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.

Bruton’s Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives

“…Tolebrutinib (SAR 442168, PRN 2246, Sanofi/Principia Biopharma, San Francisco, CA, USA) is an investigational irreversible BTK inhibitor. It covalently binds to a specific conserved cysteine present in only 11 kinases, with potential immunomodulatory and anti-inflammatory activities [ 39 , 40 ]. Tolebrutinib can cross the blood–brain barrier and inhibit the activity of BTK in the central nervous system and has potential efficacy in MS.…”

“…Tolebrutinib (PRN2246, SAR442168) is a covalent BTKi that crosses the blood–brain barrier and potently inhibits BTK in microglial cells isolated from the central nervous system (CNS) [ 40 ]. Tolebrutinib was investigated in a phase 2b, randomized, double-blind, placebo-controlled trial in relapsing-remitting or relapsing secondary progressive MS [ 125 ].…”

Bruton’s Tyrosine Kinase Inhibitors in Multiple Sclerosis: Pioneering the Path Towards Treatment of Progression?

“…Recently published and early results suggest that due to molecular size and properties, the inhibitors are able to cross the BBB [65][66][67], but preliminary evidence shows that the inhibitors differ in their capacity to efficiently cross the BBB and accumulate within the CNS [68]. A study presented at a scientific meeting compared the CNS exposure and potency of evobrutinib, tolebrutinib, and fenebrutinib.…”

New drugs for multiple sclerosis: new treatment algorithms

“…Evobrutinib was the first BTKI to show therapeutic potential in a phase 2 study in RMS [21] and is now being investigated in twinned phase 3 study (NCT04338022, NCT04338061). Tolebrutinib was developed to be a CNS penetrant BTKI [22] and showed activity on gadolinium-DPTA lesion formation in RMS [23 ▪ ]. Three phase 3 trials with tolebrutinib are underway in RMS, primary progressive MS (PPMS) and secondary progressive MS (SPMS) (NCT04879628, NCT04544449, NCT04411641).…”