Etrasimod: A New Oral Treatment Option for Ulcerative Colitis

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The S1PR modulators are currently positioned to serve as a great treatment option for patients with moderate disease who are hesitant to escalate to a biologic treatment.

Etrasimod: A New Oral Treatment Option for Ulcerative Colitis

Shubha Bhat, PharmD

ELEVATE Studies Summary

Etrasimod, a sphingosine 1-phosphate receptor (S1PR) modulator that targets S1PR 1,4, and 5, was approved by the US Food and Drug Administration (FDA) for the treatment of moderately to severely active ulcerative colitis (UC) in October 2023 based on findings from ELEVATE UC 52 and ELEVATE UC 12, a pair of randomized, multicenter, double-blinded, placebo-controlled phase 3 studies.1

ELEVATE UC 12 included 354 patients on etrasimod 2 mg oral daily or placebo followed over 12 weeks, with clinical remission achieved in 25% on etrasimod versus 15% on placebo (P = .026). Participants in this study were primarily females (41%) and White (75%), with the average age being 40 years. Most participants had left-sided colitis or proctosigmoiditis, with the average disease duration being approximately 7 years.

ELEVATE UC 52 included 439 patients on oral etrasimod 2 mg daily or placebo followed for 12 weeks for induction, 40 weeks for maintenance, and 4 weeks for follow-up. The coprimary endpoint of clinical remission (defined as composite of stool frequency subscore = 0 or stool stool frequency subscore = 1 with >1-point decrease from baseline, rectal bleeding subscore = 0, and endoscopic subscore <1 without friability) was achieved with etrasimod at week 12 (27% vs 7%; P <.0001) and week 52 (32% vs 7%; P <.0001). Participants in this study were primarily females (45%) and White (89%), with the average age being 40 years. Most had left-sided colitis or proctosigmoiditis, with the average disease duration ranging from 6 - 8 years.

A greater portion of participants on etrasimod also achieved key secondary endpoints such as endoscopic improvement, symptomatic remission, and endoscopic improvement-histologic remission in both ELEVATE studies. Participants in both studies concurrently took corticosteroids (33%) and 5-aminosalicyclates (80%) with approximately 33% reporting prior exposure to biologics or Janus Kinase (JAK) inhibitors. In ELEVATE UC 52, additional key secondary endpoints met by etrasimod 2 mg daily versus placebo at week 52 included sustained clinical remission (difference, 15.8% [95% CI, 10.7 - 21.0]; P <.0001), defined as clinical remission at weeks 12 and 52, and corticosteroid-free clinical remission (difference, 25.4% [95% CI, 18.4 - 32.4]; P <.0001), defined as clinical remission without corticosteroids for 12 weeks.

Etrasimod was overall well tolerated, with the most common adverse effects observed being UC worsening or flare, anemia, and headaches. As a result of its mechanism of action, a 40-45% mean reduction in lymphocytes count was observed with etrasimod but did not result in treatment discontinuation. No malignancy nor deaths were reported in the ELEVATE studies.

Implications and Future Directions

S1PR modulators have been hypothesized to contribute to the inflammatory processes associated with ulcerative colitis by permitting lymphocyte tracking. With etrasimod binding with high infinity to S1PR1, 4, and 5, lymphocytes are prohibited from leaving the lymph node and migrating to the intestine via peripheral blood, thereby decreasing inflammation. Etrasimod is administered orally and can be taken with or without food.

As the second S1PR modulator available, etrasimod provides patients with another therapeutic option in addition to ozanimod. However, there are several notable differences between the 2 medications including differences in half-life (30 hours with etrasimod vs 11 days with ozanimod), which could have implications with pregnancy/lactation and surgery (e.g., shorter half-life means the medication is out of the patient’s system faster); dose up-titration at initiation being only recommended for ozanimod; tyramine interactions with ozanimod only; and varying baseline assessment requirements (electrocardiogram and labs for both, ophthalmology and dermatology evaluation for etrasimod, and ophthalmology evaluation only in select patients for ozanimod).2,3

Additionally, etrasimod targets 1 more receptor site (S1PR4), which has been associated with inflammation. One positive strength of the ELEVATE studies was the inclusion of participants with isolated proctitis (with <10 cm rectal involvement), which is a patient population historically excluded from randomized controlled trials. These differences could potentially favor or disfavor etrasimod. Head-to-head studies would be valuable in further understanding how to position etrasimod versus ozanimod in UC treatment, and whether etrasimod would be a treatment option for patients previously exposed to ozanimod without significant clinical benefits.

The S1PR modulators are currently positioned to serve as a great treatment option for patients with moderate disease who are hesitant to escalate to a biologic treatment after receiving treatment with corticosteroids and 5-aminosalicyclates. All patients considering treatment with S1PR modulators should be thoroughly assessed for candidacy, including additional evaluations for drug-disease and drug-drug interactions.

Reference

  1. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401(10383):1159-1171. doi:10.1016/S0140-6736(23)00061-2
  2. Pfizer. Velsipity (etrasimod) [package insert]. Published 2023.https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216956s000lbl.pdf.
  3. Bristol Myers Squibb. Zeposia (ozanimod) [package insert]. Published 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209899s000lbl.pdf
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