Fenebrutinib (GDC-0853)

When tested at 1 μM against a broad panel of human kinase biochemical assays, GDC-0853 inhibits only 3 of 286 off-target kinases. Based on the determined IC50 values, the selectivity for Btk is >100-fold against each of these 3 off-targets: Bmx (153-fold), Fgr (168-fold), and Src (131-fold). GDC-0853 blocks both B-cell BCR and monocyte FcγR signaling. In in vitro biochemical Btk enzyme assay, GDC-0853 displays an average residence time with Btk of 18.3 ± 2.8 hours. GDC-0853 blocks cellular autophosphorylation of WT Btk and the C481S mutant^[1]. CLL (chronic lymphocytic leukemia) cells treated with GDC-0853 in vitro before BCR stimulation demonstrate reduced levels of BTK phosphorylation and diminished activation of downstream targets including PLCγ2, AKT, and ERK. GDC-0853 inhibits NF-κB–dependent transcription, reduces activation, and impairs migration. GDC-0853 lacks inhibition of EGFR and ITK in cellular system and does not affect T-cell receptor activation^[3].

Cells are treated with 1 µM BTK inhibitor for 48 hours and measured for viability by flow cytometry.

In rats administrated 0.2 mg/kg GDC-0853 via intraperitoneal injection or 1 mg/kg PO, GDC-0853 has moderate clearance of 27.4 mL/min/kg and excellent bioavailability (F=65%). The plasma clearance is 27.4 mL/min/kg, the volume of distribution (Vd) is 5.42 L/kg and the plasma half-life (t_1/2) is 2.2 h. GDC-0853 also demonstrates favorable PK properties in dogs. The 3.8-hour half-life (Cl_p 10.9 mL/min/kg, V_d 2.96 L/kg) and high oral bioavailability (85%) also enable attainment of sufficient exposures in dog toxicology studies. GDC-0853 is well tolerated in both rats and dogs and displays an overall favorable safety profile. GDC-0853 is useful in treating rheumatoid arthritis and other B-cell or myeloid cell mediated autoimmune diseases. In a single ascending dose (SAD) study (0.5 mg to 600 mg) and multiple ascending dose (MAD) study for 14 days (250 mg BID to 500 mg QD), GDC-0853 is very well tolerated with no severe adverse events, no safety signals, and no dose limiting toxicities. GDC-0853 is well absorbed and had linear, doseproportional pharmacokinetics^[1]. In Sprague-Dawley (SD) rats, administration of GDC-0853 and other structurally diverse BTK inhibitors for 7 days or longer cause 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 are not observed in mice or dogs at much higher exposures^[2].