Background

Considering the autoimmune pathogenesis of multiple sclerosis (MS), most of the treatments have been based on the immunomodulatory and immunosuppressive properties of drugs such as interferons, glatiramer, azathioprine, cyclophosphamide and mitoxantrone.

Fingolimod, was the first agent to gain approval as an oral treatment in 2010. It is efficiently absorbed, its absorption is unaffected by dietary intake and, as an oral therapy, it has aroused great interest in patients, having a more acceptable route of administration than injections.

Aim of the review

To assess the safety and the benefits of fingolimod in reducing disease activity in people with relapsing-remitting MS (RRMS). A number of safety concerns have already emerged, including serious infections and adverse cardiac effects.

Study characteristics

Six studies, published between 2006 and 2014, were included in this review, comprising a total of 5152 participants suffering from RRMS. The treatment duration was six months in three studies, 12 months in one study, and 24 months in two studies.

Key results and quality of evidence

The main conclusion of this review was that fingolimod, administered as monotherapy at the approved dose of 0.5 mg once-daily increases the probability of being relapse-free at 24 months compared to placebo. The benefit was confirmed with disease activity measures defined by magnetic resonance imaging (MRI) scans. However, there was no effect on preventing disability worsening; treatment was not associated with an increased risk of patient withdrawals due to adverse events.

Comparing the same dose of fingolimod to intramuscular interferon beta-1a, the drug at one year slightly increased the number of participants free from relapse or from inflammatory enhancing lesions and decreased the relapse rate. Again, we did not detect any advantage for preventing disability progression. We found a greater likelihood of discontinuation due to adverse events in the short-term (six months) for fingolimod as compared to immunomodulating drugs, and no significant difference compared to interferon beta at 12 months.

The duration of all studies was equal or inferior to 24 months, so that the efficacy (but mostly the safety) of fingolimod over 24 months remains uncertain. This is a key point for a lifetime disease with the probability of chronic treatments as in MS.

The risk of adverse events requires careful monitoring of patients over time and suggests the need for studies with longer follow-up, particularly considering the recent warning on the development of progressive multifocal leukoencephalopathy.

The six studies included in this review were sponsored by Novartis Pharma, and most co-authors of the published papers were affiliated to the pharmaceutical company; this is recognised as a potential source of bias.