Fingolimod - factsheet
Date of issue: June 2010
Contents
- Introduction
- How fingolimod works
- Current research
- Side effects and contraindications
- References
- Note on drug trials
1. Introduction
Fingolimod (also known as FTY720, brand name Gilenia) is a new oral treatment currently being tested in phase III clinical trials for relapsing remitting and primary progressive multiple sclerosis (MS).
Laboratory tests investigating the properties of fingolimod indicated that it was able to affect the immune system. Initially, fingolimod was investigated as a treatment to prevent rejection of kidney transplants. Clinical studies were discontinued when it was found that fingolimod offered no additional benefit over the standard treatment.
However, encouraging results were observed in animal models of MS and this provided the rationale for testing its safety and efficacy in the treatment of MS.
The National Institute for Health and Clinical Excellence (NICE) intends to appraise fingolimod through its Single Technology Appraisal (STA) process and has already drawn up a draft scope for the appraisal for both relapsing remitting [1] and primary progressive [2] MS.
The manufacturers, Novartis, submitted fingolimod for licensing in Europe and the USA at the end of 2009. In February 2010 the Food and Drug Administration (FDA) in the US granted priority review to fingolimod.
Priority review is granted to medicines for conditions with high unmet need or with inadequate available treatments and means that the review time will be reduced from ten months to six months. A Novartis press release announced that the FDA has extended its review period by three months, to September 2010 [3]. The European review process is not affected.
2. How fingolimod works
The autoimmune attack that is seen in MS results in the destruction of myelin, the substance covering and protecting nerves in the central nervous system.
Fingolimod acts on certain types of white blood cells (lymphocytes) which are involved in this immune attack. It attaches to special locations (or receptors) on the surface of lymphocytes, called sphingosine-1-phosphate receptors (S1P-R). This causes a large proportion of the lymphocytes to be retained in lymph nodes which are part of the body's immune system. This reduces the number of lymphocytes circulating in the blood. The number of lymphocytes reaching the central nervous system is decreased, resulting in reduced immune attack on nerve cells in the brain and spinal cord [4].
In addition, there is evidence that fingolimod may have a direct effect on nerve cell damage and enhance remyelination by acting on sphingosine receptors in the central nervous system [5,6].
3. Current research
Phase II
Phase III
TRANSFORMS
FREEDOMS
FREEDOMS II
INFORMS
The first study reporting the results of fingolimod in relapsing remitting MS was published in 2007 [7]. In this six month clinical trial 255 people took one of two daily doses of fingolimod (1.25 mg or 5.0 mg) or placebo. Inflammation measured on MRI scans was significantly reduced in the two treatment groups when compared to placebo. The relapse rate for people in the two treatment groups was also significantly lower.
In an extension of this study, those receiving fingolimod continued with their treatment, while those on placebo switched to one of the two doses of fingolimod. 227 people completed the six-month extension; the number of MRI lesions and relapse rates remained low in the groups receiving continuous treatment with fingolimod and decreased in those switching from placebo.
Results of a further extension of this study have also been published. At two years, 79 to 91% of participants were free from inflammation measured on MRI scans and up to 77% remained relapse free. During the course of this extension those on the higher dose of fingolimod were switched to 1.25 mg because analysis of the data indicated that the higher dose offered no advantage in effectiveness and was associated with a higher incidence of side effects [8].
155 people have subsequently been followed for up to 48 months. Relapse rates and inflammatory activity on MRI scans have remained low [9].
Following the promising results from the phase II studies, several phase III studies have been set up.
TRANSFORMS (Trial assessing injectable interferon vs FTY720 oral in RRMS) was a one year phase III study, which has now completed. It compared two doses of fingolimod (0.5 mg and 1.25 mg) against interferon beta-1a (Avonex) in 1292 people with relapsing remitting MS.
Analysis of the data reported the relapse rates at one year were 0.33 for interferon beta-1a, 0.16 on the lower dose of fingolimod (a reduction of 52% compared to interferon beta-1a) and 0.2 on the higher dose (a 38% reduction).
80 to 83% of the fingolimod groups remained relapse-free over the year compared with 69% of those on interferon beta-1a [10].
Patients who completed the TRANSFORMS study were given the option to continue in an extension study; 1027 of the initial 1153 participants (89%) chose to continue. Those already taking either dose of fingolimod stayed on the same dose. Those taking interferon beta-1a were reassigned to 0.5 or 1.25 mg fingolimod. One year into this extension study, relapse rates and inflammatory activity on MRI scans were significantly lower for those taking fingolimod for the entire two year period, compared to those switching to fingolimod at the beginning of the second year [11].
FREEDOMS (FTY720 research evaluating effects of daily oral therapy in multiple sclerosis) was a double-blind, placebo-controlled study involving 1,272 people with relapsing remitting MS in 22 countries. Participants received one of two doses of fingolimod or placebo over two years.
Fingolimod reduced the relapse rate by 54% for the lower dose (0.5 mg) and by 60% for the higher dose (1.25 mg) compared to placebo. The reduction of progression of disability was 30% and 32% respectively compared to placebo [12].
Participants in the FREEDOMS trial will be invited to take part in an extension of this study, to measure long-term safety and effectiveness [13].
This study is essentially the same as FREEDOMS, recruiting over 1000 participants mostly in North America [14].
Initial findings suggest that fingolimod may have a direct effect on nerve repair [5,6]. The purpose of the INFORMS (FTY720 in Patients With Primary Progressive Multiple Sclerosis) study is to evaluate whether fingolimod (0.5mg or 1.25mg tablets taken daily for 3 years) is effective in delaying disability progression compared to placebo in 654 people with primary progressive MS [15]. This study is not due to finish until December 2013.
4. Side effects and contraindications
Although the trials so far have shown fingolimod to be well tolerated, the side effects that have occurred include headache, upper respiratory tract infection, shortness of breath, diarrhoea and nausea. In addition, increased levels of liver enzymes and blood pressure have been observed although these are generally mild.
In the TRANSFORMS clinical trial, two deaths resulting from herpes virus infections occurred in patients taking the higher dose of fingolimod. Other aspects of the treatments these two patients received may have contributed, but a role for fingolimod cannot be excluded given its immunomodulatory action, which could lead to an increased risk of infections.
In addition, in the TRANSFORMS trial, eight cases of localised skin cancer occurred in the fingolimod groups and were successfully removed. Macular oedema (swelling in the back of the eye) also occurred more frequently in the fingolimod-treated participants. In the extension to the TRANSFORMS study, side effects were similar to those reported in the initial trial year, and included further new cases of skin cancer, herpes virus infections, cardiac disorders and macular oedema, all of which were more common in those on the higher dose [11]. No instances of macular oedema or skin cancer occurred during the FREEDOM trial [12].
5. References
- National Institute for Health and Clinical Excellence (NICE).
Draft scope for the proposed appraisal of fingolimod for the treatment of relapsing-remitting multiple sclerosis. Issue Date: December 2008. [cited 2009: July 28]
Available from NICE website - National Institute for Health and Clinical Excellence (NICE).
Draft scope for the proposed appraisal of fingolimod for the treatment of primary progressive multiple sclerosis. Issue Date: December 2008. [cited 2009: July 28]
Available from NICE website - Novartis press release.
Novartis announces extension of US regulatory priority review period for FTY720, an investigational once-daily oral multiple sclerosis therapy. Issue Date: 25 May 2010 [cited 2010: June 4]
Available from Novartis website - Brinkmann V, et al.
FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function.
American Journal of Transplantation 2004; 4: 1019-25. - Miron VE, et al.
Cyclical and dose-dependent responses of adult human mature oligodendrocytes to fingolimod.
American Journal of Patholology 2008; 173: 1143-1152 - Miron VE, et al.
Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices.
American Journal Pathology 2010;176:2682-2694 - Kappos L, et al.
Oral fingolimod (FTY720) for relapsing multiple sclerosis.
New England Journal of Medicine 2007; 355: 1088-1091. - O'Connor P, et al.
Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study.
Neurology 2009; 72: 73-79. - Montalban X, et al.
[P06.128] Oral Fingolimod (FTY720) Shows Sustained Low Rates of Clinical and MRI Disease Activity in Patients with Relapsing Multiple Sclerosis: Four-Year Results from a Phase II Extension.
American Academy of Neurology 61st Annual Meeting; 2009 Apr 25 - May 2; Seattle, USA. - Cohen J, et al.
Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
New England Journal of Medicine 2010; 362:402-415 - Khatri B, et al.
[P03.125] 24-Month efficacy and safety outcomes from the TRANSFORMS extension study of oral fingolimod (FTY720) in patients with relapsing-remitting multiple sclerosis.
American Academy of Neurology 62nd Annual Meeting; 2010 April 10-17; Toronto, Canada - Kappos L, et al.
A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.
New England Journal of Medicine 2010; 362:387-401 - FREEDOMS extension study on the ClincalTrials.gov website
- FREEDOMS II on the ClincalTrials.gov website
- INFORMS on the ClincalTrials.gov website
Note - Drug trials
Phase I studies primarily assess the safety of a drug or procedure. They usually involve a small number of healthy volunteers (10-100) all of whom are given the same treatment.
Once a medical intervention has been proven safe, phase II trials test its effectiveness and whether it has the potential to be of benefit. These trials are larger, typically involving 100-300 people with the condition for which the intervention has been developed - in this case MS.
If the phase II study shows the treatment to be beneficial, phase III studies are conducted to gain a definitive understanding of the effectiveness, benefits and potential side effects in a large group of people (300-3,000) with the condition to be treated. Interventions have to successfully complete a phase III trial before they can be considered for a licence by regulatory authorities.
- Find out more
- This factsheet in also available in pdf format
MS Trust Information Service
If this information doesn't answer your questions, contact the MS Trust's personal information service on 0800 032 38 39 or by email
