Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168)

Abstract

Bruton's tyrosine kinase (BTK), expressed in B cells and cells of innate immunity, including microglia, is an essential signaling element downstream of the B-cell receptor and Fc-receptors. Tolebrutinib (PRN2246, SAR442168) is a potent BTK inhibitor that covalently binds the kinase, resulting in durable inhibition with the potential to target inflammation in the periphery and central nervous system (CNS). Tolebrutinib crosses the blood-brain barrier and potently inhibits BTK in microglial cells isolated from the CNS. A first-in-human randomized, double-blind, placebo-controlled study of tolebrutinib was conducted. The trial design consisted of five single ascending dose arms with oral administration of a single dose of 5, 15, 30, 60, and 120 mg (n = 6 per arm, n = 2 placebo), five multiple ascending dose arms with oral administration of 7.5, 15, 30, 60, and 90 mg (n = 8 per arm, n = 2 placebo) over 10 days, and one arm (n = 4) in which cerebral spinal fluid (CSF) exposure was measured 2 h after a single 120 mg dose. Tolebrutinib was well-tolerated in the study and all treatment-related treatment emergent adverse events were mild. Tolebrutinib was rapidly absorbed following oral administration with a rapid half-life of ~ 2 h. Peripheral BTK occupancy was assessed at various timepoints by an enzyme-linked immunosorbent assay-based readout using an irreversible probe. Assessments demonstrated extensive and prolonged peripheral BTK occupancy at steady-state with once daily doses as low as 7.5 mg. Further, CSF exposure was demonstrated 2 h after administration at 120 mg.

FIGURE 1

Mean SAD and steady‐state (MAD day 10) concentration‐time profiles. MAD, multiple ascending dose; SAD, single ascending dose

FIGURE 2

Mean total, free, and individual (N = 4) CSF concentration‐time profiles after 120 mg single dose administration of tolebrutinib. Individual concentrations (Conc) of tolebrutinib measure in CSF at 2 h are shown. CSF, cerebrospinal fluid

FIGURE 3

BTK occupancy observed during MAD (part B). Levels of BTK occupancy were measured at 4, 12, and 24 h after dosing on day 1, predose on days 3, 7, and 10, and at multiple timepoints out to 168 h (7 days) after administration of the final dose. All occupancy measurements were normalized to predose levels from day 1. BTK, Bruton’s tyrosine kinase; MAD, multiple ascending dose

FIGURE 4

Changes in CD19 B cell counts by dose during MAD (part B). Numbers of CD19+ B cells were measured predose on days 1, 4, and 10 by flow cytometry in part B only. Notes: Error bars represent the SD. MAD, multiple ascending dose