Why is this important?
UC would in particular involve a high rate of inflammatory T lymphocytes in the gastrointestinal tract, the circulation of which is under the influence of sphingosine-1-phosphate (S1P), lipids that regulate many physiological functions following interaction with certain cell receptors. Etrasimod is an oral selective modulator of S1P1, S1P4 and S1P5 receptors. It is developed in several autoimmune diseases including UC. After conclusive phase II data (OASIS study), in moderate to severe forms of the disease, phase III data were awaited. The laboratory submitted a marketing authorization request to the American and European authorities at the end of 2022.
Methodology
ELEVATE UC 12 and ELEVATE UC 52 are randomized, multicenter, double-blind phase 3 trials that enrolled patients aged 16 to 80 years with moderate to severe UC, and having an insufficient response or intolerance to at least least one other treatment. The subjects included were randomized (2:1) between etrasimod 2mg and placebo. ELEVATE UC12 included a 12-week induction treatment period and a 4-week follow-up period following which patients might participate in the open-label extension study. ELEVATE UC 52 consisted of a 12-week induction treatment period followed by a 52-week maintenance treatment period, with those who had worsening disease at the end of the induction period having the option to switch to the open study. The primary endpoint of both studies was the proportion of patients who achieved clinical remission at the end of the treatment period (i.e. 12 or 52 weeks, respectively for the two studies).
Principle results
In total, ELEVATE UC 12 and ELEVATE UC 52 enrolled 238 and 289 patients in the treated groups, respectively, compared to 144 and 116 in the placebo groups. The average age of patients in each group was between 39 and 41 years old, and each was between 53 and 63% male). At the end of the ELEVATE UC 52 induction period, the rate of patients who had stopped treatment was 8% in the etrasimod group and 14% in the placebo group, most often for worsening of the disease.
At the end of the induction period, the rate of patients who achieved clinical remission was 25% and 27% in the etrasimod groups of the ELEVATE UC 12 and ELEVATE UC 52 studies respectively, compared to 15% and 7% of those on placebo respectively (p<0.0001 for both). At the end of the maintenance period, this rate was 32% under etrasimod versus 7% under placebo (p<0.0001).
At the end of the ELEVATE UC 52 induction period, all three specified secondary endpoints were more significantly improved on treatment: 35% endoscopic improvement vs 14% on placebo, 46% clinical remission vs 21 % and 21% clinical and endoscopic improvements combined versus 4% (p significant). The improvements were similar in the ELEVATE UC 12 study.
Finally, in terms of safety, 47% and 71% of patients on etrasimod in the ELEVATE UC 12 and ELEVATE UC 52 studies had presented adverse events, compared to 47% and 56% respectively on placebo: these were mainly anemia, headaches or progression of UC. The frequency of serious or opportunistic infections was comparable in the treatment and placebo groups.
Funding
The study was sponsored by Arena Pharmaceuticals.
