Bruton’s Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats

Abstract

Bruton's tyrosine kinase (BTK) is a member of the Tec family of cytoplasmic tyrosine kinases involved in B-cell and myeloid cell signaling. Small molecule inhibitors of BTK are being investigated for treatment of several hematologic cancers and autoimmune diseases. GDC-0853 ((S)-2-(3'-(hydroxymethyl)-1-methyl-5-((5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6-oxo-1,6-dihydro-[3,4'-bipyridin]-2'-yl)-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one) is a selective and reversible oral small-molecule BTK inhibitor in development for the treatment of rheumatoid arthritis and systemic lupus erythematosus. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer caused pancreatic lesions consisting of multifocal islet-centered hemorrhage, inflammation, fibrosis, and pigment-laden macrophages with adjacent lobular exocrine acinar cell atrophy, degeneration, and inflammation. Similar findings were not observed in mice or dogs at much higher exposures. Hemorrhage in the peri-islet vasculature emerged between four and seven daily doses of GDC-0853 and was histologically similar to spontaneously occurring changes in aging SD rats. This suggests that GDC-0853 could exacerbate a background finding in younger animals. Glucose homeostasis was dysregulated following a glucose challenge; however, this occurred only after 28 days of administration and was not directly associated with onset or severity of pancreatic lesions. There were no changes in other common serum biomarkers assessing endocrine and exocrine pancreatic function. Additionally, these lesions were not readily detectable via Doppler ultrasound, computed tomography, or magnetic resonance imaging. Our results indicate that pancreatic lesions in rats are likely a class effect of BTK inhibitors, which may exacerbate an islet-centered pathology that is unlikely to be relevant to humans.

Pancreatic Effects of a Bruton’s Tyrosine Kinase Small-molecule Inhibitor in Rats Are Strain-dependent

“…The lack of a functional effect may correlate to the observations that, even in the more severely affected animals, there are a proportion of islets that are not affected and there may be adequate islet cell reserve capacity. These findings are consistent with Erickson et al’s observation that mild glucose dysregulation levels observed after treatment with GDC-0853 at 100 mg/kg/day for 28 consecutive days did not correlate to the pancreatic changes noted (Erickson et al 2017).…”

“…The current study is not the first to suggest that susceptibility to the pancreatic effects of a BTK inhibitor varies by rat strain. A recent report investigating the pancreatic effect of other small-molecule BTKi showed that that Crl:CD(SD) rats were the most susceptible to this pancreatic effect, F344 Fischer rats had intermediate (but minimal) susceptibility and Crl:WI(Han) rats had the lowest susceptibility that appeared only with longer treatment (Erickson et al 2017). Based on the data presented in this article and in Erickson et al, the susceptibility of rat strains to these pancreatic effects would be ranked as follows: Crl:CD(SD) > F344 Fischer > Crl:WI(Han) > Hsd: SD.…”

“…In assessing data from multiple repeat-dose toxicity studies using non-BTKi (BTKi, BTK inhibitors) molecules in rats that ranged from 3-month studies to 2-year carcinogenicity studies, the authors observed that the incidence and severity of the pancreatic islet finding were significantly higher in control male Crl:CD(SD) rats when compared to other rat strains (data not shown). Also, a recent report investigating the pancreatic effects of multiple reversible oral small-molecule BTKi showed that BTKi, regardless of BTK selectivity, induced effects similar to LY3337641 in Crl:CD(SD) rats (Erickson et al 2017). Consistent with our observations, the pancreatic effects noted by Erickson et al were also generally not dose-responsive and occurred predominantly in male rats.…”

First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL

“…BTK is a proximal kinase in B-cell receptor (BCR) signaling that amplifies activation of several down-stream factors, including PLCg2, ERK, and NFκB, which contribute to both proliferation and survival [ 13 – 15 ]. BTK is also involved in integrin-mediated adhesion and migration of tumor cells, and contributes to TLR9 signaling via an adaptor function of MYD88 as well [ 16 – 18 ].…”

On the dynamics of the human endocrine pancreas and potential consequences for the development of type 1 diabetes

“…In animals on maintenance treatment with these specific Syk inhibitors, glucose metabolism starts to deteriorate after only 14 days [42]. The sensitivity of rats to Syk and Bruton's tyrosine kinase inhibitors seems to be strain dependent and to correlate with the background rate of spontaneous hemorrhagic islets [41,43].…”