Bruton's Tyrosine Kinase Small Molecule Inhibitors Induce a Distinct Pancreatic Toxicity in Rats
Rebecca I Erickson1, Leah K Schutt2, Jacqueline M Tarrant1
1Genentech, Inc., South San Francisco, California (R.I.E., L.K.S., J.M.T., M.M., L.L., A.R.J., S.-C.L.-K., M.H., J.R., R.A.D.C., K.S., F.Z., J.J.C., S.Z., K.R., A.K., W.B.Y., D.M.D., D.L.M.); and University of British Columbia, Vancouver, British Columbia (H.W.); Primary Laboratory of Origin: Genentech, Inc., 1 DNA Way, MS59, South San Francisco, CA 94080.
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.
Insights
Bruton's tyrosine kinase (BTK) inhibitors like GDC-0853 caused pancreatic lesions in rats, potentially exacerbating a background pathology. These findings in rats are unlikely to be relevant to humans and did not impact glucose homeostasis.
Area of Science:
- Pharmacology
- Toxicology
- Oncology
Background:
- Bruton's tyrosine kinase (BTK) is crucial for B-cell and myeloid cell signaling.
- BTK inhibitors are investigated for hematologic cancers and autoimmune diseases.
- GDC-0853 is an oral, selective BTK inhibitor for rheumatoid arthritis and systemic lupus erythematosus.
Purpose of the Study:
- To investigate the toxicological effects of GDC-0853 and other BTK inhibitors on pancreatic tissue.
- To assess the relevance of observed pancreatic lesions in rats to human patients.
Main Methods:
- Administration of GDC-0853 and other BTK inhibitors to Sprague-Dawley rats, mice, and dogs.
- Histopathological examination of pancreatic tissues.
- Assessment of glucose homeostasis and serum biomarkers.
- Evaluation of imaging techniques for lesion detection.
Main Results:
- Rats treated with BTK inhibitors developed pancreatic lesions including hemorrhage, inflammation, and atrophy.
- Similar lesions were not observed in mice or dogs at higher exposures.
- Glucose homeostasis was dysregulated after 28 days, but not directly linked to lesion severity.
- Lesions were not readily detectable by common imaging modalities.
Conclusions:
- Pancreatic lesions in rats appear to be a class effect of BTK inhibitors.
- These lesions may exacerbate a background islet-centered pathology with low human relevance.
- BTK inhibitors warrant continued investigation for autoimmune diseases and cancers.
