Background/Purpose: Bruton’s Tyrosine Kinase (BTK) is a cytoplasmic tyrosine kinase selectively expressed in B cells, macrophages, mast cells and basophils. The essential role of BTK in B cell antigen receptor and Fc receptor signaling is validated by human and mouse genetics, as well as by preclinical pharmacological intervention. BTK inhibition is expected to positively impact autoimmune diseases driven by autoreactive B cells and inflammatory immune-complexes, such as Sjoegren’s Syndrome (SjS).

We report preclinical characteristics and selected clinical data of the highly selective BTK inhibitor LOU064 with a potential best in class profile for the therapy of SjS.

Methods: LOU064 was profiled in a series of in vitro assays for its effect on BTK dependent signaling, as well as in in vivo models for systemic B cell response and inflammation.

LOU064 was assessed in studies with healthy volunteers and asymptomatic atopic subjects. Single doses from 0.5 to 600 mg and multiple doses from 10 to 600 mg/day over 12 days were assessed with regard to safety, pharmacokinetics and pharmacodynamics.

Results: LOU064 potently inhibited in vitro BTK activity (IC50 range 0.6 to 1.3 nM) and showed excellent selectivity against 456 other kinases. At the cellular level, LOU064 showed potent inhibition of BTK dependent in vitro signaling in human blood B cells (IC50 18.3 nM) and basophils (IC50 66.5 nM), both clinically relevant target cells.

Consistent with covalent target binding, brief systemic LOU064 exposures were sufficient for full and sustained BTK occupancy and PD effects in several animal models. In an in vivo model for the inhibition of B cell dependent antibody formation in female rats LOU064 inhibited the IgM antibody response to sheep red blood cells by 96 % at a dose of 3 mg/kg. In the rat collagen induced arthritis model LOU064 induced fast and complete reduction of paw swelling and inhibited histological bone/cartilage erosion and inflammatory infiltrates at a dose of 3 mg/kg. The efficacy of LOU064 was dose proportional and correlated to BTK occupancy.

In healthy volunteer studies, oral LOU064 administration showed rapid absorption, with fast onset of action and sustained blood BTK occupancy starting from 30 mg. The ex vivo blood B cell activation marker CD69 was inhibited by 50% or more at doses of 30 mg and higher 24hrs post dose. All doses tested up to 600 mg daily for 12 days were well tolerated, and no safety stopping criteria were met at any time. No SAEs or AEs leading to study discontinuation or dosing interruption occurred.

Conclusion: LOU064 is a novel covalent BTK inhibitor that showed excellent in vitro selectivity against relevant kinases and very high potency and efficacy in preclinical models of inflammation and B cell function with a very fast onset of action.

In healthy volunteers, LOU064 administration of single and repeated doses up to 600 mg were well tolerated. Short systemic exposure of LOU064 enabled full and sustained BTK occupancy and blood B cell inhibition.

These data make LOU064 a strong candidate for the treatment of chronic diseases driven by B cell autoimmunity and immune-complex mediated macrophage inflammation including SjS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lou064-a-highly-selective-and-potent-covalent-oral-btk-inhibitor-with-promising-pharmacodynamic-efficacy-on-b-cells-for-sjoegrens-syndrome/