Consumer medicine information

Velsipity

Etrasimod

BRAND INFORMATION

Brand name

Velsipity

Active ingredient

Etrasimod

Schedule

SUMMARY CMI

VELSIPITY^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using VELSIPITY?

VELSIPITY contains the active ingredient etrasimod. VELSIPITY is used to treat ulcerative colitis (UC). It is used when a patient's UC is still active after other medicines have not worked or were not tolerated.

For more information, see Section 1. Why am I using VELSIPITY? in the full CMI.

2. What should I know before I use VELSIPITY?

Do not use if you have ever had an allergic reaction to etrasimod or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use VELSIPITY? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VELSIPITY and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use VELSIPITY?

The recommended dose of VELSIPITY is one 2 mg tablet taken once a day
VELSIPITY should be swallowed whole and can be taken with or without food

More instructions can be found in Section 4. How do I use VELSIPITY? in the full CMI.

5. What should I know while using VELSIPITY?

Things you should do	Remind any doctor, dentist, pharmacist, or optometrist you visit that you are taking VELSIPITY. Use effective contraception while taking VELSIPITY. Tell your doctor if you become pregnant. Contact your doctor immediately if you notice changes in your skin or vision, or experience a severe headache, dizziness or if you develop any signs or symptoms of an infection. Check with your doctor before receiving any vaccinations. Make regular appointments to monitor your skin and blood pressure and check your blood results.
Things you should not do	Do not stop using this medicine suddenly. Do not give your medicine to anyone else, even if they have the same condition as you. Do not breastfeed while taking VELSIPITY.
Driving or using machines	VELSIPITY may cause dizziness in some people. Be careful before you drive or use any machines or tools until you know how VELSIPITY affects you.
Looking after your medicine	Store tablets below 30°C.

For more information, see Section 5. What should I know while using VELSIPITY? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Common (less serious) sides effects include headache and dizziness. More serious side effects include serious infections (e.g., urinary tract), slow or irregular heartbeat, high blood pressure, low white blood cells disturbance or loss of vision, progressive weakness, clumsiness, memory loss or confusion, severe headache, seizures (fits). For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/safety/reporting-problems.

FULL CMI

VELSIPITY^®

Active ingredient(s): etrasimod

Consumer Medicine Information (CMI)

This leaflet provides important information about using VELSIPITY. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using VELSIPITY.

Where to find information in this leaflet:

1. Why am I using VELSIPITY?
2. What should I know before I use VELSIPITY?
3. What if I am taking other medicines?
4. How do I use VELSIPITY?
5. What should I know while using VELSIPITY?
6. Are there any side effects?
7. Product details

1. Why am I using VELSIPITY?

VELSIPITY contains the active ingredient etrasimod. VELSIPITY is a sphingosine 1-phosphate (S1P) receptor modulator.

VELSIPITY is used to treat moderately to severely active ulcerative colitis (inflammation of the large bowel) in adults who have not responded or had an intolerance to other medicines also used to treat ulcerative colitis.

2. What should I know before I use VELSIPITY?

Warnings

Do not use VELSIPITY if:

you are allergic to etrasimod, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
in the last 6 months, you have had a heart attack, unstable angina, stroke, or certain types of heart failure.
you have irregular or abnormal heartbeat (arrhythmia).

Check with your doctor if you:

have a history of heart disease, heart attack, heart failure, irregular heartbeat, stroke, or uncontrolled high blood pressure;
have an active infection, or have a lowered immune system (due to a disease or because you take medicines that lower your immunity);
recently had or are planning to have a vaccination, as it is recommended that you do this at least 4 weeks before starting treatment with VELSIPITY;
have not had chickenpox or not been vaccinated against chickenpox;
have had any eye or vision problems. Your doctor will arrange an eye examination before you start treatment with VELSIPITY if you have a history of diabetes or eye conditions such as uveitis or retinal disease;
have severe lung disease, such as pulmonary fibrosis, asthma or chronic obstructive pulmonary disease;
have a fever or high temperature;
have low levels of white blood cells called lymphocytes
have cancer;
have problems with your liver. VELSIPITY is not recommended if you have severe liver problems. Your doctor will check your liver function before you start treatment with VELSIPITY;
have progressive multifocal leukoencephalopathy (PML). PML is a rare viral brain infection that may lead to severe disability or death. PML symptoms include disturbance of vision, progressive weakness, clumsiness, memory loss or confusion;
have Posterior reversible encephalopathy syndrome (PRES, swelling and narrowing of blood vessels in your brain): sudden severe headache, feeling like you might throw up or throwing up, confusion, drowsiness, personality change, paralysis, abnormal speech, convulsion, vision changes
have any other medical conditions;.
take any medicines for any other condition;
drive or use machine. VELSIPITY may cause dizziness, which can affect your ability to drive and use machines

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

First dose monitoring

If you have certain heart conditions, your doctor will also monitor you for at least the first 4 hours after your first dose. Your doctor will ask you to stay at the hospital or clinic for 4 hours and will measure your pulse and blood pressure every hour after taking the first dose of Velsipity. You should have an electrocardiogram (ECG) performed before the first dose of Velsipity and after the 4-hour monitoring period. If after the 4-hour period you have a very slow or decreasing heart rate, or if your ECG shows abnormalities, you may need to be monitored for a longer period until these have resolved.

Pregnancy and breastfeeding

There is potentially a serious risk to your baby if you are taking VELSIPITY while you are pregnant. Check with your doctor if you are pregnant or intend to become pregnant. Your doctor will discuss with you the risks and benefits involved.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is unknown whether VELSIPITY is excreted in breast milk. You should not breastfeed while taking VELSIPITY.

Contraception

You should use effective contraception to avoid becoming pregnant while using VELSIPITY and for 7 days after you stop using it.

Sun protection

Skin cancers have been reported with medicines similar to VELSIPITY. Talk to your doctor straight away if you develop changes with your skin. Since there is a risk for skin cancer, you should have periodic skin examinations and limit your exposure to sun light and UV (ultraviolet) light, by wearing protective clothing and applying regular sunscreen (with high sun protection factor (SPF)).

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with VELSIPITY and affect how it works.

Medicines that regulate your heartbeat such as quinidine, procainamide, amiodarone, or sotalol.
Medicines that reduce your heartbeat.
Before you start taking VELSIPITY, your healthcare professional will check your heart using a test called an electrocardiogram (ECG) to check if you have any heart problems. This is because when you start taking VELSIPITY, your heart rate might decrease. Talk to your healthcare professional if you get any symptoms of bradycardia (slow heart rate). These include: dizziness, tiredness, confusion, fainting, feeling lightheaded, feeling like your heart is beating slowly or skipping beats, shortness of breath, chest pain. You might also experience a slow heart rate and not have any symptoms. Your healthcare professional might also check your blood pressure while you are taking VELSIPITY. This is because VELSIPITY can increase your blood pressure.
Medicines that reduce your immune system such as chemotherapy agents, or other medicines used to treat ulcerative colitis.
Vaccinations may be less effective while you are using VELSIPITY and for up to 2 weeks after stopping it. Live vaccines may also carry the risk of infection and should be avoided during treatment with VELSIPITY and for 2 weeks after stopping treatment.

Medicines that may increase the effect of VELSIPITY include:

CYP2C8, CYP2C9 and CYP3A4 inhibitors e.g., fluconazole used to treat fungal infections.

Medicines that may reduce the effect of VELSIPITY include:

CYP2C8, CYP2C9 and CYP3A4 inducers e.g., rifampicin used to treat bacterial infections.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect VELSIPITY.

4. How do I use VELSIPITY?

How much to take

The recommended dose of VELSIPITY is one 2 mg tablet taken once a day.
Follow the instructions provided and use VELSIPITY until your doctor tells you to stop.

When and how to take VELSIPITY

VELSIPITY should be taken once a day at about the same time each day.
Swallow the tablets whole.
VELSIPITY can be taken with or without food in your stomach.
Do not stop taking VELSIPITY or change your dose without talking to your doctor.

If you forget to use VELSIPITY

VELSIPITY should be used regularly at the same time each day. If you miss your dose at the usual time, take it as soon as you remember, and then go back to taking VELSIPITY as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you use too much VELSIPITY

If you think that you have used too much VELSIPITY, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre
(by calling 13 11 26), or
contact your doctor, or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using VELSIPITY?

Things you should do

if you are of childbearing age, use effective contraception to avoid becoming pregnant including for 7 days after you stop treatment with VELSIPITY.
have regular skin checks.
tell your doctor before you receive any vaccine.
monitor your blood pressure regularly.
keep all your appointments so that your progress can be checked.
limit your exposure to sunlight and UV light.

Call your doctor straight away if you:

develop any signs or symptoms of an infection.
experience any changes in your vision.
notice any unusual spots or changes on your skin.
develop a severe headache, feel confused or have seizures (fits) and loss of vision.

Remind any doctor, dentist or pharmacist you visit that you are using VELSIPITY.

Things you should not do

do not stop taking this medicine suddenly or change your dose without talking to your doctor first.
do not give your medicine to anyone, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how VELSIPITY affects you.

VELSIPITY may cause dizziness in some people.

Looking after your medicine

Store the tablets below 30°C.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects and what to do about them
Symptom/Effect	Talk to your healthcare professional		Stop taking medicine and get immediate help
Symptom/Effect	Only if severe	In all cases	Stop taking medicine and get immediate help
VERY COMMON
Infection: fever, chills, headache, feeling very tired, flu-like symptoms, feeling like you might throw up, swollen lymph nodes.		x
Lymphopenia (decreased white blood cells): fever, cough, mouth ulcers, get infections more easily.		x
COMMON
Urinary tract infection: pain or burning sensation when urinating frequent urination, blood in urine, pain in the pelvis, strongsmelling urine, cloudy urine.		x
Bradycardia (slow heartbeat): dizziness, tiredness, confusion, fainting, feeling lightheaded, feeling like your heart is beating slowly or skipping beats, shortness of breath, chest pain.		x
Hypertension (high blood pressure): blurry vision, feeling lightheaded, feeling short of breath, measure high blood pressure, sometimes with headache of nosebleed.		x
Headache		x
Feeling dizzy		x
Neutropenia (low white blood cells): fever, chills and sweats, fatigue, sore throat, swollen lymph nodes, mouth ulcers.		x
Visual impairment (low or loss of vision): blurred or double vision, seeing flashes or floaters, sensitivity to light, eye pain.		x
RARE
Macular oedema (a vision problem): blurriness or shadows in the centre of your vision, feeling sensitive to light. A blind spot in the centre of your vision, colours look unusual.		x
Irregular heartbeat: feeling dizzy or fainting, chest pain, feeling short of breath, feeling like your heart is beating faster, feeling like you might throw up.		x
Breathing problems: shortness of breath.		x
Liver problems: yellowing of your skin or the whites of your eyes, abnormally dark urine, unexplained nausea or throwing up, tiredness, upper abdominal pain, loss of appetite.		x
FREQUENCY UNKNOWN
Posterior reversible encephalopathy syndrome (PRES, swelling and narrowing of blood vessels in your brain): sudden severe headache, feeling like you might throw up or throwing up, confusion, drowsiness, personality change, paralysis, abnormal speech, seizures (fits), vision changes.			x
Progressive multifocal leukoencephalopathy (PML, a serious brain infection): vision problems, weakness in arms or legs that gets worse, clumsiness, lack of coordination, memory loss or confusion, problems speaking, personality changes.			x
Skin cancer: skin lesions or moles that appear or if existing skin lesions change appearance.		x

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people. Some of these side effects (high cholesterol, high blood pressure, irregular heartbeat, change in liver function, abnormal blood test results) can only be found when your doctor does blood tests from time to time to check your progress.

Call your doctor straight away if you develop any signs or symptoms of an infection and you have recently stopped taking VELSIPITY.

VELSIPITY may continue to work and cause side effects for up to 2 weeks after you stop taking it.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/safety/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What VELSIPITY contains

Active ingredient (main ingredient)	Etrasimod
Other ingredients (inactive ingredients)	Magnesium stearate Mannitol Microcrystalline cellulose Sodium starch glycollate type A Opadry^® II Complete Film Coating System 85F110190-CN Green (ID: 144806)
Potential allergens	Tartrazine

Do not take this medicine if you are allergic to any of these ingredients.

VELSIPITY does not contain lactose, sucrose, or gluten.

What VELSIPITY looks like

VELSIPITY is supplied as a green, round, film-coated tablet, debossed with "ETR" on one side and "2" on the other side (AUST R 405529).

Who distributes VELSIPITY

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free number: 1800 675 229
www.pfizermedicalinformation.com.au

® = Registered Trademark

This leaflet was prepared in January 2025.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Velsipity

Active ingredient

Etrasimod

Schedule

1 Name of Medicine

Etrasimod.

2 Qualitative and Quantitative Composition

Each film-coated tablet contains 2.762 mg of etrasimod arginine, equivalent to 2 mg etrasimod.

Excipient(s) with known effect.

Contains tartrazine.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film-coated tablet.
Velsipity is a green, round, film-coated tablet of approximately 6 mm diameter, debossed with "ETR" on one side and "2" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Velsipity is indicated for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had inadequate response, loss of response or intolerance to conventional, biologic or Janus kinase (JAK) inhibitor therapies.

4.2 Dose and Method of Administration

Dosage.

The recommended dose of Velsipity is 2 mg taken orally once daily.
Treatment with Velsipity should be initiated under the supervision of a physician experienced in the management of conditions for which Velsipity is indicated.
Before initiating treatment with Velsipity, assess the following in Table 1.

Method of administration.

Velsipity should be swallowed whole and can be administered with or without food (see Section 5.1 Pharmacodynamic Properties; Section 5.2 Pharmacokinetic Properties).

Missed dose.

If a dose is missed, the prescribed dose should be taken at the next scheduled time; the next dose should not be doubled.

Dosage adjustments.

Paediatric population.

The safety and effectiveness of Velsipity in paediatric patients have not been established.

Elderly.

No dose adjustment is needed in patients over 65 years of age.
There are limited data available on patients over 65 years of age. No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age from a population pharmacokinetics model (see Section 5.2 Pharmacokinetic Properties). In general, use of etrasimod in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic impairment.

No dose adjustment is needed for patients with mild or moderate hepatic impairment. Velsipity is not recommended in patients with severe hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Velsipity is contraindicated in the following circumstances:
Patients who in the last 6 months, have experienced a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalisation, or New York Heart Association (NYHA) Class III/IV heart failure.
Patients with a history or presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker.
Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.
During pregnancy and in women of childbearing potential not using effective contraception.
In breastfeeding women.
Active malignancies.

4.4 Special Warnings and Precautions for Use

Bradyarrhythmia and atrioventricular conduction delays.

Prior to treatment initiation with Velsipity, an electrocardiogram (ECG) in all patients should be obtained to assess for pre-existing cardiac conduction abnormalities.
Initiation of Velsipity may result in a transient decrease in heart rate and AV conduction delays (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties).
Caution should be applied when Velsipity is initiated in patients receiving treatment with a beta‑blocker because of the 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 antiarrhythmic substances (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), since co-administration of these substances with Velsipity may lead to additive effects. Temporary interruption of beta blocker or other antiarrhythmic treatments may be needed prior to initiation of Velsipity, depending on the resting HR before initiation of Velsipity (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If interruption is deemed necessary, consider seeking the advice of a cardiologist.
Beta blocker or other antiarrhythmic agents treatment can be initiated in patients who have received Velsipity for at least 7 consecutive days.
On Day 1, after the first dose of Velsipity 2 mg in UC patients, the greatest mean decrease from baseline in heart rate was 7.3 bpm at Hour 3 in ELEVATE UC 52 and Hour 2 in ELEVATE UC 12. In ELEVATE UC 12, two subjects in the etrasimod group had a heart rate of less than 50 bpm, leading to withdrawal from study and recovery without medical intervention for heart rate post termination.
Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, such as dizziness, and these symptoms resolved without intervention.
If treatment with Velsipity is considered, advice from a cardiologist should be sought, for those individuals:
with significant QT prolongation (QTcF ≥ 450 msec in males, ≥ 470 msec in females);
with arrhythmias requiring treatment with Class Ia or Class III antiarrhythmic drugs;
with unstable ischemic heart disease, heart failure, history of cardiac arrest, cerebrovascular disease (occurring more than 6 months prior to treatment initiations), or uncontrolled hypertension;
with resting heart rate of less than 50 bpm;
with history of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleep apnea;
with history of Mobitz type I second-degree AV block, unless the patient has a functioning pacemaker.

First dose monitoring in patients with certain pre-existing cardiac conditions.

Due to risk of transient decreases in heart rate with the initiation of etrasimod 4-hour monitoring of signs and symptoms of symptomatic bradycardia after the first dose is recommended in patients with resting heart rate < 50 bpm, second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure.
Patients should be monitored with hourly pulse and blood pressure measurement during this 4-hour period. An ECG period to and at the end of this 4-hour period is recommended.
Additional monitoring is recommended in patients, if at the end of 4-hour period:
Heart rate is < 45 bpm.
Heart rate is the lowest value post dose, suggesting that the maximum decrease in heart rate may not have occurred yet.
ECG shows evidence of a new onset second-degree or higher AV block.

Infections.

Risk of infections.

Velsipity causes a mean reduction in peripheral blood lymphocyte count to approximately 45% of baseline values at Week 52 because of reversible sequestration of lymphocytes in lymphoid tissues (see Section 5.1 Pharmacodynamic Properties). Velsipity may, therefore, increase the susceptibility to infections (see Section 4.8 Adverse Effects (Undesirable Effects)).
Before initiating treatment, obtain a recent complete blood count (CBC), including lymphocyte count (i.e. within the last 6 months or after discontinuation of prior UC therapy). Clinicians should monitor complete blood count (CBC) periodically during treatment and to interrupt treatment with etrasimod in patients with a confirmed absolute lymphocyte count < 0.2 x 10⁹/L until the level reaches > 0.5 x 10⁹/L when re-initiation of etrasimod can be considered. Patients need to report symptoms of infection promptly to their physician.
The initiation of Velsipity in patients with any active infection should be delayed until the infection is resolved.
Consider interruption of treatment with Velsipity if a patient develops a serious infection.
Because residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist up to 2 weeks after discontinuation of Velsipity, vigilance for infection should be continued throughout this period (see Section 5.1 Pharmacodynamic Properties).

Progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) that typically occurs in patients who are immunocompromised, and that may lead to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
No cases of PML have been reported in Velsipity-treated patients in the development program; however, PML has been reported in multiple sclerosis patients treated with other sphingosine 1-phosphate (S1P) receptor modulators and has been associated with some risk factors (e.g. immunocompromised patients, polytherapy with immunosuppressants). Physicians should be vigilant for clinical symptoms or unexplained neurologic findings that may be suggestive of PML. If PML is suspected, treatment with Velsipity should be suspended until PML has been excluded by an appropriate diagnostic evaluation.
If PML is confirmed, treatment with Velsipity should be discontinued.

Prior and concomitant treatment with antineoplastic, immune-modulating, or immunosuppressive therapies.

In ELEVATE UC 52 and ELEVATE UC 12, patients who received Velsipity were not to receive concomitant treatment with antineoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies used for the treatment of UC. In ELEVATE UC 52 and ELEVATE UC 12, concomitant use of corticosteroids was allowed; however long-term data on concomitant use of etrasimod and corticosteroids are limited and did not appear to influence the safety or efficacy of Velsipity (see Section 5.1 Pharmacodynamic Properties).
Caution should be used when co-administering etrasimod and antineoplastic, immune-modulating, or immunosuppressive (including corticosteroid) therapies to patients, because of the risk of additive immune system effects during such therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
When switching to Velsipity from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immune system effects.
An appropriate washout period may need to be applied.
After stopping Velsipity, lymphocyte counts returned to the normal range in 90% of subjects within 1 to 2 weeks of stopping Velsipity based on a population pharmacokinetic/pharmacodynamic model (see Section 5.1 Pharmacodynamic Properties). Use of immunosuppressants within this period may lead to an additive effect on the immune system, and therefore monitor patients receiving concomitant immunosuppressants for infectious complications up to 2 weeks after the last dose of Velsipity.

Vaccinations.

No clinical data are available on the safety and efficacy of vaccinations in patients taking Velsipity. Vaccinations may be less effective if administered during Velsipity treatment. If live attenuated vaccine immunisations are required, administer at least 4 weeks prior to initiation of Velsipity. Avoid the use of live attenuated vaccines during and for at least 2 weeks after treatment with Velsipity.
Patients without a healthcare professional-confirmed history of varicella (chickenpox) or without documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before initiating Velsipity. A full course of VZV vaccination of antibody-negative patients is recommended prior to commencing treatment with Velsipity, following which initiation of treatment with Velsipity should be postponed for 4 weeks to allow the full effect of vaccination to occur.
Update immunisations in agreement with current immunisation guidelines prior to initiating Velsipity therapy.

Increased blood pressure.

In clinical studies, hypertension was more frequently reported in patients treated with Velsipity than in patients treated with placebo (see Section 4.8 Adverse Effects (Undesirable Effects)). Blood pressure should be monitored during treatment with Velsipity and managed appropriately.

Fetal risk.

Based on animal studies, Velsipity may cause fetal harm (see Section 4.6 Fertility, Pregnancy and Lactation). Before initiation of Velsipity treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with Velsipity.
Because it takes approximately 7 days for pharmacokinetic/pharmacodynamic effects of Velsipity to be washed out from the body, women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 7 days after stopping Velsipity (see Section 4.6 Fertility, Pregnancy and Lactation).

Macular oedema.

S1P receptor modulators, including Velsipity, have been associated with an increased risk of macular oedema (see Section 4.8 Adverse Effects (Undesirable Effects)).
An ophthalmic evaluation of the fundus, including the macula, is recommended in all patients at any time if there is any change in vision while taking Velsipity.
Patients with a history of diabetes mellitus, uveitis, or underlying/co-existing retinal disease, uncontrolled hypertension and older patients are at increased risk of macular oedema during Velsipity therapy. Arrange an ophthalmological assessment in patients with a history of diabetes mellitus, uveitis, or retinal disease prior to treatment initiation with Velsipity and have follow up evaluations while receiving therapy.
Continuation of Velsipity therapy in patients who develop macular oedema has not been evaluated. It is recommended that Velsipity be discontinued in patients who develop macular oedema. A decision on whether or not Velsipity should be re-initiated after resolution needs to take into account the potential benefits and risks for the individual patient.

Malignancies.

Cases of malignancies (including skin malignancies) have been reported in patients treated with S1P receptor modulators. If a suspicious skin lesion is observed, it should be promptly evaluated.
Since there is a potential risk of malignant skin growths, patients treated with Velsipity should have periodic skin examinations and be cautioned against exposure to sunlight without protection. These patients should not receive concomitant phototherapy with UV-B radiation or PUVA photochemotherapy.

Posterior reversible encephalopathy syndrome.

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving other S1P receptor modulators. Such events have not been reported for Velsipity-treated patients in the development program. Should a Velsipity-treated patient develop any neurological or psychiatric symptoms/signs (e.g. cognitive deficits, behavioural changes, cortical visual disturbances, or any other neurological cortical symptoms/signs), any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, the physician should promptly schedule a complete physical and neurological examination and should consider an MRI. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with Velsipity should be discontinued.

Respiratory effects.

Reductions in absolute forced expiratory volume over 1 second (FEV₁) and forced vital capacity (FVC) were observed in patients treated with S1P receptor modulators, including Velsipity (see Section 5.1 Pharmacodynamic Properties). Patients with a forced expiratory volume in 1 second (FEV₁) or forced vital capacity (FVC) < 70% predicted values and FEV₁/FVC ratio < 0.70 at screening were not eligible to participate in ELEVATE 12 and ELEVATE 52. Velsipity should be used with caution in patients with severe respiratory disease (i.e. pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease).

Use in hepatic impairment.

Elevations of aminotransferases may occur in patients receiving Velsipity (see Section 4.8 Adverse Effects (Undesirable Effects)).
Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Velsipity.
Patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine, should have hepatic enzymes checked and Velsipity should be discontinued if significant liver injury is confirmed.
Velsipity is not recommended in severe hepatic impairment. See Section 5.2 Pharmacokinetic Properties.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Dosage adjustments, Elderly; Section 5.2 Pharmacokinetic Properties.

Paediatric use.

The safety and effectiveness of Velsipity in paediatric patients have not been established.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Infections, Risk of infections and Use in hepatic impairment; Section 4.8 Adverse Effects (Undesirable Effects), Description of selected adverse reactions, Blood lymphocyte count reduction and Elevated hepatic enzymes; Section 5.1 Pharmacodynamic Properties, Pharmacodynamic effects, Reduction in blood lymphocyte counts and Reduction in tissue lymphocyte counts.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of other medicinal products on etrasimod.

In vitro studies indicate that metabolism of etrasimod occurs through multiple distinct enzyme systems, including multiple CYP450 (CYP2C8, CYP2C9, and CYP3A4), non-CYP450 oxidative enzymes and UGTs. Metabolism by sulfotransferases was observed in clinical excreta samples based on metabolite profiling. Overall, the disposition of etrasimod is mediated by several enzymes without major contribution by any single enzyme.
Etrasimod is not a substrate of P-gp, BCRP, OATP1B1/3, OAT1/3, OCT1/2 transporters. Drugs that are inhibitors of these transporters are unlikely to impact the pharmacokinetics of etrasimod.

CYP2C8, CYP2C9 and CYP3A4 inhibitors.

The co-administration of etrasimod with steady state fluconazole (moderate CYP2C9 and CYP3A4 inhibitor) increased exposure (AUC) of etrasimod by 84%. Co-administration of etrasimod with a therapeutic agent or a combination of agents that are moderate to strong inhibitors of two or more of the following CYPs (CYP2C8, CYP2C9, and CYP3A4) (e.g. fluconazole) increases the exposure of etrasimod and is not recommended.
Due to the potential for increased exposure of etrasimod, co-administration of etrasimod in patients who are known or suspected to be CYP2C9 poor metabolisers and who take medicinal products that are moderate or strong inhibitors of CYP2C8 or CYP3A4 is not recommended.

CYP2C8, CYP2C9, and CYP3A4 inducers.

The co-administration of etrasimod with rifampicin (strong CYP3A4, moderate CYP2C8, and CYP2C9 inducer) decreased exposure (AUC) of etrasimod by 49%. Co-administration of Velsipity with a therapeutic agent or a combination of agents that are moderate to strong inducers of two or more of the main metabolizing CYPs (CYP2C8, CYP2C9, and CYP3A4) decreases the exposure of etrasimod. Co-administration with Velsipity and such agents (e.g. rifampicin) is not recommended.

Concomitant drugs that may decrease heart rate.

Beta blockers and calcium channel blockers.

The co-administration of Velsipity in patients receiving stable beta blocker treatment did not result in additive effects on heart rate reduction. Velsipity can be initiated in patients receiving stable doses of beta blocker treatment. Following the first dose of etrasimod 2 mg, the Day 1 maximum mean change from baseline heart rate reduction in patients on stable beta blocker treatment was comparable to patients not taking a beta blocker (mean [SD]: -6.5 [7.15] bpm compared with -7.2 [9.27] bpm).
The initiation of a beta blocker in patients receiving stable treatment of Velsipity has not been studied.
The effect of co-administration of Velsipity and a calcium channel blocker has not been studied.
Caution is recommended for patients receiving medicinal products that slow heart rate or atrioventricular conduction because of the potential additive effects on lowering heart rate (see Section 4.4 Special Warnings and Precautions for Use).

Antiarrhythmic drugs and QT prolonging drugs.

Velsipity has not been studied in patients taking QT prolonging drugs.
Class Ia (e.g. quinidine, procainamide) and Class III (e.g. amiodarone, sotalol) antiarrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. If treatment with Velsipity is considered in patients on Class Ia or Class III antiarrhythmic drugs, advice from a cardiologist should be sought (see Section 4.4 Special Warnings and Precautions for Use).
Because of the potential additive effects on heart rate, if treatment initiation with Velsipity is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought (see Section 4.4 Special Warnings and Precautions for Use).

Antineoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies.

Velsipity has not been studied in combination with antineoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies. Caution should be used during concomitant administration because of the risk of additive immune system effects during such therapy and in the weeks following administration (see Section 4.4 Special Warnings and Precautions for Use).

Vaccination.

Vaccinations may be less effective if administered during and for up to 2 weeks after discontinuation of Velsipity treatment. The use of live attenuated vaccine may carry the risk of infection and should therefore be avoided during Velsipity treatment and for at least 2 weeks after discontinuation of Velsipity treatment (see Section 4.4 Special Warnings and Precautions for Use).

Effect of etrasimod on other drugs.

In vitro studies indicate that at the recommended dose of 2 mg once daily, etrasimod is unlikely to show any clinically relevant drug-drug interaction potential for CYP450 or UGT enzymes or membrane transporters.

Oral contraceptives.

No clinically significant differences in the pharmacokinetics and pharmacodynamics of oral contraceptive containing 30 microgram ethinylestradiol and 150 microgram levonorgestrel were observed when co-administered with etrasimod.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of etrasimod on human fertility has not been evaluated.
When etrasimod was administered orally to male (up to 200 mg/kg/day) and female (up to 4 mg/kg/day) rats daily from pre-mating to conception and conception to implantation, there were no adverse effects observed on male or female fertility. Estimated plasma etrasimod exposure (AUC) at the highest dose tested was approximately 750 (males) and 22 (females) times that in humans at the maximum recommended human dose (MRHD) or 2 mg.
(Category D)
There are no adequate and well-controlled studies on the developmental risk associated with the use of Velsipity in pregnant women. Velsipity should not be used during pregnancy (see Section 4.3 Contraindications).
In animal studies, administration of etrasimod during pregnancy produced adverse effects on development, including embryolethality and fetal malformations, in both rats and rabbits at clinically relevant maternal exposures.
When etrasimod was orally administered to pregnant rats during the period of organogenesis, post-implantation loss with a corresponding lower mean number of viable fetuses was observed at 4 mg/kg/day. Etrasimod-related fetal external malformations of anasarca and localised oedema (at 4 mg/kg/day) and visceral malformations (including aortic vessel anomalies and septal defects) and variations (short brachiocephalic trunk) at ≥ 1 mg/kg/day were noted. Maternal plasma AUC at the lowest dose tested (1 mg/kg/day), which was a teratogenic dose, was 6 times that in humans at the MRHD of 2 mg/day.
When etrasimod was orally administered to pregnant rabbits during the period of organogenesis, post-implantation loss with a corresponding lower number of viable fetuses was observed at ≥ 10 mg/kg/day. Etrasimod-related fetal visceral malformations of the aortic arch (bulbous aortic arch, retroesophageal aortic arch and/or coarction of the aortic arch) were observed at ≥ 10 mg/kg/day and fetal skeletal malformations (fused sternebrae) at 20 mg/kg/day. The fetal skeletal variation of extra ossification site anterior to the sternebra was also noted at ≥ 10 mg/kg/day. There were no effects on embryofetal development at 2 mg/kg/day. Maternal plasma exposure (AUC) at the no-adverse-effect dose (2 mg/kg/day) was 0.9 times that in humans at the MRHD of 2 mg/day.
Oral administration of etrasimod to female rats throughout pregnancy and lactation resulted in prolonged gestation, increased post-implantation loss and an increased number of stillbirths at ≥ 2 mg/kg/day. Maternal plasma exposure (AUC) at the no observed adverse effect level (0.4 mg/kg/day) was 1.2 times that in humans at the MRHD of 2 mg/day.

Women of childbearing potential.

Before initiation of Velsipity treatment, women of childbearing potential should be counseled on the potential for a serious risk to the fetus and the need for effective contraception during treatment with Velsipity.
Because of the time it takes to eliminate the drug from the body after stopping treatment, the potential risk to the fetus may persist and women of childbearing potential should use effective contraception for 7 days after stopping Velsipity (see Section 4.3 Contraindications).
It is unknown whether Velsipity is excreted in human milk. When etrasimod was orally administered to female rats during pregnancy and lactation, etrasimod was detected in the plasma of the offspring, suggesting excretion of etrasimod in milk. A risk to newborns/infants cannot be excluded. Women receiving Velsipity should not breastfeed.
Oral administration of etrasimod (0, 0.4, 2, or 4 mg/kg/day) to female rats throughout pregnancy and lactation resulted in decreased mean pup weights at all dose levels during the preweaning period, lower pup viability at 2 and 4 mg/kg/day, and reduced fertility and reproductive performance (reduction in implantations and increased preimplantation loss) in F1 pups at the highest dose tested. No effects were noted on neurobehavioural function in offspring at any dose level tested. Plasma exposure (AUC) in dams at the lowest dose tested was equivalent (1.2 times) to those in humans at the MRHD of 2 mg/day.

4.7 Effects on Ability to Drive and Use Machines

Velsipity has no or negligible influence on patient's ability to drive and use machines. However, when driving or using machines, it should be taken into account that dizziness has been reported (see Section 4.8 Adverse Effects (Undesirable Effects)). No studies on the effects on the ability to drive and the use of machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

The most common adverse drug reactions are lymphopenia (11%) and headache (7%).

Tabulated list of adverse reactions.

The adverse reactions observed in patients treated with etrasimod are listed by system organ class (SOC) and frequency for all adverse reactions. Within each SOC and frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000). See Table 2.

Description of selected adverse reactions.

Bradyarrhythmia.

In ELEVATE UC 52, bradycardia was reported on the day of treatment initiation in 1.0% of patients treated with Velsipity compared to none in patients who received placebo. On Day 2, bradycardia was reported in 1 patient (0.3%) treated with Velsipity compared to none in patients who received placebo. In ELEVATE UC 12, bradycardia was reported on the day of treatment initiation in 2.1% of patients treated with Velsipity compared to none in patients who received placebo. On Day 2, bradycardia was reported in 1 patient (0.4%) treated with Velsipity compared to none in patients who received placebo.
At initiation of Velsipity 2 mg, events of first- or second-degree Mobitz type I AV blocks were observed in 0.7% of Velsipity-treated patients compared to none in placebo in ELEVATE UC 52 and in 0.4% of Velsipity-treated patients compared to none in placebo in ELEVATE UC 12; however, in ELEVATE UC 52 and ELEVATE UC 12, Mobitz type II second- or third-degree AV blocks were not reported in patients treated with Velsipity.

Infections.

In ELEVATE UC 52, the overall rate of infections and rate of serious infections in patients treated with Velsipity was comparable to that in patients who received placebo (24.9% vs. 22.2%, and 1.0% vs. 3.5%, respectively). In ELEVATE UC 12, the overall rate of infections and rate of serious infections in patients treated with Velsipity was comparable to that in patients who received placebo (11.3% vs. 12.1%, and none in both groups, respectively). The most common adverse reaction for infections was urinary tract infection.

Blood lymphocyte count reduction.

The proportion of patients treated with Velsipity who experienced lymphocyte counts less than 0.2 x 10⁹/L was 5.6% in ELEVATE UC 52 and 0.9% in ELEVATE UC 12. These events did not lead to treatment discontinuation.

Elevated hepatic enzymes.

In ELEVATE UC 52, elevations of alanine aminotransferase (ALT) to 5-fold the upper limit of normal (ULN) or greater occurred in 0.7% of patients treated with Velsipity and 0.7% of patients who received placebo, and in ELEVATE UC 12 elevations occurred in 0.8% of patients treated with Velsipity and no patients who received placebo. In ELEVATE UC 52, elevations of ALT to 3-fold the ULN or greater occurred in 4.5% of patients treated with Velsipity and 0.7% of patients who received placebo, and in ELEVATE UC 12 elevations occurred in 2.5% of patients treated with Velsipity and no patients who received placebo.
The majority (75%) of patients with ALT greater than 3-fold the ULN continued treatment with Velsipity with values returning to less than 3-fold the ULN while on treatment.
Overall, the percentage of discontinuation because of elevations in hepatic enzymes was 0.4% in patients treated with Velsipity, and 0.4% in patients who received placebo.

Increased blood pressure.

In ELEVATE UC 52 and ELEVATE UC 12, patients treated with Velsipity had an average increase of approximately 1 to 4 mmHg in systolic blood pressure and approximately 1 to 2 mmHg in diastolic blood pressure compared to < 1.5 mmHg and < 1 mmHg in patients receiving placebo, respectively. The increase was first detected after 2 weeks of treatment and remained within the specified average range in blood pressure increases throughout treatment. Hypertension was reported as an adverse reaction in 2.1% of patients treated with Velsipity and in 1.0% of patients who received placebo. The majority of the events were mild to moderate in severity.

Macular oedema.

In ELEVATE UC 52, macular oedema was reported in 0.3% of patients treated with Velsipity and in no patients receiving placebo. In ELEVATE UC 12, macular oedema was reported in 0.4% of patients treated with Velsipity and in 0.9% of patients receiving placebo.

Herpes viral infections.

Cases of localised herpes viral infection were seen with S1P receptor modulators, including Velsipity. In ELEVATE UC 52, herpes zoster was reported in 0.7% of patients treated with Velsipity and in none of the patients who received placebo. In ELEVATE UC 12, herpes zoster was reported in none of the patients treated with Velsipity and in 1.7% of patients who received placebo.

Tabulated list of adverse events.

Treatment-emergent adverse events (TEAE) reported by ≥ 2% of subjects in any treatment group for the 12-week induction period (pool includes APD334-301, APD334-302 studies) and 40-week maintenance period (APD334-301) are provided in Table 3 and Table 4, respectively.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/safety/reporting-problems.

4.9 Overdose

In patients with overdosage of etrasimod, monitor for signs and symptoms of bradycardia, which may include overnight monitoring. Regular measurements of heart rate, blood pressure, and ECGs should be performed. There is no specific antidote to etrasimod available.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Etrasimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1, 4 and 5 (S1P1,4,5). Etrasimod has no activity on S1P2 or S1P3. Etrasimod partially and reversibly blocks the capacity of lymphocytes to egress from lymphoid organs, reducing the number of lymphocytes in peripheral blood thereby lowering the number of activated lymphocytes in the tissue.
The mechanism by which etrasimod exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines.

Pharmacodynamic effects.

Heart rate and rhythm.

Velsipity may result in a transient decrease in heart rate and AV conduction upon treatment initiation (see Section 4.4 Special Warnings and Precautions for Use). On Day 1, in UC patients from ELEVATE UC 52 and ELEVATE UC 12, the greatest mean decrease in heart rate was observed at Hour 2 or 3 post dose. On day 1, the mean (SD) change in PR interval from predose to 4 hours post dose with etrasimod was 5.5 msec (18.84). PR interval prolongation > 200 msec was recorded on ECG in 5.1% and higher degree prolongation (> 230 msec) in 1.8% of subjects. The first dose heart rate lowering effect of etrasimod over the first few hours post dose may be partially attenuated following administration with food (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).

Effect on QT interval.

In a thorough QT study, daily administration of etrasimod doses 2 mg (recommended dose) to 4 mg (two times recommended dose) were evaluated in healthy subjects. Etrasimod did not prolong QTc interval to any clinically relevant extent.

Reduction in blood lymphocyte counts.

In controlled clinical studies, mean lymphocyte counts decreased to approximately 50% of baseline at 2 weeks (approximate mean blood lymphocyte counts 0.9 x 10⁹/L) consistent with the mechanism of action, and lowered lymphocyte counts were maintained during once daily treatment with Velsipity.
Peripheral blood B cells [CD19+] and T cells [CD3+], T-helper [CD3+CD4+], and T-cytotoxic [CD3+CD8+] cell subsets were all reduced, while natural killer cells and monocytes were not. T-helper cells were more sensitive to the effects of etrasimod than T-cytotoxic cells.
Peripheral blood absolute lymphocyte counts returned to the normal range in 90% of patients within 1 to 2 weeks of stopping therapy based on a population pharmacokinetic/pharmacodynamic model.

Reduction in tissue lymphocyte counts.

In ELEVATE UC 52 and ELEVATE UC 12, etrasimod reduced activated lymphocytes in colon biopsies from patients with UC.

Peripheral inflammatory proteins.

Etrasimod reduces peripheral inflammatory proteins including those related to UC.

Pulmonary function.

Reductions in FEV₁ and FVC were observed in patients treated with Velsipity. In ELEVATE UC 52 and ELEVATE UC 12, by Week 12, the absolute change in mean FEV₁ in patients treated with Velsipity was -49 mL, compared to -19 mL for placebo. There was no further decline relative to placebo by Week 52. By Week 12 the absolute change in mean FVC in patients treated with Velsipity was -12 mL, compared to -5 mL for placebo, and at Week 52 it was -39 mL vs. 8 mL. The absolute change in mean FEV₁/FVC in patients treated with Velsipity was 0.026, compared to 0.024 for placebo. There was no further decline relative to placebo by Week 52.

Clinical trials.

The efficacy of etrasimod was evaluated in 2 randomised, double-blind, placebo-controlled clinical studies (ELEVATE UC 52 and ELEVATE UC 12) in patients 16 to 80 years of age with moderately to severely active ulcerative colitis.
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 (JAK) inhibitors, 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 were also included in the study provided they met all other inclusion criteria.
Disease severity was assessed on the modified Mayo score (mMS), a 3-component Mayo score (0 to 9) which consists of the following subscores (0 to 3 for each subscore): stool frequency (SF), rectal bleeding (RB), and findings on centrally read endoscopy score (ES). An ES of 2 was defined by marked erythaema, lack of vascular pattern, any friability, and/or erosions, and a score of 3 was defined by spontaneous bleeding and ulceration. Enrolled patients had a mMS of 4 to 9 with an ES ≥ 2 and RB subscore ≥ 1.
Patients in these studies may have received other concomitant UC therapies including stable daily doses of oral aminosalicylates and/or oral corticosteroids (≤ 20 mg prednisone, ≤ 9 mg budesonide, or equivalent steroid). Concomitant treatment with immunomodulators, biologic therapies, rectal 5 ASA, or rectal corticosteroids was not permitted.
ELEVATE UC 52. ELEVATE UC 52 was a treat-through study, with a total of 433 patients randomised to receive etrasimod 2 mg or placebo at a 2:1 ratio administered orally once daily. Patients remained on their assigned treatment for the duration of the study.
At baseline, enrolled patients had a median mMS of 7, with 5.5% of patients having mMS of 4, 66.5% having mMS 5 to 7 (moderately active disease), and 28% having mMS > 7 (severely active disease). 8% of enrolled patients presented with isolated proctitis. A total of 30% of patients had prior exposure to biologic/JAK inhibitors; a total of 14% of patients had exposure to > 1 biologic/JAK inhibitor and 11% of patients had prior exposure to anti-integrins. At baseline, 77% of patients were receiving oral aminosalicylates and 31% of patients were receiving oral corticosteroids.
The co-primary endpoints were the proportion of patients achieving clinical remission at Week 12 and at Week 52, with clinical remission defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline), RB subscore of 0, and ES ≤ 1 (excluding friability). The secondary endpoints included the proportion of patients achieving endoscopic improvement, symptomatic remission, mucosal healing, clinical response, corticosteroid-free clinical remission, and sustained clinical remission. The primary analysis was conducted at Week 12 and at Week 52 in patients with moderately to severely active disease, defined as mMS 5 to 9 (see Table 5).
A significantly greater proportion of patients treated with etrasimod achieved clinical remission, endoscopic improvement, symptomatic remission, and mucosal healing at Week 12 and at Week 52, corticosteroid-free clinical remission and sustained clinical remission at Week 52, compared to placebo (see Table 5).

Supplementary analysis of mMS 4 to 9.

Consistent with the primary analysis (mMS of 5 to 9 including ES ≥ 2 and RB subscore ≥ 1), a greater proportion of patients with mMS of 4 to 9 (including ES ≥ 2 and RB subscore ≥ 1) treated with etrasimod compared to placebo achieved clinical remission (28% vs. 8%, 2-sided p-value < 0.001), endoscopic improvement (37% vs 17%, 2-sided p-value < 0.001), symptomatic remission (46% vs. 22%, 2-sided p-value < 0.001), and mucosal healing (23% vs. 6%, 2-sided p-value < 0.001) at Week 12, clinical remission (33% vs. 8%, 2-sided p-value < 0.001), endoscopic improvement (39% vs. 13%, 2-sided p-value < 0.001), symptomatic remission (44% vs. 19%, 2-sided p-value < 0.001), mucosal healing (27% vs. 10%, 2-sided p-value < 0.001), corticosteroid-free clinical remission (33% vs. 7%, 2-sided p-value < 0.001), and sustained clinical remission (19% vs. 3%, 2-sided p-value < 0.001) at Week 52.

Isolated proctitis.

A greater proportion of patients with isolated proctitis at baseline treated with etrasimod compared to placebo achieved clinical remission at Week 12 (46% vs. 29%) and Week 52 (42% vs. 14%).

Symptomatic remission by week 2.

At Week 2 (first study visit), a greater proportion of patients treated with etrasimod compared to placebo achieved symptomatic remission (16% vs. 11%).

Complete symptomatic remission.

Complete symptomatic remission was defined as a SF subscore of 0 and RB subscore of 0. At Week 4, a greater proportion of patients treated with etrasimod compared to placebo achieved complete symptomatic remission (11% vs. 4%).

Stool frequency and rectal bleeding subscores.

Decreases in SF and RB subscores were observed as early as Week 2 in patients treated with etrasimod compared to placebo.

Cessation of rectal bleeding.

A greater proportion of patients achieved an RB subscore of 0 as early as Week 4 with etrasimod compared to placebo (44% vs. 27%).

Endoscopic and histologic assessment.

Normalisation of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of patients treated with etrasimod compared to placebo achieved endoscopic remission by Week 12 (15% vs. 4%), Week 52 (26% vs. 6%), and both Week 12 and Week 52 (11% vs. 2%).
Endoscopic remission and Geboes histologic score < 2.0 (indicating no neutrophils in crypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue) were achieved by a greater proportion of patients treated with etrasimod compared to placebo at Week 12 (11% vs. 2%) and at Week 52 (18% vs. 5%).
When defined as ES ≤ 1 and Geboes ≤ 3.1 (indicating neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue), a greater proportion of patients treated with etrasimod compared to placebo achieved histologic-endoscopic mucosal improvement at Week 12 (31% vs. 10%) and Week 52 (40% vs. 11%).

Abdominal pain and bowel urgency.

At Week 12, a greater proportion of patients treated with etrasimod compared to placebo had absence of abdominal pain (27% vs. 13%) and absence of bowel urgency (19% vs. 7%). At Week 52, a greater proportion of patients treated with etrasimod compared to placebo had absence of abdominal pain (22% vs. 7%) and absence of bowel urgency (19% vs. 8%).

Inflammatory bowel disease questionnaire (IBDQ).

Patients treated with etrasimod compared to placebo demonstrated greater improvement from baseline in the total and all 4 domain scores of the IBDQ (bowel symptoms, systemic function, emotional function, and social function) at Week 12 and at Week 52.
ELEVATE UC 12. In ELEVATE UC 12, a total of 354 patients were randomised to receive etrasimod 2 mg or placebo at a 2:1 ratio administered orally once daily.
At baseline, enrolled patients had a median mMS of 7, with 5.6% of patients having mMS of 4, and 67% having mMS 5 to 7 (moderately active disease), and 27.4% having mMS > 7 (severely active disease). 8% of enrolled patients presented with isolated proctitis. A total of 33% of patients had prior exposure to biologic/JAK inhibitors; a total of 18% of patients had exposure to > 1 biologic/JAK inhibitor and 12% of patients had prior exposure to anti-integrins. At baseline, 83% of patients were receiving oral aminosalicylates and 28% of patients were receiving oral corticosteroids.
The primary endpoint was the proportion of patients achieving clinical remission at Week 12. The secondary endpoints included the proportion of patients achieving endoscopic improvement, symptomatic remission, mucosal healing, and clinical response at Week 12.
The primary analysis was conducted at Week 12 in patients with moderately to severely active disease, defined as mMS 5 to 9 (see Table 6).
A significantly greater proportion of patients treated with Velsipity achieved clinical remission, endoscopic improvement, symptomatic remission, and mucosal healing compared to placebo at Week 12 (see Table 6).

Supplementary analysis of mMS 4 to 9.

Isolated proctitis.

A greater proportion of patients with isolated proctitis at baseline treated with Velsipity compared to placebo achieved clinical remission at Week 12 (39% vs. 8%).

Symptomatic remission by week 4.

At Week 4, a greater proportion of patients treated with Velsipity compared to placebo achieved symptomatic remission (28% vs. 16%).

Complete symptomatic remission.

Complete symptomatic remission was defined as a SF subscore of 0 and RB subscore of 0. At Week 4, a greater proportion of patients treated with Velsipity compared to placebo achieved complete symptomatic remission (12% vs. 4%).

Stool frequency and rectal bleeding subscores.

Decreases in SF and RB subscores were observed as early as Week 2 in patients treated with Velsipity compared to placebo.

Cessation of rectal bleeding.

A greater proportion of patients achieved an RB subscore of 0 as early as Week 4 with Velsipity compared with placebo (47% vs. 25%).

Endoscopic and histologic assessment.

Normalisation of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of patients treated with Velsipity compared to placebo achieved endoscopic remission by Week 12 (17% vs. 8%).
Endoscopic remission and Geboes histologic score < 2.0 (indicating no neutrophils in crypts or lamina propria and no increase in eosinophil, no crypt destruction, and no erosions, ulcerations, or granulation tissue) were achieved by a greater proportion of patients treated with Velsipity compared to placebo at Week 12 (10% vs. 5%).
When defined as ES ≤ 1 and Geboes ≤ 3.1 (indicating neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue), a greater proportion of patients treated with Velsipity compared to placebo achieved histologic-endoscopic mucosal improvement at Week 12 (29% vs. 12%).

Abdominal pain and bowel urgency.

At Week 12, a greater proportion of patients treated with Velsipity compared to placebo had absence of abdominal pain (32% vs. 18%) and absence of bowel urgency (21% vs. 12%).

Inflammatory bowel disease questionnaire (IBDQ).

Patients treated with Velsipity compared to placebo demonstrated greater improvement from baseline in the total and all 4 domain scores of the IBDQ (bowel symptoms, systemic function, emotional function, and social function) at Week 12.

5.2 Pharmacokinetic Properties

Absorption.

Following etrasimod single oral dosing, C_max and AUC increased approximately dose proportionally in the dose range studied (0.1 mg to 5 mg). Following multiple dosing, mean C_max and AUC increased slightly more than dose proportional from 0.7 mg to 2 mg.
Steady state plasma concentrations are reached within 7 days following 2 mg once daily dosing, with a mean C_max of 113 nanogram/mL and AUC_tau of 2163 h*nanogram/mL. Steady state etrasimod accumulation is approximately 2- to 3-fold greater than single dose.
The pharmacokinetics of Velsipity is similar in healthy subjects and subjects with UC.
The time (T_max) to reach maximum plasma concentrations (C_max) after oral administration of immediate release oral dosage forms of etrasimod is approximately 4 hours (range 2 - 8 hours). Etrasimod absorption is extensive, based on high permeability and observation of relatively little intact etrasimod eliminated in the feces (11.2% of administered radioactive dose). Steady state exposure was reached within 7 days of dose initiation of etrasimod.

Effect of food.

Food intake can result in slightly delayed absorption (the median T_max increased by 2 hours). Food does not have an effect on etrasimod exposure measures (C_max and AUC); therefore, Velsipity can be administered without regard to meals.

Distribution.

Etrasimod distributes to body tissues with a mean oral volume (Vz/F) of distribution of 66 L. Etrasimod is highly protein bound, 97.9% to human plasma protein and mainly distributed in the plasma fraction of whole blood.

Metabolism.

Etrasimod is extensively metabolised by oxidation and dehydrogenation involving CYP2C8, CYP2C9, and CYP3A4, and with minor contribution via CYP2C19 and CYP2J2. UGTs and sulfotransferases are also involved in the metabolism of etrasimod. Unchanged etrasimod is the main circulating component in plasma.

Excretion.

After oral administration, the apparent steady state oral clearance (CL/F) was approximately 1 L/h. The mean plasma elimination half-life (t_1/2) of etrasimod is approximately 30 hours.
Etrasimod is primarily eliminated hepatically with 82% recovery of total radioactive dose in the faeces and 4.89% in the urine. Unchanged etrasimod was only detected in faeces, but not in urine.