Last updated on November 18th, 2025 at 06:25 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
Sphingosine 1-phosphate (S1P) receptor modulators block the capacity of lymphocytes to egress from lymph nodes, causing their redistribution, rather than depletion.
Efficacy
High.
Class
Maintenance, immunosuppressive.
Immunosuppression
Yes, systemic.
Dosing
Fingolimod dosing
- Adults: one 0.5 mg capsule orally once daily.
- Children (10 years and above): one 0.25 mg or 0.5 mg capsule orally once daily, dependent on body weight.
Siponimod dosing
Treatment is titrated upwards for days 1 ̶ 6 to reduce off-target side effects. Genotyping is carried out before starting treatment to determine dose, based on your speed of metabolising siponimod.
- Slow metabolisers: should not take siponimod
- Intermediate metabolisers: 1 mg per day
- Rapid metabolisers: 2 mg per day.
Ozanimod dosing
0.92 mg once daily; treatment is titrated upwards for days 1 ̶ 7, to reduce off-target side effects.
Ponesimod dosing
20 mg once daily; treatment is titrated upwards for days 1 ̶ 14, to reduce off-target side effects.
Dose reduction
In cases of persistent lymphopaenia, the European Medicines Agency recommends stopping S1P modulator administration until lymphocyte counts recover.
Main adverse events and monitoring requirements
- Transient slowing of the heart rate; raised liver enzymes.
- Infection risk (opportunistic infections, lymphomas, fungal infections); skin cancer; progressive multifocal leukoencephalopathy.
- Macular oedema; regular self-monitoring advised; routine clinic monitoring in at-risk patients.
- Rebound disease activity: repeat MRI scan recommended 3 ̶ 6 months after treatment start.
Rare adverse events of special interest
- Rare potential for heart block (associated with slowed heart rate) necessitates initial dose titration for all S1P modulators and cardiac monitoring with fingolimod.
- Rare cases of posterior reversible encephalopathy syndrome; requires urgent medical attention.