The ELEVATE trial revealed the achievement of significant and sustained clinical remission in patients with moderately to severely active ulcerative colitis (UC) with the induction and maintenance treatment of etrasimod, a novel oral sphingosine 1-phosphate (S1P) receptor modulator. Based on the positive efficacy and safety results of this study, the United States (US) Food and Drug Administration (FDA) has approved etrasimod for the treatment of moderately to severely active UC.²

UC is a chronic inflammatory bowel disease that occurs in young adults and persists throughout their lives, impacting their quality of life and increasing their risk of colorectal cancer.³ Over the years, the worldwide incidence and prevalence of UC has been rising, with up to 17% of patients experiencing an aggressive course of disease and 20% of patients requiring hospitalization.³ The pathogenesis of UC is thought to involve both innate and adaptive cellular immunity, with S1P being a possible extracellular signaling molecule to regulate lymphocyte migration into the blood and lymph.^4,5 Etrasimod, a novel oral S1P receptor modulator currently under development, selectively binds to S1P receptors 1, 4, and 5 with no detectable activity on SIP receptors 2 and 3.² Previous phase 1 and 2 studies of etrasimod have highlighted its safety and benefits compared with placebo among UC patients.²

The ELEVATE trials were designed to assess the safety and efficacy of etrasimod in adult patients with moderately to severely active UC.¹ It consists of two phase 3 trials: ELEVATE UC 52, which included a 12-week induction period followed by a 4-week  follow-up period and a 40-week maintenance period; and ELEVATE UC 12, which included a 12-week induction period and a 4-week follow-up period only.¹ Patients aged 16 to 80 years who had moderately to severely active UC (confirmed via endoscopy with ≥10cm rectal involvement and based on a modified Mayo score of 4-9 with a centrally read endoscopic subscore ≥2 and rectal bleeding subscore ≥1) and a history of inadequate response or intolerance towards ≥1 therapy for UC were randomized (2:1) into receiving either etrasimod 2mg orally once daily or placebo during the 12-week induction period of both the ELEVATE UC 12 and ELEVATE UC 52 trials. Concomitant treatment of oral aminosalicylates or corticosteroids with stable doses initiated 2-weeks or 4-weeks prior screening were permitted.¹ The coprimary endpoints of the ELEVATE UC 52 were the proportion of patients who achieved clinical remission at week 12 and week 52, while the primary endpoint of the ELEVATE UC 12 was the proportion of patients who achieved clinical remission at week 12.¹ Key secondary endpoints for both trials included endoscopic improvement, symptomatic remission, and endoscopic improvement-histological remission with histological remission at week 12.¹

A total of 409 patients were included in the ELEVATE UC 52 efficacy analysis, with 67% of patients assigned to etrasimod.¹ At week 12,  patients who received etrasimod possessed a significantly higher achievement rate of clinical remission compared with patients receiving placebo (difference=19.8%; 95% CI: 12.9-26.6; p<0.0001).¹ The significant improvement in remission rates was sustained at week 52  (difference=25.4%; 95% CI: 18.4-32.4; p<0.0001).¹ For the 3 secondary endpoints, the etrasimod group demonstrated significantly higher achievement rates at week 12 when compared to the placebo group (p<0.0001 for all), which were also retained at week 52 (p<0.0001 for all).¹

In the ELEVATE UC 12 trial (n=334), the efficacy analysis included 222 and 112 patients in the etrasimod and placebo group respectively, in which the former group exhibited a significantly higher remission rate  compared to the latter group at week 12 (difference=9.7%; 95% CI: 1.1-18.2%; p=0.026).¹ Significant improvements in the secondary endpoints  at week 12 were associated with etrasimod compared to placebo (p=0.092 for endoscopic improvement, p=0.0013 for symptomatic remission, and p=0.036 for endoscopic improvement-histological remission).¹

In terms of safety, etrasimod was generally well tolerated with acceptable and manageable toxicities in both trials.¹ The incidence of serious adverse events (SAEs) were comparable across etrasimod and placebo groups in both studies (ELEVATE UC 12: 3% vs. 2%;  ELEVATE UC 52: 7% vs. 6%).¹ The most common treatment-emergent adverse events (TEAEs) occurring in ≥1% of patients were anemia, headache, and worsening of UC or UC flares.¹ Treatment discontinuation rates due to TEAEs were comparable in the etrasimod groups of both trials (ELEVATE UC 12: 5%; ELEVATE UC 52: 4%).¹

In summary, etrasimod demonstrated a remarkable and durable rate of clinical remission as well as a favorable safety profile when used as an induction and maintenance therapy in the phase 3 ELEVATE UC 52 and ELEVATE UC 12 trials.¹