10-05-2025
Secondary Progressive Multiple Sclerosis (SPMS) and Switching Treatments
Improvements in safety, efficacy, and specificity have raised questions around the benefits and risks of switching treatments for this type of MS, especially from fingolimod to siponimod.
There are four main types of multiple sclerosis (MS), with relapsing remitting MS (RRMS) being the most common.
However, some people who have RRMS may eventually develop secondary progressive multiple sclerosis (SPMS). SPMS features a steady decline in neurological function that can occur with or without relapses.
With SPMS, a relapsing-remitting disease pattern is still possible, though relapses may become less frequent. Neurological symptoms may also continue to decline as underlying nerve damage and neuron loss naturally worsen through age, stress, and other degenerative processes.
Like other presentations of MS, doctors treat SPMS using disease-modifying therapies (DMTs). In 2010, the drug fingolimod (Gilenya) became the first oral DMT approved by the Food and Drug Administration (FDA) for certain types of MS, including RRMS and SPMS.
Since then, advancements in MS treatment have continued to evolve. In particular, a new drug therapy called siponimod (Mayzent) was approved in 2019 specifically for use in SPMS. As a result, researchers have started to weigh the pros and cons of switching people who have SPMS from fingolimod to siponimod.
Reasons why you might want to switch treatments
According to a review from 2023, there are several reasons you may want to consider switching from fingolimod to siponimod for SPMS.
Specific approval from the FDA
Siponimod is specifically approved for treating SPMS, which is supported by clinical trial data.
Fingolimod is approved for relapsing forms of MS, which can include SPMS. However, the medication does not have significant clinical trial data focused specifically on SPMS.
Fewer side effects
Both siponimod and fingolimod are S1P receptor modulators. These drugs activate S1P receptors and prevent immune cells from attacking the myelin sheath around nerves.
However, siponimod is more selective than fingolimod when it comes to which S1P receptors it targets. This helps reduce the risk of side effects.
Less intensive monitoring
The broad S1P action of fingolimod means the drug is associated with certain risks, particularly:
slowed heart rate (bradycardia)
liver damage
eye swelling
increased infection risk
When you're prescribed fingolimod, the first dose is given under medical supervision, and heart monitoring is required for 6 hours afterward. If no problems are detected, you can continue to take the medication on your own at home. But you'll need to work with your doctor to set a schedule for ongoing routine monitoring.
Siponimod appears to have a lower risk of heart-related side effects due to its more targeted mechanism of action. As a result, it requires less strict monitoring. However, you still need to work with your doctor to discuss how often to schedule checkups to monitor how well the medication is working.
Shorter washout time
Siponimod has a shorter half-life (30 hours) than fingolimod (6 to 9 days). A shorter half-life suggests it may clear from your system faster.
Better remyelination
Siponimod targets specific S1P receptor subtypes, particularly S1P5, which is involved in myelin-producing cell survival and function. Myelin is the protective layer around the nerves that can become inflamed and damaged in MS.
As a result, research suggests that this targeted approach that siponimod provides may offer enhanced repair of myelin (remyelination) effects compared with the broad S1P action of fingolimod.
Factors to consider when switching
Not everyone may benefit from switching from fingolimod to siponimod.
If your SPMS is well managed on fingolimod and you're not experiencing significant side effects, there's no guarantee your MS will do better on siponimod. Switching off an effective treatment isn't always recommended just because a new medication might offer some benefits.
Switching off fingolimod has also been associated with certain risks, like disease reactivation, in some people. When you switch from fingolimod to a more targeted drug like siponimod, experts believe your inflammatory response may become upregulated, which can promote active disease.
Another consideration before switching from fingolimod to siponimod is genetic testing. Siponimod is not recommended for use in people who have certain variants of the CYP2C9 gene, which slow siponimod metabolism and can increase the risk of side effects.
Switching from fingolimod to siponimod
Clinical trial data on siponimod suggests most people can immediately switch to it from fingolimod with no major side effects or reactions.
Before you make the switch, your doctor will order genetic screening to check for known CYP2C9 variants.
If your results indicate you're a candidate for siponimod, the next step is to discontinue your current DMT. Some DMTs, like teriflunomide (Aubagio), may require a washout period where you have to wait for the medication to fully clear from your system before starting siponimod.
Even though siponimod has more favorable safety parameters than fingolimod, it can still cause the same types of side effects. Before starting siponimod, a cardiac evaluation, blood screening, eye exam, and skin exam are all recommended to ensure no underlying conditions might increase your risk.
Other disease-modifying therapies for SPMS
In addition to fingolimod and siponimod, FDA-approved DMTs used in the treatment of SPMS include:
ocrelizumab (Ocrevus)
mitoxantrone (Novantrone)
Additional DMTs for SPMS are in development and in clinical trials. In December 2024, the FDA granted the designation of 'breakthrough therapy' to the drug tolebrutinib for use in non-remitting SPMS. Tolebrutinib belongs to a class of medications called Bruton's tyrosine kinase (BTK) inhibitors.
Other BTK inhibitors being investigated for use in MS include:
orelabrutinib
fenebrutinib
BIIB091
Talking with your healthcare team
SPMS is a complex condition that affects each person differently. Finding the right combination of medication and supportive therapies often requires trial and error.
Switching from fingolimod to siponimod starts with a conversation with your healthcare team. Discuss with your doctor why you want to switch medications, and come prepared with a list of your questions and concerns.
Questions you may want to ask your doctor include:
Do you recommend switching from fingolimod to siponimod?
How will siponimod change my treatment plan?
What tests do I need to have done?
Am I at an increased risk of certain side effects?
Is there a washout period?
Do any of my other medications prevent me from taking siponimod?
How will I know if the treatment is effective? How soon?
What happens if I miss a dose?
What should I expect from the first few weeks of treatment?
