Research: subgroup analyses from the Fingolimod FREEDOMS 1 study

Epub ahead of printDevonshire et al. Relapse and disability outcomes in patients with multiple sclerosis treated with fingolimod: subgroup analyses of the double-blind, randomised, placebo-controlled FREEDOMS study. Lancet Neurol. 2012 Apr 5. 

BACKGROUND: Fingolimod 0·5 mg once daily is approved for treatment of relapsing MS. In the phase 3, 2-year FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in MS) study, fingolimod significantly reduced annualised relapse rates (ARRs) and the risk of confirmed disability progression compared with placebo. The investigators aimed to investigate whether the beneficial treatment effect reported for the overall population is consistent in subgroups of patients with different baseline characteristics.

METHODS: The investigators did subgroup analyses of ARRs (primary outcome) and confirmed disability progression (a secondary outcome) over 24 months in the FREEDOMS study, a randomised, double-blind study that included 1272 patients with RRMS who were assigned 1:1:1 to fingolimod (0·5 mg or 1·25 mg) or placebo once daily for 24 months. Subgroups were predefined, predefined and slightly modified, or defined post hoc, by demographic factors (including sex and age), disease characteristics (including baseline disability scores, relapse rates, and lesion parameters), and response to previous therapy (including analyses in patients eligible for fingolimod treatment according to the European label). Data were analysed by intention to treat. 

FINDINGS: Treatment with fingolimod 0·5 mg was associated with significantly lower ARRs versus placebo across all subgroups except for patients aged over 40 years. ARR ratios ranged from 0·76 (95% CI 0·54-1·09; p=0·13) in patients aged over 40 years to 0·29 (0·16-0·52; p<0·0001) in patients who had relapse activity despite receiving interferon beta during the year before study enrolment. Hazard ratios for confirmed disability progression over 24 months with fingolimod 0·5 mg versus placebo ranged from 0·85 (95% CI 0·53-1·36; p=0·50) in patients with a T2 lesion volume of 3300 mm(3) or less to 0·32 (0·14-0·73; p=0·0066) in patients with an EDSS over 3·5. In patients who relapsed and had lesion activity despite treatment with interferon beta in the previous year, the ARR ratio for fingolimod 0·5 mg versus placebo was 0·38 (95% CI 0·21-0·68, p=0·0011), and for treatment-naive patients with rapidly evolving severe disease it was 0·33 (0·18-0·62, p=0·0006). Hazard ratios for confirmed disability progression over 24 months were 0·68 (0·29-1·62; p=0·39) and 0·73 (0·25-2·07; p=0·55), respectively, in these groups.

INTERPRETATION: Patients with relapsing-remitting MS with a wide spectrum of clinical and MRI features including subgroups specified by the European label can potentially benefit from treatment with 0·5 mg fingolimod.

FUNDING: Novartis.

“These results confirm that Fingolimod is effective in the majority of subgroups. The possible exception is older MSers, over 40 years of age, who did not seem to derive any benefit. The latter statement needs to tempered because this was a subgroup analysis and the numbers of MSers in each group is small and therefore not powered to give a definitive answer. The bottom line is if you are 40+ years of age and have highly active MS you should consider a trial of fingolimod; that is if you are offered the choice by your neurologist.”

“The interesting observation of efficacy decreasing with age is very interesting and raises the question of whether or not premature senescence (ageing) plays a role in the pathogenesis of MS? More on this later.”

“Please note there are still safety concerns about Fingolimod and the EMA will issue a statement later this month about the issue of sudden deaths on Fingolimod. You may be interested in seeing previous posts on this topic.”

08 Feb 2012
“Sudden death is very topical in view of the recent death of a patient on Fingolimod and the European Medicine Agency’s decision to review the safety of the drug. I would be very interested to know if the unfortunate MS’er who 
17 Mar 2012
The NICE approval of fingolimod yesterday has nothing to do with the ongoing safety review that the EMA is carrying out in relation to the unexplained sudden deaths that have been reported in PwMS taking fingolimod.
03 Mar 2012
“The European Medicines Agency has been criticised for refusing to supply the French independent drug bulletin, Prescrire, with data on cases of sudden death after the first dose of the multiple sclerosis drug fingolimod.
12 Dec 2011
Fingolimod death. Novartis have confirmed that an MS’ers died after starting fingolimod. It was an unexplained sudden death. This suggests it was probably due to off-target effects of fingolimod on the cardiovascular system.

CoI: Multiple

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