On October 13, 2023, the FDA approved VELSIPITY (etrasimod), an oral, once-daily medicine for adults with moderate to severe ulcerative colitis (UC).
Moderate and severe ulcerative colitis is commonly treated with injectable medications such as:
IL-12 and IL-23 Inhibitors:
- Ustekinumab (Stelara)
The only oral biological medicine approved for treating Ulcerative colitis is Tofacitinib, a JAK inhibitor.
The FDA approval of Velsipity (Etrasimod) will add another oral tablet to the list of biologicals for managing moderately active or severely active ulcerative colitis.
Because ulcerative colitis is a seriously disabling disease with frequent flares, more novel biologicals are important to help patients who have an inadequate response to the treatment.
In addition, safer treatment choices are the need of the hour as most immunosuppressants are associated with severe and sometimes fatal opportunistic infections.
Etrasimod (VELSIPITY) MOA (Mechanism of Action):
Etrasimod (VELSIPITY) is an oral tablet that interacts with sphingosine-1 phosphate receptors (SIP) in the body, primarily SIP-1, 4, and 5.
It doesn’t affect S1P3 much and has no impact on S1P2. By attaching to SIP receptors, it slows down the movement of lymphocytes from the lymphoid tissue to the site of inflammation in the gut.
This leads to fewer cells circulating in the blood and the inflammatory processes at the intestines are blocked.
However, the exact mechanism of the drug is not known.
VELSIPITY (Etrasimod) Indications:
It has been approved for the treatment of moderately active to severely active ulcerative colitis.
In clinical trials, it was also proven to be effective in patients who had little improvement with JAK inhibitors.
VELSIPITY (Etrasimod) Dose and Assessment Before Treatment Initiation:
The usual dose of VELSIPITY is 2 mg orally once daily with or without food. VELSIPITY helps adults with UC achieve remission without steroids. It’s a convenient once-daily pill with a good safety profile.
However, before initiating VELSIPITY treatment, the following investigations are recommended [Ref]:
- Blood Complete Counts:
To monitor pretreatment lymphocyte counts.
- Cardiac Evaluation:
An electrocardiogram (ECG) is done to look for cardiac conduction blocks and arrhythmias.
- Liver Function Tests:
Liver function tests include liver enzymes and bilirubin levels.
- Eye Exam:
Fundus examination including examination of the fundus is recommended before treatment initiation.
Cardiac medications especially those that can slow the heart or cause AV block may need to be discontinued or treatment using Velsipity may not be appropriate.
Other medications, especially immunosuppressants and biologicals may also need to be stopped because of the risk of severe immunosuppression.
Live vaccinations are not recommended for use during the treatment. Importantly, varicella zoster vaccination is recommended at least four weeks before VELSIPITY treatment.
- Skin Check:
Skin examination is recommended before treatment initiation to look for suspicious lesions such as melanoma.
VELSIPITY FDA Approval was based on ELEVATE UC Trials:
The ELEVATE UC trials demonstrated the safety and efficacy of Velsipity (Etrasimod) in managing moderately active to severely active ulcerative colitis.
The results of the 12-week and 52-week ELEVATE UC trials, ELEVATE UC 12 and ELEVATE UC 52 were the basis of the FDA’s approval of VELSIPITY (Etrasimod) for managing ulcerative colitis patients.
In these trials, nearly two-thirds of patients were new to biologic or JAK inhibitor therapy.
The table below summarizes the results of the two trials:
ELEVATE UC 52
ELEVATE UC 12
Randomized, double-blind, placebo-controlled
|Duration||52 weeks (12-week induction + 40-week maintenance)||12 weeks|
|Primary Objective||Assess the safety and efficacy of etrasimod on clinical remission at 12 and 52 weeks||Assess the safety and efficacy of etrasimod on clinical remission at 12 weeks|
|Clinical Remission at Week 12||27.0% for etrasimod vs. 7.0% for placebo
(20.0% difference, P˂.001)
|26.0% for etrasimod vs. 15.0% for placebo
(11.0% difference, P<.05)
|Clinical Remission at Week 52||32.0% for etrasimod vs. 7.0% for placebo
(26.0% difference, P≤˂.001)
|Key Secondary Endpoints||
|Adverse Events (AEs)
|More AEs in etrasimod 2 mg group vs. placebo in ELEVATE UC 52
The most common AEs included:
|A similar proportion of AEs between etrasimod and placebo in ELEVATE UC 12.
The most common AEs included:
As seen in the table above, Etrasimod resulted in clinically significant improvement in inducing and maintaining remission in patients with moderately active to severely active ulcerative colitis.
Velsipity (Etrasimod) Contraindications:
VELSIPITY is not to be used in the following patient scenarios:
Individuals who have had a:
- myocardial infarction,
- unstable angina,
- CVA or TIA,
- decompensated heart failure requiring hospitalization, or
- have been diagnosed with Class III or IV heart failure within the last 6 months.
Those with a history of:
- Mobitz type II second-degree or third-degree AV block,
- sick sinus syndrome, or
- sino-atrial block, except if the patient has a functional pacemaker.
Velsipity (Etrasimod) Side Effects:
VELSIPITY (Etrasimod) may reduce peripheral blood lymphocyte counts by up to 45% from the baseline.
A CBC is essential before treatment initiation. The most common infections observed in the clinical trials were urinary tract infections and herpes viral infections.
Serious infections that may put the patient’s life at risk while on VELSIPITY (Etrasimod) treatment include:
- PML (progressive multifocal leukoencephalopathy)
- Herpes encephalitis, varicella meningoencephalitis, and disseminated herpes infections
- Cryptococcal infections
In cases of serious infections, VELSIPITY (Etrasimod) treatment may need to be stopped.
The risk of infections may persist for up to 5 weeks. This is the time for recovery of lymphocytes after the drug is stopped.
In addition, liver-attenuated vaccines should be avoided during the treatment. A history of varicella infection should be provided or vaccination should be done at least 4 weeks before treatment initiation.
Bradyarrhythmia and AV blocks:
An EKG should be performed before starting the treatment. All patients with a:
- heart rate of less than 50 beats per minute,
- AV block,
- Uncontrolled hypertension,
- cerebrovascular accident,
- unstable angina or heart failure,
- a history of cardiac arrest,
- sleep apnea,
- Cardiogenic shock
- and increased QTc (>450 msec in males and >470 msec in females)
should consult a cardiologist before treatment initiation.
Liver problems may develop manifesting as nausea, and yellowing of the skin, or raised liver enzymes may develop during the treatment.
Macular edema may develop during the treatment manifesting as visual blurring or unusual colors. The treatment should be stopped in patients who develop macular edema. If it persists, it may result in complete loss of consciousness.
There is a risk of a rise in blood pressure with the treatment. Monitor blood pressure during the treatment.
There is an increased risk of cancers, skin cancer in particular. Patients must be advised to avoid prolonged UV exposure because of the increased risk of skin cancer and melanoma.
PRES syndrome (posterior reversible encephalopathic syndrome) may develop with SIP modulators.
Symptoms may include:
- Cognitive deficits,
- Behavioral changes,
- Cortical visual disturbances,
- Signs of increased intracranial pressure, and
- accelerated neurological deterioration.
A complete physical and neurological examination is essential. MRI may be required as a delay in the diagnosis may result in a permanent neurological deficit including ischemic stroke and cerebral hemorrhage.
SIP modulators should be stopped if PRES is the likely diagnosis.
Velsipity treatment has been associated with a decline in FEV-1. Monitoring of lung function is recommended during the treatment.
Caution should be taken when the treatment is initiated in patients with Asthma or COPD.
Other less common side effects include:
- Elevated liver tests
- Urinary tract infection
- Herpes viral infection