Safety, Pharmacokinetics, Food effect, and Pharmacodynamics of AJM347, a Selective α4β7 Integrin Antagonist: A First-in-Human Single- and Multiple-Ascending Dose Study in Healthy Male Volunteers.

This first-in-human study evaluated the safety, pharmacokinetics (PK), food effect, and pharmacodynamics (PD) of AJM347, a novel orally active, selective α4β7 integrin antagonist, in healthy Caucasian and Japanese adult males. The study consisted of three parts. In the single-ascending dose (SAD) study (Part 1), AJM347 was administered in doses ranging from 6 to 2420 mg. The effect of food was evaluated in Part 2. In the multiple-ascending dose (MAD) study (Part 3), AJM347 was administered twice daily (200-800 mg) for 7 days. Single and multiple oral doses of AJM347 were safe and well tolerated. No changes in lymphocyte counts in whole blood and cerebrospinal fluid were observed. AJM347 was rapidly absorbed and the active metabolite, CAN2281, was rapidly formed. Administration of AJM347 after meals achieved higher trough concentrations of CAN2281 compared with administration under fasted conditions. AJM347 rapidly and dose-dependently inhibited mucosal addressin cell adhesion molecule-1 binding to CD4+ T cells. Doses ≥200 mg twice daily maintained >90% inhibition (α4β7 receptor occupancy) for up to 24 h. PD effects correlated well with plasma concentrations of the active metabolite CAN2281. AJM347 demonstrated a favorable safety profile, effective target engagement, and promising PK properties for oral administration. The timing of dosing relative to meals did not affect the safety or overall PK profiles, but postprandial administration led to higher trough concentrations, suggesting that dosing after meals may represent the optimal regimen for the continued clinical development of AJM347. Blood samples were collected to assess PK and PD (α4β7 receptor occupancy). Samples were also collected to measure lymphocyte counts in peripheral blood and cerebrospinal fluid (CSF).