Class: Sphingosine-1-phosphate (S1P) modulators

Name: Fingolimod (Gilenya®); siponimod (Mayzent®); ozanimod (Zeposia®); ponesimod (Ponvory®)

Frequency: All are daily oral medications. When starting the drug: all may slow heart rate and lower BP with first doses. Thus, Gilenya requires first dose monitoring over 6-10 hours at home by a licensed professional (paid for by the drug company, Novartis) and the other three drugs use a slow escalation over 1-2 weeks. Mayzent also requires the use of a genetic test to define the final dose. Doses are different for each of these DMTs.

Mechanism of Action: Trapping of lymphocytes within lymph nodes and possibly inhibiting proinflammatory astrocytes.

Effectiveness: Moderately effective — decreases relapses by 60%; decreases MRI activity by 60-70%; decreases brain atrophy by 34%.

Possible Side Effects: First-dose bradycardia, heightened risk of serious infection, PML***, macular edema, posterior reversible encephalopathy syndrome, increased respiratory function, liver toxicity, heightened blood pressure , basal cell carcinoma, melanoma (rarely). Only available through REMS**.

 

Fingolimod and its similar formulations are a class of MS medications known as “S1P receptor agonists.” They work by keeping certain immune cells out of function by “locking” them up in the spleen and lymph nodes. This means that if patients stop the medication, their immune system will be back to normal within a week.

Fingolimod was approved for use in MS by the FDA in 2010. The first study of fingolimod lasted 24 months and enrolled 1,272 relapsing-remitting patients, 1,033 of whom completed the study.  Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo and were evaluated based on their relapse rate and disability progression.  The most frequently reported adverse events were nasopharyngitis, influenza, headache, and fatigue.

Video recorded in 2015. Dr. Augusto Miravalle worked with the Rocky Mountain MS Center from 2009 to 2017.

 

** REMS (Risk Evaluation and Mitigation Strategy): REMS is a drug safety program that the U.S. Food and Drug Administration (FDA) can require for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks.

*** PML (Progressive Multifocal Leukoencephalopathy): PML is a rare but serious brain infection that is caused by the JC Virus (JCV). PML is seen in MS patients who are JC virus (JCV) positive and on disease modifying therapies known to increase the risk of PML. At least 50% of the general population has been exposed to JCV, but the infection is generally asymptomatic. But, in immunocompromised patients, including those taking certain MS DMTs, the JC Virus can infect the brain and result in PML. PML The first case of PML in MS was discovered in 2005 with the use of Tysabri.

 

 

 

 

 

 

 

 

 

 

 

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Study results were encouraging. Both fingolimod doses were found to be more effective than placebo in slowing participants’ relapse rate and disease progression. Specifically, the annualized relapse rate was significantly lower (0.18 with 0.5 mg dose and 0.16 with 1.25 mg dose) than placebo (0.40). Additionally, the probability of disease progression was 17.7% with 0.5 mg dose and 16.6% with 1.25 mg dose, whereas for placebo it was 24.1%.

The second study compared fingolimod (1.25 mg or 0.5 mg) to intramuscular interferon beta-1a (Avonex) at a weekly dose of 30 micrograms. Similar to the first study, patients on fingolimod were found to have lower annualized relapse rates. However, no significant difference was seen in disability progression among the 1,153 relapsing-remitting patients who completed the one-year study.

The study did result in two, fatal infections—disseminated primary varicella zoster and herpes simplex encephalitis—in the group of participants on the 1.25-mg dose of fingolimod.