FDA-Approved Medications: Medications Recently Approved
- Starting dose for most patients: 0.25 mg orally on Day 1, increasing in 25-mg increments over five days to 1.25 mg.
- For patients with CYP2C9*1/*3 or *2/*3 genotype, 0.25 mg on Days 1 and 2, increasing to 0.5 mg on Day 3 and 0.75 on Day 4.
- Maintenance dose: 2 mg daily orally for most patients; 1 mg daily orally for patients with CYP2C9*1/*3 or *2/*3 genotype
- Approved in 2019 for relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary-progressive disease, in adults.
Mayzent® (siponimod) is a sphingosine 1-phosphate (S1P)-receptor modulator, meaning that it binds to two receptors, called S1P1 and S1P5, on the surface of cells. As a result of this binding, Mayzent blocks lymphocytes (a type of white blood cell) from leaving the lymph nodes and entering the peripheral blood. While the mechanism by which Mayzent exerts its therapeutic effects in MS is not fully understood, it may involve reduction of lymphocyte migration into the central nervous system (CNS).25 Further, Mayzent binds to S1P1 and S1P5 receptors on oligodendrocytes and astrocytes, cells within the CNS, which are thought to promote remyelination and prevent inflammation.1 Gilenya is also an S1P-receptor modulator.
Mayzent is the first oral drug to treat secondary-progressive MS in adults experiencing active disease. This represents an important advance because up to 80% of patients with relapsing forms of MS will develop secondary-progressive MS (SPMS) at some point. As a side note, just a few days after the FDA approved Mayzent to treat SPMS, it approved Mavenclad® (cladribine) for this use, which is discussed in the following section. Mayzent is also approved for use in clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS), giving it a fairly broad range of indications relative to many other disease-modifying therapies (DMTs).26
The FDA’s approval of Mayzent followed positive findings from the Phase III EXPAND study, a randomized, double-blind, placebocontrolled study that compared the efficacy and safety of Mayzent with placebo in people with SPMS.1, 22 In EXPAND, 1,645 patients were randomized in a 2:1 ratio to receive siponimod (n = 1099) or placebo (n = 546). At baseline, the participants had a mean age of 48 years and had been living with MS for approximately 16 years; more than half had a median Expanded Disability Status Scale (EDSS) score of 6.0 and relied on a walking aid. The trial’s primary endpoint was time to three-month confirmeddisability progression (CDP). Mayzent reduced the risk of such progression by 21% compared to placebo in the overall study population, and cut the risk by 33% relative to placebo in those who had experienced relapse activity in the two years prior to screening. Both reductions were statistically significant. Further, Mayzent delayed the risk of six-month CDP by 26% versus placebo and reduced the annualized relapse rate (ARR) by 55%. Treatment with Mayzent also showed favorable outcomes in other measures of MS disease activity, including cognition, MRI disease activity, and brain volume loss. The most common adverse events were headache, high blood pressure, and an increase in liver enzyme levels.1, 22
The FDA-approved prescribing information for Mayzent advises clinicians to assess patients for specific cardiovascular, ophthalmic, and other conditions before starting them on Mayzent. It recommends obtaining an electrocardiogram (ECG) for all patients, and monitoring those with sinus bradycardia or certain other heart rate and rhythm conditions when they take their first dose of Mayzent. The medication is contraindicated for individuals who in the past six months experienced a myocardial infarction (heart attack) or certain other heart and cerebrovascular conditions, who have various heart rhythm conditions, or whose genetic make-up, or phenotype, affects how their bodies metabolize certain drugs.23 In other cases, a person’s phenotype may require that the individual take a lower ongoing dose of the oral medication.23
Phenotype is an individual’s characteristics as determined by a combination of genetic and environmental factors. The phenotype-related recommendations reflect a growing understanding of how genetics influence a specific person’s response to a medication. Agents approved several years ago do not carry such requirements, because the science was not sufficiently advanced at that time to perform the in-depth genetic analyses that are possible today. Going forward, it is likely that many more medications will have phenotypespecific guidance regarding their use.