Background ASP015K is an oral Janus kinase (JAK) inhibitor with moderate selectivity for JAK3, a key enzyme for interleukin-2 (IL-2) signaling. With IL-2 stimulation, JAK1/3 augments STAT5 phosphorylation (STAT5-P), which is an integral step in the T cell activation pathway.
Objectives In two phase1 dose-escalation trials, we evaluated the pharmacodynamics (PD) of ASP015K after single and multiple doses in healthy subjects measuring STAT5-P as a biomarker of JAK1/3 activity.
Methods Study A: single doses of ASP015K (3, 10, 30, 60, 120, 200, 300 mg) or placebo (PBO) were given in 9 sequential groups (n=6 active and 2 PBO per group). Study B: 3 groups of men received ASP015K (30, 100, 200 mg twice daily [BID]) or PBO, and 1 group of women received ASP015K (100 mg BID) or PBO (n=9 active and 3 PBO per group) for 13.5 days. PD variables included serial measures of percentage reduction of IL-2–stimulated STAT5-P in T cells; total lymphocyte count and peripheral lymphocyte subtypes pre- and postdose.
Results The median peak STAT5-P inhibition occurred at 1–2 hours after a single dose, consistent with the median tmax in plasma ASP015K concentrations. ASP015K inhibited STAT5-P in a dose dependent manner, with mean peak percentage inhibitions of 84%, 85%, 92%, and 93% after 60, 120, 200, and 300 mg doses, respectively. The relationship between plasma ASP015K concentration and percentage STAT5-P inhibition was described by an Emax model with 50% of maximum effect (EC50) achieved at 48 ng/mL, estimated Emax close to 100%, and a shape factor (γ) of ~1.2. With multiple doses on days 1, 7, and 14, median percentage of STAT5-P inhibition peaked at ~2 hours postdose, median peak inhibition ranged from 89%–98% with ASP015K at 100 and 200 mg on all days. The percentage STAT5-P inhibition was similar in men and women after single-dose 30 mg as well as with multiple doses (100 mg BID). After multiple doses, a small decrease in lymphocyte count from baseline was seen with 100 and 200 mg BID doses in men on day 17, with no dose dependency. Dose-dependent decreases in NK cells, a lymphocyte subset, were seen with ASP015K on day 17.
Conclusions ASP015K showed dose- and concentration-dependent inhibition of STAT5-P. Total lymphocyte count showed no dose-dependent changes. A dose-dependent reduction in NK cells was seen with multiple doses. These results are consistent with the pharmacologic effect of JAK1/3 inhibition by ASP015K. In a phase 2a study, ASP015K decreased disease severity in psoriasis patients; studies to test safety and efficacy of ASP015K in rheumatoid arthritis patients are underway.
Disclosure of Interest T. Zhu Employee of: Astellas Pharma Global Development, U. Valluri Employee of: Astellas Pharma Global Development, M. Lewand Employee of: Astellas Pharma Global Development, Y. Cao Employee of: Astellas Pharma Global Development, K. Cho Employee of: Astellas Pharma Global Development, J. Holman Employee of: Astellas Pharma Global Development, T. Sawamoto Employee of: Astellas Pharma, Inc., J. Keirns Employee of: Astellas Pharma Global Development