Etrasimod for moderate to severe ulcerative colitis

Background:
Ulcerative colitis is an immune-mediated inflammatory bowel disease. It involves chronic, relapsing intestinal manifestations, such as diarrhoea, urgency or tenesmus, and blood in the stools, but can also be associated with extra-intestinal manifestations (e.g. arthropathy).¹ The mainstays of induction treatment are 5-aminosalicylates (5-ASAs) and corticosteroids. Most patients need ongoing therapy to maintain remission; options include 5-ASAs, thiopurines and biologic therapies.¹

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator. Previously, ozanimod was the only S1P receptor modulator approved for treatment of ulcerative colitis.

Mechanism of action:
S1P receptor modulators prevent lymphocytes leaving lymphoid tissues, such as lymph nodes. Etrasimod has a high affinity for the S1P receptor subtypes 1, 4 and 5 on the surface of lymphocytes. After 2 weeks of treatment, the lymphocyte count in the blood is halved, with both B and T cells reduced. Colonic biopsies in patients with ulcerative colitis show that etrasimod decreases the number of activated lymphocytes in the tissues.² Etrasimod also reduces inflammatory proteins.

Clinical trials:
Etrasimod was studied in two phase 3 randomised, placebo-controlled trials – ELEVATE UC 12, which only studied induction of remission, and ELEVATE UC 52, which studied both induction and maintenance of remission. Both trials recruited adults with active, moderate to severe ulcerative colitis who were intolerant of, or had not responded to, other treatments. Most patients had been previously treated with corticosteroids. The primary endpoint for both trials was clinical remission, assessed using the modified Mayo score, that considers stool frequency, rectal bleeding and endoscopy.²

In ELEVATE UC 12, symptoms began to improve within a month. After 12 weeks, 26% of the 238 patients randomised to receive etrasimod were in remission compared with 15% of the 116 patients randomised to the placebo group.² Similar results were seen in ELEVATE UC 52, although symptom improvement began by week 2. After 12 weeks, 28% of the 289 patients in the etrasimod group and 8% of the 144 patients in the placebo group were in clinical remission.²

Continuing treatment did not change the rate of remission in the placebo group, but after 52 weeks 33% of the etrasimod group were in clinical remission. The patients in remission had not required corticosteroid treatment for at least 12 weeks.² While endoscopy only found histological remission in 27% of the patients after 52 weeks of etrasimod, 44% had remission of their symptoms.²Sustained remission (clinical remission at both week 12 and week 52) occurred in 19% of the patients treated with etrasimod compared with 3% of patients treated with placebo.²

Adverse effects:
In ELEVATE UC 12 the frequency of adverse events was the same (47%) for patients taking etrasimod and placebo, but in ELEVATE UC 52 adverse events were more frequent in patients taking etrasimod (71% compared with 56%). The most frequent adverse effects were headache, dizziness and fever.

Bradycardia or sinus bradycardia occurred in 9 patients when starting etrasimod and 3 patients developed atrioventricular block (compared with no events in the placebo group).² Hypertension occurred in 3% of patients taking etrasimod in ELEVATE UC 52 (compared with 1% of patients taking placebo).²

As the S1P receptor modulators reduce the lymphocyte count, patients may have an increased rate of infection; however, in ELEVATE UC 52 serious infections were less frequent with etrasimod than with placebo (1% versus 3%).²

In the ELEVATE UC trials, increases in liver enzymes were more frequent with etrasimod than with placebo, but only 2 patients stopped treatment because of this.²

Dosage and administration:
The dose of etrasimod is 2 mg orally daily. Although etrasimod tablets can be taken with or without food, taking the first dose with food may attenuate the effect on heart rate.

No dosage adjustments are required in patients with mild or moderate hepatic impairment, but etrasimod is not recommended for patients with severe hepatic impairment. No dosage adjustments are required in patients with renal impairment.

Precautions:
If the patients are not already immune to the varicella-zoster virus, varicella zoster vaccination is recommended before treatment. Live vaccines should be avoided from 4 weeks before treatment and for at least 2 weeks after treatment.

Etrasimod is contraindicated in patients with active malignancies. The risk of skin cancer may be increased by S1P receptor modulators. Sun protection is important and phototherapy should be avoided.

Full blood count and liver function should be checked before starting etrasimod. Etrasimod is not recommended for patients with severe hepatic impairment.

Examination of the eyes is recommended before starting treatment in patients with a history of diabetes mellitus, uveitis or retinal disease, because of the increased risk of macular oedema.

Patients should have a cardiovascular assessment, including an electrocardiogram, before treatment. Etrasimod is contraindicated if there is a history of heart block or recent cardiovascular events, such as myocardial infarction, heart failure or stroke.

Etrasimod is extensively metabolised, including by cytochrome P450 (CYP) 2C8, CYP2C9 and CYP3A4. Co-administration with drugs that induce or inhibit these enzymes is not recommended. The risk of interactions should also be considered with drugs that affect the heart rate or immune system.

Use in pregnancy and breastfeeding:
Etrasimod is contraindicated in pregnancy based on animal studies showing adverse effects on fetal development. It is classified as Therapeutic Goods Administration pregnancy category D. Etrasimod is not recommended for use while breastfeeding as a risk of harm to the infant cannot be excluded.

Place in therapy:
Etrasimod has an overall advantage over placebo for patients with ulcerative colitis, but few patients will have a prolonged response. Outcomes tended to be less favourable for patients who had previously been treated with a biologic drug or Janus kinase inhibitor.²

The approved indication for etrasimod is similar to ozanimod. However, there are no trials directly comparing etrasimod with ozanimod, which has different receptor affinities (ozanimod has high affinity for S1P subtypes 1 and 5). Unlike ozanimod, etrasimod does not require dose titration to minimise first-dose heart rate effects. Etrasimod has a half-life of approximately 30 hours, so lymphocyte counts will recover more quickly at the end of treatment compared with ozanimod, which has a long-acting active metabolite with a half-life of up to 11 days. Faster clearance may be important in situations such as planned pregnancy.

This new drug comment was finalised on 16 December 2024.

At the time this new drug comment was prepared, the Australian Public Assessment Report was available from the Therapeutic Goods Administration. The sponsor did not provide the clinical evaluation report.

 

References

1. Gastrointestinal. In: Therapeutic Guidelines. Melbourne: Therapeutic Guidelines Limited; 2022. [cited 2024 Dec 12]
2. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet 2023;401:1159-71.

 

The new drug comments in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. Before new drugs are prescribed, it is important that more detailed information is obtained from the approved product information, a medicines information centre or some other appropriate source.

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