PI-034 - A MULTI-PURPOSE FIRST-IN-HUMAN STUDY TO INVESTIGATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF ACT-777991, AN ORAL C-X-C MOTIF CHEMOKINE RECEPTOR 3 (CXCR3) ANTAGONIST.

M. BOOF¹, M. GEHIN¹, C. ROMEIJN², V. SIPPEL¹, D. STRASSER¹, J. Dingemanse¹; ¹Idorsia Pharmaceuticals Ltd,, Allschwil, Switzerland, ²QPS Netherlands, Groningen, The Netherlands.

Background: CXCR3 and its ligands are highly upregulated in inflamed tissues of patients with inflammatory diseases. Recruitment of CXCR3-expressing immune cells, such as T cells, to diseased tissue suggests a role in pathogenesis. Antagonizing CXCR3 may reduce the infiltration of these cells in such diseases.

Methods: This was a double-blind, placebo-controlled, randomized single- and multiple-ascending dose (SAD/MAD) study in 70 healthy male and female subjects. Doses up to 100 mg (SAD) and 40 mg twice daily for 5.5 days (MAD) were investigated. Food effect was integrated in the SAD subpart by applying a two-period fixed-sequence design. Safety and tolerability (adverse events [AEs], clinical laboratory, vital signs, 12-lead ECG), pharmacokinetics (PK), and pharmacodynamics (blockade of CXCR3 internalization, biomarker of target engagement [TE]) data were collected up to 4 days after (last) dosing.

Results: In both SAD and MAD subparts, ACT-777991 was rapidly absorbed with a time to reach maximum concentration between 0.5 and 1.5 h post (last) dose, followed by a biphasic disposition with a terminal half-life between 9.7 and 10.3 h. Increase in exposure and maximum concentration of ACT-777991 was dose-proportional. Steady state was reached after 48 h with no accumulation. The rate but not the extent of absorption was modified by food intake. TE was demonstrated for all doses tested, and a trend of a dose-response relationship was observed. ACT-777991 was well tolerated. Neither a treatment-related pattern nor dose-response relationship could be determined for AEs or any safety variable.

Conclusion: In this first-in-human study, ACT-777991 showed good tolerability for all doses tested and a PK and TE profile suitable for further clinical development.