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Relevant BNF section: BNF 8.2.4
Abstract
▼Fingolimod (Gilenya - Novartis) is a new treatment for patients with highly active relapsing-remitting multiple sclerosis. It is the first oral disease-modifying drug for the treatment of patients with multiple sclerosis. Here we assess the place of this drug.
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Relevant BNF section: BNF 8.2.4
Background
Most patients with multiple sclerosis present with relapsing-remitting disease that, over years, typically leads to a progressive phase of permanent and increasing disability (secondary progressive disease).1 About 10-15% of patients have progressive symptoms from the outset, with no relapses and remissions (primary progressive disease). Some patients have a relatively benign form of the disease with no significant disability for many years.
The underlying pathogenic mechanisms in multiple sclerosis appear to be heterogeneous and involve inflammation and axon degeneration.2 Disease-modifying treatments for use in multiple sclerosis that are licensed in the UK include two forms of interferon beta (-1b and -1a), glatiramer, and ▼natalizumab.1,3,4,5 All of these treatments are administered parenterally.
Changes in disability in patients with multiple sclerosis are usually measured using Kurtzke's Expanded Disability Status Scale (EDSS), which ranges from 0 to 10, with higher scores indicating greater disability. Progression in disability is usually defined as an increase in EDSS of 1 point, sustained for 3-6 months.5 Gadolinium-enhancement in magnetic resonance imaging (MRI)† of the brain is a sensitive indicator of features associated with inflammatory lesions causing relapse, but is a poor predictor of cumulative impairment or disability.
The unpredictability and relative infrequency of relapses makes it inherently difficult to assess the effects of disease-modifying drugs in multiple sclerosis through clinical trials; in addition, clinical trials are not usually long enough to assess the effects on the long-term risk of disability.6
The National Institute for Health and Clinical Excellence (NICE) considered the clinical and cost-effectiveness of beta interferons and glatiramer in a technology appraisal in 2002. NICE concluded that it was not appropriate to recommend use of the treatments on the NHS because there was insufficient evidence to show their cost-effectiveness over the expected lifetime of a patient with multiple sclerosis.7 However, the four UK health administrations and the pharmaceutical companies subsequently reached agreement on a risk-sharing scheme for the NHS to supply interferon beta and glatiramer for patients with multiple sclerosis.7 Access to the drugs was set up through the ‘Multiple Sclerosis Risk Sharing Scheme’ in which the manufacturers agreed to provide the drugs on the basis that, over time, they would meet certain clinical outcomes. The scheme involves a long-term observational study that is collecting data from more than 5,000 patients to measure effectiveness of the treatments. Following consideration under its single technology appraisal process, NICE has recommended natalizumab as an option for the treatment of rapidly evolving severe relapsing-remitting multiple sclerosis.8
What is fingolimod?
Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator,9 derived from myriocin, a metabolite of the fungus ascomycete Isaria sinclairii.10 Myriocin and fingolimod are structural analogues of sphingosine and its phosphorylated metabolite S1P. Sphingosine is an essential structural component of the lipid bilayer of the plasma membrane and plays an important role in cell signalling. After oral ingestion, fingolimod is phosphorylated by sphingosine kinase into the active form, which binds to specific S1P receptors on lymphocytes. This binding affects the ability of lymphocytes to leave lymph nodes, causing a redistribution rather than depletion of lymphocytes. It is thereby thought to reduce the number of pathogenic lymphocytes entering the central nervous system and causing damage to myelin sheaths.9
Licensed indication and dose
Fingolimod is licensed in the EU as “single disease modifying therapy in highly active relapsing remitting multiple sclerosis” for the following adult patient groups:
Patients with high disease activity despite treatment with a beta interferon. These patients may be defined as having failed to respond to a full and adequate course (normally at least 1 year of treatment) of beta interferon. Patients should have had at least one relapse in the previous year while on therapy, and have at least nine T2-hyperintense lesions in cranial MRI or at least one gadolinium-enhancing lesion. A non-responder could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared with the previous year; or
Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by two or more disabling relapses in 1 year and with one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared with a previous recent MRI.9
The licensed dose of fingolimod is one 0.5mg capsule taken orally once daily. The summary of product characteristics (SPC) states that the drug should be started and supervised by a physician experienced in multiple sclerosis.
Clinical efficacy
Compared with placebo
One double-blind randomised placebo-controlled trial investigated the effects of fingolimod over 24 months.11 The FREEDOMS study (‘FTY720 research evaluating effects of daily oral therapy in multiple sclerosis’) included adults (aged 18-55 years) with relapsing-remitting multiple sclerosis, at least one documented relapse in the previous year or at least two in the previous 2 years, and a score of 0-5.5 on the EDSS. In all, 1,272 patients received fingolimod 0.5mg or 1.25mg or matching placebo, once daily. There were fewer confirmed relapses per year (the primary outcome measure) with both doses of fingolimod compared with placebo (0.18 with 0.5mg vs. 0.16 with 1.25mg vs. 0.40 with placebo, p<0.001 for both comparisons with placebo). The risk of disability progression (a secondary outcome measure) was lower with both fingolimod doses (hazard ratio for disability progression, 0.70 with 0.5mg and 0.68 with 1.25mg, p=0.02). There were no significant differences between the two doses of fingolimod for both outcome measures.
Compared with other treatments for multiple sclerosis
A double-blind double-dummy randomised controlled trial compared fingolimod with intramuscular interferon beta-1a.12 The TRANSFORMS (‘trial assessing injectable interferon versus FYT720 oral in relapsing-remitting multiple sclerosis’) study included 1,292 adults (aged 18-55 years) with the same entry criteria as in the placebo-controlled trial described above. They received oral fingolimod (0.5mg or 1.25mg) or intramuscular interferon beta-1a (30µg weekly) for 12 months. There were fewer confirmed relapses per year with both doses of fingolimod compared with interferon beta-1a (0.16 with 0.5mg vs. 0.20 with 1.25mg vs. 0.33 with interferon beta-1a; p<0.001 for both doses compared with the control). At 1 year, there was no significant difference between fingolimod and interferon beta-1a in the time to disability progression (a secondary outcome measure).
Unwanted effects
In the clinical trials (involving a total of 1,703 patients who took fingolimod), the most serious reported unwanted effects were infections, macular oedema, and transient atrioventricular block. The most commonly reported effects (in at least 10% of patients) were: headache, influenza, diarrhoea, back pain, cough, and raised liver enzymes (the most common reason for stopping treatment). Effects on the heart (a slowing of heart rate and atrioventricular block at the time of the first dose) seem to relate to binding of the drug to S1P receptors in cardiac tissue.11 Animal studies have suggested that fingolimod has teratogenic potential.13
The European regulatory authority considered that “fingolimod exhibits a heterogenous and complex safety profile”.13 Safety concerns include bradycardia, atrioventricular-blocks, leucopenia, risk of increased frequency and seriousness of infections, occurrence of lymphoma related to the drug's immunosuppressant effect, neurological manifestations including posterior reversible encephalopathy syndrome, a risk of liver toxicity and strong signals of teratogenicity.
Contraindications and cautions
Fingolimod is contraindicated in patients with known immunodeficiency syndrome, and in those with increased risk for opportunistic infections, severe active infections, or active chronic infections. It is also contraindicated in patients with known active malignancies (except cutaneous basal cell cancer) or severe liver impairment (Child-Pugh class C).
Information for prescribers
Under the terms of the marketing authorisation for fingolimod, the company is required to provide to doctors who intend to prescribe the drug an information pack containing: the SmPC, a checklist, information about a fingolimod pregnancy exposure registry, and a patient reminder card.14 The checklist includes the following key messages (which are abbreviated here):
to monitor the patient's heart rate;
to avoid co-administration of fingolimod with certain antiarrhythmic drugs;
to be cautious when using fingolimod in patients with heart disease or taking drugs that decrease heart rate;
to monitor peripheral lymphocyte count;
the action to take regarding fingolimod if the patient has a severe active infection;
the need for ophthalmic assessment;
the importance of avoiding pregnancy during treatment with fingolimod and for at least 2 months after stopping treatment; and
to monitor liver function.
The patient reminder card mentions the need to monitor heart rate and liver function; to inform the prescriber of signs or symptoms of infection; to report signs of visual impairment; and for women of childbearing potential to use effective contraception.14
One review has recommended that treatment with fingolimod should be “initiated and supervised by a physician experienced in multiple sclerosis“.15
A restricted indication
The patient population defined in the licensed indication as suitable for fingolimod therapy is much more specific than the population included in the clinical trials.13 This is because the European regulators judged that the benefit-risk balance was negative for the broader population of patients with relapsing-remitting multiple sclerosis. They therefore decided to restrict the indication for fingolomod to the treatment of specific subgroups of patients with highly active disease (which they identified through a retrospective analysis of the efficacy results).13
Cost
The basic cost to the NHS of fingolimod 0.5mg daily for 1 year is around £19,000. By comparison, the annual cost of glatiramer, interferon beta (-1a and -1b), and natalizumab at doses for adults ranges from £6,700 to £14,700 (drug costs alone).
National guidance
NICE is due to publish an appraisal of fingolimod in April 2012.16 The Scottish Medicines Consortium is due to publish its advice on the drug in March 2012.17
Conclusion
▼Fingolimod is a new oral immunosuppressant for the treatment of multiple sclerosis. In a trial lasting up to 2 years, it reduced the risk of relapse compared with placebo, and in a trial lasting 1 year it was more effective than interferon beta-1a in reducing the risk of relapse. However, data suggest that fingolimod might increase the risk of serious unwanted effects such as bradycardia, leucopenia, infections and liver toxicity. Such concerns are the basis of the licensed indication being restricted to subgroups of patients with highly active disease despite treatment with a beta interferon, or rapidly evolving severe disease. In addition, it is too soon to know whether the suppression of relapses translates into a long-term reduction in disability.
Given the restricted indication and the risk of serious unwanted effects, the use of fingolimod should only be managed by specialists experienced in the treatment of multiple sclerosis. In our view, fingolimod has a very limited role in the management of patients with multiple sclerosis. Availability of fingolimod through the NHS will be determined by the outcome of guidance issued by NICE and the Scottish Medicines Consortium.
Footnotes
↵† To read more about MRI scans, see DTB, 2011; 49: 141–4.