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Trial DesignEvaluated in two phase 3 trials1,2

UC-1 and UC-2 were randomized, double-blind, placebo-controlled trials1,2

 Adapted with permission from Sandborn et al, Lancet. 2023.2

Select inclusion criteria1,2:

  • Adults with moderately to severely active UC with an inadequate response, a loss of response, or an intolerance to ≥1 treatment options: oral aminosalicylates, corticosteroids, thiopurines, JAKi, or biologics (eg, TNF blockers, anti-integrins, and anti-IL 12/23)
  • Disease severity was assessed in patients with a modified Mayo score (mMS)† of 5 to 9 at baseline
  • Concomitant use of select UC therapies‡ was permitted, including stable daily doses of oral 5-ASAs and/or oral corticosteroids
  • Patients with isolated proctitis were allowed to enroll (<10 cm of rectal involvement at baseline and met all other inclusion criteria)
Select exclusion criteria1:
  • Concomitant treatment with immunomodulators, biologics, JAKi, rectal 5-ASAs, or rectal corticosteroids

Primary efficacy analysis was done in patients with an mMS† of 5 to 9.1

Primary endpoints1:
Clinical remission at week 12 (UC-1 and UC-2) and at week 52 (UC-1)

Select key secondary endpoints1,2:
Corticosteroid-free remission (UC-1), symptomatic remission, and endoscopic improvement

Other prespecified secondary endpoint2:
Clinical response

In UC-1, patients whose disease had not improved or had worsened vs baseline (per investigator judgment), could discontinue treatment and, if objective disease worsening criteria were met (having an RB subscore ≥2 or an RB subscore and an SF subscore ≥4 at 2 time points ≥7 and ≤14 days apart), enroll in the OLE. In UC-2, at the end of week 12, patients could enroll in the OLE. In both trials, patients who did not enroll in the OLE entered a 4-week follow-up period, with visits at week 2 and at week 4.2Modified Mayo score (an mMS of 0 to 9) consists of stool frequency (0 to 3), rectal bleeding (0 to 3), and findings on a centrally read endoscopy score (0 to 3).1Oral aminosalicylates and/or oral corticosteroids (≤20 mg/day prednisone, ≤9 mg/day budesonide, or equivalent steroid). Therapies not permitted were immunomodulators, biologics, JAKi, rectal 5-ASAs, or rectal corticosteroids.1OLE=open-label extension; R=randomization; TNF=tumor necrosis factor.View inclusion and exclusion criteriaInclusion criteria included1,2:
  • Adults with moderately to severely active UC (an mMS* of 5 to 9) who had an inadequate response, a loss of response, or an intolerance to ≥1 treatment options: oral aminosalicylates, corticosteroids, thiopurines, JAKi, or biologics (eg, TNF blockers, anti-integrins, anti-IL 12/23)
  • Concomitant use of select UC therapies† was permitted, including stable daily doses of oral 5-ASAs and/or oral corticosteroids (prednisone [≤20 mg/day], budesonide [≤9 mg/day], or equivalent steroid), provided they were on a stable dose 2 weeks or 4 weeks, respectively, before trial screening
  • Patients with isolated proctitis were allowed to enroll (<10 cm of rectal involvement at baseline and met all other criteria); enrollment was capped at 15% of total patients
Exclusion criteria included1,2:
  • Concomitant treatment with immunomodulators, biologics, JAKi, rectal 5-ASAs, or rectal corticosteroids
  • Previous treatment with ≥3 biologics or ≥2 biologics plus a JAKi
  • A clinically relevant cardiovascular condition‡
  • A history of opportunistic infections or macular edema
  • Pregnancy or lactation
Modified Mayo score (an mMS of 0 to 9) consists of stool frequency (0 to 3), rectal bleeding (0 to 3), and findings on a centrally read endoscopy score (0 to 3).1Therapies not permitted were immunomodulators, biologics, JAKi, rectal 5-ASAs, or rectal corticosteroids.1Contraindicated in patients with specific cardiovascular conditions. Select cardiovascular Warnings & Precautions: Bradyarrhythmia & AV Conduction Delays. See USPI.1View baseline characteristics

UC-1 and UC-2 included patients1,3:

  • Who were biologic or JAKi naive or who had prior exposure*
  • Who may have received concomitant treatment for UC at baseline
 
UC-1
(N=408)
UC-2
(N=333)
Mean age (range) 41 years (18-78) 41 years (18-73)
Gender (female) 45% 41%
Race or ethnicity    
     White 89% 76%
     Asian 7% 19%
     Black or African American 2% 1%
     American Indian or Alaska Native 1% 2%
     Multiple ethnic groups or did not report 1% 2%
Biologic/JAKi exposure*    
     Biologic or JAKi naive 70% 66%
     Biologic or JAKi prior exposure
         >1 biologic or JAKi exposure		 30%
14%		 34%
17%
Concomitant treatment for UC at baseline    
     Oral corticosteroids 31% 28%
     Oral aminosalicylates (5-ASAs) 68% 66%
     Median high-sensitivity C-reactive
     protein, mg/dL (range)           		 4.2 (0.2-108.4) 3.3 (0.2-96.7)
     Median fecal calprotectin, μg/g (range)
1137
(3.8-46,189.8)
953
(4.2-41,194.2)
Prior biologics included TNF blockers, anti-integrins, and anti-IL 12/23.1View baseline characteristics

UC-1 and UC-2 included patients1,3:

  • Who were biologic or JAKi naive or who had prior exposure*
  • Who may have received concomitant treatment for UC at baseline
 
UC-1
(N=408)
UC-2
(N=333)
Mean age (range) 41 years (18-78) 41 years (18-73)
Gender (female) 45% 41%
Race or ethnicity    
White 89% 76%
Asian 7% 19%
Black or African American 2% 1%
American Indian or Alaska Native 1% 2%
Multiple ethnic groups or did not report 1% 2%
Biologic/JAKi exposure*    
Biologic or JAKi naive 70% 66%
Biologic or JAKi prior exposure
>1 biologic or JAKi exposure		 30%
14%		 34%
17%
Concomitant treatment for UC at baseline    
Oral corticosteroids 31% 28%
Oral aminosalicylates (5-ASAs) 68% 66%
Median high-sensitivity C-reactive
protein, mg/dL (range)           		 4.2 (0.2-108.4) 3.3 (0.2-96.7)
Median fecal calprotectin, μg/g (range)
1137
(3.8-46,189.8)
953
(4.2-41,194.2)
Prior biologics included TNF blockers, anti-integrins, and anti-IL 12/23.1See endpoints and definitions

Primary and secondary endpoints1,2

Scroll left to view table
  Time points when endpoints were assessed Met endpoints
  Endpoints UC-1 UC-2 ELEVATE
UC-52
(UC-1)		 ELEVATE
UC-12
(UC-2)
Primary
endpoint		 Clinical remission
  • SF subscore of 0 or 1
  • RB subscore of 0
  • ES ≤1 (excluding friability)
 Week 12;
week 52
(co-primary endpoints)		 Week 12
(primary endpoint)
Key secondary endpoints Endoscopic improvement
  • ES ≤1 (excluding friability)
 Week 12;
week 52		 Week 12
Symptomatic remission
  • SF subscore of 0 (or SF subscore of 1 with a ≥1-point decrease from baseline)
  • RB subscore of 0
Histologic-endoscopic mucosal improvement
  • ES ≤1 (excluding friability)
  • Histologic remission measured by a Geboes Index score <2.0
Corticosteroid-free clinical remission
  • Clinical remission at week 52 in patients who had not received corticosteroids for ≥12 weeks prior to week 52
 Week 52 N/A
Maintenance of clinical remission
  • Clinical remission at week 12 and at week 52 
Scroll left to view table
Other prespecified
secondary endpoint		 Definitions Time points when endpoint was assessed
Clinical response
  • ≥2-point and a ≥30% decrease from baseline in mMS
  • ≥1-point decrease from baseline in RB subscore or absolute RB ≤1
 Week 12; week 52 Week 12
Not controlled for multiplicity.
Learn about treat-through vs rerandomization trial design

Treat-through trials include nonresponders or patients who respond late to treatment2,4

  • In a treat-through trial, patients remain in their treatment arm for the duration of the trial
  • UC-1 remains the first and only 52-week, phase 3, treat-through trial of an S1P receptor modulator in UC
  • Treat-through trials have been used previously to assess the efficacy of TNF inhibitors for UC

Rerandomization trial design4-6

  • In a rerandomization trial, induction responders are rerandomized for maintenance treatment; therefore, maintenance data only reflect potential outcomes for induction responders4
  • Rerandomization trials have been used previously to assess the efficacy of JAK inhibitors and majority of biologics in UC5,6

Cross-trial comparisons should not be made.

RR=rerandomization.

Safety

Take a look at safety information for VELSIPITY.

 View Safety Data LoadingReferences:VELSIPITY [prescribing information]. New York, NY: Pfizer Inc.; June 2024.Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies [published correction appears in Lancet. 2023;401(10381):1000]. Lancet. 2023;401(10383):1159-1171.Data on file. Pfizer Inc.Ghosh S, Sandborn WJ, Colombel JF, et al. Interpreting registrational clinical trials of biological therapies in adults with inflammatory bowel diseases. Inflamm Bowel Dis. 2016;22(11):2711-2723.Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis [published correction appears in N Engl J Med. 2006;354(20):2200]. N Engl J Med. 2005;353(23):2462-2476.Sandborn WJ, Baert F, Danese S, et al. Efficacy and safety of vedolizumab subcutaneous formulation in a randomized trial of patients with ulcerative colitis. Gastroenterology. 2020;158(3):562-572.e12.Efficacy

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PP-V1A-USA-0857
IndicationVELSIPITY® (etrasimod) is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults.
Important Safety Information Contraindications
  • Patients in the last 6 months who experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure
  • Patients with a history or presence of Mobitz type II second-degree or third-degree AV block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker
Infections 

VELSIPITY may increase the susceptibility to infections. Life-threatening and rare fatal infections have been reported in association with other sphingosine 1-phosphate (S1P) receptor modulators. Before starting VELSIPITY, obtain a recent (i.e., within 6 months) CBC, including lymphocyte count. Delay initiation of VELSIPITY in patients with an active infection until the infection is resolved. Consider interruption of treatment with VELSIPITY if a patient develops a serious infection. Continue monitoring for infections up to 5 weeks after discontinuing VELSIPITY.

  • Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and usually leads to death or severe disability. PML has been reported in multiple sclerosis (MS) patients treated with S1P receptor modulators and has been associated with risk factors and duration of use. Longer treatment duration (≥18 months) increases the risk of PML. VELSIPITY is not indicated in MS. If PML is suspected, suspend VELSIPITY and discontinue if PML is confirmed by appropriate diagnostic evaluation. Immune reconstitution inflammatory syndrome (IRIS) has been reported in patients with MS treated with S1P receptor modulators who developed PML and discontinued treatment. Clinical decline may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic MRI changes. Onset was generally within a few months after S1P receptor modulator discontinuation. Monitoring for IRIS should be undertaken.
  • Herpes simplex encephalitis, varicella zoster meningitis, and localized herpes viral infections have been reported with S1P receptor modulators. In UC-1, herpes zoster was reported in 0.7% of subjects treated with VELSIPITY and in none of the subjects who received placebo. 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 for antibody-negative patients is recommended prior to commencing treatment with VELSIPITY.
  • Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. VELSIPITY treatment should be suspended until a cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • VELSIPITY has not been studied in combination with anti-neoplastic, immune-modulating, or non-corticosteroid immunosuppressive therapies. Avoid concomitant administration of these therapies with VELSIPITY. 
  • Update immunizations according to current guidelines prior to VELSIPITY treatment. Avoid the use of live attenuated vaccines during and for 5 weeks after treatment with VELSIPITY. If live attenuated vaccine immunizations are required, administer at least 4 weeks prior to initiation of VELSIPITY.
Bradyarrhythmia and Atrioventricular (AV) Conduction Delays 
Initiation of VELSIPITY may result in a transient decrease in heart rate and AV conduction delays. Before starting VELSIPITY, obtain an ECG to assess for preexisting cardiac conduction abnormalities. Seek advice of a cardiologist for patients with: significant QT prolongation; arrhythmia requiring treatment with Class Ia or Class III anti-arrhythmic drugs or QT prolonging drugs; unstable ischemic heart disease, Class I or Class II heart failure, history of cardiac arrest, cerebrovascular disease, or uncontrolled hypertension; resting HR<50bpm; history of symptomatic bradycardia, recurrent cardiogenic syncope, or severe untreated sleep apnea; history of Mobitz type I second-degree AV block in the absence of a functioning pacemaker.

Liver Injury 
Elevations of aminotransferases may occur in patients receiving VELSIPITY. Obtain transaminase and bilirubin levels, if not recently available (i.e., within the last 6 months), before initiation of VELSIPITY or in patients who develop symptoms suggestive of hepatic dysfunction. Discontinue VELSIPITY if significant liver injury is confirmed. Use of VELSIPITY in patients with severe hepatic impairment is not recommended.

Macular Edema 
S1P receptor modulators have been associated with an increased risk of macular edema. Obtain baseline evaluation of the fundus, including the macula near the start of VELSIPITY treatment. Periodically assess the fundus, including the macula, during treatment or if there is a change in vision. Consider discontinuing VELSIPITY if macular edema develops. 

Increased Blood Pressure 
VELSIPITY patients in clinical trials had average increases of 1 to 4 mm Hg systolic and 1 to 2 mm Hg diastolic blood pressure (BP). Increases were first detected after 2 weeks of treatment and remained within the specified average range of BP increases throughout treatment. Monitor BP during treatment with VELSIPITY and manage appropriately.

Fetal Risk 
Based on animal studies, VELSIPITY may cause fetal harm. Advise pregnant females and females of reproductive potential of the potential risk to a fetus and to use effective contraception to avoid pregnancy during and for one week after stopping VELSIPITY. Pregnant females exposed to VELSIPITY are encouraged to contact the pregnancy registry by calling 1-800-616-3791.

Cutaneous Malignancies 
Risk of cutaneous malignancies is increased in patients treated with S1P receptor modulators in clinical trials and cutaneous malignancies have been reported in the postmarketing setting. 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. Monitor for suspicious skin lesions. Limit UV exposure including phototherapy.

Posterior Reversible Encephalopathy Syndrome
Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving S1P receptor modulators. If a patient develops neurological or psychiatric symptoms/signs or any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration, complete a physical and neurological examination promptly and 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, discontinue treatment with VELSIPITY.

Respiratory Effects 
VELSIPITY may cause a decline in pulmonary function. Spirometric evaluation should be conducted during therapy if clinically indicated.

Unintended Additive Immune System Effects from Prior Treatment with Immunosuppressive or Immune-Modulating Drugs 
When switching to VELSIPITY from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs to avoid unintended additive immunosuppressive effects.

Immune System Effects After Stopping VELSIPITY 
After stopping VELSIPITY, lymphocyte counts returned to the normal range in 90% of subjects within 4 to 5 weeks. 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 5 weeks after the last dose of VELSIPITY.

Most Common Adverse Reactions 
Most common adverse reactions reported in ≥ 2% of subjects and at a higher rate than placebo included: headache, elevated liver tests, dizziness, arthralgia, nausea, hypertension, bradycardia, UTI, hypercholesterolemia, and herpes viral infection.

Please see full Prescribing Information, including Medication Guide.Indication

VELSIPITY is indicated for the treatment of moderately to severely active ulcerative colitis (UC) in adults.