P-180 Etrasimod (APD334), a Potent, Selective, Oral S1P Receptor Modulator with Autoimmune Disease-Modifying Activity Exhibiting Favorable PK/PD Properties in Healthy Volunteers

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APD334 is an oral, next-generation S1P receptor modulator with the potential to provide effective systemic and local immune cell modulation for inflammatory bowel disease, while avoiding S1P receptors that may be associated with adverse effects.


The aim of this study was to evaluate the safety, tolerability, pharmacokinetic (PK) properties and pharmacodynamic (PD) response (lymphopenia) of repeat dosing with ascending doses of APD334, administered as a single oral daily dose for 21 days in healthy adults. A multiple ascending-dose, randomised, double-blind, placebo controlled study design was utilised. For the first 3 dose cohorts (0.7, 1.35 and 2.0 mg), up to 12 subjects received APD334 or placebo once daily (od) at the same dose for 21 days. In each cohort, 2 subjects were assigned to placebo and 10 to APD334. Dosing in Cohort 4 started at 0.35 mg for 7 days with titration to 2.0 mg. Cohort 5 employed the same dosing scheme but started at 0.5 mg with titration to 3.0 mg. PK sampling was conducted; pre-dose, day 1 (also day 4 and 8 for Cohorts 4/5), day 21 and day 28/Follow-up. Additionally, PD blood samples were collected through-out the study and included CBC with differential, platelet count and lymphocyte counts. Peripheral blood lymphocyte immunophenotyping was performed on blood samples drawn at day 1 and day 21 for Cohort 3 (2 mg od). Safety monitoring was completed pre-dose and throughout the study period until study exit.


Sixty subjects were enrolled in the study; 59 subjects completed the study and were included in the safety analysis; all subjects were included in the PK analyses. The PK of APD334 (AUC0-24 hr and AUC0-inf) was dose proportional after single oral doses of 0.7 mg to 2.0 mg (Cohorts 1–3). AEs were more commonly reported in APD334-treated subjects than in placebo-treated subjects and included contact dermatitis and leukopenia, followed by constipation, diarrhoea, nausea, and abdominal pain. The PD analysis demonstrated a dose-dependent effect on lymphocyte lowering, plateauing at 2 mg od; no increase in lymphopenia was observed at 3 mg od. Mean lymphocyte counts returned to baseline levels within 7 days of dosing discontinuation (by day 28/Exit). There was a median reduction in lymphocyte counts of approximately 67% for the higher doses of APD334 (2 and 3 mg od) after 21 days of dosing. Primary effects were seen in the T-Helper and T-Naive subpopulations, and to a lesser extent in T-Central Memory cells; T-Suppressor and T-Effector memory populations were relatively spared, consistent with the expected retention of CCR7+ cells in secondary lymphoid tissue. Immunophenotyping demonstrated a substantially greater decrease from baseline in T-cells in both APD334 and placebo groups both as a percentage of white blood cells (WBC) and lymphocytes (L); WBC −48.8% versus −18.8%, L −29% versus −3.6%. B-cell changes were; WBC −73.7% versus −63.1%, L −48.7% versus −53.8%.


APD334 appears safe to use at a 2 mg od dose for 21 days with dose-proportional PK parameters up to 2.0 mg and modulates lymphocyte subpopulations involved in IBD pathogenesis.

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