitor of BTK for pemphigus. We characterized the pharmacology of PRN1008 and tested the human safety, tolerability and PK/PD profile of PRN1008 in a phase 1 clinical trial. Clinical efficacy of a surrogate BTK inhibitor molecule, possessing a similar kinase inhibition profile and with good canine oral bioavailability, PRN473, was investigated in 7 cases of naturally occurring canine pemphigus foliaceus (PF).

Methods:
PRN1008 was tested for potency, durability and selectivity in biochemical and cell-based functional assays. The in vivo efficacy of PRN1008 was tested in a rat model of collagen-induced arthritis (CIA). The first-in-human study (N=80) included four multiple dose cohorts with 10 days treatment (300mg and 600mg QD, 300mg and 450mg BID). PRN1008 pharmacodynamics was assessed by BTK occupancy in PBMCs. Canine PF cases were administered a dose of 15mg/kg QD of PRN473 as monotherapy, designed to achieve trough BTK occupancy of 50-70% 24 hours after the first dose. Skin disease activity was measured with a modified, canine pemphigus disease activity index (cPDAI).

Results:
PRN1008 was very potent against BTK in vitro (IC50=1.3±0.5 nM). Human B cell proliferation and activation (CD69 expression) were inhibited by PRN1008 with IC50 of 5±2.4 nM and 12338 nM, respectively. Dose-dependent efficacy in rat CIA was observed at trough BTK occupancies of 16-79%. PRN1008 was safe and well-tolerated in the human clinical trial with mean (±SD) BTK occupancy of 90±6% and 93±2% 4 hours post-dose on Days 1 and 10, respectively. BTK occupancy at trough on day 10 ranged from 54±15 to 77±7%. Seven of 7 dogs with PF had an initial reduction in skin disease activity with mean cPDAI 55±29 at baseline vs. 27±16 at Week 2. BTK occupancy 24 hours after the first dose ranged from 49-77%. Four of 7 dogs went on to a full or near-full remission without the use of corticosteroids. Retreatment, 9 days and 4 months after PRN473 cessation, resulted in repeat, complete responses in 2 of 2 cases.
Original languageEnglish
Publication statusPublished - 2016
EventAnnual Meeting of the Am Acad Derm - Washington DC, United States
Duration: 4 Mar 20166 Mar 2016

Conference

ConferenceAnnual Meeting of the Am Acad Derm
Country/TerritoryUnited States
CityWashington DC
Period4/03/166/03/16

Fingerprint

Dive into the research topics of 'A new treatment for autoimmune blistering diseases- the efficacy of Bruton's tyrosinase kinase inhibitor PRN473 in canine pemphigus foliaceus'. Together they form a unique fingerprint.

Cite this