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P369 Safety and lymphocyte-lowering properties of etrasimod (APD334), an oral, potent, next-generation, selective S1P receptor modulator, after dose escalation in healthy volunteers

Peyrin-Biroulet L.1, Christopher R.2, Trokan L.2, Lassen C.2, Adams J.2, Kühbacher T.*3

1Nancy University Hospital and Lorraine University, Department of Gastroenterology, Nancy, France 2Arena Pharmaceuticals, Inc., San Diego, United States 3Asklepios Westklinikum Hamburg and Christian Albrechts University, Department of Internal Medicine/Gastroenterology, Kiel, Germany

Background

Etrasimod is an oral, potent, next-generation S1P modulator with an optimized S1P receptor activity profile that is in Phase 2 clinical development for ulcerative colitis.

Methods

Two randomised, double-blind studies evaluated safety and pharmacodynamics of etrasimod, administered orally as single dose (Study 001; dose-escalation design) or repeat once daily (QD) dosing (Study 002; multiple ascending-dose design) in healthy adults. In Study 001, up to 8 subjects per cohort were randomised to etrasimod (n=6) or placebo (n=2), starting at 0.1mg. Following screening (21 days), single doses were administered on Day 1 and observations undertaken until at least Day 7. In Study 002, up to 12 subjects in each of 3 cohorts (0.7, 1.35 and 2.0mg) received etrasimod (n=10) or placebo (n=2) for 21 days. Dosing in Cohorts 4 and 5 started at 0.35 and 0.5mg for 7 days with titration to 2.0 and 3.0mg, respectively.

Results

In single doses, etrasimod was well tolerated at 0.1, 0.35, 1 and 3mg. Mild-to-moderate headache (1/6–3/6 of subjects) and contact dermatitis (1/6–2/6) were the most commonly reported AEs, occurring with similar/lower frequency to placebo (2/3 each). In the 5mg cohort, 4 events of first or second degree AV block, with and without bradycardia, occurred in 3/6 subjects; although asymptomatic, further dose escalation was stopped. Dose-related declines in blood pressure and heart rate from baseline (vs placebo) were statistically significant with 3.0 and 5.0mg doses only (p<0.05); all resolved without intervention. With multiple dosing, common AEs with etrasimod versus placebo included contact dermatitis (1/10–7/10 of subjects vs. 6/10), constipation (2/10–3/10% vs. 0), headache (1/10–3/10% vs. 4/10) and diarrhoea (2/10–3/10% vs. 1/10). These were mild-to-moderate, and not dose related. Small asymptomatic declines in blood pressure and heart rate were noted. 3 subjects developed first degree AV block (placebo: 1; 2mg: 1; 0.5/3mg: 1). No serious AEs or deaths were reported. Single etrasimod doses of 3mg and 5mg decreased total peripheral blood lymphocyte counts to 52.5% and 35.9% of baseline and with time to nadir of ∼15 hours and ∼11 hours post-dose, respectively. With multiple dosing, etrasimod had a dose-dependent effect on lymphocyte lowering, plateauing at 2mg QD. Median reduction in lymphocyte counts was ∼67% for the higher doses (2 and 3mg QD for 21 days). For both studies, mean counts returned to baseline levels within 7 days of dosing discontinuation.

Conclusion

In Phase I studies, etrasimod was well tolerated and modulated lymphocyte levels when administered orally at dose levels ≤3mg in healthy volunteers. These findings support further evaluation of this S1P modulator in clinical studies.