Last updated on July 4th, 2023 at 03:41 pm

Summary

‘S1P modulators’ is the ‘short-hand’ we use to describe a group of drugs called sphingosine 1-phosphate receptor modulators (see Mode of action below). Fingolimod was the first of the S1P modulators to be licensed in MS (in 2010) and the first oral tablet approved for use in MS. Since then, three more S1P modulators have been licensed: siponimod, ozanimod and ponesimod. These are highly effective drugs, decreasing the relapse rate by over 50%, reducing worsening disability and the development of new lesions on magnetic resonance imaging (MRI), and slowing the loss of brain volume. S1P modulators work by trapping lymphocytes in lymph nodes and causing a low lymphocyte count in virtually all people with MS on the drugs. These drugs are maintenance therapies taken continuously and hence cause systemic immunosuppression. As a result, S1P modulators are associated with rare opportunistic infections and secondary malignancies, for example, lymphomas and skin cancers. They are anti-trafficking drugs, i.e. they block lymphocytes migrating into the CNS of people with MS, so when they are stopped, they are associated with rebound disease activity. Rebound typically occurs at around 6 ̶ 8 weeks after stopping fingolimod and siponimod and may also occur with ozanimod and ponesimod. S1P modulators have off-target side effects; for example, they slow the heart rate down and may need to be started in a hospital or under observation.

Trade names

Gilenya (fingolimod), Mayzent (siponimod), Zeposia (ozanimod), Ponvory (ponesimod).

Mode of action

Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator. Fingolimod is converted to an active drug, fingolimod phosphate, in the body. Fingolimod phosphate binds to its receptor (the S1P receptor) subtype 1 located on lymphocytes, which causes the receptors to be internalised and removed from the surface of the cells. By preventing S1P receptors from recirculating onto the surface of lymphocytes, fingolimod blocks the capacity of lymphocytes to egress from lymph nodes, causing their redistribution rather than depletion. Siponimod, ozanimod and ponesimod are active drugs and do not need to be phosphorylated, but they work in the same way as fingolimod.

Efficacy

High; fingolimod is licensed in the UK and Europe as a second-line therapy for people with highly active MS. In other countries, fingolimod can be used first-line. Siponimod is licensed for people with MS with active secondary progressive MS. Ozanimod and ponesimod are licensed as first-line treatments for people with active MS.

Class

Maintenance, immunosuppressive.

Immunosuppression

Yes, systemic.

Dosing

Fingolimod dosing

In adults, the recommended dose of fingolimod is one 0.5 mg capsule taken orally once daily. In children with MS (10 years of age and above), the recommended dose is dependent on body weight:

• body weight ≤40 kg: one 0.25 mg capsule taken orally once daily
• body weight >40 kg: one 0.5 mg capsule taken orally once daily.

When people with MS start on 0.25 mg capsules and reach a stable body weight above 40 kg, they should be switched to 0.5 mg capsules. Fingolimod can be taken with or without food. Fingolimod capsules should always be swallowed intact without opening them.

Although the Gilenya SmPC states that when switching from a 0.25 mg to a 0.5 mg daily dose it is recommended to repeat the same first dose monitoring as for treatment initiation, we have not done this. The following text is from the Gilenya SmPC:

Siponimod dosing

The dose of siponimod depends on how rapidly you can metabolise the drug. Before starting treatment, people with MS must be genotyped to determine their metaboliser status. In people with MS who metabolise the drug slowly and have the so-called 3-3 genotype, siponimod should not be used. In intermediate metabolisers (genotype 2-3 or 1-3), the recommended maintenance dose is 1 mg taken once daily (four tablets of 0.25 mg). In people with all other genotypes who are rapid metabolisers, the dose of siponimod is 2 mg per day.

To reduce off-target side effects, siponimod treatment is started with a titration pack that lasts for 5 days, as follows:

• days 1 and 2: 0.25 mg once daily
• day 3: 0.5 mg once daily
• day 4: 0.75 mg once daily
• day 5: 1.25 mg once daily
• day 6: increase to the patient’s prescribed maintenance dose of siponimod.

During the first 6 days of treatment initiation, the recommended once-daily dose should be taken in the morning with or without food (see SmPC for more details).

Ozanimod dosing

The recommended dose is 0.92 mg of ozanimod once daily. To reduce off-target side effects, an initial dose titration period of ozanimod is required over the first 7 days (see SmPC for more details):

• days 1 ̶ 4: 0.23 mg once daily
• days 5 ̶ 7: 0.46 mg once daily
• day 8 onwards: 0.92 mg once daily.

Ponesimod dosing

The recommended dose is 20 mg of ponesimod once daily. To reduce off-target side effects, an initial dose titration period of ponesimod is required over the first 14 days. The dose starts at 2 mg per day and builds up over 14 days to the maintenance dose of 20 mg per day (see SmPC for specific details).

Dose reduction

The European Medicines Agency recommends that if someone with MS has a persistent lymphopaenia of below 200/mm³ (grade 4), then S1P modulators should be stopped until the lymphocyte counts recover. It is our practice to put these patients on alternate-day dosing or to reduce the daily dose and to rechallenge them with the full dose once the counts have recovered to above 200/mm³. Now that fingolimod has been licensed for treating children with MS, with a dose based on weight, a 0.25 mg tablet is available. So instead of taking 0.5 mg on alternate days, there is also the possibility of taking 0.25 mg daily.

As the response to fingolimod or other S1P modulators and the risk of opportunistic infections are unrelated to the lymphocyte counts, the US Food and Drug Administration has not recommended routine monitoring of lymphocyte counts. Because of this, I am not unduly concerned about lymphocyte counts in patients on fingolimod and other S1P modulators and tend only to respond to counts of less than 100/mm³.

Main adverse events of special interest

Cardiac

The main adverse event of S1P modulators is a transient slowing of the heart rate that can, rarely, be associated with a heart block. This is why fingolimod is started in hospital with cardiac monitoring. With the newer generation S1P modulators, this is managed by a dose titration. Cardiac conduction abnormalities are usually transient and asymptomatic. Owing to the cardiac side effects, concurrent therapy with beta-blockers, heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem), or other substances which may decrease heart rate (e.g. ivabradine, digoxin, anticholinesterase inhibitors or pilocarpine) is not recommended. The effects on heart rate and cardiac conduction may recur on the reintroduction of S1P modulator treatment, depending on the duration of the interruption and the time since the start of treatment. S1P modulators may prolong the so-called QT interval on your ECG, so they are best avoided in individuals with relevant risk factors, for example, low potassium or congenital QT prolongation.

Immunosuppressive effects

S1P modulators predispose people with MS to an infection risk, including opportunistic infections, and increase the risk of developing lymphomas and other malignancies, particularly those of the skin. Potential opportunistic infections include fungal infections, for example, cryptococcal meningitis and progressive multifocal leukoencephalopathy (PML). Before initiating treatment with S1P modulators, it is important to do a baseline infection screen and to check the full blood count. You must have antibodies or immunity to varicella (chickenpox) prior to starting treatment. If you are varicella negative, it is recommended that you receive a full course of one of the varicella vaccines. Similarly, you must have a full vaccine review before starting this class of treatment. Human papillomavirus (HPV) infection, including papilloma, dysplasia, warts and HPV-related cancers, has been reported in people with MS on S1P modulators, which is why we recommend cervical smears or HPV testing at baseline before starting treatment.

Macular oedema

Swelling of the macular, the central part of the retina, occurs in ~ 1 in 200 people with MS treated with fingolimod or another S1P modulator. This can cause symptoms and can be detected using the so-called Amsler grid (see below). You must be assessed at an eye clinic 3 ̶ 4 months after initiating an S1P modulator to screen for this complication. Some clinicians do baseline testing of the eye before initiating S1P modulators; in fact, this is in the SmPC for ponesimod. Please note that if you have a history of uveitis (inflammation in the eye) or have diabetes mellitus, you are at increased risk of developing macular oedema. I tend to avoid prescribing S1P modulators to patients with diabetes.

The Amsler grid (left) is a simple square containing a grid pattern and a dot in the middle. If there are problem spots in your field of vision, areas of the grid may appear blank or distorted (right, example).

Liver

Increased liver enzymes have been reported in people with MS on S1P modulators such as fingolimod. This is why your LFTs (liver function tests) are monitored after starting fingolimod and other S1P modulators, and if they exceed five times the upper limit of normal fingolimod needs to be stopped. LFTs are recommended at 1, 3, 6, 9 and 12 months after therapy and then 6 monthly after that. Please be aware that if you develop any symptoms suggestive of liver problems, such as unexplained nausea, vomiting, abdominal pain, fatigue, loss of appetite, or jaundice and/or dark urine, you should have liver enzymes checked. If you have pre-existing liver disease, most neurologists will avoid using this class of therapy.

High blood pressure

S1P modulators increase your blood pressure by a small amount. If you develop hypertension, you may need to start antihypertensive medications; hypertension occurs in ~ 1 in 20 people with MS treated with fingolimod and is less common with the newer generation S1P modulators.

Respiratory effects

S1P modulators cause a minor reduction in lung function, so neurologists tend to avoid using fingolimod and other S1P modulators in people with MS with pre-existing lung disease.

Vascular effects

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported on S1P modulators. Symptoms can include sudden onset of severe headache, nausea, vomiting, altered mental status, visual disturbances and seizures. If you suspect you have PRES, you should contact your doctor urgently.

Cutaneous neoplasms

Basal cell carcinoma (BCC) and other cutaneous neoplasms, including malignant melanoma, squamous cell carcinoma, Kaposi’s sarcoma and Merkel cell carcinoma, have all been reported in people with MS on fingolimod, and there is the potential for these conditions to occur with the other S1P modulators. Please be vigilant for any new skin lesions and bring them to the attention of your doctor, who may need to refer you to a dermatologist. In our centre, we encourage our patients to take pictures of lesions with their smartphone camera and email them to us. We often get back a dermatology opinion very quickly this way. In people with MS at high risk, i.e. those with a dysplastic naevus syndrome, severe sun damage and/or prior history of skin cancer, we refer to dermatology for regular (annual) skin cancer screening. At present, annual skin screening is not justified in low-risk patients. Owing to the potential risk of malignant skin lesions, you need to be careful with excessive sunlight exposure or phototherapy with UV-B-radiation or PUVA-photochemotherapy.

Rebound disease activity

Severe exacerbation of disease has been observed in people with MS stopping fingolimod and siponimod treatment and may also occur with ozanimod and ponesimod. The possibility of recurrence of exceptionally high disease activity needs to be carefully considered when deciding on the sequence of treatments. Rebound typically occurs 6 ̶ 8 weeks after stopping fingolimod, siponimod and ozanimod. If it occurs with ponesimod, it will likely happen much earlier because ponesimod washes out more rapidly than the other S1P modulators.

Neutralising antibodies (NABs)

These are not a problem with S1P modulators as they are all small molecules and not a biological (protein) therapy.

Pharmacovigilance monitoring requirements

Baseline

Full blood count, urea and electrolytes, liver function tests, thyroid function tests, serum immunoglobulin levels, serology (varicella zoster virus, human immunodeficiency virus 1 and 2, hepatitis B and C, syphilis), tuberculosis enzyme-linked immune absorbent spot (TB ELISpot), up-to-date cervical smear and/or human papillomavirus testing, pregnancy test, blood pressure and electrocardiogram. Lung function tests are recommended for anyone with a history of asthma or lung disease.

Follow-up

FBC, LFTs and blood pressure should be monitored at months 1, 3, 6, 9 and 12 on therapy and 6-monthly thereafter.

Visual function

Macular oedema screening should be done 3 ̶ 4 months after treatment start in an eye clinic. The SmPC for ponesimod recommends a baseline eye scan, but this may not be necessary in people with low-risk MS.

Self-monitoring

All people with MS should be warned about opportunistic infections and informed to look out for symptoms suggestive of infections, suspicious skin lesions and symptoms of liver dysfunction. Women should be reminded to self-examine their breasts monthly and should have cervical smears and/or HPV testing done every 3 years. People with MS need to be aware of visual symptoms and can self-assess their macular function with an Amsler grid. There are several Amsler grid apps available for smartphones. Routine blood pressures also need to be taken.

Rebaselining

A rebaseline MRI scan needs to be done after the S1P modulator has had sufficient time to work. As S1P modulators work quite rapidly, I would recommend that an MRI is done 3 ̶ 6 months after starting treatment and that Gd-enhancement is included as part of the rebaselining MRI.

Women of childbearing potential and pregnancy

If you are a woman of childbearing age, before starting S1P modulator treatment, I would recommend a negative pregnancy test result. S1P modulators are potentially teratogenic, i.e. they can cause birth defects, therefore, you must have effective contraception whilst on treatment. It takes approximately 2 months to eliminate fingolimod, siponimod and ozanimod from the body, and about 7 days for ponesimod; therefore, on stopping treatment the potential risk to the foetus may persist and contraception should be continued during the drug elimination period. If you do fall pregnant whilst on an S1P modulator, we would not automatically recommend termination of pregnancy but, rather, refer you to a high-risk antenatal clinic for counselling and foetal screening. Many babies exposed to S1P modulators in the uterus have been born without any overt problems.

Breastfeeding

S1P modulators are excreted in the breast milk of lactating women and have the potential for serious adverse reactions in nursing infants, so women on these drugs should not breastfeed.

Fertility

I am not aware of any data to suggest that S1P modulators are associated with reduced female fertility.

Male fertility

S1P modulators have not been shown to affect sperm counts or sperm motility. There is no need for men with MS to stop fingolimod if they want to father a child.

Vaccination

It is safe to receive component or inactivated vaccines, but the antibody responses may be blunted. Live vaccines are contraindicated in people with MS on S1P modulators. Live viruses, particularly ones that can infect the central nervous system, are potentially dangerous.

Travel

People with MS need to be aware that being on an S1P modulator may affect travel; for example, some countries require you to be vaccinated against yellow fever, which involves a live attenuated vaccine and is hence contraindicated. If you travel to places associated with exotic infections, for example, dengue fever, you may be at risk of complications from these infections because S1P modulators are immunosuppressive.

Summaries of Product Characteristics (SmPC)

Gilenya, Mayzent, Zeposia, Ponvory.

Switching to an S1P modulator

Interferon and glatiramer acetate

In general, S1P modulators can be started immediately after discontinuation of interferon or glatiramer acetate. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting S1P modulators.

SIP modulator to S1P modulator switch

In general, switching from one S1P modulator to another is possible. I would recommend rechecking baseline investigations before making the switch and a 4-week wash-out with fingolimod, siponimod and ozanimod prior to starting the new agent. With ponesimod, I limit the washout to 7 days. Overlapping the washout of one S1P modulator with the titration phase of the newer agent should prevent rebound activity and limit off-target effects, particularly cardiac events.

Natalizumab

Most often the reason for switching from natalizumab to an S1P modulator is to reduce the risk of carry-over PML from natalizumab. In our centre, we do an MRI and lumbar puncture for cerebrospinal fluid analysis to exclude JC virus DNA on PCR (polymerase chain reaction test). Provided these two tests are clear, we typically initiate S1P modulators within 4 weeks of the last natalizumab infusion. A prolonged wash-out period (8 weeks or longer) is associated with rebound disease activity on stopping natalizumab and is therefore not recommended. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Teriflunomide

Because teriflunomide has such a long half-life, some neurologists would recommend an accelerated washout using cholestyramine or activated charcoal. Rheumatologists rarely do this when switching patients with rheumatoid arthritis from leflunomide (teriflunomide prodrug) to other DMTs, so I am not sure this accelerated washout is necessary. It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

If the main reason for switching from teriflunomide is leukopaenia or lymphopaenia I would recommend waiting for the neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³ respectively. Similarly, if the switch is for abnormal LFTs on teriflunomide you would ideally want the liver enzymes to normalise or at least drop to below 3x the upper limit of normal.

Fumarates

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. If the main reason for switching from a fumarate is lymphopaenia, I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively.

Alemtuzumab

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively.

Anti-CD20 therapies (selective cell depleting DMTs)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator.

Cladribine (selective cell depleting DMT)

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting and S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³, respectively.

Mitoxantrone

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the total peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³ respectively.

HSCT

It is important that all the recommended baseline screening tests and vaccination reviews are done before starting an S1P modulator. I would recommend first waiting for the peripheral blood neutrophil and lymphocyte counts to go above 1,000/mm³ and 800/mm³ respectively.