World Congress of Gastroenterology

WCOG 2019


 
Steady-State Trough Concentrations and Their Relationship to Selected Demographic and Clinical Response Measures in Etrasimod-Treated Patients With Moderately-to-Severely Active Ulcerative Colitis
D. ALEXANDER OH 1 CAROLINE A. LEE 1 YONG TANG 1 CHRISTOPHER H. CABELL 1 JOHN S. GRUNDY 1

1- ARENA PHARMACEUTICALS
 
Background/Aims:

Etrasimod is a once-daily, oral, selective, sphingosine-1-phosphate receptor modulator in development for immune-mediated inflammatory disorders. We examined etrasimod steady-state plasma trough concentrations (Css,trough) and their relationship to demographics and clinical responses in patients with ulcerative colitis (UC).

Materials and Methods:

Etrasimod Css,trough and clinical responses were evaluated from the randomized, double-blind, parallel-group, 12-week, Phase 2 OASIS study of once-daily etrasimod 1 mg (n=52 [30 males]), 2 mg (n=50 [27 males]), or placebo (n=54 [32 males]) in patients with moderately-to-severely active UC (modified Mayo Clinic Score [mMCS] 4–9, endoscopic subscore ≥2, rectal bleeding subscore ≥1). We measured etrasimod Css,trough in pre-dose blood samples drawn at weeks 1, 2, 4, 8, and 12, averaged across weeks (Css,avg trough), and summarized by treatment and gender. We explored relationships of dose-normalized Css,avg trough values with patient age and total body weight (TBW) using linear regression. Exposure-response (E-R) relationships of Css,trough with clinical responses (change from baseline [BL] in mMCS and lymphocyte count at week 12) were assessed using Spearman’s correlation and locally weighted regression line fit.

Results:

 Arithmetic mean Css,trough was similar across time points (range: 31.8–42.5 ng/mL and 64.1–71.1 ng/mL for 1 mg and 2 mg, respectively), indicating that steady-state was achieved in week 1. Css,avg trough values were dose-proportional (geometric mean [GM]: 33.96 and 65.48 ng/mL, respectively), with moderate intersubject variability (Table 1). The GM Css,avg trough was ~30% higher in women than men. Dose-normalized Css,avg trough values negatively correlated with age (slope −0.359, P = 0.035) and TBW (slope −0.379, = 0.006). Exploratory E-R relationships between Css,trough and clinical responses were statistically significant; the highest response was seen with Css,trough levels of 4550 ng/mL for mMCS (Fig. 1) and ≥30–60 ng/mL for lymphocyte count (Fig. 2).

Conclusion:

Dose-proportional etrasimod Css,trough levels were achieved and maintained from weeks 1 to 12 in patients with moderately-to-severely active UC. Modest gender, age, and TBW effects contributed to variability in trough exposure which was not clinically meaningful. Exploratory E‑R relationships were consistent with previously reported dose-response relationships in the Phase 2 study and support an etrasimod 2-mg once-daily dosing regimen for Phase 3. ClinicalTrial.gov: NCT02447302

Keywords:

Ulcerative colitis, etrasimod, sphingosine-1-phosphate receptor modulator