Pharmacodynamics Of a Novel Jak1 Selective Inhibitor In Rat Arthritis and Anemia Models and In Healthy Human Subjects

Jeffrey Voss¹, Candace Graff², Annette Schwartz³, Deborah Hyland⁴, Maria Argiriadi⁴, Heidi Camp⁵, Lori Dowding⁴, Michael Friedman⁴, Kristine Frank⁵, Jonathon George⁴, Eric Goedken⁴, Gloria Lo Schiavo⁴, Michael Morytko⁴, Robert o'Brien⁴, Robert Padley⁶, Matthew Rosebraugh⁵, Michael Rozema⁵, Kent Stewart⁵, Grier Wallace⁴, Neil Wishart⁴, Anwar Murtaza⁷ and Lisa Olson³, ¹Immunology, AbbVie Pharmaceuticals, Worcester, MA, ²Drug Metabolism and Pharmacokinetics, Abbvie Pharmaceuticals, worcester, MA, ³AbbVie Inc, AbbVie Bioresearch Center, Worcester, MA, ⁴Abbvie Pharmaceuticals, worcester, MA, ⁵abbvie pharmaceuticals, north chicago, IL, ⁶AbbVie, Inc, North Chicago, IL, ⁷Broad Institute, Cambridge, MA

Meeting: ACR/ARHP Annual Meeting 2013

Keywords: Anemia, Biomarkers, Janus kinase (JAK), Natural killer (NK) cells and rheumatoid arthritis (RA)

Session Information

Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy III

Session Type: Abstract Submissions (ACR)

Background/Purpose: Anti-cytokine therapies have become the mainstay of treatment for rheumatoid arthritis (RA) disease symptoms and can arrest disease progression. Despite numerous treatment options there are still many RA patients who fail to experience substantial decreases in disease activity. Recently, Jak kinase blockade was shown clinically to be effective in managing disease and in some cases achieving remission. However, these first generation Jak inhibitors have failed to meet expectations due to dose-limiting tolerability and safety issues. ABT-494 is a second generation Jak kinase inhibitor with high selectivity for Jak1 thereby minimizing the potential for side effects related to Jak2 and Jak3 inhibition. Here we describe preclinical and early clinical data that suggest ABT-494 has potential to address some of the current unmet medical needs of RA patients.

Methods:

ABT-494 was engineered for increased selectivity for Jak1 using structural predictions that indicated the potential for differential binding interactions outside the ATP-binding active site of Jak1 but not Jak2. The efficacy and selectivity of ABT-494 were tested in a battery of relevant cellular and in vivopharmacology assays including bone marrow colony formation, adjuvant induced arthritis (AIA), erythropoietin induced reticulocyte deployment and NK/NKT cell suppression. The potency of ABT-494 in a variety of complementary pharmacodynamic assays was also assessed at multiple dosages in healthy human subjects administered orally for 14 days.

Results:

ABT-494 demonstrates approximately 74 fold selectivity for Jak1 over Jak2 in cellular assays dependent on specific, relevant cytokines. ABT-494 is a potent inhibitor of inflammation and bone loss in rat AIA and, compared to Tofacitinib, spares relevant essential physiological processes such as erythropoietin signaling and peripheral NK cell counts at similarly efficacious doses in rats. When dosed orally for 14 days in healthy human subjects ABT-494 did not decrease reticulocyte or NK cell counts at predicted efficacious doses consistent with its pharmacodynamic properties in rats.

Conclusion:

ABT-494 is a Jak1-selective inhibitor that demonstrates efficacy in rat arthritis models. Preliminary evidence suggests that pharmacodynamic properties of ABT-494 are consistent between those observed in rodent models and in healthy human subjects. Taken together, these encouraging observations support further testing of ABT-494 in RA patients in Phase II randomized placebo controlled trials and indicate it may have increased potential to address patient needs over existing agents.

The design, study, conduct and financial support for the clinical trial and research was provided by AbbVie. AbbVie participated in the interpretation of data, review and approval of this disclosure. AM was an employee of AbbVie at the time of data collection and analysis. .

Disclosure:

J. Voss,