Velsipity Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

1. 1.

   Indications ....................................................................................................................... 4

   1.1. Pediatrics .................................................................................................................. 4

   1.2. Geriatrics .................................................................................................................. 4

2. 2. Contraindications ............................................................................................................ 4
3. 4.

   Dosage and Administration ............................................................................................. 5

   4.1. Dosing Considerations .............................................................................................. 5

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 6

   4.4. Administration .......................................................................................................... 6

   4.5. Missed Dose ............................................................................................................. 7

4. 5. Overdose ......................................................................................................................... 7
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 7
6. 7.

   Warnings and Precautions ............................................................................................... 8

   Carcinogenesis and Genotoxicity .......................................................................................... 8

   Cardiovascular ...................................................................................................................... 8

   Driving and Operating Machinery ......................................................................................... 9

   Hepatic/Biliary/Pancreatic .................................................................................................... 9

   Immune ................................................................................................................................ 9

   Monitoring and Laboratory Tests ....................................................................................... 11

   Neurologic .......................................................................................................................... 11

   Ophthalmologic .................................................................................................................. 11

   Reproductive Health ........................................................................................................... 11

   Respiratory ......................................................................................................................... 12

   7.1. Special Populations ................................................................................................ 12

   7.1.1. Pregnancy ...................................................................................................... 12

   7.1.2. Breastfeeding ................................................................................................ 12

   7.1.3. Pediatrics ....................................................................................................... 13

   7.1.4. Geriatrics ....................................................................................................... 13

7. 8.

   Adverse Reactions ......................................................................................................... 13

   8.1. Adverse Reaction Overview .................................................................................... 13

   8.2. Clinical Trial Adverse Reactions .............................................................................. 13

   8.3. Less Common Clinical Trial Adverse Reactions ....................................................... 17

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................... 17

8. 9.

   Drug Interactions ........................................................................................................... 18

   9.3. Drug-Behaviour Interactions .................................................................................. 18

   9.4. Drug-Drug Interactions ........................................................................................... 18

   9.5. Drug-Food Interactions........................................................................................... 21

   9.6. Drug-Herb Interactions ........................................................................................... 21

   9.7. Drug-Laboratory Test Interactions ......................................................................... 21

9. 10.

   Clinical Pharmacology ................................................................................................... 21

   10.1. Mechanism of Action .............................................................................................. 21

   10.2. Pharmacodynamics ................................................................................................ 21

   10.3. Pharmacokinetics ................................................................................................... 23

10. 11. Storage, Stability, and Disposal ...................................................................................... 24

Part 2: Scientific Information ................................................................................................ 25

1. 13. Pharmaceutical Information .......................................................................................... 25
2. 14.

   Clinical Trials .................................................................................................................. 25

   14.1. Clinical Trials by Indication ..................................................................................... 25

3. 15. Microbiology ................................................................................................................. 31
4. 16. Non-Clinical Toxicology .................................................................................................. 31

Patient Medication Information ........................................................................................... 33

Part 1: Healthcare Professional Information

1. Indications

VELSIPITY (etrasimod) is indicated for:

• the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response, lost response, or were intolerant to either conventional therapy or an advanced treatment.

  1.1. Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2. Geriatrics

There are limited data available on patients aged 65 years and older. No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (see 10.3 Pharmacokinetics). No dose adjustment is needed in patients over 65 years of age. In general, use of VELSIPITY 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.

2. Contraindications

VELSIPITY is contraindicated in the following circumstances:

• In patients with hypersensitivity to the active substance or to any of the non-medicinal ingredients listed in 6 Dosage Forms, Strenght, Composition and Packaging (see Table 1).
• In patients who, in the last 6 months, have experienced a myocardial infarction, unstable angina pectoris, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or New York Heart Association (NYHA) Class III/IV heart failure.
• In patients with a history of 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.
• In patients with increased risk of opportunistic infections, including those who are immunocompromised due to treatment (e.g., antineoplastic, immunosuppressive or immunomodulating therapies, total lymphoid irradiation or bone marrow transplantation) or disease (e.g., immunodeficiency syndrome) (see 7 Warnings and Precautions).
• In patients with severe active infections, active chronic infections.
• In patients with active malignancies.
• During pregnancy and in women of childbearing potential not using effective contraception (see 7 Warnings and Precautions and 7.1.1 Pregnancy).
• In breast-feeding women (see 7.1.2 Breastfeeding).

4. Dosage and Administration

4.1. Dosing Considerations

Before initiation of treatment with VELSIPITY, assess the following:

Cardiac Evaluation

Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist should be sought (see 2 Contraindications and 7 Warnings and Precautions).

Complete Blood Count

Obtain a recent complete blood count (CBC), including lymphocyte count (i.e., within the last 6 months or after discontinuation of prior ulcerative colitis (UC) therapy. See 7 Warnings and Precautions.

Liver Function Tests

Obtain recent (i.e., within the last 6 months) transaminase and bilirubin levels (see 7 Warnings and Precautions).

Ophthalmic Assessment

Obtain an evaluation of the fundus, including the macula near the start of treatment with VELSIPITY (see 7 Warnings and Precautions)

Current or Prior Medications

• Determine if patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction (see 7 Warnings and Precautions).
• If patients are taking anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immune system effects before initiating treatment with VELSIPITY (see 2 Contraindications, 7 Warnings and Precautions and 9.4 Drug-Drug Interactions).

Vaccinations

Update immunizations in agreement with current immunization guidelines prior to initiating VELSIPITY therapy (see 7 Warnings and Precautions and 9.4 Drug-Drug Interactions).

If live attenuated vaccine immunizations are required, administer at least 4 weeks prior to initiation of VELSIPITY.

Pregnancy

Pregnancy must be excluded before start of treatment as VELSIPITY may cause fetal harm. Consult the patient about the risk of becoming pregnant while taking etrasimod (see 2 Contraindications, 7 Warnings and Precautions and 7.1.1 Pregnancy).

Respiratory

Etrasimod should be used with caution in patients with severe respiratory disease (e.g., pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease). Spirometric evaluation of respiratory function should be performed at baseline and during therapy with VELSIPITY if clinically indicated.

4.2. Recommended Dose and Dosage Adjustment

The recommended dose of VELSIPITY is 2 mg taken once daily taken orally.

Special populations

Elderly

There are limited data available on patients aged 65 years and older. No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (10.3 Pharmacokinetics). No dose adjustment is needed in patients over 65 years of age. In general, VELSIPITY in elderly patients should be used with caution, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal impairment

No dose adjustment is needed for patients with renal impairment (10.3 Pharmacokinetics).

Hepatic impairment

Use of VELSIPITY in patients with severe hepatic impairment is not recommended. No dosage adjustment is needed in patients with mild to moderate hepatic impairment. (10.3 Pharmacokinetics).

Pediatric population

The safety and efficacy of VELSIPITY in children and adolescents has not been established.

4.4. Administration

Oral use.

VELSIPITY should be swallowed whole and can be administered with or without food (see 10.3 Pharmacokinetics).

First dose cardiac monitoring

Due to the risk of transient decreases in heart rate with the initiation of etrasimod, first dose, 4-hour monitoring for signs and symptoms of symptomatic bradycardia after the first dose is recommended in patients with resting heart rate < 50 bpm, first degree or 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 prior 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 periods:

• 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.
• QTc interval is ≥ 500 msec.

In these cases, appropriate management should be initiated, and observation should continue until the symptoms/findings have resolved. If medical treatment is required, monitoring should be continued overnight, and a 4 -hour monitoring period should be repeated after the second dose of etrasimod (see section 10.2 Pharmacodymanics).

4.5. Missed Dose

If a dose is missed, the patient should be advised to take the dose as soon as remembered. However, if a missed dose is forgotten for the whole day, the patient should skip the missed dose and take the next dose at the usual time. The patient should not double the dose to make up for a forgotten dose. Patients who miss a dose for 2 or more consecutive days within the first week of treatment or for more than seven consecutive days should contact their health care provider to discuss treatment re-initiation.

5. 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. The decrease in heart rate induced by etrasimod can be reversed by parenteral atropine.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

1. 6. Dosage Forms, Strengths, Composition, and Packaging

Table 1 – Dosage Forms, Strengths, and Composition

Description

Tablet: 2 mg VELSIPITY are green, round, film-coated tablets, debossed with “ETR” on one side and “2” on the other side.

Packaging

VELSIPITY is packaged in blister or bottle. Each blister pack contains 28 tablets (2x14 aluminum blister strips) or 98 tablets (7x14 aluminum blister strips). Each bottle will contain 30 tablets.

7. Warnings and Precautions

Carcinogenesis and Genotoxicity

Malignancies

Cases of malignancies (including cutaneous malignancies) have been reported in patients treated with S1P receptor modulators. Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. These patients should not receive concomitant phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Cardiovascular

Prior to treatment initiation with etrasimod, an ECG in all patients should be obtained to assess for pre-existing cardiac abnormalities. Initiation of etrasimod may result in a transient decrease in heart rate and AV conduction delays (see 8 Adverse Reactions and 10 Clinical Pharmacology).

Decrease in heart rate

Transient decreases in heart rate were observed in healthy subjects and UC patients that were most pronounced following the first dose of 2 mg etrasimod. In UC patients, the largest mean decrease in heart rate occurred 2-3h post dose (see 10 Clinical Pharmacology).

Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, such as dizziness, and these symptoms resolved without intervention.

AV Conduction Delays

PR interval prolongation was observed in healthy subjects and UC patients that was most pronounced following the first dose of 2mg etrasimod. This resulted in incidences of first- or second-degree Mobitz type I AV blocks in UC patients administered etrasimod that were not observed in patients administered placebo (see 8 Adverse Reactions and 10 Clinical Pharmacology).

If treatment with VELSIPITY is considered, consultation with a cardiologist should be sought, for those individuals:

• With significant QT prolongation (QTcF ≥ 450 msec in males, ≥ 470 msec in females) or receiving QT prolonging drugs.
• With arrhythmias requiring treatment with Class Ia or Class III anti-arrhythmic drugs.
• With ischemic heart disease, heart failure, history of cardiac arrest, cerebrovascular disease (occurring more than 6 months prior to treatment initiation). It should be noted that VELSIPITY may be contraindicated in patients who, in the last 6 months, have experienced these conditions (see 2 Contraindications).
• With 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 with Mobitz type I second-degree AV block, unless the patient has a functioning pacemaker.

Driving and Operating Machinery

No studies on the effects on the ability to drive and the use of machines have been performed. However, patients who experience dizziness after taking etrasimod should refrain from driving or operating dangerous equipment until the dizziness resolves (see 8 Adverse Reactions).

Hepatic/Biliary/Pancreatic

Liver injury: Elevations of aminotransferases may occur in patients receiving etrasimod (see 8 Adverse Reactions). Recent (i.e., within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with etrasimod.

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 etrasimod should be discontinued if significant liver injury is confirmed.

Use of VELSIPITY in patients with severe hepatic impairment is not recommended. No dosage adjustment is needed in patients with mild to moderate hepatic impairment (see 7 Warnings and Precautions and 10.3 Pharmacokinetics).

Immune

Risk of infections: Etrasimod 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 10 Clinical Pharmacology). Etrasimod may, therefore, increase the susceptibility to infections (see 8 Adverse Reactions).

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).

The initiation of etrasimod in patients with any active infection should be delayed until the infection is resolved (see 2 Contraindications).

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 5 weeks after discontinuation of etrasimod, vigilance for infection should be continued throughout this period (see 10 Clinical Pharmacology). In 90% of subjects, peripheral blood absolute lymphocyte counts returned to normal range within 2 weeks of stopping therapy.

Progressive multifocal leukoencephalopathy (PML)

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 etrasimod-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 etrasimod should be suspended until PML has been excluded by an appropriate diagnostic evaluation.

If PML is confirmed, treatment with etrasimod should be discontinued.

Herpes Viral Infection

In a 52 week pivotal UC clinical study, herpes zoster was reported in 0.7% of subjects treated with etrasimod, and none in subjects who received placebo. Herpes simplex encephalitis and varicella zoster meningitis have been reported with other S1P receptor modulators. Physicians should be vigilant for clinical symptoms that may be suggestive of serious herpetic infections.

Cryptococcal Infection

Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with other S1P receptor modulators. Physicians should be vigilant for clinical symptoms or signs of CM. Patients with symptoms or signs consistent with a cryptococcal infection should undergo prompt diagnostic evaluation and treatment. Etrasimod treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.

Prior and concomitant treatment with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies

In ELEVATE UC 52 and ELEVATE UC 12, patients who received etrasimod were not to receive concomitant treatment with anti-neoplastic, 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 and did not appear to influence the safety or efficacy of etrasimod; however long-term data on concomitant use of etrasimod and corticosteroids are limited (see 10 Clinical Pharmacology).

VELSIPITY is contraindicated in patients with increased risk of opportunistic infections, including those who are immunocompromised due to treatment (e.g., antineoplastic, immunosuppressive or immunomodulating therapies, total lymphoid irradiation or bone marrow transplantation) or disease (e.g., immunodeficiency syndrome) immunodeficient state.

When switching to etrasimod 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.

Immunizations: No clinical data are available on the safety and efficacy of vaccinations in patients taking etrasimod. Vaccinations may be less effective if administered during etrasimod treatment. If live attenuated vaccine immunizations are required, administer at least 4 weeks prior to initiation of etrasimod. Avoid the use of live attenuated vaccines during and for 2 weeks after treatment with etrasimod.

Update immunizations in agreement with current immunization guidelines prior to initiating VELSIPITY therapy.

Monitoring and Laboratory Tests

Increased blood pressure: In clinical studies, hypertension was more frequently reported in patients treated with etrasimod than in patients treated with placebo (see 8 Adverse Reactions). Blood pressure should be monitored during treatment with etrasimod and managed appropriately.

Neurologic

Posterior reversible encephalopathy syndrome (PRES): Rare cases of PRES have been reported in patients receiving other S1P receptor modulators. Such events have not been reported for etrasimod-treated patients in the development program. Should an etrasimod-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 haemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with etrasimod should be discontinued.

Ophthalmologic

Macular oedema: S1P receptor modulators, including VELSIPITY, have been associated with an increased risk of macular oedema. Macular oedema with or without visual symptoms has been reported in 0.3% of patients in ELEVATE UC 12 and ELEVATE UC 52 trials treated with etrasimod.

Patients with a history of diabetes mellitus, uveitis, or underlying/coexisting retinal disease, are at increased risk of macular oedema during etrasimod therapy (see 8 Adverse Reactions).

An ophthalmic evaluation of the fundus, including the macula, should be conducted near the start of treatment with VELSIPITY, periodically while on therapy, and at any time if there is change in vision.

Patients who present with visual symptoms of macular oedema should be evaluated and, if confirmed, treatment with etrasimod should be discontinued. 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.

Reproductive Health

VELSIPITY is contraindicated in women who are pregnant or of childbearing potential not using effective contraception. Females of childbearing potential must use effective contraception (See 2 Contraindications, 7.1.1 Pregnancy).

• Fertility

  The effect of etrasimod on human fertility has not been evaluated. In animal studies, no adverse effects on fertility were observed (see 16 Non-Clinical Toxicology).

Respiratory

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 etrasimod (see 10 Clinical Pharmacology). Etrasimod should be used with caution in patients with severe respiratory disease (e.g., pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease). Spirometric evaluation of respiratory function should be performed at baseline and during therapy with VELSIPITY if clinically indicated.

7.1. Special Populations

Women of childbearing potential: Before initiation of etrasimod 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 etrasimod (see 7.1.1 Pregnancy).

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 etrasimod.

7.1.1. Pregnancy

• effective contraception. There are no adequate and well-controlled studies on the developmental risk associated with the use of etrasimod in pregnant women. Based on the data from animal reproductive and developmental toxicity studies and its mechanism of action, VELSIPITY may cause fetal harm when administered to a pregnant woman.

Teratogenic Risk

There are no adequate and well-controlled studies in pregnant women. When etrasimod was orally administered to pregnant rats and rabbits during the period of organogenesis foetal visceral and or skeletal malformations and variations were observed. Maternal plasma AUC at the lowest dose tested in rats was approximately 5 times that in humans at the recommended human dose (RHD) of 2 mg per day and in rabbits, maternal plasma AUC at the no-adverse effect dose (2 mg/kg/day) was approximately 0.8 times that in humans of the RHD of 2 mg/day (see 7.1.1 Pregnancy and 16 Non-Clinical Toxicology).

• development, including embryolethality and fetal malformations, in both rats and rabbits at clinically relevant maternal exposures (see 16 Non-Clinical Toxicology).

• VELSIPITY during pregnancy. Pregnant females exposed to VELSIPITY and healthcare providers are encouraged to contact the pregnancy registry by calling 1-800-616-3791.

  7.1.2. Breastfeeding

• -feeding women. Although it is unknown whether etrasimod 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.

  7.1.3. Pediatrics

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4. Geriatrics

There are limited data available on patients aged 65 years and older. No clinically significant differences in the pharmacokinetics of etrasimod were observed based on age (see 10.3 Pharmacokinetics). No dose adjustment is needed in patients over 65 years of age. In general, use of VELSIPITY 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.

8. Adverse Reactions

8.1. Adverse Reaction Overview

The most common adverse drug reactions are lymphopenia (11%), headache (7%) and elevated liver enzymes (5%).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

The safety of VELSIPITY was evaluated in 2 randomized, double-blind, placebo-controlled clinical studies (ELEVATE UC 52, n = 289; and ELEVATE UC 12, n = 238) in patients 16 to 80 years of age with mMS 4 to 9. Additional data from a phase 2 (12-week placebo-controlled) (OASIS UC) study included 50 patients who received VELSIPITY 2 mg once daily. Elevate UC 52-week study safety data and pooled safety data from 12 week studies (Elevate UC 12 and OASIS UC) are presented separately.

Table 2: Treatment- Emergent Adverse Events Reported by ≥1% of Patients Treated with VELSIPITY and ≥1% higher than placebo- UC Phase 3 52-week Study

Note: TEAEs are defined as any adverse event that started on or after the first dose of study treatment. Terms are coded using MedDRA v24.1. Percentages are based on the number of subjects in the analysis set. Adverse events are sorted by decreasing frequency of preferred term in the etrasimod treatment group. Subjects are counted only once per summarization level; [n] is defined as the number of events.

^a Bradycardia includes bradycardia and sinus bradycardia

^b Urinary tract infection includes urinary tract infection and cystitis

^c Herpes viral infection includes herpes zoster, oral herpes and herpes simplex

^d Upper respiratory tract infection includes pharyngitis, rhinorrhoea and sinusitis

^e Elevated liver enzymes includes alanine aminotransferase increased, gamma-glutamyltransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased, blood alkaline phosphatase increased, cholestasis, hyperbilirubinaemia and liver function test increased

^f Hypercholesterolaemia includes hypercholesterolaemia and blood cholesterol increased

^g Dizziness includes dizziness, dizziness exertional and dizziness postural

^h Headache includes headache, migraine and tension headache

ⁱ Hypertension includes hypertension and blood pressure increased

Table 3: Treatment- Emergent Adverse Events Reported by ≥1% of Patients Treated with VELSIPITY and ≥1% higher than placebo- UC 12-week Studies

Note: TEAEs are defined as any adverse event that started on or after the first dose of study treatment. Terms are coded using MedDRA v24.1. Percentages are based on the number of subjects in the analysis set. Adverse events are sorted by decreasing frequency of preferred term in the etrasimod treatment group. Subjects are counted only once per summarization level ^a Bradycardia includes bradycardia and sinus Bradycardia

^b Urinary tract infection includes urinary tract infection and cystitis

^c Upper respiratory tract infection includes pharyngitis, rhinorroea and sinusitis

^d Herpes viral infection includes herpes zoster, oral herpes and herpes simplex

^e Elevated liver enzymes includes alanine aminotransferase increased, gamma-glutamyltransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, transaminases increased, blood alkaline phosphatase increased, cholestasis, hyperbilirubinaemia and liver function test increased

^f Hypercholesterolaemia includes hypercholesterolaemia and blood cholesterol increased

^g Dizziness includes dizziness, dizziness exertional and dizziness postural

^h Headache includes headache, migraine and tension headache

ⁱ Hypertension includes hypertension and blood pressure increased

Bradyarrhythmia

In ELEVATE UC 52, bradycardia was reported on the day of treatment initiation in 3 (1.0%) 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 both UC 12 week studies, bradycardia was reported on the day of treatment initiation in 7 (2.4%) 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 2 (0.6%) VELSIPITY -treated patients compared to none in placebo in ELEVATE UC 52 and in 1 (0.4%) of VELSIPITY treated patient compared to none in placebo in pooled both UC 12 week studies. No events of second degree Mobitz type II AV block or higher AV block were reported in patients treated with VELSIPITY in any of these studies.

Infections

In ELEVATE UC 52, the overall rate of infections in subjects treated with VELSIPITY was 24.9% compared to 22.2% in subjects who received placebo. In both UC12 week studies, the overall rate of infections in subjects treated with VELSIPITY was 14.0% compared to 11.8% in subjects who received placebo. The most common infections were urinary tract infections, which were higher in VELSIPITY treated subjects.

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 both UC 12 Week studies.

Elevated hepatic enzymes

In ELEVATE UC 52, elevations of ALT to 5-fold the ULN or greater occurred in 2 (0.7%) patients treated with VELSIPITY and 1 (0.7%) patients who received placebo, and in both UC 12 week studies elevations of ALT to 5-fold the ULN or greater occurred in 2 (0.7%) 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 13 (4.5%) patients treated with VELSIPITY and 1 (0.7%) patient who received placebo, and in both UC 12 week studies elevations of ALT to 3-fold the ULN or greater occurred in 6 (2.1%) 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.

Increased blood pressure

In ELEVATE UC 52 and both UC-12 week studies, patients treated with VELSIPITY had an average increase of approximately 1 to 4 mm Hg in systolic blood pressure and approximately 1 to 2 mm Hg in diastolic blood pressure compared to < 1.5 mm Hg and < 1 mm Hg 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. In ELEVATE UC 52, hypertension was reported as an adverse event in 9 (3.1%) patients treated with VELSIPITY and 1 (0.7%)

patient who received placebo. In both UC 12 week studies, hypertension was reported as an adverse event in 5 (1.7%) patients treated with VELSIPITY and 2 (1.2%) patients who received placebo. The majority of hypertension events were mild or moderate in severity.

Macular oedema

In ELEVATE UC 52, macular oedema was reported in 1 patient (0.3%) treated with VELSIPITY and in no patients receiving placebo. In both UC 12 week studies, macular oedema was reported in 1 patient (0.4%) treated with VELSIPITY and in 1 patient (0.9%) receiving placebo.

Herpes viral infections

Cases of localized herpes viral infection were seen with S1P receptor modulators, including VELSIPITY. In ELEVATE UC 52, herpes zoster was reported in 2 (0.7%) patients treated with VELSIPITY and in none of the patients who received placebo. In both UC 12 week studies, herpes zoster was reported in none of the patients treated with VELSIPITY and in 2 (1.2%) patients who received placebo. In ELEVATE UC 52, oral herpes was reported in 2 (0.7%) patients treated with VELSIPITY and in 1 (0.7%) patient who received placebo. In both UC 12 week studies, oral herpes was reported in 1 (0.3%) patient treated with VELSIPITY and in none of the patients who received placebo. In ELEVATE UC 52, herpes simplex was reported in 1 (0.3%) patient treated with VELSIPITY and in none of the patients who received placebo.

8.3. Less Common Clinical Trial Adverse Reactions

The following is a list of treatment-emergent adverse events reported by patients treated with VELSIPITY 2mg during the Induction and Maintenance studies at an incidence of < 1% but at an incidence of ≥ 0.5% higher in the VELSIPITY group than placebo.

Cardiac disorders: atrioventricular block

Gastrointestinal disorders: abdominal pain lower

Infections and Infestations: anal abscess, hordeolum

Investigations: blood triglycerides increased

Metabolism and nutrition disorders: hypophosphataemia

Nervous system disorders: somnolence

Psychiatric disorders: anxiety

Skin and Subcutaneous Tissue Disorders: night sweats

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Clinical Trial Findings

Table 4 - Abnormal lab findings with an incidence of greater than or equal to 1% for VELSIPITY and ≥1% higher than placebo- UC 12-week Studies

Table 5 - Abnormal lab findings with an incidence of greater than or equal to 1% for VELSIPITY and ≥1% higher than placebo- UC 52-week Study

9. Drug Interactions

9.3. Drug-Behaviour Interactions

The interactions with behavioral risks have not been studied.

9.4. Drug-Drug 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, or 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.

The strong CYP2C8 inhibitor gemfibrozil and the strong CYP3A4 inhibitor itraconazole increased exposure (AUC) of etrasimod by 36% and 32%, respectively. These changes in exposure are unlikely to be clinically significant.

CYP2C9 Polymorphisms Due to the potential for increased exposure of etrasimod, co-administration of etrasimod in patients who are known or suspected to be CYP2C9 poor metabolizers 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 CYPs (CYP2C8, CYP2C9, and CYP3A4) (e.g., rifampicin) decreases the exposure of VELSIPITY and is not recommended.

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).

Initiation of a beta blocker in patients receiving stable VELSIPITY therapy has not been studied.

The effect of co-administration of VELSIPITY and a calcium channel blocker has not been studied.

Anti-arrhythmic drugs, QT prolonging drugs, drugs that may decrease heart rate

VELSIPITY has not been studied in patients taking QT prolonging drugs.

Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic 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 anti-arrhythmic drugs, advice from a cardiologist should be sought (see 7 Warnings and Precautions).

Because of the potential additive effects on heart rate and/or QT interval, if treatment initiation with VELSIPITY is considered in patients on QT prolonging drugs, advice from a cardiologist should be sought (see 7 Warnings and Precautions).

Anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies

VELSIPITY is contraindicated in patients with increased risk of opportunistic infections, including those who are immunocompromised due to treatment (e.g., antineoplastic, immunosuppressive or immunomodulating therapies, total lymphoid irradiation or bone marrow transplantation) or disease (e.g., immunodeficiency syndrome) immunodeficient state. (see 2 Contraindications and 7 Warnings and Precautions).

Vaccination

Vaccinations may be less effective if administered during and for up to 2 weeks after discontinuation of treatment with VELSIPITY. The use of live attenuated vaccine may carry the risk of infection and should therefore be avoided during VELSIPITY treatment and for 2 weeks after discontinuation of treatment with VELSIPITY (see 7 Warnings and Precautions).

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 CYPs or membrane transporters. and therefore not expected to impact exposures of coadministered drugs.

Oral contraceptives

No clinically significant differences in the pharmacokinetics and pharmacodynamics of an oral contraceptive containing 30 mcg ethinyl estradiol and 150 mcg levonorgestrel were observed when coadministered with etrasimod. In patients susceptible to oral contraceptive-induced elevated liver enzymes and cholestasis, the risk may be increased by etrasimod coadministration.

Table 6 - Established or Potential Drug-Drug Interactions

Legend: CT = Clinical Trial

9.5. Drug-Food Interactions

Food (high-fat meal) intake had no effect on etrasimod exposure (C_max and AUC)

9.6. Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7. Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10. Clinical Pharmacology

10.1. Mechanism of Action

Etrasimod is a sphingosine 1-phosphate receptor modulator that exhibits selectivity to S1P receptors 1, 4 and 5 (S1P1,4,5), with no activation of S1P2 receptors and minimal activation of S1P3 receptors. At the S1P1 receptor, etrasimod activates G-protein signalling and beta-arrestin recruitment. 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 sites of inflammation. The etrasimod-induced reduction of lymphocytes in the peripheral circulation has differential effects on leucocyte subpopulations, with greater decreases in cells involved in the adaptive immune response. Etrasimod has minimal impact on cells involved in innate immune response, which contribute to immunosurveillance.

10.2. Pharmacodynamics

Heart rate and rhythm

VELSIPITY may result in a transient decrease in heart rate and AV conduction upon treatment initiation (see 7 Warnings and Precautions and 8 Adverse Reactions). On Day 1, in UC patients from ELEVATE UC 52 and ELEVATE UC 12, the greatest mean decrease in heart rate was 7.3 bpm and observed at Hour 2 or 3 post dose.

Effect on PR interval

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 in ELEVATE UC 52 and ELEVATE UC 12 clinical trials.

All PR interval prolongations (including those reported as adverse events) post 1^st dose of etrasimod on Study Day 1 were overall transient, asymptomatic, did not require any treatment and participants remained hemodynamically stable.

Effect on QT interval

Exposure-response modelling showed that at plasma concentrations approximately 1.4-fold higher than expected clinically, the placebo-corrected, change from baseline increase in QTcF was 4.3msec (90% CI: 1.46, 7.18). Advice from a cardiologist should be sought prior to initiation of VELSIPITY treatment in patients with significant QT prolongation (QTcF ≥ 450 msec in males, ≥ 470 msec in females), or in patients receiving QT prolonging drugs or Class Ia or Class III anti-arrhythmic drugs because of the potential for these patients to exceed acceptable QTcF intervals (see 7 Warnings and Precautions and 9 Drug Interactions).

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.

Fecal Calprotectin (FCP)

In controlled clinical studies, treatment with etrasimod resulted in a reduction from baseline of fecal calprotectin at Week 12 compared to placebo.

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 etrasimod 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 etrasimod 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.

10.3. Pharmacokinetics

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 ng/mL and AUC_tau of 2163 h*ng/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 (See Table 7).

Table 7- Summary of etrasimod Mean (SD) Pharmacokinetic Parameters in Healthy Subjects Following Oral Dosing of VELSIPITY 2 mg Once Daily for 21 Days

^aMedian (min-max)

Absorption

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

Administration of etrasimod with food 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, etrasimod can be administered without regard to meals.

Distribution

Etrasimod distributes to body tissues with a mean oral volume of distribution (Vz/F) 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 metabolized by oxidation and dehydrogenation mediated primarily by CYP2C8 (38%), CYP2C9 (37%), and CYP3A4 (22%), with minor contributions of CYP2C19 and CYP2J2. In addition, etrasimod undergoes glucuronidation and sulfation mediated by UGTs and sulfotransferases. Unchanged etrasimod is the major circulating component in plasma.

Elimination

After oral administration, the apparent steady state oral clearance (CL/F) was approximately 1 L/h. The mean plasma effective elimination half-life (t_1/2) of etrasimod is approximately 30 hours. The primary route of excretion of etrasimod is via the hepatobiliary pathway. Administration of a radioactive single dose resulted in 82% being recovered in the feces and 4.9% being recovered in the urine after 336 hours. 11.2% of the recovered dose in feces was unchanged etrasimod, while no unchanged etrasimod was detected in urine.

Special populations and conditions

• Pediatrics: The safety and efficacy of VELSIPITY in children and adolescents have not been established.
• Geriatrics: Population pharmacokinetic analyses showed that age did not have an effect on the pharmacokinetics of etrasimod in patients over 65 years of age. There is no meaningful difference in the pharmacokinetics in elderly patients compared to younger patients.
• Sex: Sex has no clinically significant influence on etrasimod pharmacokinetics.
• Ethnic origin: No clinically relevant pharmacokinetic differences were observed between Japanese, Chinese, and Caucasian patients.
• Hepatic Insufficiency: Use of VELSIPITY in patients with severe hepatic impairment is not recommended. No dosage adjustment is needed in patients with mild to moderate hepatic impairment. The total etrasimod exposure (AUC) are 13%, 29%, and 57% higher in subjects with mild, moderate, and severe hepatic impairment, respectively, compared with subjects with normal liver function for the 2 mg single dose studied. The unbound etrasimod AUC in subjects with mild, moderate, and severe hepatic impairment was similar to subjects with normal liver function.
• Renal Insufficiency: No dose adjustments are needed in patients with renal impairment as Cmax and AUC were comparable between subjects with severe renal impairment (comprised of subjects with eGFR ≤ 29 mL/min) and subjects with normal renal function. The effect of hemodialysis on the pharmacokinetics of etrasimod was not evaluated.
• Body weight: Based on a population pharmacokinetic analysis, the predicted steady-state Cmax and AUC values of etrasimod are 25% and 23% higher in a low weight individual (50 kg) and 25.9% and 24.3% lower in a high weight individual (110 kg) compared to those in a reference individual (70 kg), respectively. The differences in Etrasimod exposure by body weight are not clinically significant.
• Storage, Stability, and Disposal

VELSIPITY does not require any special storage conditions.

Store VELSIPITY at room temperature (15°C to 30°C).

Keep out of reach and sight of children.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance(s): etrasimod L-arginine

Chemical name: L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl) acetic acid

Molecular formula and molecular mass: C₃₂H₄₀F₃N₅O₅ and 631.69 g/mol

Structure (for biologics)/Structural formula:

Physicochemical properties: Etrasimod L-arginine is a white, off-white to light brown solid that is slightly soluble in water.

14. Clinical Trials

14.1. Clinical Trials by Indication

Description of Clinical Studies

The efficacy of VELSIPITY was evaluated in 2 randomized, 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 (See Table 8).

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 erythema, 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.

Table 8 - Summary of patient demographics for clinical trials in ulcerative colitis

ELEVATE UC 52

ELEVATE UC 52 was a treat-through study, with a total of 433 patients randomized to receive VELSIPITY 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, histologic-endoscopic mucosal improvement, 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 9).

A significantly greater proportion of patients treated with etrasimod achieved clinical remission, endoscopic improvement, symptomatic remission, and histologic-endoscopic mucosal improvement at Week 12 and at Week 52, corticosteroid-free clinical remission and sustained clinical remission at Week 52, compared to placebo (see Table 9).

Table 9: Proportion of patients meeting efficacy endpoints at Week 12 and at Week 52 in ELEVATE UC 52

CI = confidence interval

^a Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).

^b Clinical remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline), RB subscore of 0, and ES ≤ 1 (excluding friability).

^c Endoscopic improvement was defined as ES ≤ 1 (excluding friability).

^d Symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline) and RB subscore of 0.

^e Histologic-endoscopic mucosal improvement was defined as ES ≤ 1 (excluding friability) with histologic remission (Geboes Index score < 2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue).

^f Corticosteroid-free clinical remission was defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks prior to Week 52.

^g Maintenance of clinical remission was defined as clinical remission at both Week 12 and Week 52.

Isolated proctitis

A greater proportion of patients with isolated proctitis at baseline treated with VELSIPITY compared to placebo achieved clinical remission at Week 12 (11 (46%) vs 2 (29%)) and Week 52 (10 (42%) vs 1 (14%)).

Corticosteroid-free clinical remission among patients treated with corticosteroids at baseline

At Week 52, a greater proportion of patients treated with VELSIPITY achieved corticosteroid-free clinical remission (defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks prior to Week 52) among patients treated with corticosteroids at baseline compared to placebo (n = 27 of 87, 31% vs n = 3 of 40, 8%).

Symptomatic remission by Week 2

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

ELEVATE UC 12

In ELEVATE UC 12, a total of 354 patients were randomized to receive VELSIPITY 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, and mucosal healing 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 10).

A significantly greater proportion of patients treated with VELSIPITY achieved clinical remission, endoscopic improvement, symptomatic remission, and histologic-endoscopic mucosal improvement compared to placebo at Week 12 (see Table 10).

Table 10 - Proportion of patients meeting efficacy endpoints at Week 12 in ELEVATE UC 12

CI = confidence interval

^a Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group).

^b Clinical remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline), RB subscore of 0, and ES ≤ 1 (excluding friability).

^c Endoscopic improvement was defined as ES ≤ 1 (excluding friability).

^d Symptomatic remission was defined as SF subscore of 0 (or 1 with a ≥ 1-point decrease from baseline) and RB subscore of 0.

^e Histologic-endoscopic mucosal improvement was defined as ES ≤ 1 (excluding friability) with histologic remission (Geboes Index score < 2.0, indicating no neutrophils in the epithelial crypts or lamina propria, no increase in eosinophils, and no crypt destruction, erosions, ulcerations, or granulation tissue).

Isolated proctitis

A greater proportion of patients with isolated proctitis at baseline treated with VELSIPITY compared to placebo achieved clinical remission at Week 12 (5 (39%) vs 1 (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%).

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General toxicology

Repeat-dose toxicity studies for up to 6 months in rats, 9 months in dogs and 91 days in mice were found with the no observed adverse effect levels (NOAELs) to be ≥102 times the exposure at RHD. Non-adverse effects were commonly associated with other S1P modulators, including reductions in lymphoid cell populations in lymphoid tissues, erythrocytosis or erythrophagocytosis were observed in treatment groups across all species. Higher lung weights with or without microscopic findings (alveolar histiocytosis, fibrin deposition, fibrosis of pleura), centrilobular/panlobular hepatocyte hypertrophy, and lower body weights were also observed. Treatment-related effects in the left ventricular arteries (hypertrophy/hyperplasia of the tunica media) were also observed in 3- and 9-month repeat-dose toxicity studies in dogs at ≥24 times RHD exposure in humans based on AUC.

Genotoxicity

Etrasimod was negative in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (rat micronucleus) assays.

Carcinogenicity

Oral carcinogenicity studies of etrasimod were conducted in mice and rats. In mice administered etrasimod (0, 2, 6, or 20 mg/kg/day) for up to 104 weeks, there was an increase in hemangiosarcoma and hemangioma at 6 and 20 mg/kg/day in males and females. The no-observed-effect level for tumors was 2 mg/kg/day (19 times that in humans at the recommended human dose (RHD). In rats, oral administration of etrasimod (0, 2, 6, or 20 mg/kg/day) for up to 91 weeks, did not result in an increase in tumors. Plasma VELSIPITY exposure (AUC) at the highest dose tested in male and female rats is approximately 80 to 179 times (respectively) that in humans at the RHD.

Reproductive and developmental toxicology

When etrasimod was administered orally to male (0, 25, 100, or 200 mg/kg/day) and female (0, 1, 2, or 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. Plasma etrasimod exposure (AUC) at the highest dose tested was approximately 467 (males) and 21 (females) times that in humans at the RHD.

When etrasimod (0, 1, 2, or 4 mg/kg/day) 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 (4 mg/kg/day) and visceral (all dose levels) malformations and skeletal variations (2 and 4 mg/kg/day) were noted. At ≥1 mg/kg/day (the lowest dose tested), the visceral malformations of aorticopulmonary septal defect, as well as the developmental variation of short brachiocephalic trunk were observed. A NOAEL was not established in this study, and maternal plasma AUC at 1 mg/kg/day was approximately 5 times that in humans at the RHD of 2 mg/day.

When etrasimod (0, 2, 10, or 20 mg/kg/day) was orally administered to pregnant rabbits during the period of organogenesis, postimplantation loss with a corresponding lower mean number of viable fetuses was observed at 10 and 20 mg/kg/day. Etrasimod-related fetal visceral malformations of the aortic arch (bulbous aortic arch and/or coarctation of the aortic arch) were observed at ≥10 mg/kg/day and fetal skeletal malformations (fused sternebrae) at 20 mg/kg/day. There were no effects on embryofetal development at 2 mg/kg/day. Maternal plasma exposure (AUC) at the NOAEL dose (2 mg/kg/day) was approximately 0.8 times that in humans at the RHD of 2 mg/day.

Oral administration of etrasimod (0, 0.4, 2, or 4 mg/kg/day) to female rats throughout pregnancy and lactation resulted in increased gestation length in F0 dams at 2 and 4 mg/kg/day, decreased mean pup weights at all dose levels during the preweaning period, lower pup viability at 2 and 4 mg/kg/day, lower pup survival during the lactation period at 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 neurobehavioral function in offspring at any dose level tested. Plasma exposure (AUC) in dams at the NOAEL was equivalent (1.1 times) to those in humans at the RHD. Etrasimod was detected in the plasma of F1 pups, indicating exposure from the milk of the lactating dam.