Fingolimod-phosphate (fingolimod-P), the active form of fingolimod, was approved in 2010 by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis (MS) in adults, and the indication was expanded in 2018 to include children and adolescents aged ≥10 years.1 Fingolimod is a sphingosine 1-phosphate receptor (S1PR) modulator that inhibits lymphocyte egression from peripheral lymph nodes, resulting in reduced migration of pathogenic lymphocytes into the central nervous system (CNS). Fingolimod also penetrates the CNS but it is ineffective in mice lacking the S1P₁S1PR subtype on astrocytes despite normal expression in the immune compartment. These findings suggest that fingolimod S1PR modulation is active in the immune system and the CNS, resulting in both anti-inflammatory and possibly neuroprotective downstream effects. Fingolimod has resulted in improved disease symptoms in experimental autoimmune encephalomyelitis, the animal model of MS.
As noted, fingolimod has been available for treatment of relapsing MS in adults since 2010. The TRANSFORMS (ClinicalTrials.gov Identifier: NCT00340834) and FREEDOMS (ClinicalTrials.gov Identifier: NCT00289978) trials compared fingolimod with interferon (IFN) β-1a and placebo, respectively, in adults and demonstrated the superior efficacy of fingolimod with respect to annual relapse rate (ARR) and magnetic resonance imaging (MRI) outcomes.2,3
PARADIGMS (ClinicalTrials.gov Identifier: NCT01892722) was the first randomized controlled trial ever completed in children with MS.4 The design was similar to the adult TRANSFORMS trial: a randomized, double-blind, parallel-group trial comparing the efficacy and safety of fingolimod vs IFN β-1a. This trial included 215 children and adolescents recruited from 80 MS centers in 26 countries who had experienced at least 1 relapse in the prior year, at least 2 relapses in the prior 2 years, or at least 1 new lesion in the 6 months preceding randomization. The investigators reported an 82% reduction in the ARR and less new or newly enlarged T2 lesions on MRI over 2 years, with overall fewer adverse events in the fingolimod group compared with IFN β-1a. Leukopenia, upper respiratory infections, and increased liver enzymes were the most frequent side effects associated with fingolimod administration.
The frequency of serious adverse events was also found to be increased in the fingolimod treatment group compared with the IFN β-1a treatment group. Serious adverse events included convulsions, isolated cases of agranulocytosis, liver dysfunction, gastrointestinal necrosis/obstruction, hypersensitivity reactions, uveitis, and atrioventricular blockade. No cases of cancer, varicella, or opportunistic infections were reported in the fingolimod group, and macular edema was reported in only one child.4
A subsequent analysis of PARADIGMS investigated differences between treatment groups in different subpopulations — including treatment-naive patients and younger or prepubertal patients — and disability progression.5 Treatment with fingolimod was associated with consistent control of disease activity among all subgroups and potentially less disability progression than IFN β-1a for up to 2 years. Interestingly, the ARR reduction was inversely proportional to age, a finding already noted in the TRANSFORMS trial in which younger adults appeared to have less relapses with fingolimod therapy compared with older patients.
Overall, the PARADIGMS trial favored the efficacy of fingolimod over that of IFN β-1a, which was the standard of care for pediatric MS until recently. As a result of this trial, fingolimod became the first disease-modifying drug approved by the FDA for the treatment of children and adolescents aged ≥10 years with relapsing forms of MS.6 Fingolimod had already been approved in Europe7 and other parts of the world for the treatment of pediatric MS.
When considering initiating treatment with fingolimod in pediatric patients, complete blood counts and liver function tests should be conducted at baseline and then every 3 to 6 months, as fingolimod can cause dose-dependent lymphopenia and liver dysfunction. In our practice, if a patient’s absolute lymphocyte count drops to <200/μL, then we either switch to another therapy or change the dosage of fingolimod to every other day. I also obtain JC virus antibody titers, QuantiFERON®, and varicella zoster virus (VZV) immunoglobulin G at baseline. If a patient has no VZV titers or no history of chickenpox, I recommend that they undergo immunization at least 1 month prior to starting treatment. A baseline electrocardiogram (ECG) is also needed to rule out underlying cardiac arrhythmia. If the ECG is abnormal, fingolimod is probably not the best treatment option.
The first dose of fingolimod can be given at an infusion center or a nurse can monitor it at home, depending on the patient’s preference. It should be given in a setting where symptomatic bradycardia can be managed. We usually monitor ECG, blood pressure, and heart rate at baseline followed by hourly checks for 6 hours after the first dose. I have seen transient decreases in heart rate, but I have never had a case of complete atrioventricular blockade in children as a result of treatment with fingolimod.
With regard to risk-benefit discussions I have with parents considering fingolimod therapy for their children, adult clinical trial data suggest that infusible MS treatments like natalizumab, ocrelizumab, and rituximab, together with fingolimod, may have the best efficacy compared with older injectable agents or even teriflunomide. Although no definitive consensus exists, I believe that early initiation with highly effective therapy is more beneficial in the long run versus drug escalation strategies.
Fingolimod efficacy in children has been demonstrated in clinical trials, and it is clearly superior to IFN β-1a in terms of ARR and fewer new lesions on MRI per year. Side effects overall are less frequently encountered with fingolimod vs IFN β-1a. Moreover, the improvement in quality of life and rates of medication adhesion derived from using an oral medication vs an intramuscular injection in children, cannot be dismissed. When speaking to fingolimod downsides, I review the risk for transient bradycardia, as I mentioned earlier, and describe the need for first-dose monitoring. Leukopenia, recurrent infections, and high liver enzymes are the most frequent side effects encountered in children, and I make sure patients and families are aware of the need of periodic laboratory testing in order to assess these risks.
In adults, there have been reported cases of skin carcinomas, disseminated herpes zoster, herpes encephalitis, fungal and opportunistic infections including JC virus in patients using fingolimod. Macular edema, which is more frequently seen in adults, occurred only in 1 of the 107 children treated with fingolimod in PARADIGMS.4 I usually perform an eye examination 3 to 4 months after initiating treatment with fingolimod and then twice a year afterward to monitor for the development of macular edema. Macular edema typically resolves with discontinuation of treatment.
Convulsions were another surprising side effect encountered in 5.6% of the children treated with fingolimod in PARADIGMS,4 a rate that seems higher in children than in adults. This potential side effect should be discussed with patients and their parents. In addition, I stress the need for all female patients of childbearing age considering treatment with fingolimod to be on effective contraception, as fingolimod may increase the risk for congenital malformations. If patients want to become pregnant, they should tell their neurologists and switch to a more suitable medication.
In general, the choice of which disease-modifier treatment is the best for a specific child should evolve from a discussion involving the child, the family, and the healthcare professional. Healthcare professionals should offer the options they feel most comfortable with and discuss pros and cons for each, so families and patients can make an informed decision regarding which treatment is best.
Response to fingolimod or any other MS treatment is difficult to assess as no standard definition of treatment failure exists. It is true that with the recognition of no evidence of disease activity (NEDA) as a treatment goal, disease activity levels that were previously tolerated with disease-modifying treatment are now frequently considered unacceptable by many physicians. Monitoring should include clinical and radiographic signs of breakthrough disease, as well as surveillance for potential side effects and long-term safety concerns. In general, disease activity in MS is usually measured by ARR and new T2 lesions or new enlarged T2 lesions on MRI.
As mentioned, the PARADIGMS trial included children <18 years of age with evidence of at least 1 relapse per year or at least 1 new lesion in the 6 months prior to starting treatment, parameters that would generally be considered as suboptimal response by many. Although no consensus exists, I would rather see less than 1 clinical relapse per year and less than 1 new lesion per year to consider a ‘good therapeutic response’ to fingolimod. I tend to see the patients I start on a new medication every 3 months for the first year, with more frequent MRIs at treatment initiation, in order to monitor response. Hopefully, the 5-year open-label extension of the PARADIGMS trial will provide more evidence on the long-term response to fingolimod, including disability or brain volume changes and better insight into disease monitoring requirements.
1. FDA approves first oral treatment for relapsing forms of MS. News release. Multiple Sclerosis Society of America. September 23, 2010. Accessed March 3, 2020. https://mymsaa.org/news/gilenya
2. Cohen JA, Barkhof F, Comi G, et al; for the TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):401-415.
3. Kappos L, Radue EW, O’Connor P, et al; for the FREEDOMS Study Group. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med. 2010;362(5):387-401.
4. Chitnis T, Arnold DL, Banwell B, et al; for the PARADIGMS Study Group. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. N Engl J Med. 2018;379(11):1017-1027.
5. Deiva K, Huppke P, Banwell B, et al. Consistent control of disease activity with fingolimod versus IFN β-1a in paediatric-onset multiple sclerosis: further insights from PARADIGMS. J Neurol Neurosurg Psychiatry. 2020;91(1):58-66.
6. FDA expands approval of Gilenya to treat multiple sclerosis in pediatric patients. News Release. US Food and Drug Administration. May 11, 2018. Accessed March 3, 2020. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gilenya-treat-multiple-sclerosis-pediatric-patients
7. EMA approves Gilenya for childhood MS. News Release. November 29, 2018. Accessed March 3, 2020. https://www.mssociety.org.uk/what-we-do/news/ema-approves-gilenya-for-childhood-ms