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Mayzent (Siponimod) Approved for Relapsing Forms of Multiple Sclerosis, Including Active Secondary Progressive Disease

August 2020 Vol 13, Eleventh Annual Payers' Guide - FDA Approvals
Lisa A. Raedler, PhD, RPh
Medical Writer
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Multiple sclerosis (MS) affects nearly 1 million adults in the United States.1 MS is a chronic, inflammatory, autoimmune disease of the central nervous system (CNS) that disrupts communications between the brain and other parts of the body. In most patients, the first symptoms of MS appear between age 20 years and 50 years.1 This condition is more common among women than men, and among Caucasians of northern European ancestry.1

MS usually starts with a relapsing-remitting course, in which episodes of worsening function (relapses or exacerbations) are followed by recovery periods (remissions).2 Within 15 to 20 years, more than 50% of patients with relapsing-remitting MS (RRMS) will transition to secondary progressive MS.2-4 Patients with secondary progressive MS have a progressive worsening of neurologic function over time.

During the first few years of this transition process, many patients with secondary progressive MS continue to have relapses, a phase called “active secondary progressive MS.” Because active secondary progressive MS is one of the relapsing forms of MS, drugs that are approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS can be used to treat secondary progressive MS.

Over time, patients with secondary progressive MS stop having new relapses, a phase known as “nonactive secondary progressive MS.”2

In 2010, fingolimod (Gilenya), a sphingosine 1-phosphate (S1P) receptor modulator, became the first oral disease-modifying drug approved by the FDA to reduce relapses and delay disability progression in patients with relapsing forms of MS.5

Until recently, few treatments had consistently demonstrated the ability to slow the progression of disability in patients with secondary progressive MS, leaving a significant unmet need in clinical practice.

FDA Approves Mayzent for Multiple Sclerosis

On March 26, 2019, the FDA approved siponimod (Mayzent; Novartis), an oral S1P receptor modulator, for the treatment of adults with relapsing forms of MS, including clinically isolated syndrome, RRMS, and active secondary progressive MS.6,7 Siponimod is the second S1P receptor modulator to be approved by the FDA for the treatment of patients with MS, and the first drug approved for the treatment of active secondary progressive MS in more than a decade.8,9

“Multiple sclerosis can have a profound impact on a person’s life. We are committed to continuing to work with companies that are developing additional treatment options for patients with multiple sclerosis,”6 said Billy Dunn, MD, FDA’s Director of the Division of Neurology Products.

Mechanism of Action

Siponimod, an S1P receptor modulator, binds with high affinity to S1P receptors 1 and 5. Siponimod blocks lymphocytes from leaving the lymph nodes, thereby reducing the number of lymphocytes in peripheral blood. The mechanism by which siponimod exerts therapeutic effects in MS may relate to reduced lymphocyte migration into the CNS.7

Dosing and Administration

Siponimod is available in 0.25-mg and 2-mg tablets. Before initiating siponimod treatment, patients must be tested to determine their cytochrome (CY) P2C9 genotype.7

Treatment should be initiated with a 5-day dose titration. A starter pack is available for titrating patients to the recommended maintenance 2-mg once-daily dose. The dose should be adjusted in patients with CYP2C9*1/*3 or *2/*3 genotype.7

First-dose monitoring is recommended for patients with sinus bradycardia, first- or second-degree (Mobitz type I) atrioventricular block, or a history of myocardial infarction or heart failure.7

Pivotal Clinical Trial: EXPAND

The efficacy of siponimod was shown in EXPAND, a randomized, double-blind, parallel-group, placebo-­controlled, time-to-event clinical trial that included patients with secondary progressive MS whose disability progressed in the previous 2 years but with no evidence of disease relapse in the previous 3 months. Patients’ Expanded Disability Status Scale (EDSS) score had to be between 3.0 and 6.5 to qualify for the study.10

The primary efficacy end point was time to 3-month confirmed disability progression, defined as an EDSS increase of at least 1 point from baseline and sustained for 3 months. A prespecified hierarchical analysis consisted of the primary end point and 2 secondary end points, time to 3-month confirmed worsening of at least 20% from baseline on the timed 25-foot walk test and change from baseline in T2 lesion volume.10

A total of 1651 patients were randomized to siponimod (N = 1105) or to placebo (N = 546), and the patients’ median duration of MS was 16 years. The median EDSS score at baseline was 6, with 56% of patients having an EDSS score of ≥6 at baseline. Most (78%) patients had previously received an MS therapy. A total of 22% of patients with available imaging data had 1 or more gadolinium-enhancing lesions on their baseline MRI scan.7,10

Siponimod led to a significant reduction of disability progression compared with placebo in patients with active secondary progressive MS (ie, had MS relapse in the past 2 years before the study; Table). However, in patients with nonactive secondary progressive MS, the reduction in disability progression with siponimod was not statistically significant compared with placebo.7,10

Table

Adverse Events

The safety of siponimod is based on data from 1737 patients who received the drug at doses of at least 2 mg daily. These patients were included in the EXPAND study and in a phase 2 placebo-controlled study in patients with MS.10,11 In EXPAND, 67% of patients who received treatment with siponimod completed the double-blind part of the study compared with 59% of patients who received placebo.10

Adverse events leading to treatment discontinuation were 8.5% among siponimod-treated patients and 5.1% among those who received placebo.10,11

The most common (≥10%) adverse reactions with siponimod in the EXPAND study were headache (15%), hypertension (13%), and increases in transaminase levels (11%).10,11

Contraindications

Siponimod is contraindicated in 3 patient groups, including (1) those with a CYP2C9*3/*3 genotype, which is seen in approximately 0.4% to 0.5% of Caucasians and less common in other ethnic groups7; (2) patients who have myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV congestive heart failure in the past 6 months; and (3) patients with Mobitz type II second- or third-degree atrioventricular block, or sick sinus syndrome, unless the patient has a pacemaker.7

Drug Interactions

Patients should avoid live attenuated vaccines during and up to 4 weeks after siponimod treatment.7

The concomitant use of siponimod with moderate CYP2C9 and moderate or strong CYP3A4 inhibitors is not recommended.7

A decrease in siponimod exposure is likely with the concomitant use of moderate CYP2C9 inducers or strong CYP3A4 inducers, and concomitant use should be avoided.7

Use in Specific Populations

Because siponimod can cause fetal harm, women of reproductive potential should use effective contraception during treatment and for at least 10 days after the final dose of siponimod.7

The presence of siponimod in human milk is unknown.7

Because of the small number of older patients (aged ≥65 years) in clinical trials, whether siponimod affects patients differently based on age is not known.7 The safety and efficacy of siponimod in children have not been established.7

Warnings and Precautions

Siponimod may increase the risk for infections. Before initiating treatment, patients should have complete blood count testing and be monitored for infections during treatment.7

Because of the risk for macular edema, an ophthalmic evaluation is recommended before starting siponimod treatment and if change in vision is detected while taking siponimod. Diabetes mellitus and uveitis increase this risk.7

A cardiologist should be consulted before the concomitant use of siponimod with drugs that slow heart rate.7

Siponimod can cause a decline in pulmonary function.7

Liver enzymes should be assessed before initiating siponimod treatment, and patients with severe liver disease should be closely monitored.7

Blood pressure should be monitored during treatment with siponimod.7

Conclusion

Siponimod is the second S1P receptor modulator to receive FDA approval for patients with active secondary progressive MS, and the first drug to be approved by the FDA for this indication in the past decade. A large clinical trial in this patient population demonstrated that siponimod significantly reduced the risk for disability progression in patients with active secondary progressive disease. Its safety profile is consistent with the other S1P modulator drug approved for MS.

References

  1. National Multiple Sclerosis Society. Who gets MS? (epidemiology). www.nationalmssociety.org/What-is-MS/Who-Gets-MS. Accessed November 28, 2019.
  2. National Multiple Sclerosis Society. Types of MS. www.nationalmssociety.org/What-is-MS/Types-of-MS. Accessed November 28, 2019.
  3. Tremlett H, Zhao Y, Devonshire V. Natural history of secondary-progressive multiple sclerosis. Mult Scler. 2008;14:314-324.
  4. Scalfari A, Neuhaus A, Daumer M, et al. Onset of secondary progressive phase and long-term evolution of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2014;85:67-75.
  5. Drugs.com. FDA approves Gilenya. www.drugs.com/newdrugs/novartis-gains-­fda-approval-gilenya-novel-first-line-multiple-sclerosis-shown-significantly-­reduce-2305.html. Accessed February 10, 2020.
  6. US Food and Drug Administration. FDA approves new oral drug to treat multiple sclerosis. March 26, 2019. www.fda.gov/news-events/press-announce ments/fda-approves-new-oral-drug-treat-multiple-sclerosis. Accessed November 27, 2019.
  7. Mayzent (siponimod) tablets, for oral use [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2019.
  8. Siponimod (Mayzent) - a new drug for multiple sclerosis. Med Lett Drugs Ther. 2019;61:70-72.
  9. Hoffman M. Siponimod provides large-scale evidence for the ability to treat SPMS. NeurologyLive. March 29, 2019. www.neurologylive.com/clinical-focus/siponimod-provides-large-scale-evidence-ability-treat-spms. Accessed November 28, 2019.
  10. Kappos L, Bar-Or A, Cree BAC, et al; for the EXPAND clinical investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391:1263-1273. Erratum in: Lancet. 2018;392:2170.
  11. Selmaj K, Li DKB, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013;12:756-767. Erratum in: Lancet Neurol. 2013;12:846.
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Last modified: September 28, 2020
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