VELSIPITY™ (etrasimod) 14 CLINICAL STUDIES

(etrasimod)

Prescribing Information

14 CLINICAL STUDIES

The efficacy of VELSIPITY was evaluated in 2 randomized, double-blind, placebo-controlled clinical studies [UC-1 (NCT03945188) and UC-2 (NCT03996369)] in adult subjects with moderately to severely active ulcerative colitis 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 biologic therapies (e.g., TNF blocker, anti-integrin, anti-IL12/23). UC-1 was a 52-week study and UC-2 was a 12-week study. In both studies, subjects were randomized to VELSIPITY or placebo and continued on treatment for the entire duration of the study.

Disease severity was assessed based 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.

Subjects in these studies may have received other concomitant UC therapies including stable daily doses of oral aminosalicylates and/or oral corticosteroids (≤20 mg/day prednisone, ≤9 mg/day budesonide, or equivalent steroid). Concomitant treatment with immunomodulators (e.g., thiopurines, methotrexate), biologic therapies, JAK inhibitors, rectal 5-ASA, or rectal corticosteroids was not permitted.

Endpoints and Results Study UC-1

In UC-1, efficacy was evaluated in 408 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 78 years); 45% were female; and 89% identified as White, 7% as Asian, 2% as Black or African American, 1% as American Indian or Alaska Native, and 1% did not report their racial group. A total of 30% of subjects had prior exposure to biologic/JAK inhibitors and a total of 14% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 68% of subjects were receiving oral aminosalicylates and 31% of subjects were receiving oral corticosteroids.

The coprimary endpoints were the proportion of subjects achieving clinical remission at Week 12 and at Week 52. The secondary endpoints included the proportion of subjects achieving endoscopic improvement, histologic-endoscopic mucosal improvement, corticosteroid-free clinical remission, and maintenance of clinical remission (see Table 4).

Table 4: Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-1 at Week 12 and at Week 52
CI = confidence interval
* Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group). † Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability). ‡ p <0.001. § Endoscopic improvement is defined as ES ≤1 (excluding friability). ¶ Histologic-endoscopic mucosal improvement is defined as ES ≤1 (excluding friability) with 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. # Corticosteroid-free clinical remission is defined as clinical remission at Week 52 without receiving corticosteroids for at least 12 weeks prior to Week 52. Þ Maintenance of clinical remission is defined as achievement of clinical remission at both Week 12 and Week 52.
Endpoints	Placebo	VELSIPITY	Treatment Difference* (95% CI)
Coprimary Endpoints
Clinical Remission† at Week 12
Total population	N = 134 7%	N = 274 27%	20%‡ (13%, 27%)
No prior biologic/ JAK inhibitor exposure	N = 93 10%	N = 194 31%
Prior biologic/ JAK inhibitor exposure	N = 41 2%	N = 80 18%
Clinical Remission† at Week 52
Total population	N = 134 7%	N = 274 32%	26%‡ (19%, 33%)
No prior biologic/ JAK inhibitor exposure	N = 93 8%	N = 194 37%
Prior biologic/ JAK inhibitor exposure	N = 41 5%	N = 80 21%
Week 12 Endpoints
Endoscopic Improvement§
Total population	N = 134 14%	N = 274 35%	21%‡ (13%, 29%)
No prior biologic/ JAK inhibitor exposure	N = 93 18%	N = 194 39%
Prior biologic/ JAK inhibitor exposure	N = 41 5%	N = 80 25%
Histologic-Endoscopic Mucosal Improvement¶
Total population	N = 134 4%	N = 274 21%	17%‡ (11%, 23%)
No prior biologic/ JAK inhibitor exposure	N = 93 6%	N = 194 24%
Prior biologic/ JAK inhibitor exposure	N = 41 0%	N = 80 14%
Week 52 Endpoints
Endoscopic Improvement§
Total population	N = 134 10%	N = 274 37%	27%‡ (19%, 34%)
No prior biologic/ JAK inhibitor exposure	N = 93 13%	N = 194 40%
Prior biologic/ JAK inhibitor exposure	N = 41 5%	N = 80 30%
Histologic-Endoscopic Mucosal Improvement¶
Total population	N = 134 8%	N = 274 27%	18%‡ (11%, 25%)
No prior biologic/ JAK inhibitor exposure	N = 93 11%	N = 194 28%
Prior biologic/ JAK inhibitor exposure	N = 41 2%	N = 80 23%
Corticosteroid-free Clinical Remission#
Total population	N = 134 7%	N = 274 32%	26%‡ (19%, 33%)
No prior biologic/ JAK inhibitor exposure	N = 93 8%	N = 194 37%
Prior biologic/ JAK inhibitor exposure	N = 41 5%	N = 80 21%
Maintenance of Clinical RemissionÞ
Total population	N = 134 2%	N = 274 18%	16%‡ (11%, 21%)
No prior biologic/ JAK inhibitor exposure	N = 93 2%	N = 194 22%
Prior biologic/ JAK inhibitor exposure	N = 41 2%	N = 80 10%

The relationship of histologic-endoscopic mucosal improvement at Week 12 or Week 52 to disease progression and longer-term outcomes after Week 52 was not evaluated in Study UC-1.

Clinical Response

A greater proportion of subjects treated with VELSIPITY compared to placebo achieved clinical response, defined as a ≥2 point and ≥30% decrease from baseline in mMS, and a ≥1 point decrease from baseline in RB subscore or an absolute RB subscore ≤1 at Week 12 (62% vs 34%).

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Normalization of the endoscopic appearance of the mucosa (endoscopic remission) was defined as ES of 0. A greater proportion of subjects treated with VELSIPITY 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 1%).

Endpoints and Results Study UC-2

In UC-2, efficacy was evaluated in 333 adult subjects with a baseline mMS of 5 to 9 (median of 7), including a centrally read endoscopy subscore of 2 or 3. Subjects were randomized 2:1 to receive VELSIPITY 2 mg or placebo administered orally once daily. Subjects had a mean age of 41 years (range 18 to 73 years); 41% were female; and 76% identified as White, 19% as Asian, 2% as American Indian or Alaska Native, 1% as Black or African American, and 2% as multiple racial groups or did not report their racial group. A total of 34% of subjects had prior exposure to biologic/JAK inhibitors and a total of 17% of subjects had exposure to >1 biologic/JAK inhibitor. At baseline, 66% of subjects were receiving oral aminosalicylates and 28% of subjects were receiving oral corticosteroids.

The primary endpoint was the proportion of subjects achieving clinical remission at Week 12. The secondary endpoints included the proportion of subjects achieving endoscopic improvement and histologic-endoscopic mucosal improvement at Week 12 (see Table 5).

Table 5: Proportion of Subjects with Ulcerative Colitis Meeting Efficacy Endpoints in UC-2 at Week 12
CI = confidence interval
* Treatment difference (adjusted for stratification factors of prior biologic/JAK inhibitor exposure, corticosteroid use at baseline, and baseline mMS group). † Clinical remission is defined as SF subscore of 0 or 1, RB subscore of 0, and ES ≤1 (excluding friability). ‡ p <0.05. § Endoscopic improvement is defined as ES ≤1 (excluding friability). ¶ Endoscopic-histologic mucosal improvement is defined as ES ≤1 (excluding friability) with 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.
Endpoints	Placebo	VELSIPITY	Treatment Difference* (95% CI)
Clinical Remission†
Total population	N = 112 15%	N = 221 26%	11%‡ (3%, 20%)
No prior biologic/ JAK inhibitor exposure	N = 74 16%	N = 147 30%
Prior biologic/ JAK inhibitor exposure	N = 38 13%	N = 74 19%
Endoscopic Improvement§
Total population	N = 112 19%	N = 221 30%	12%‡ (3%, 21%)
No prior biologic/ JAK inhibitor exposure	N = 74 19%	N = 147 34%
Prior biologic/ JAK inhibitor exposure	N = 38 18%	N = 74 23%
Histologic-Endoscopic Mucosal Improvement¶
Total population	N = 112 9%	N = 221 16%	8%‡ (1%, 15%)
No prior biologic/ JAK inhibitor exposure	N = 74 11%	N = 147 19%
Prior biologic/ JAK inhibitor exposure	N = 38 5%	N = 74 11%

The relationship of histologic-endoscopic mucosal improvement at Week 12 to disease progression and longer-term outcomes after Week 12 was not evaluated in Study UC-2.

Clinical Response

Stool Frequency and Rectal Bleeding Subscores

Decreases in SF subscores were observed as early as Week 2 and decreases in RB subscores were observed as early as Week 4 in subjects treated with VELSIPITY compared to placebo.

Endoscopic Assessment

Medication Guide

MEDICATION GUIDE

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 06/2024
MEDICATION GUIDE VELSIPITY™ (Vel-sip-itee) (etrasimod) tablets, for oral use
Read this Medication Guide before you start taking VELSIPITY and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking with your healthcare provider about your medical condition or treatment.
What is the most important information I should know about VELSIPITY? VELSIPITY can cause serious side effects, including:
1. Infections. VELSIPITY can increase your risk of serious infections. These infections can be life-threatening and cause death. VELSIPITY lowers the number of white blood cells (lymphocytes) in your blood. This usually returns to normal within 4 to 5 weeks after you stop taking VELSIPITY. Your healthcare provider will test your blood before you start taking VELSIPITY. Call your healthcare provider right away if you have any of these symptoms of an infection during treatment with VELSIPITY, and for 5 weeks after you stop taking VELSIPITY:
	• fever or high temperature • tiredness • flu-like symptoms	• pain when peeing or peeing more often than usual. These can be signs of a urinary tract infection. • headache with fever, neck stiffness, sensitivity to light, nausea, or confusion. These may be symptoms of meningitis, an infection of the lining around your brain and spine.
Your healthcare provider may delay or stop your VELSIPITY treatment if you have an infection. 2. Slow heart rate (also known as bradyarrhythmia) when you start taking VELSIPITY. VELSIPITY may cause your heart rate to temporarily slow down especially after you take your first dose. You will have a test called an electrocardiogram (ECG) to check the electrical activity of your heart before you take your first dose of VELSIPITY. Call your healthcare provider if you experience these symptoms of slow heart rate:
	• feeling dizzy • feeling lightheaded • feeling like your heart is beating slowly or skipping beats • feeling short of breath			• feeling confused • feeling tired • chest pain
See "What are the possible side effects of VELSIPITY?" for more information about side effects.
What is VELSIPITY? • VELSIPITY is a prescription medicine used to treat adults with moderately to severely active ulcerative colitis. It is not known if VELSIPITY is safe and effective in children.
Do not take VELSIPITY if you: • have had a heart attack, chest pain (unstable angina), stroke or mini stroke (transient ischemic attack or TIA), and certain types of heart failure requiring hospitalization in the last 6 months. • have or have had a history of unusual heartbeats (arrhythmia) that is not corrected by a pacemaker. Talk to your healthcare provider before taking VELSIPITY if you have any of these conditions or do not know if you have any of these conditions.
Before taking VELSIPITY, tell your healthcare provider about all of your medical conditions, including if you: • have a serious infection or an infection that does not go away or that keeps coming back (chronic). • are unable to fight infections due to a disease. • have received a vaccine in the past 4 weeks or are scheduled to receive a vaccine. You should be brought up to date with all age required vaccines before starting treatment with VELSIPITY. VELSIPITY may affect how well a vaccine works. Tell your healthcare provider that you are receiving treatment with VELSIPITY before receiving a vaccine. • have chickenpox or received the vaccine for chickenpox. Your healthcare provider may do a blood test for the chickenpox virus. You may need to get the full course of the chickenpox vaccine and then wait 4 weeks before you start taking VELSIPITY. • have a slow heart rate. • have an irregular or abnormal heartbeat (arrhythmia). • have heart disease, Class I or II heart failure, history of a heart attack, high blood pressure or uncontrolled high blood pressure. • have cerebrovascular disease or history of a stroke or ministroke. • history of repeated fainting. • have or have had liver problems. • have or have had skin cancer. • have breathing problems, including untreated sleep apnea. • are pregnant or plan to become pregnant. VELSIPITY may harm your unborn baby. Talk with your healthcare provider if you are pregnant or plan to become pregnant. If you are a female who can become pregnant, you should use effective birth control during your treatment with VELSIPITY and for 7 days after you stop taking VELSIPITY. Talk to your healthcare provider about what birth control method is right for you during this time. Tell your healthcare provider right away if you become pregnant while taking VELSIPITY or within 7 days after you stop taking VELSIPITY. Pregnancy Registry: There is a registry for women who become pregnant during treatment with VELSIPITY. If you become pregnant while taking VELSIPITY, talk to your healthcare provider about registering with the VELSIPITY Pregnancy Registry. The purpose of this registry is to collect information about your health and your baby’s health. Either you or your healthcare provider can contact this registry by calling 1-800-616-3791. • are breastfeeding or plan to breastfeed. It is not known if VELSIPITY passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take VELSIPITY. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Using VELSIPITY with other medicines can cause serious side effects. Especially tell your healthcare provider if you take or have taken: • medicines to control your heart rhythm (antiarrhythmics), heartbeat, or blood pressure. These may be called beta blockers or calcium channel blockers. • medicines that affect your immune system. • certain medicines known as moderate to strong inhibitors of both CYP2C9 and CYP3A4, medicines such as fluconazole. If you are taking fluconazole, you should not take VELSIPITY. • Rifampin. If you are taking rifampin, you should not take VELSIPITY. You should not receive live vaccines at least 4 weeks before starting VELSIPITY, during treatment with VELSIPITY and for 5 weeks after you stop taking VELSIPITY. Talk to your healthcare provider before you receive a vaccine during treatment and for 5 weeks after treatment with VELSIPITY. If you receive a live vaccine, you may get the infection the vaccine was meant to prevent. Vaccines may not work as well when given during treatment with VELSIPITY. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of your medicines to show the list to your healthcare provider and pharmacist when you get a new medicine.
How should I take VELSIPITY? • Take VELSIPITY exactly as your healthcare provider tells you to take it. • Take VELSIPITY 1 time each day. • Swallow VELSIPITY tablets whole. • Take VELSIPITY with or without food. • If a dose is missed, take the missed dose at the next scheduled time; do not double the next dose.
What are the possible side effects of VELSIPITY? VELSIPITY can cause serious side effects, including: • See "What is the most important information I should know about VELSIPITY?" • Liver problems. VELSIPITY may cause liver problems. Your healthcare provider will do blood tests to check your liver before you start taking VELSIPITY. Call your healthcare provider right away if you have any of the following symptoms:
	• unexplained nausea • vomiting • stomach area (abdominal pain) • tiredness		• loss of appetite • yellowing of the whites of your eyes or skin • dark colored urine
If you develop any of these symptoms, your healthcare provider will do blood tests to check your liver and may stop your treatment with VELSIPITY. • Increased blood pressure. Your healthcare provider should check your blood pressure during treatment with VELSIPITY and treat you as needed. • A problem with your vision called macular edema. Your healthcare provider should test your vision around the time you start taking VELSIPITY or at any time you notice vision changes during your treatment with VELSIPITY. Call your healthcare provider right away if you have any of the following symptoms:
	• blurriness or shadows in the center of your vision • sensitivity to light				• a blind spot in the center of your vision • unusually colored vision
• Types of skin cancer. Certain types of skin cancer have happened with medicines in the same class as VELSIPITY. Limit the amount of time you spend in sunlight and ultraviolet (UV) light while taking VELSIPITY. Wear protective clothing and use a sunscreen with a high sun protection factor. Tell your healthcare provider if you have any changes in the appearance of your skin. • Swelling and narrowing of the blood vessels in your brain. A condition called Posterior Reversible Encephalopathy Syndrome (PRES) has happened with drugs in the same class. Symptoms of PRES usually get better when you discontinue treatment. If not treated, PRES may cause a stroke. Call your healthcare provider right away if you have any of the following symptoms: o sudden severe headache o sudden confusion o sudden loss of vision or other changes in your vision o seizure o If you develop any of these symptoms, your healthcare provider will stop treatment with VELSIPITY. • Breathing problems. Some people who take medicines in the same class as VELSIPITY may experience shortness of breath. Your healthcare provider may do tests to check your breathing during treatment with VELSIPITY. Call your healthcare provider right away if you have new or worsening breathing problems. The most common side effects of VELSIPITY include headache, elevated liver tests, and dizziness. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all of the possible side effects of VELSIPITY. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Pfizer at 1-800-438-1985.
How should I store VELSIPITY? • Store VELSIPITY at room temperature between 68°F to 77°F (20°C to 25°C). Keep VELSIPITY and all medicines out of the reach of children.
General information about the safe and effective use of VELSIPITY. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VELSIPITY for a condition for which it was not prescribed. Do not give VELSIPITY to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about VELSIPITY that is written for health professionals.
What are the ingredients in VELSIPITY? Active ingredient: etrasimod arginine. Inactive ingredients: Tablet core: magnesium stearate, mannitol, microcrystalline cellulose, and sodium starch glycolate. Tablet coating: FD&C blue #1/brilliant blue FCF aluminum lake, FD&C blue #2/indigo carmine aluminum lake, FD&C yellow #5/tartrazine aluminum lake, macrogol 4000 JP/PEG 3350, polyvinyl alcohol (partially hydrolyzed), talc, and titanium dioxide. LAB-1541-2.0

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