Shubha Bhat, PharmD, MS, BCACP

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 

 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.

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 (

= .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%; 

<.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]; 

<.0001), defined as clinical remission at weeks 12 and 52, and corticosteroid-free clinical remission (difference, 25.4% [95% CI, 18.4 - 32.4]; 

<.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.

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).

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.

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

Pfizer. Velsipity (etrasimod) [package insert]. Published 2023.https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216956s000lbl.pdf.

Bristol Myers Squibb. Zeposia (ozanimod) [package insert]. Published 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209899s000lbl.pdf

Articles

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

 (Skyrizi), the first specific interleukin (IL)-23 inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of moderate-to-severe 

Risankizumab demonstrated significant improvement in clinical and endoscopic responses in two randomized placebo-controlled induction studies, ADVANCE and MOTIVATE, and one maintenance study, FORTIFY.

The ADVANCE clinical trial included 850 patients who were either biologic-naïve (treated with or had intolerance to conventional therapies) or biologic-experienced. On average, participants in this study were 38 years old, male, Caucasian, and had CD for 9 years.

ADVANCE: Risakinzumab (Prior Bio-Failure)

Chart Adapted from Ferrent M, et. Al, The Lancet. 2022. 399(10340):2031-2046.

1 biologic medication. In MOTIVATE, 569 patients who were biologic-experienced were enrolled. On average, participants were 40 years old, male, Caucasian, and had CD for 9 years.

MOTIVATE: Risakinzumab (Prior Bio-Failure)

Approximately, 53% had prior exposure to at 

2 biologics. In both induction studies, enrollment of patients who had been treated with ustekinumab was capped at 

At 12 weeks, clinical remission (defined as Crohn’s Disease Activity Index <150 or patient-reported outcomes of average daily liquid or very soft stool frequency of 

2.8, plus average daily abdominal pain score of 

1) for intravenous (IV) risankizumab 1200 mg versus 600 mg versus placebo was 42%, 45%, and 25% (

= .0001) in ADVANCE and 40%, 42%, and 20% in MOTIVATE (

Endoscopic response (defined as 50% decrease in Simple Endoscopic Score [SES-CD] from baseline or if isolated ileal disease and SES-CD of 4, ≥2 point reduction from baseline) at week 12 for IV risasnkizumab 1200 mg versus 600 mg vs. placebo was 32%, 40%, and 12% in ADVANCE and 34%, 29%, and 11% in MOTIVATE (

= .0001). In regards to safety, the overall incidence of adverse events in ADVANCE and MOTIVATE was similar across all treatment groups, with headaches, nasopharyngitis, and arthralgia being the most commonly reported events.

One patient treated with risankizumab 600 mg in ADVANCE experienced a rash and increase in liver enzymes that resolved with hospitalization and steroid administration.

Although not consistent with drug-induced liver injury, current monitoring parameters for risankizumab involve monitoring liver enzymes and bilirubin levels at baseline and during induction up to 12 weeks of treatment. Overall, risasnkizumab was deemed to be effective and well tolerated as induction treatment. The results of the study are presented in the tables below.

In FORTIFY, 462 patients with clinical response to IV risankizumab from ADVANCE and MOTIVATE were randomized to subcutaneous (SQ) risankizumab 360 mg or 180 mg every 8 weeks or medication discontinuation (placebo). On average, participants were 39 years old, male, Caucasian, and had CD for 9 years.

At week 52, rates of clinical remission with risankizumab 360 mg vs. 180 mg vs placebowas 53%, 55%, and 41% (

 = .001) and endoscopic response was 46%, 47%, and 21% (

= .001). Risankizumab was overall well tolerated, with most common adverse effects consisting nasopharyngitis, arthralgia, headache, nausea, abdominal pain, diarrhea, anemia, and injection site 

Of note, the maintenance dose is administered through a novel device known as the on-body injector, which consists of series of steps and requires patients to be trained prior to use to ensure optimal medication 

With the last therapeutic advance for moderate to severe CD occurring 6 years ago, risankizumab offers a much needed new treatment option for patients. It may also be used for patients with plaque psoriasis and psoriatic arthritis.

Risankizumab’s efficacy rate for CD is comparable to other available treatments, and we await findings from additional studies, such as the ongoing head-to-head study between risankizumab and ustekinumab (an IL-12 and -23 inhibitor), to:

Understand how to best position use of risankizumab in both biologic-naïve and biologic-experienced patients and

Further develop our understanding of IBD pathophysiology.

D’Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. 

. 2022;399(10340):2015-2030. doi:10.1016/s0140-6736(22)00467-6

Ferrante M, Panaccione R, Baert F, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet. 2022;399(10340):2031-2046. doi:10.1016/S0140-6736(22)00466-4

SKYRIZI® (risankizumab-rzaa) Dosing for Crohn’s disease. www.skyrizi.com. Accessed October 10, 2022. https://www.skyrizi.com/crohns/about-skyrizi/dosing#isi

Risankizumab represents the first ever IL-23 treatment for adult patients with Crohn's disease approved by the FDA.