Gastroenterology · Medical Literature
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.
Abstract
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).
Clinical relevance
In healthy adult male volunteers (Caucasian and Japanese), are single and multiple ascending oral doses of AJM347, a novel selective α4β7 integrin antagonist, safe and well tolerated, and does the compound achieve sufficient pharmacodynamic receptor occupancy (>90% α4β7 inhibition) at clinically relevant doses across a 24-hour dosing interval? __SNAPSHOT__ {"studyDesign":"First-in-human, Phase 1, three-part study: single-ascending dose (SAD, Part 1), food effect evaluation (Part 2), and multiple-ascending dose (MAD, Part 3); randomized within each part (design details not fully reported in abstract)","setting":"Not reported (industry-sponsored early-phase unit; EA Pharma Co., Ltd., Japan)","sampleSize":"Not reported (total N across all three parts not specified in the abstract)","population":"Healthy Caucasian and Japanese adult males; specific age range, BMI criteria, and exact inclusion/exclusion criteria not reported in the abstract","intervention":"AJM347 oral administration: SAD (6–2420 mg, single doses); MAD (200–800 mg twice daily for 7 days); food effect arm compared fed vs. fasted administration","comparator":"Placebo (implied by SAD/MAD design convention, though not explicitly confirmed in the abstract); fasted conditions served as comparator for food effect evaluation","primaryOutcome":"Safety and tolerability (primary); pharmacokinetics (PK) of AJM347 and active metabolite CAN2281, and pharmacodynamics (PD) as measured by α4β7 receptor occupancy (MAdCAM-1 binding inhibition on CD4+ T cells) were co-primary or key secondary endpoints","followUp":"7 days of active dosing in MAD phase; total follow-up duration not reported in the abstract","fundingSource":"Industry (EA Pharma Co., Ltd., a subsidiary of Eisai Co., Ltd.)"}
Key findings
AJM347 was reported to be safe and well tolerated across all SAD (6–2420 mg) and MAD (200–800 mg twice daily × 7 days) dose levels. No changes in lymphocyte counts were observed in either whole blood or cerebrospinal fluid (CSF), a finding of particular mechanistic importance given the CNS safety concerns historically associated with the pan-α4 antagonist natalizumab. AJM347 was rapidly absorbed and its active metabolite, CAN2281, was rapidly formed. Fed administration produced higher trough concentrations (Cmin) of CAN2281 compared with fasted administration; the magnitude of this food effect is not quantified in the abstract. PD assessment demonstrated that AJM347 rapidly and dose-dependently inhibited MAdCAM-1 binding to CD4+ T cells. At doses ≥200 mg twice daily, >90% α4β7 receptor occupancy was maintained for up to 24 hours across the dosing interval. PD effects correlated well with plasma concentrations of CAN2281 (PK-PD correlation reported qualitatively; specific correlation coefficients, r² values, Emax, or EC50 are not reported in the abstract). No specific adverse events, dose-limiting toxicities, maximum tolerated dose, or formal statistical comparisons (p-values, confidence intervals) are reported in the abstract. NNT and NNH are not calculable from the available data.
Practice implications
This first-in-human study establishes a preliminary safety and tolerability signal for AJM347, an orally bioavailable, selective small-molecule α4β7 integrin antagonist intended for IBD. The absence of CSF lymphocyte changes is clinically meaningful, as it suggests gut-selectivity of the α4β7 pathway and distinguishes this compound mechanistically from natalizumab (a pan-α4 antagonist associated with PML). The demonstration of >90% α4β7 receptor occupancy sustained over 24 hours at doses ≥200 mg twice daily provides a pharmacologically plausible rationale for twice-daily dosing in future efficacy trials. However, this study does NOT establish clinical efficacy in any disease, does not involve patients with IBD, and cannot confirm that peripheral blood receptor occupancy translates to therapeutic effect at the intestinal mucosa. The finding that fed administration increases CAN2281 trough concentrations has practical dosing implications but requires formal food-effect quantification. Findings apply exclusively to healthy adult males (Caucasian and Japanese); women, elderly, patients with hepatic or renal impairment, and pediatric populations were not represented. Importantly, only the abstract is available for review, limiting assessment of statistical methodology, adverse event characterization, randomization, blinding, sample size justification, and data integrity. No phase II/III trials appear currently registered. Practice should not change on the basis of this study alone. __LIMITATIONS__ Only the abstract is available; full methodology, adverse event tables, PK parameters (Cmax, AUC, t½, Tmax), statistical analyses, and dose-proportionality data cannot be evaluated.,Exclusively healthy adult male volunteers enrolled; findings cannot be generalized to patients with active IBD, females, elderly, or those with organ impairment.,No placebo-controlled efficacy data; receptor occupancy in peripheral blood is a pharmacodynamic surrogate and may not reflect mucosal tissue occupancy or therapeutic effect.,Short follow-up (7 days in MAD phase); long-term safety, immunogenicity, tachyphylaxis, or rebound lymphocytosis cannot be assessed.,Sample size per cohort not reported, precluding evaluation of statistical power for safety endpoints.,Industry funding (EA Pharma/Eisai) introduces potential for sponsorship bias in reporting and interpretation.,The food effect magnitude (quantitative change in CAN2281 Cmin) is not reported in the abstract.,Ethnic subgroup PK/PD comparisons between Caucasian and Japanese volunteers are not detailed in the abstract.,Blinding and randomization procedures within each dose cohort are not described in the abstract.,No maximum tolerated dose or dose-limiting toxicity was identified or reported, leaving the upper therapeutic window undefined from the abstract alone. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ AJM347, an oral selective α4β7 integrin antagonist, demonstrated an acceptable safety profile and no CSF lymphocyte changes in healthy male volunteers at doses up to 2420 mg (single) and 800 mg twice daily (multiple), with >90% α4β7 receptor occupancy sustained over 24 hours at doses ≥200 mg twice daily—supporting its pharmacological rationale for IBD. Administration with food produced higher CAN2281 trough concentrations, suggesting food co-administration may be preferred in future studies. These are early Phase 1 findings in healthy volunteers only; efficacy and long-term safety in IBD patients remain entirely unestablished, and confirmatory Phase 2/3 trials in target disease populations are required before any clinical application.