The development of new medications for inflammatory bowel disease (IBD) has been a subject of increased interest, as numerous pharmaceutical companies are searching for compounds with unique and innovative mechanisms of action. Biologic agents such as tumor necrosis factor-α inhibitors, interleukin-12/23 inhibitors, and integrin inhibitors remain the mainstay of many IBD treatment regimens; however, treatments have the potential to fail or be associated with adverse events that require discontinuation.

Etrasimod — a new treatment for IBD with a unique mechanism of action — is currently under investigation in ulcerative colitis (UC). Etrasimod is a selective modulator of the sphingosine 1-phosphate (S1P) receptor; specifically S1P1, S1P4, and S1P5.1 Sphingosine 1-phosphate receptors are intricately involved in the immune system, with ligand binding leading to internalization of the receptor and reduced lymphocyte trafficking.2,3 In early healthy volunteer studies, etrasimod was shown to decrease lymphocyte counts within 3 days and have a prolonged effect on these counts at day 21.4, 5 Upon discontinuation, lymphocyte counts returned near baseline within 7 days. According to these promising data, etrasimod was recently evaluated in patients with moderate to severe UC in a phase 2 study, with results published in Gastroenterology.1

A research group evaluated etrasimod in a phase 2, randomized, double-blind, placebo-controlled, parallel-group induction study at 87 centers in 17 countries. Patients received oral placebo, etrasimod 1 mg or etrasimod 2 mg once daily for a total of 12 weeks. The study included adult patients aged 18 to 80 years old with UC with a modified Mayo Clinic Score (MCS) between 4 and 9. Patients with isolated disease in the rectum were excluded. The study did allow patients on stable dosing of corticosteroids (no tapering permitted) and/or mesalamine to participate in the study; however, all rectal medications had to be stopped at least 2 weeks before administration of the first dose of the study drug. Patients discontinued biologics ≥60 days before the first dose of the study drug and stopped immunosuppressants at randomization. 

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The study met its primary efficacy endpoint with the etrasimod groups showing statistically significant improvement in mean modified MCS from baseline to week 12 compared with placebo. The etrasimod 2-mg group had a mean improvement in modified MCS from baseline of 2.49±0.31 compared with 1.94±0.31 for etrasimod 1 mg and 1.5±0.3 for placebo. Between the etrasimod 2-mg and placebo groups, specifically, the difference in modified MCS was 0.99 (90% CI, 0.3-1.68; P =.009).

In addition to meeting the primary endpoint, compared with placebo the 2-mg dose also had more patients with endoscopic improvement (41.8% vs 17.8%; P =.003), histologic remission (19.5% vs 6.1%; P =.03), clinical remission (33% vs 8.1%; P <.001), and clinical response (50.6% vs 32.5%; P =.03), respectively.

With respect to safety outcomes, etrasimod did have a slightly higher number of patients with treatment-emergent adverse events (TEAEs) compared with placebo (56%-59.6% vs 50%), as well as discontinuation rates secondary to at least 1 TEAE. Only 7.7% of patients had TEAEs deemed related to the study drug. Similar numbers of patients reported serious TEAEs in both treatment and placebo groups. All treatment-related TEAEs in both etrasimod groups were either mild or moderate in severity.

Overall, both treatment and placebo groups had similar TEAEs, including worsening of UC, upper respiratory tract infection, nasopharyngitis, and anemia. The authors did point out that 3 patients were found to have asymptomatic atrioventricular block that was transient and self-resolving. After reviewing these patient’s cardiac evaluations before study initiation, they were all found to have evidence of atrioventricular block before etrasimod exposure. 

The authors concluded that etrasimod 2 mg once daily was effective at inducing remission in patients with moderate to severe UC after 12 weeks. It is important to note the cardiac findings in the safety analysis, as S1P receptor modulators have been associated with conduction abnormalities in prior studies. Several subtypes of the S1P receptors are found within the heart; therefore, activation of these receptors can cause a reduction in excitability, leading to bradycardia. These effects were seen in the phase 1 studies of etrasimod and were typically associated only with the first dose.

Future studies will help clarify the safety and efficacy profile of etrasimod and its place in the UC treatment landscape; however, these current findings are promising. A once-daily, oral medication with receptor specificity and limited expected immunogenicity could potentially be considered early in certain patients to induce remission, similar to the Janus kinase inhibitors, including tofacitinib. According to this and prior studies, it appears that relatively rapid clinical improvement can be achieved with etrasimod. Long-term efficacy and safety studies are needed with etrasimod to determine if the effects are sustainable and if additional or different maintenance medications are required. It will be important to note what future safety studies will show with respect to cardiac toxicities, as this could be a potential prescribing concern among healthcare providers.

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References

1. Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al. Efficacy and safety of etrasimod in phase 2 randomized trial of patients with ulcerative colitis. Gastroenterology. 2020;158(3):550-561.

2. Pérez-Jeldres T, Tyler CJ, Boyer JD, et al. Cell trafficking interference in inflammatory bowel disease: therapeutic interventions based on basic pathogenesis concepts. Inflamm Bowel Dis. 2019;25(2):270-282.

3. Peyrin-Biroulet L, Christopher R, Behan D, et al. Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev. 2017;16(5):495-503.

4. Schreiber S, Morgan M, Christopher R, et al. Etrasimod (APD334), a potent, selective, oral S1P receptor modulator with preclinical autoimmune disease-modifying activity exhibits favorable PK/PD properties in healthy volunteers. Presented at: Advances in Inflammatory Bowel Diseases (AIBD) 2016; December 8-10, 2016; Orlando, FL.

5. Peyrin-Biroulet L, Adams J, Turner S, Trokan L, Panes J. Safety and immune modulatory properties of etrasimod (APD334), a next-generation oral, selective sphingosine 1-phosphate receptor (S1PR) modulator, in healthy volunteers. J Crohns Colitis. 2018;12(suppl 1):S397.