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23 March 2010
Data from the 24 month FREEDOMS trial has shown that fingolimod, a once daily, oral drug for the treatment of relapsing-remitting multiple sclerosis (RRMS), was more effective than placebo at decreasing the relapse rate. In the 12 month TRANSFORMS trial fingolimod was more effective than intramuscular interferon beta-1a. Adverse events associated with fingolimod included bradycardia, hypertension and macular oedema.
Level of Evidence: Level 1 (good-quality patient-oriented evidence) according to the SORT criteria.
Action
Fingolimod is in licensing at the present time and, if licensed, could be available in about a year’s time. A NICE single technology appraisal is proposed, but the timeline is still to be set. The publication of these phase III studies, along with a study of oral cladribine, has attracted much publicity. Local decision making bodies may wish to plan ahead with stakeholders for their possible introduction.
What is the background to this?
MS is characterised by periods of relapse and remission but some patients have a single episode whilst others have a progressive form of the disease without remissions. The exact prevalence is unknown, but it has been estimated that 85,000 people in the UK currently have MS, with 2500 new cases diagnosed each year. RRMS accounts for approximately 40% of all MS cases, which equates to roughly 34,000 people in the UK. Information on the management of MS can be found on the NICE website. The clinical guideline is due for review and a NICE single technology appraisal on the use of fingolimod in RRMS is planned.
Currently available preparations for MS are given by injection. Fingolimod was recently submitted to the European Medicines Agency and, as it is an oral preparation, it is likely to generate considerable interest from patients if it should receive a licence.
What do these studies claim?
In the TRANSFORMS study both doses of fingolimod were superior to interferon beta-1a. The annualised relapse rate was 0.20 (95% confidence interval [CI] 0.16 to 0.26) in the fingolimod 1.25mg group, 0.16 (0.12 to 0.21) in the fingolimod 0.5mg group and 0.33 (0.26 to 0.42) in the interferon group (P<0.001 for either dose vs. interferon). This reduces the frequency of relapses by 0.13 to 0.17 per patient per year. Those adverse events which were more common in the fingolimod patients, included herpes virus infection, hypertension, bradycardia and atrioventricular block. This was particularly the case in patients who received the higher dose.
In the FREEDOMS study, the annualised rate of relapse was 0.16 (95% CI 0.13 to 0.19) and 0.18 (0.15 to 0.22) with 1.25mg and 0.5mg doses of fingolimod, respectively, and 0.40 (0.34 to 0.47) with placebo (P<0.001 for either dose vs. placebo). This corresponds to a reduction of relapses by 0.22 to 0.24 per patient per year. Serious adverse events which occurred most frequently in the fingolimod groups included bradycardia and macular oedema.
The key secondary outcome was absence of disability progression, confirmed after three months, during the 24 month period. This was slightly better in the fingolimod groups: hazard ratio (HR) 0.68 (95% CI 0.50 to 0.93) for 1.25mg strength and 0.70 (95% CI 0.52 to 0.96) for 0.5mg group, P=0.02 for both compared to placebo.
How does this relate to other studies?
A placebo-controlled trial of oral cladribine was published at the same time as the fingolimod trials and has been covered in a recent blog. Cladribine, administered in short courses, reduced the annualised rate of relapse compared to placebo. The adverse events that were more frequent in the cladribine patients included lymphocytopenia and herpes zoster. As with the fingolimod trials, the authors noted that the benefits need to be weighed against the risks.
An NPC blog has discussed a trial of alemtuzumab▼increases in RRMS. Although alemtuzumab was more effective than interferon beta-1a at reducing the annualised risk of relapse and sustained disability, treatment in the alemtuzumab groups was stopped early due to the development of immune thrombocytopenic purpura in three patients, one of whom died.
Several more clinical trials are in progress to assess the role of fingolimod for both RRMS and the primary progressive form of the disease. As there is no head-to-head study versus cladribine, we do not know where these agents will be placed in relation to each other in the management of patients with MS.
So what?
An oral preparation will be more acceptable and convenient for patients and, if confirmed by other studies, the superiority to interferon will be of great interest to patients, clinicians and commissioners. However, although fingolimod has been shown to reduce the annualised relapse rate compared to both placebo and interferon beta-1a, and disability progression compared to placebo over 2 years, the long term benefits (for example, on disability) and the safety profile need further assessment. Follow-up trials are on-going and it is hoped these will provide further information; particularly regarding ophthalmic and cardiovascular effects.
TRANSFORMS study details
Cohen JA, Barkhof F, Comi G et al for the TRANSFORMS Study Group. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis. New Eng J Med 2010;362:402-15
Design: Phase III, randomised, double-blind, double-dummy study with concealed allocation.
Patients: 1,292 adults (mean age 36 years) with RRMS were included. They had a history of at least one documented relapse during the previous year, or at least two documented relapses during the previous 2 years, and had a score of 0 to 5.5 on the Expanded Disability Status Scale (EDSS). This ranges from 0 to 10 with higher doses indicating greater disability. Patients had had MS for about 7.5 years and approximately 55% had received previous therapy for MS.
Intervention and comparison: Oral fingolimod at a daily dose of either 1.25mg (n=426) or 0.5mg (n=431) or intramuscular interferon beta-1a at a weekly dose of 30microgram (n=435) were taken for 12 months.
Outcomes and results: The primary end point was the annualised relapse rate, which was defined as the number of confirmed relapses during a 12-month period. Time to confirmed disability progression was included in the secondary outcomes. Outcomes were analysed using a modified intention-to-treat cohort (all patients who underwent randomisation and received at least one dose of a study drug). 1,153 patients (89%) completed the study. The annualised relapse rate was lower in both fingolimod groups: 0.20 (95% CI 0.16 to 0.26) in the 1.25mg group (n=420) and 0.16 (0.12 to 0.21) in the 0.5mg group (n=429) than in the interferon (n=431) group 0.33 (0.26 to 0.42), P<0.001 for both doses compared to interferon. In the secondary outcomes, there was no difference between the three groups in the number of patients with no progression of disability (approximately 93 to 94%).
Discontinuation due to adverse events occurred in 3.7% of the interferon group, 10.0% of the fingolimod 1.25mg group and in 5.6% of those receiving 0.5mg. The most common serious adverse events with fingolimod were bradycardia and atrioventricular block. A dose-dependent decrease in heart rate was observed within the hour after fingolimod administration. Other adverse events among patients receiving fingolimod were hypertension, macular oedema, skin cancer, and elevated liver enzyme levels. Eight patients in the fingolimod groups were found to have skin cancer and one in the interferon group. Alanine aminotransferase levels three times the upper limit of normal occurred in 7% of 1.25mg, 8% of the 0.5mg group and 2% of the interferon patients. Two fatal infections occurred in the 1.25mg fingolimod group: disseminated primary varicella zoster (in a patient exposed to a child with chicken pox) and herpes simplex encephalitis.
Sponsorship: Novartis Pharma
FREEDOMS study details
Kappos L, Radue E-W, O’Connor P et al for the FREEDOMS Study Group. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis. New Eng J Med 2010; 362:387-401
Design: Phase III, double-blind, randomised study with concealed allocation.
Patients: 1,272 adults (mean age 37 years) with active RRMS lasting an average of eight years were included. Patients had experienced at least one documented relapse in the previous year or two or more in the previous two years. In addition, they had EDSS scores of between 0 and 5.5. Interferon beta and glatiramer acetate were stopped at least three months before randomisation. Approximately 59% of patients had not received disease-modifying treatment previously.
Intervention and comparison: Oral fingolimod capsules 0.5mg (n=425) or 1.25mg (n=429) or matching placebo (n=418) were taken once daily for 24 months.
Outcomes and results: The primary end point was the annualised relapse rate: 0.16 (95% CI 0.13 to 0.19) with fingolimod 1.25mg, 0.18 (95% CI 0.15 to 0.22) with fingolimod 0.5mg and 0.40 (95% CI 0.34 to 0.47) with placebo (P<0.001 for either dose vs. placebo) in the intention-to-treat population.
The key secondary outcome was absence of disability progression, confirmed after three months, during the 24 month period. This was slightly better in the fingolimod groups: hazard ratio (HR) 0.68 (95% CI 0.50 to 0.93) for 1.25mg strength and 0.70 (95% CI 0.52 to 0.96) for 0.5mg group, P=0.02 for both compared to placebo.
81% of patients completed the study. Adverse events that led to discontinuation of the study medication were more common with fingolimod 1.25mg (14.2%) than with fingolimod 0.5mg (7.5%) or with placebo (7.7%). Serious adverse events were reported by 11.9% of those receiving fingolimod 1.25mg, 10.1% of the 0.5mg group and 13.4% of those receiving placebo. The most common serious adverse events in the fingolimod patients were bradycardia, multiple sclerosis relapse and macular oedema. Seven fingolimod patients were found to have skin cancer, with four in the placebo group. There were two deaths in the placebo group and one in the 1.25mg fingolimod group. Hypertension and transient decreases in heart rate, after the first dose, were more commonly seen in fingolimod patients. Herpes zoster was reported in three patients receiving fingolimod 1.25mg, seven receiving fingolimod 0.5mg and four receiving placebo. Two cases of herpes virus infection were classified as serious adverse events.
Increases in the alanine aminotransferase level to three times the upper limit of normal or more were more frequent in the fingolimod groups (12.5% of patients in the 1.25mg group and 8.5% in the 0.5mg group) than in the placebo group (1.7%) but returned to normal in all patients.
Sponsorship: Novartis Pharma
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