Siponimod (Mayzent®) is a newly approved medication for the treatment of active secondary progressive multiple sclerosis. Like Fingolimod (Gilenya®), which is produced by the same manufacturer, Siponimod belongs to the class of so-called S1P receptor agonists. This class of substance prevents activated inflammatory cells from leaving their site of activation (the secondary lymphatic organs such as lymph nodes) and triggering inflammation or an inflammatory relapse in the brain. Overall, this concept has proven to be very effective in relapsing-remitting MS in recent years – and now a significant effect on the course of secondary progressive MS patients has also been demonstrated for Siponimod. Therefore, many patients with this late form of MS have high hopes for the medication.
In terms of contraindications and side effects, Fingolimod (which we have been using since 2011) and Siponimod are quite similar. However, there are two essential differences between the two substances in practical application, which may not yet be well known and are briefly explained here.
The first difference is that the dose of Siponimod, which is usually 2 mg, is “titrated” to mitigate the so-called “first dose effect” (= the effect after the first intake). This refers to the drop in heart rate after taking an S1P agonist, because of which, for example, after taking the first Fingolimod tablet, a 6-hour monitoring period was necessary in the doctor’s office.
To mitigate this effect, Siponimod is taken at 0.25 mg for the first two days – there are special tablets available for this low dose of 0.25 mg. On the third day, 2 x 0.25 mg (=0.5 mg), on the fourth day 3 x 0.25 mg (=0.75 mg) and on the fifth day 5 x 0.25 mg (=1.25 mg) are taken before the final dose of Sipnomid is administered on the 6th day. Due to this cautious dosage, unlike Fingolimod, monitoring can be omitted in MS patients without a history of cardiac disease. However, patients with previous cardiac conditions (such as sinus bradycardia = heart rate < 55/minute, an AV block of grade I or II, a heart attack or narrowing of the coronary arteries in the past, or heart failure) should still be monitored for at least six hours in a center capable of performing 24-hour monitoring if needed or ensuring on-site cardiological care in case of complications.
The second major difference to Fingolimod is that the final dose of Siponimod depends on the patient’s metabolism status. What exactly does this mean?
Siponimod is broken down in the liver by an enzyme called CYP2C9. Broadly speaking, there are different genetically determined variants of this enzyme. In patients with CYP2C9*1/*1, *1/*2 or *2/*2 genotype, all of which show normal metabolism of the substance, Siponimod is administered at the standard dose of 2 mg once daily. This will be the case in about 90% of MS patients – hence there is a tablet with a dose of 2 mg for daily intake.
In about 10% of patients, the genotype CYP2C9*1/*3 or *2/*3 will be found. These patients do not metabolize Siponimod as well and should only be treated with 1 mg daily to avoid overdose symptoms. This dose is not available as a single tablet, patients with this genotype must take 4 tablets of 0.25 mg once daily and they should only take four instead of five of the 0.25 tablets on the fifth day of titration.
In less than 1% of MS patients, the genotype CYP2C9*3/*3 will be found. This group of people metabolizes Siponimod very slowly (=slow metabolizer). Here, the use of Siponimod is contraindicated.
Until recently, one had to apply for cost coverage from the respective health insurance company for the genetic testing of the metabolism status. This has often led to a delay in the start of therapy. Meanwhile – and this is good news – it has been communicated that the genetic test for the metabolism status is covered by insurance from 01.04.2020. Therefore, the approval process is no longer necessary. However, a detailed explanation according to the Genetic Diagnosis Act still needs to be made – so do not be surprised if you are presented with a lot of paperwork for explanation and consent.
If the result is available and there are also no other contraindications (including severe heart/circulatory diseases, higher grade arrhythmias or heart failure, active infections, liver failure or malignant underlying diseases), titration of Siponimod can be started. In general, however, it is advisable to update the vaccination status beforehand if necessary – for patients who have never had contact with chickenpox (varicella, VZV), vaccination against VZV is mandatory. Since this is a live vaccine, treatment can then only be started 6 weeks later.
