Discovery and Preclinical Characterization of BIIB091, a Reversible, Selective BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple Sclerosis is a chronic autoimmune neurodegenerative disorder of the central nervous system (CNS) that is characterized by inflammation, demyelination, and axonal injury leading to permeant disability. In the early stage of MS, inflammation is the primary driver of the disease progression. There remains an unmet need to develop high efficacy therapies with superior safety profiles to prevent the inflammation processes leading to disability. Herein, we describe the discovery of BIIB091, a structurally distinct orthosteric ATP competitive, reversible inhibitor that binds the BTK protein in a DFG-in confirmation designed to sequester Tyr-551, an important phosphorylation site on BTK, into an inactive conformation with excellent affinity. Preclinical studies demonstrated BIB091 to be a high potency molecule with good drug-like properties and a safety/tolerability profile suitable for clinical development as a highly selective, reversible BTKi for treating autoimmune diseases such as MS.

Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration.

BACKGROUND: Many studies have focused on the challenges of small molecule uptake across the blood-brain barrier, whereas few in-depth studies have assessed the challenges with the uptake of antibodies into the central nervous system (CNS). In drug development, cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. In this report, we have studied the kinetic correlation between CSF and serum drug concentration-time profiles for five humanized monoclonal antibodies in rats and cynomolgus monkeys and analyzed factors that affect their CSF exposure. RESULTS: Upon intravenous (IV) bolus injection, antibodies entered the CNS slowly and reached maximum CSF concentration ( CSF T max ) in one to several days in both rats and monkeys. Antibody serum and CSF concentration-time curves converged until they became parallel after CSF T max was reached. Antibody half-lives in CSF ( CSF t ½ ) approximated their serum half-lives ( serum t ½ ). Although the intended targets of these antibodies were different, the steady-state CSF to serum concentration ratios were similar at 0.1-0.2% in both species. Independent of antibody target and serum concentration, CSF-to-serum concentration ratios for individual monkeys ranged by up to tenfold from 0.03 to 0.3%. CONCLUSION: Upon systemic administration, average antibodies CSF-to-serum concentration ratios in rats and monkeys were 0.1-0.2%. The CSF t ½ of the antibodies was largely determined by their long systemic t ½ ( systemic t ½ ).