Contraindications [Velsipity SmPC]
See section 4.3 of the SmPC for further details

• Hypersensitivity to the active substance or to any of the excipients
• Immunodeficient state
• Patients who in the last 6 months experienced myocardial infarction, unstable angina pectoris, stroke, transient ischaemic attack (TIA), decompensated heart failure requiring hospitalisation, or New York Heart Association (NYHA) Class III/IV heart failure
• Patients with history or presence of Mobitz type II second‑degree or third‑degree AV block, sick sinus syndrome, or sino‑atrial block, unless patient has a functioning pacemaker
• Severe active infections, active chronic infections such as hepatitis or tuberculosis
• Active malignancies
• Severe hepatic impairment
• During pregnancy and in women of childbearing potential not using effective contraception

Special warnings and precautions [Velsipity SmPC]
See section 4.4 of the SmPC for further details 

Undesirable Effects
See section 4.8 of the SmPC for further details.

• Summary of the safety profile: The most common adverse reactions are lymphopenia (11%) and headache (7%).
• Tabulated list of adverse reactions: The adverse reactions observed in patients treated with etrasimod are listed below by system organ class (SOC) and frequency category. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Risk Materials for Velsipity are available to view on the emc website.

The efficacy of etrasimod was evaluated in two randomised, double-blind, placebo-controlled clinical studies (ELEVATE UC 52 and ELEVATE UC 12) in patients aged 16 to 80 years with moderately to severely active UC.

Both studies included patients who had an inadequate response, loss of response, or intolerance to one or more of the following treatment options: oral aminosalicylates, corticosteroids, thiopurines, Janus kinase inhibitors (JAKi), or a biologic (e.g., TNF blocker, anti-integrin, anti-IL12/23). Enrolled patients had UC confirmed by endoscopy and histopathology with the extent of disease being ≥10 cm from the anal verge. Patients with isolated proctitis (<10 cm rectal involvement) at baseline were also included in the study provided they met all other inclusion criteria. Enrolment of patients with proctitis was capped at 15% of the total patient population.

The primary efficacy analysis was performed in patients with a baseline modified Mayo score (mMS) of 5-9, comprising of all randomised patients who received ≥1 dose of study drug (primary analysis population).

ELEVATE UC 52
ELEVATE UC 52 was a treat-through study in which 433 patients were randomised to receive etrasimod 2 mg or placebo orally once daily. A 12-week induction period was followed by a 40-week maintenance period. Patients remained on their assigned treatment for the duration of the study. 

Clinical remission (co-primary endpoint)
The co-primary endpoint of ELEVATE UC 52 was the proportion of patients achieving clinical remission at Week 12 (induction period) and at Week 52 (maintenance period). Clinical remission was defined as: stool frequency subscore of 0 (or 1 with a ≥1-point decrease from baseline), rectal bleeding subscore of 0 and endoscopic subscore ≤1 (excluding friability).

Secondary endpoints
The key secondary endpoints included the proportion of patients achieving endoscopic improvement, mucosal healing, symptomatic remission, corticosteroid-free clinical remission, and sustained clinical remission. 

ELEVATE UC 12
ELEVATE UC 12 comprised of a 12-week induction period with a 4-week follow-up period. Patients were randomised to receive etrasimod 2 mg (n=238) or placebo (n=116) orally once daily.

Primary endpoint
The primary endpoint of ELEVATE UC 12 was the proportion of patients achieving clinical remission at the end of the 12-week induction period. 

Secondary endpoints
The key secondary endpoints included the proportion of patients achieving endoscopic improvement, symptomatic remission and mucosal healing at week 12. 

See section 4.4 of the SmPC for further details

Bradyarrhythmia and atrioventricular conduction delays

• Prior to treatment initiation with etrasimod, an electrocardiogram (ECG) should be obtained in all patients to assess for pre-existing cardiac abnormalities. In patients with certain pre-existing conditions, first dose monitoring is recommended.
• Initiation of etrasimod may result in a transient decrease in heart rate and atrioventricular conduction delays.
• Caution should be applied when etrasimod is initiated in patients receiving treatment with a beta‑blocker because of potential additive effects on lowering heart rate. Similar caution should be applied if patients receive calcium channel blockers, QT‑prolonging medicinal products, Class Ia and Class III anti‑arrhythmic substances, since co‑administration of these substances with etrasimod may lead to additive effects.
• Temporary interruption of beta‑blocker treatment may be needed prior to initiation of etrasimod, depending on the resting heart rate before initiation. If interruption is deemed necessary, beta‑blocker treatment can be re‑initiated depending on the time of reaching baseline heart rate. Beta‑blocker treatment can be initiated in patients receiving stable doses of etrasimod.

Risk of infections

• Before initiating treatment, a recent complete blood count (CBC), including lymphocyte count (i.e., within the last 6 months or after discontinuation of prior UC therapy), should be obtained.
• Etrasimod may increase susceptibility to infections.
• In patients with active infection, delay initiation of etrasimod until the infection is resolved.
• Patients should be instructed to promptly report symptoms of infection to their physician.
• If a patient develops a serious infection, interruption of etrasimod should be considered.

• Progressive multifocal leukoencephalopathy (PML) has been reported in multiple sclerosis patients treated with S1P receptor modulators and has been associated with certain risk factors, e.g. immunocompromised patients and polytherapy with immunosuppressants. If PML is suspected, treatment should be suspended until PML has been excluded by an appropriate diagnostic evaluation. If PML is confirmed, etrasimod should be discontinued.