ABT-494: A Promising Second-Generation JAK1 Inhibitor for Rheumatoid Arthritis and Anemia

Anti-cytokine treatments are a primary approach for managing rheumatoid arthritis (RA), aiming to alleviate symptoms and halt disease progression. However, a significant number of RA patients do not achieve significant reductions in disease activity despite the availability of various treatment options. Jak kinase inhibition has emerged as a promising therapeutic strategy, with the potential to manage the disease and induce remission. Nonetheless, the first-generation Jak inhibitors have not fully met expectations due to issues with tolerability and safety at higher doses.

ABT-494, a second-generation Jak kinase inhibitor, has been developed with a high degree of selectivity for Jak1, which could minimize side effects associated with the inhibition of Jak2 and Jak3. This paper presents preclinical and early clinical findings that indicate ABT-494's potential to fulfill some of the current unmet medical requirements for individuals with RA.

The drug was designed with increased specificity for Jak1, utilizing structural predictions to identify differential binding interactions outside the ATP-binding site of Jak1. Its efficacy and selectivity were evaluated through a series of cellular and in vivo pharmacology tests, such as bone marrow colony formation, adjuvant-induced arthritis (AIA), erythropoietin-induced reticulocyte deployment, and NK/NKT cell suppression. Additionally, the potency of ABT-494 was assessed in pharmacodynamic assays across various dosages in healthy human subjects who were orally administered the drug for 14 days.

ABT-494 has shown around 74 times more selectivity for Jak1 compared to Jak2 in cellular assays that are dependent on specific cytokines. It is a potent anti-inflammatory agent and bone loss inhibitor in rat AIA models. Notably, ABT-494, unlike Tofacitinib, preserves essential physiological processes such as erythropoietin signaling and peripheral NK cell counts at efficacious doses. In a 14-day oral administration study in healthy human subjects, ABT-494 did not reduce reticulocyte or NK cell counts at doses expected to be efficacious, aligning with its pharmacodynamic profile in rats.

The findings suggest that ABT-494 is a Jak1-selective inhibitor that has demonstrated efficacy in rat arthritis models. The preliminary data indicate that the pharmacodynamic properties of ABT-494 are consistent across rodent models and healthy human subjects. These promising results support the continuation of ABT-494's evaluation in Phase II randomized, placebo-controlled trials for RA patients and suggest that it may offer greater potential in addressing patient needs compared to current treatments.

The authors disclose their affiliations with AbbVie, with the exception of one author who has no declared interests. The study is registered with the DOI provided.