Fingolimod (FTY720)

Fingolimod (FTY720) is an experimental new drug treatment for people with relapsing remitting multiple sclerosis (MS) that is taken by mouth.

Other names: FTY720, Gilenia
In development for: Relapsing remitting multiple sclerosis (MS) and primary progressive MS
Status: Phase III, applied to US and European regulators for license December 2009.
Last updated: June 2010

How does it work?

Fingolimod acts on certain types of white blood cells (lymphocytes) which are involved in the autoimmune attack on myelin seen in MS. It binds to special locations (or receptors) on the surface of the lymphocytes, called sphingosine-1-phosphate receptors (S1P-R). This causes a larger proportion of lymphocytes to be retained in the lymph glands. The number of activated lymphocytes reaching the brain is decreased, resulting in reduced immune attack on nerve cells in the brain and spinal cord.

In addition, laboratory data suggest that fingolimod may have a direct effect on reducing nerve damage and enhance repair of nerve cells by acting on S1P-R in the central nervous system.

How is it given?

Fingolimod is taken orally as tablets.

Clinical studies

A six month, phase II controlled clinical trial of fingolimod involving 255 people with relapsing remitting MS found inflammation measured on MRI scans was significantly reduced in treatment groups when compared to people on placebo. More people in the treatment group stayed relapse-free.

In an extension of this original study, those previously taking a placebo started treatment. Relapse rates remained low with up to 70% remaining relapse-free after four years. These results were reported at the 2009 annual meeting of the Academy of American Neurologists (AAN) [P06.128].

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 witha a higher incidence of side effects.
TRANSFORMS

TRANSFORMS (Trial assessing injectable interferon vs FTY720 oral in RRMS) was a one year phase III study involving 1,292 participants. It compared two doses of fingolimod (0.5 mg and 1.25 mg) with interferon beta-1a (Avonex).

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 compared with 69% of those on interferon beta-1a.
Read abstract.

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 of fingolimod. One year into this extension study, relapse rates and inflammatory activity on MRI scans was 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. These results were reported at the 2010 annual meeting of the Academy of American Neurologists (AAN) [P03.125].
FREEDOMS

FREEDOMS (FTY720 research evaluating effects of daily oral therapy in multiple sclerosis) was a double-blind, placebo-controlled phase III 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..
Read abstract.

Participants in the FREEDOMS study will be invited to take part in an extension of this study, to measure long-term safety and effectiveness. Further details of this study.

Further clinical trials

FREEDOMS II

This study is essentially the same as FREEDOMS, recruiting over 1000 participants mostly in North America. This study is not due to finish until April 2013. Further details of this study.

INFORMS (FTY720 in Patients With Primary Progressive Multiple Sclerosis)

Initial data have suggested that fingolimod may have an effect on nerve repair. The purpose of this study is to evaluate whether fingolimod (0.5 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. This study is not due to finish until December 2013. Further details of this study.

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 the TRANSFORMS clinical trial, two deaths resulting from herpes virus infections occured 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 it's immunosuppressive action, which could lead to an increased risk of infections.

In addition, eight cases of localized 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 thos 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. No instances of macular oedema or skin cancer occurred during the FREEDOM trial.

Latest update on licensing

The manufacturers, Novartis, submitted fingolimod for licensing in Europe at the end of 2009. The National Institute for Health and Clinical Excellence (NICE) has already suggested that it may include fingolimod in the next round of assessments as a treatment for both relapsing remitting and primary progressive MS.

In February 2010 the Food and Drug Administration (FDA) in the USA 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. The European review process is not affected. In June 2010, an advisory panel to the FDA recommended approval of fingolimod as a treatment for relapsing remitting multiple sclerosis.

The drug's European licensing submission is not as far advanced as it is in the USA and will not be affected by the FDA's decision.

References

Kappos L, et al.
Oral fingolimod (FTY720) for relapsing multiple sclerosis
New England Journal of Medicine 2006;355(11):1124-1140.
Read abstract

O'Connor P, et al.
Oral fingolimod (FTY720) in multiple sclerosis: two-year results of a phase II extension study
Neurology 2009;72(1):73-79.
Read abstract

Comi G, et al.
Phase II study of oral fingolimod (FTY720) in multiple sclerosis: 3-year results
Multiple Sclerosis 2010;16(2):197-207.
Read abstract

Cohen JA, et al.
Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis
New England Journal of Medicine 2010;362:402-415
Read abstract.

Kappos L, et al.
A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis
New England Journal of Medicine 2010;362:387-401
Read abstract.

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