Siponimod (Mayzent) for multiple sclerosis: why CYP2C9 testing comes first

Multiple sclerosis (MS) is a chronic autoimmune disease of the brain and spinal cord. The immune system attacks myelin, the fatty insulating sheath that protects nerve fibres, which disrupts signals between the brain and the body. MS can cause muscle weakness, stiffness and spasms, tremors, poor balance and coordination, electric-shock sensations with certain movements, fatigue, and problems with vision, memory and speech. Its causes are still not fully understood, and there is no cure, but treatments can reduce relapses, slow the progression of disability and ease symptoms.

Siponimod (Mayzent) is one of these treatments, and it is one of the few medications whose drug label requires a genetic test before the first dose. This article explains why, and how pharmacogenetic testing can also help with other medications people with MS often take.

How is multiple sclerosis treated?

Most people with MS are first diagnosed with relapsing-remitting MS, in which periods of new or worsening symptoms (relapses) are followed by partial or complete recovery. Over time, many people develop secondary progressive MS, in which disability increases steadily, with or without relapses. Starting treatment early helps slow the progression of disability.

Disease-modifying therapies work in different ways to calm the immune attack on the nervous system. They include:

• Beta interferons, injectable proteins that modulate the immune response. They often cause flu-like symptoms.
• Glatiramer acetate (Copaxone), an injection thought to shift the immune response away from attacking myelin.
• Sphingosine 1-phosphate (S1P) receptor modulators, including fingolimod (Gilenya), siponimod (Mayzent), ozanimod (Zeposia) and ponesimod (Ponvory). These oral drugs keep certain white blood cells (lymphocytes) in the lymph nodes, so fewer reach the brain and spinal cord.
• Teriflunomide (Aubagio), an oral drug that blocks an enzyme that rapidly dividing lymphocytes need, reducing their numbers.
• Dimethyl fumarate (Tecfidera) and related fumarates, oral drugs with anti-inflammatory effects that are thought to protect nerve cells.
• Monoclonal antibodies, such as ocrelizumab (Ocrevus), ofatumumab (Kesimpta), natalizumab (Tysabri) and alemtuzumab (Lemtrada), which block or remove specific immune cells.

What is siponimod, and who is it approved for?

Siponimod is an oral S1P receptor modulator. The US Food and Drug Administration (FDA) approved it in March 2019 for adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting MS and active secondary progressive MS.

In Canada, Health Canada approved siponimod in February 2020 for adults with secondary progressive MS with active disease, meaning relapses or MRI signs of inflammation, to delay the progression of physical disability.

Because siponimod keeps lymphocytes out of circulation, it reduces the body's ability to fight infections. Too much siponimod in the blood raises the risk of side effects such as infections, a slow heart rate (bradycardia), and swelling at the back of the eye (macular edema) that can affect vision.

Why is CYP2C9 testing required before siponimod?

Siponimod is broken down mainly by the liver enzyme CYP2C9, which handles about 80% of its metabolism according to the FDA label. CYP3A4 plays a smaller role. Common variations in the CYP2C9 gene reduce or eliminate the enzyme's activity, so the same dose can lead to much higher levels of siponimod in the blood. In people with two copies of the CYP2C9*3 variant, siponimod exposure is about four times higher than usual, and its half-life increases from about 30 hours to about 126 hours.

For this reason, both the FDA label and the Canadian product monograph state that a person's CYP2C9 genotype must be determined before starting siponimod. The FDA label recommends:

CYP2C9 genotype	Metabolizer status	Siponimod recommendation
*1/*1, *1/*2, *2/*2	Normal, or mildly reduced with *2	Standard maintenance dose of 2 mg daily
*1/*3, *2/*3	Intermediate metabolizer	Lower maintenance dose of 1 mg daily
*3/*3	Poor metabolizer	Do not use siponimod

The Dutch Pharmacogenetics Working Group (DPWG) also recommends half the usual maintenance dose for CYP2C9*1/*3 and *2/*3, and no change for *1/*2 or *2/*2.

How common are these genotypes? According to the FDA label, the *1/*3 and *2/*3 genotypes are found in 2% to 20% of people depending on ancestry, and *3/*3 in about 0.5% of people of European ancestry and 1% of people of Asian ancestry. Other, less common variants (such as *5, *6, *8 and *11, more frequent in people of African ancestry) can also reduce CYP2C9 function.

The FDA label notes that there is no FDA-cleared test specifically for siponimod. In Canada, the manufacturer offers CYP2C9 genotyping through its patient support program. A clinical pharmacogenetic test that reports CYP2C9, such as Pillcheck, also provides this information, along with results for many other medications you may need in the future.

Why does testing more CYP2C9 variants matter?

The siponimod dosing table is based on the *2 and *3 variants, which are most common in people of European ancestry. A test that looks only for *2 and *3 reports everyone else as a normal metabolizer (*1/*1). But people of African, Asian and mixed ancestry are more likely to carry other variants that reduce or eliminate CYP2C9 function, and the FDA label notes that these variants are also expected to increase siponimod levels.

In addition to *2 and *3, Pillcheck tests the CYP2C9 *4, *5, *6, *8, *9, *11, *12, *13, *15 and *27 alleles. This means it can identify people of non-European ancestry who are CYP2C9 intermediate or poor metabolizers, and therefore at higher risk of siponimod side effects, who would be missed by a test limited to *2 and *3. Your neurologist can then use this information to choose a lower dose, monitor you more closely, or consider a different treatment.

Which drug interactions matter with siponimod?

Because siponimod depends on CYP2C9 and, to a lesser extent, CYP3A4, other medications that block or speed up these enzymes can change its levels. According to the FDA label:

• Strong CYP2C9 inhibitors are not recommended with siponimod. Moderate CYP2C9 inhibitors and moderate dual CYP2C9/CYP3A4 inhibitors, such as the antifungal fluconazole, require monitoring for side effects. In one study, fluconazole doubled siponimod exposure.
• Medications that speed up both enzymes, such as rifampin and carbamazepine, are not recommended with siponimod because they can reduce its levels by up to 70%, making it less effective.
• In people with CYP2C9*1/*3 or *2/*3, medications that speed up CYP3A4 (such as efavirenz) can also lower siponimod levels, so loss of effect should be monitored.

Cannabidiol (CBD), found in many cannabis products, can inhibit both CYP2C9 and CYP3A4. Its effect on siponimod has not been studied, but if you use cannabis products, tell your doctor and pharmacist.

Your genes and your other medications work together. A person who is already a CYP2C9 intermediate metabolizer and also takes a CYP2C9 inhibitor may end up with much higher siponimod levels than either factor alone would suggest. This is why your pharmacist should review all of your medications along with your genetic results.

What about fingolimod?

Fingolimod (Gilenya) is a similar drug to siponimod but is more expensive. Fingolimod is metabolized by a different enzyme called CYP4F2, as stated in its FDA drug label. CYP4F2*3 reduces the activity of this enzyme and was found to be associated with a higher warfarin dose requirement.

According to the label, ketoconazole, a potent inhibitor of CYP4F enzymes, increases blood levels of fingolimod and its active form by about 70%, and people who take both should be closely monitored because the risk of side effects is greater. Reduced CYP4F2 function due to genetics is expected to have a similar effect to taking an enzyme inhibitor. People who carry reduced-function CYP4F2 variants may therefore have higher fingolimod levels and benefit from closer monitoring for side effects such as a slow heart rate. There is no genotype-specific dosing guideline for fingolimod yet. A pharmacogenetic test can help your doctor determine whether siponimod or fingolimod would be better for you.

Can genes affect other medications people with MS take?

People with MS often take several medications to manage symptoms, and some of them are strongly affected by genes:

• Depression and anxiety are common in MS. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has guidelines for many antidepressants based on CYP2D6, CYP2C19 and CYP2B6.
• Pain is also common. CPIC guidelines advise people who are CYP2D6 poor or ultrarapid metabolizers to avoid codeine and tramadol, and recommend lower doses or alternatives for some anti-inflammatory painkillers (NSAIDs such as celecoxib, ibuprofen and meloxicam) in people with reduced CYP2C9 function, the same gene that guides siponimod dosing.
• Muscle spasms and fatigue are treated with medications such as baclofen, tizanidine, cannabinoids and amantadine. Genes have less effect on most of these, but your pharmacist can check them for interactions with your other medications and your genetic results.

Taking multiple medications increases the risk of drug interactions, especially in people whose genes already reduce how quickly they break down medications.

How can Pillcheck help?

Pillcheck reports your CYP2C9 genotype, which is required before starting siponimod, and your CYP4F2 results, along with your predicted response to many medications used to manage MS symptoms. The Pillcheck service includes a review of your medications by a pharmacist trained in pharmacogenetics, who can recommend changes to your health care providers when needed.

Pillcheck testing is performed in CAP- and COLA-accredited clinical genetic laboratories located in Canada. Pillcheck reports on 24 genes, increasing coverage with new guidelines and drug labels (see the genes tab), and covers 355 medications, which account for over 70% of dispensed prescriptions. The Pillcheck test panel ensures high accuracy for people of non-European and admixed ancestries. Your results last a lifetime, and report updates are free of charge.

Pillcheck may be covered by your health benefits, depending on your plan. Canada Life, Medavie Blue Cross and Empire Life include Pillcheck in their disability benefits, and Bell Canada covers Pillcheck for eligible disability claimants. Learn more in 5 ways Pillcheck helps businesses manage benefits costs.

Read also: Your DNA and MS treatment: New personalized medicine options

Summary

• Siponimod (Mayzent) is an oral MS treatment approved in Canada for secondary progressive MS with active disease.
• A CYP2C9 genetic test is required before starting siponimod: people with *1/*3 or *2/*3 need a lower dose, and people with *3/*3 should not take it.
• Pillcheck tests more CYP2C9 variants than *2 and *3, so it can identify people of non-European ancestry at higher risk of siponimod side effects who would be missed by a *2/*3-only test.
• Medications that block or speed up CYP2C9 and CYP3A4 can change siponimod levels, especially in people with reduced CYP2C9 function.
• Fingolimod is metabolized by CYP4F2; reduced CYP4F2 function, like a CYP4F inhibitor, may raise fingolimod levels.
• Pharmacogenetic testing can also guide antidepressants and painkillers that people with MS often take.

Frequently asked questions

Do I need a genetic test before taking siponimod?

Yes. Both the FDA label and the Canadian product monograph require CYP2C9 genotyping before the first dose, because the result determines whether siponimod is safe for you and which dose to use.

What happens if I have reduced CYP2C9 function?

If you have the *1/*3 or *2/*3 genotype (intermediate metabolizer), your doctor will use a lower maintenance dose of 1 mg daily. If you have the *3/*3 genotype (poor metabolizer), siponimod should not be used, and your doctor will choose another treatment.

Can I use my Pillcheck results for siponimod?

Pillcheck reports your CYP2C9 genotype, including the *2 and *3 variants named in the siponimod label and the *4, *5, *6, *8, *9, *11, *12, *13, *15 and *27 alleles, several of which are more common in people of non-European ancestry. Share your report with your neurologist, who will decide whether siponimod is right for you and at what dose.

Does my CYP2C9 result matter for other medications?

Yes. CYP2C9 also affects some anti-inflammatory painkillers, the anticonvulsant phenytoin and the blood thinner warfarin, so your result is useful for life.

References

1. Mayzent (siponimod) prescribing information. US Food and Drug Administration; revised 2026. Drugs@FDA (current label); original 2019 label: accessdata.fda.gov
2. Health Canada. Regulatory Decision Summary: Mayzent. 2020. hpfb-dgpsa.ca
3. Kane M. Siponimod therapy and CYP2C9 genotype. In: Pratt VM, Scott SA, Pirmohamed M, et al., eds. Medical Genetics Summaries. National Center for Biotechnology Information; 2023. ncbi.nlm.nih.gov
4. Gilenya (fingolimod) prescribing information. US Food and Drug Administration; revised 2019. accessdata.fda.gov
5. Bousman CA, Stevenson JM, Ramsey LB, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther. 2023;114(1):51-68. doi:10.1002/cpt.2903
6. Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6, OPRM1, and COMT genotypes and select opioid therapy. Clin Pharmacol Ther. 2021;110(4):888-896. doi:10.1002/cpt.2149
7. Theken KN, Lee CR, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium guideline (CPIC) for CYP2C9 and nonsteroidal anti-inflammatory drugs. Clin Pharmacol Ther. 2020;108(2):191-200. doi:10.1002/cpt.1830