Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Translational Medicine of a Selective Inhibitor of Btk in Rheumatic Diseases: Pharmacology and Early Clinical Development.
Evans, Erica, Tester, Richland, Aslanian, Sharon, Chaturvedi, Prasoon, Karp, Russell, Labenski, Matt, Mazdiyasni, Hormoz
Dysregulated B cell activation and function has been demonstrated to be a critical component of the disease process in rheumatoid arthritis. The activity of Bruton's tyrosine kinase (Btk) is required for activation of B lymphocytes through the B Cell Receptor (BCR) signaling network. Due to a highly restricted expression pattern in humans (B cells, myeloid cells, mast cells), Btk is an exceptional target for a novel RA therapeutic. AVL-292 is a highly selective, orally active small molecule inhibitor of Btk in clinical development. This presentation summarizes therapeutic activity of AVL-292, including efficacy in preclinical models of RA and the results of a unique translational Phase 1a study that establishes the relationship between dose level administered, plasma drug concentration, and Btk molecular target engagement.
An ELISA assay has been developed to quantitatively determine the degree of AVL-292-Btk occupancy. In vivo activity of AVL-292 was evaluated in several models of RA including Collagen-Induced Arthritis in DBA1 male mice. AVL-292 was administered to healthy adult subjects in a Phase 1 clinical trial to assess the safety, pharmacokinetics, and Btk target occupancy in a double-blind, placebo controlled, single ascending dose study.
AVL-292 covalently bonds to Cys481 on Btk and potently inhibited Btk in vitro in biochemical (IC50 < 0.5nM) and cellular assays (EC50~3nM) including isolated human B cells. The extent of Btk target occupancy directly correlated with inhibition of Btk enzyme activity and substrate phosphorylation. AVL-292 was disease-modifying in animal models of RA with 75% inhibition of the clinical score at an oral dose of 3 mg/kg that correlated directly with 75% Btk target occupancy. Complete inhibition of disease correlated with complete target occupancy at 10 mg/kg. In healthy human subjects, AVL-292 was found to be safe and well tolerated following oral administration at dose levels ranging from 0.57.0 mg/kg. All subjects that received an oral dose of 1.0 mg/kg of AVL-292 achieved >80% Btk occupancy. Mean peak plasma levels (Cmax 365 ng/mL) of AVL-292 were rapidly achieved (Tmax median 40 min) at this dose level. By 8 hours, plasma levels of AVL-292 ranged from 2.98.1ng/mL, whereas Btk occupancy was sustained at >73% in all subjects. 5 of the 6 subjects administered AVL-292 at 2.0 mg/kg achieved complete Btk occupancy. Cmax plasma levels in this dose level cohort (542ng/mL) were achieved at a Tmax of 60 min post dose administration. Btk occupancy was sustained through 24 hours even after plasma levels of AVL-292 had declined demonstrating that covalent inhibition of Btk with AVL-292 enables continued activity without requiring persistence of circulating drug.
Using this unique translational medicine approach the relationship between dose, plasma AVL-292 concentrations, and Btk molecular target occupancy has been established in humans. AVL-292 covalently bonds to Btk in a selective and potent manner leading to sustained inhibition of Btk that has the potential to translate to substantial clinical benefit for patients with RA and other autoimmune diseases characterized by aberrant B cell activation.
To cite this abstract, please use the following information:
Evans, Erica, Tester, Richland, Aslanian, Sharon, Chaturvedi, Prasoon, Karp, Russell, Labenski, Matt, et al; Translational Medicine of a Selective Inhibitor of Btk in Rheumatic Diseases: Pharmacology and Early Clinical Development. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1757