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THU0256 Pharmacodynamics of ASP015K, A Novel Janus Kinase Inhibitor, in Healthy Volunteers
  1. T. Zhu1,
  2. U. Valluri1,
  3. M. Lewand1,
  4. Y. Cao1,
  5. K. Cho1,
  6. J. Holman1,
  7. T. Sawamoto2,
  8. J. Keirns1
  1. 1Astellas Pharma Global Development, Northbrook, United States
  2. 2Astellas Pharma, Inc., Tokyo, Japan


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

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