FDA-Approved Medications: New Data on Previously Approved Medications: Oral Medications
- Starting dose for most patients: 0.25 mg orally on Day 1, increasing in 0.25-mg increments over five days to 1.25 mg.
- 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
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. By binding to these receptors, 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 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.38
Mayzent was the first FDA-approved oral drug to treat secondary-progressive MS in adults experiencing active disease. Mayzent is also approved for use in clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS).39
A recent study found that Mayzent may delay or prevent wheelchair dependence in some people with secondary-progressive MS (SPMS). In the Phase III EXPAND study that led to Mayzent receiving FDA approval, the medication delayed disability progression and cognitive decline among those with SPMS.
Investigators subsequently performed two analyses on data for participants in the EXPAND active treatment and placebo groups. The first analysis measured time to wheelchair dependence in 412 patients with a baseline Expanded Disability Status Scale (EDSS) score of 6.5, which indicates dependence on a walking device and high risk of progression to a wheelchair. In that group, EDSS scores increased to 7.0 (indicating wheelchair dependence) in 19.8% of Mayzent-treated patients, compared with 26.1% of those in the placebo group.
In the second analysis, researchers split the overall EXPAND population of 1,645 participants into three groups by EDSS score range: 5.0 or lower; 5.5 to 6.0; and 6.5. The investigators then calculated the time each patient stayed in an EDSS range before moving to another, and used that information to predict time to wheelchair dependence for patients at any EDSS range.
Based on this analysis, the researchers found that Mayzent reduced the risk of progression from an EDSS of 5 or less to EDSS 5.5 or 6 by 21%, and reduced the risk of worsening from an EDSS of 6.5 to 7.0 by 28%, compared with placebo. Assuming that the effect of Mayzent would remain stable over time, the researchers predicted that Mayzent may extend the median time to wheelchair dependence by 4.3 years in the overall study population, compared with placebo.40
Another analysis of EXPAND data by a separate team of investigators found further evidence that Mayzent reduces the risk of confirmed disability progression (CDP) in people with active SPMS. The researchers evaluated data on 779 EXPAND study participants with active SPMS, which was defined as having suffered one or more relapses in the two years before screening, or having one or more T1 gadolinium-enhancing lesions at baseline. A total of 516 patients in the active-disease group received Mayzent, while 263 received placebo.
The analysis found that Mayzent reduced the risk of three-month CDP by 31% and the risk of six-month CDP by 37%, compared with placebo. Among patients in the treatment group, Mayzent also:
- Lowered the annualized relapse rate by 46%.
- >Reduced T1 gadolinium-enhancing lesions by 85%, and new or enlarging T2 lesions by 80%. Also, T2 lesions were smaller at 12 months and 24 months in the treatment group, compared with placebo.41
Meanwhile, a six-year analysis of Mayzent-treated patients uncovered no major safety concerns or increased incidence of adverse events (AEs), but underscored the need to monitor patients for tolerability issues. It should be noted that just because a person experiences an adverse event while taking a medication, it does not necessarily mean that the medication caused that event. Researchers record all adverse events to look for patterns that may suggest an association between the medication and the event.
Researchers typically perform long-term studies of medications to determine their safety and tolerability in real-world practice. In this analysis, researchers studied two groups of patients: a “controlled pool” of 1,755 people who received Mayzent or placebo during the medication’s core clinical trials, and a “long-term pool” of 1,737 people who received at least one 2-mg or 10-mg dose of Mayzent in either the core or extension trial phases. Mean exposure to Mayzent was 17.7 months in the controlled pool and 27.8 months in the long-term pool, and 127 people in the long-term pool received Mayzent for five years or longer.
In the long-term pool, 90% of patients had at least one adverse event, 20.7% had at least one serious adverse event (AE), and 9.6% had AEs that led to study discontinuation. Rates of infection in the long-term and controlled pools were 43.2 and 48.9, respectively, per 100 patient years (the number of infections 10 patients would suffer in 10 years). By comparison, the infection rate in the placebo group within the controlled pool was 53.8 per 100 patient years. Also, between 42.3% and 53% of Mayzent-treated patients with low levels of lymphocytes (an infection-fighting type of white blood cell) contracted infections, but these percentages were similar to those in the placebo group and did not indicate an increased infection rate compared with previous data.
The most common AEs in both groups were headache, urinary tract infection, falls, high blood pressure, and the common cold. The incident rates ranged from 4.9 to 11.3 per 100 patient years, and were similar between both patient pools.42
A new six-month, multicenter, open-label study called EXCHANGE will examine the safety of switching patients currently taking another disease-modifying therapy (DMT) to Mayzent. The study will recruit 300 patients with relapsing-remitting MS from 80 MS treatment centers throughout the United States. Individuals with the CYP2C9*3/*3 genotype are ineligible, as this genotype slows the body’s ability to process Mayzent and increases the risk of medication-related adverse effects.
Study participants will switch from their current DMT to Mayzent within 24 hours of study entry. Patients who have been taking Aubagio, which is metabolized more slowly than other DMTs,43 will stop Aubagio and wait 14 days before starting Mayzent. Participants will start Mayzent at a low dose, and then be titrated over five days to 2 mg daily at Day 6. Participants will be monitored for adverse effects throughout the six-month analysis, as well as for treatment satisfaction, treatment adherence after switching, and cardiac safety.29
Mayzent is contraindicated in those who experienced a cardiovascular event or who were diagnosed with severe heart failure in the past six months. Physicians are advised to perform an echocardiogram and check for use of other medications that affect heart function before starting Mayzent.39