Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations

Abstract

Fingolimod (FTY720), an immunotherapeutic drug targeting the sphingosine-1-phosphate receptor, is a widely used medication for relapsing-remitting multiple sclerosis (MS). Apart from the pivotal Phase III trials demonstrating efficacy against placebo and interferon-β-1a once weekly, sufficient clinical data are now available to assess its real-world efficacy and safety profile. Approved indications of fingolimod differ between countries. This discrepancy, to some extent, reflects the intermediate position of fingolimod in the expanding lineup of MS medications. With individualization of therapy, appropriate patient selection gets more important. We discuss various scenarios for fingolimod use in relapsing-remitting MS and their pitfalls: as first-line therapy, as escalation therapy after failure of previous immunotherapies, and as de-escalation therapy following highly potent immunotherapies. Potential side effects such as bradycardia, infections, macular edema, teratogenicity, and progressive multifocal leukoencephalopathy as well as appropriate safety precautions are outlined. Disease reactivation has been described upon fingolimod cessation; therefore, patients should be closely monitored for MS activity for several months after stopping fingolimod. Finally, we discuss preclinical and clinical data indicating neuroprotective effects of fingolimod, which might open the way to future indications such as stroke, Alzheimer’s disease, and other neurodegenerative disorders.

An observational study of alemtuzumab following fingolimod for multiple sclerosis

“…This results in a reduction of the number of lymphocytes available to cross the blood–brain barrier into the CNS, which is thought to be responsible for reducing disease activity. 3 …”

“…3 However, there are case reports of prolonged lymphopenia following prolonged drug exposure, up to 37 months after discontinuation. 8 Following discontinuation, there is also a risk of rebound disease activity 2–4 months from the time of withdrawal.…”

Comparative effectiveness of delayed-release dimethyl fumarate versus interferon, glatiramer acetate, teriflunomide, or fingolimod: results from the German NeuroTransData registry

“…DMF also was compared with a FTY (European) label population, which includes patients who have either highly active disease that has not responded to other disease-modifying therapies (DMTs) or rapidly progressive disease [15, 16]. …”

Neurological safety of fingolimod: An updated review

“…In accordance with this, several case reports have described rebound events approximately 2–4 months after stopping FTY 43, 44, 45, 47, 50, 51, 53, 55. Overexpression of sphingosine‐1‐phosphate receptors in entrapped lymphocytes and massive egress of lymphocytes after FTY cessation, observed in animal models, seem to be plausible explanations for such an aggressive disease reactivation in some patients 2. Alternatively, differential changes of lymphocyte subset populations might play a role in rebound 54.…”

“…CCR7 positive‐naïve T cells, central memory T cells) from lymph nodes, thereby reducing the number of lymphocytes in peripheral blood and their infiltration into the central nervous system 1, 2. It is the first disease‐modifying therapy (DMT) drug that can be orally administered, offering a clear advantage over other DMT drugs that must be injected daily (s.c., glatiramer acetate), every other day (s.c., interferon beta‐1b [IFN‐β1b]), weekly (i.m., IFN‐β1a) or monthly (i.v., natalizumab [NTZ]).…”