Multiple sclerosis (MS) is a progressive autoimmune disease affecting the brain and spinal cord, leading to weakness of limb muscles, tremors, poor coordination and electric shock sensation from certain movements. MS also causes chronic fatigue and can affect vision, memory and speech. The causes of MS are still unknown, and there currently is no cure. Existing treatments focus on slowing the disease progression and lessening symptoms. In March 2019, the FDA approved siponimod (Mayzent) as a new disease-modifying therapy for relapsing multiple sclerosis. The FDA label for it specifies that drug dose should be adjusted based on the patient’s CYP2C9 genotype to reduce the risk of severe side effects. Patients with absent CYP2C9 activity should not use Siponimod. In this overview, we will describe how pharmacogenetic testing can help to improve the safety of MS treatments, including muscle relaxants, stimulants and pain killers.

Siponimod is approved for people with active disease – clinically isolated syndrome, relapsing-remitting and secondary progressive MS. No treatments currently exist for secondary-progressive multiple sclerosis. Most MS patients suffer from impaired central nervous system, and present with symptoms of blurred vision, poor balance, fatigue, muscle stiffness and spasms, and poor memory. MS starts as a relapsing-remitting disease that can progress to secondary-progressive MS within 15-20 years. Therefore, starting therapy early is critical for patients to help slow the rate of disability progression. A variety of treatments aim to slow down MS progression. These include:

• Beta interferons induce an immune response but cause flu-like symptoms as these molecules trigger an antiviral response.
• Glatiramer acetate (Copaxone) blocks the immune system’s ability to attack myelin, which is the key protein that wraps and protects nerves.
• Sphingosine 1-phosphate receptor modulators (Gilenya and Mayzent) – sequesters lymphocytes in lymph nodes.
• Teriflunomide (Aubagio) is an immunomodulator with anti-inflammatory properties, but it is unknown how it works in MS.
• Dimethyl fumarate (DMF, Tecfidera) is thought to exert neuroprotective effects in patients with multiple sclerosis by activating the nuclear erythroid 2-related factor 2
• Monoclonal antibodies (Ocrevus, Tysabri, Campath, Lemtrada) work by blocking specific components of the immune system

Siponimod (Mayzent) metabolism and drug interactions.

Siponimod is primarily metabolized by the CYP2C9 liver enzyme. CYP3A4 also contributes to siponimod’s clearance. Since siponimod blocks lymphocyte function, it also reduces your body’s ability to fight infections. Excessive siponimod dose can significantly increase the risk of infections, affect vision (macular edema), and slow down heart rhythm (bradycardia).

The FDA drug label states that before starting treatment with Mayzent, your CYP2C9 genotype should be determined by your health care provider. People who have significantly reduced CYP2C9 function (*3/*3 genotype) should not take siponimod. People with reduced CYP2C9 function also require a lower dose. CYP2C9 variations are common, affecting up to 30% of people in North America, especially Asians, who have a higher frequency of *3 alleles. If you do not know your CYP2C9 genotype, ask your health care provider to order a pharmacogenetic test like Pillcheck.

Because the CYP2C9 enzyme also clears celecoxib, ibuprofen, meloxicam, piroxicam and other NSAIDs, long term use of these drugs can affect siponimod clearance and the risk of side effects. Warfarin is another medication that can cause drug-drug interaction with siponimod. Medical cannabis components THC and CBD are metabolized by the CYP3A4 and may affect your response to siponimod. If you are on siponimod, please consult with your physician or pharmacist before taking these medications.

Fingolimod (Gilenya), is a similar drug to siponimod but is more expensive. Fingolimod is metabolized by a different enzyme called CYP4F2. CYP4F2*3 was found to be associated with a higher warfarin dose requirement. Carriers of this variation may also have reduced response to standard fingolimod dose. A pharmacogenetic test can help your doctor to determine whether siponimod or fingolimod would be better for you.

Pillcheck can assess your response to siponimod, and also help to predict your response to other medications used to alleviate MS symptoms, including muscle relaxants (carisoprodol, cannabidiol) that may help reduce painful and uncontrollable muscle spasms. Pillcheck can also assess whether you can take stimulants (amphetamine, modafinil) that might be helpful in reducing MS-related fatigue. Painkillers and antidepressants are also frequently prescribed to help to cope with MS.

The use of multiple medications increases the risk of drug-drug interactions, particularly in people with inherently reduced drug metabolism. The Pillcheck service includes a clinical-grade pharmacogenetic test for over 200 drugs and a medication review by an expert clinical pharmacist. By assessing your metabolic drug profile, Pillcheck can help your doctors to select treatment options with fewer side effects.

Pillcheck may be reimbursed through health benefits (depending on the plan). Many insurance providers fully cover pharmacogenetic tests for people on disability.

Conclusions:

• Siponimod is a new treatment option for MS patients with pharmacogenetic testing recommended prior to use.
• PGx test can assess whether siponimod or fingolimod would better fit your metabolic drug profile
• Pillcheck can help you find the optimal prescriptions to better manage pain, depression, and spasticity symptoms in MS patients.

Selected references:

Siponimod FDA drug labelling information: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf

Dorado P et al., CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards The Pharmacogenomics Journal volume 11, pages108–112(2011)