Pharmacokinetics, pharmacodynamics and safety of the novel C‐X‐C chemokine receptor 3 antagonist ACT‐777991: Results from the first‐in‐human study in healthy adults

Aims The C‐X‐C chemokine receptor 3 (CXCR3) axis is highly upregulated in the tissue of patients with type 1 diabetes. Antagonizing CXCR3 may reduce the migration of CXCR3‐expressing cells to the pancreas. The pharmacokinetics (PKs), target engagement (TE) (inhibition of CXCR3 internalization) and safety of single‐ and multiple‐ascending doses (SADs and MADs) of ACT‐777991, a novel orally available potent CXCR3 antagonist, were assessed in a double‐blind, randomized, placebo‐controlled phase 1 study. Methods Doses up to 100 mg (SAD part) and 40 mg twice daily (MAD part) were investigated in a total of 70 male and female healthy participants. Food effect was integrated as an SAD subpart. PK, TE, safety and tolerability data were collected up to 4 days after (last) dosing. Results In both SAD and MAD parts, ACT‐777991 was rapidly absorbed with a time to reach maximum concentration between 0.5 and 1.5 h post 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 were dose‐proportional. Steady state was reached after 48 h with minimal accumulation. The rate but not the extent of absorption was modified by food intake. A dose‐dependent TE was demonstrated in both SAD and MAD parts. ACT‐777991 was well tolerated. Neither a treatment‐related pattern nor a dose‐response relationship was determined for adverse events or any safety variable. No QT prolongation liability of regulatory concern was detected. Conclusions 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.