COPENHAGEN, Denmark — Further evidence that brain volume loss correlates with long-term disability in multiple sclerosis (MS) has come from new analyses of data from the fingolimod (Gilenya, Novartis) clinical trial program.

The results also show that continued treatment with fingolimod led to a reduction in brain volume loss compared with patients who delayed fingolimod treatment by 2 years and was also associated with a higher proportion of patients remaining free of disability progression.

These observations were among new findings on brain volume ascertained from the key fingolimod trials — FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis), FREEDOMS II, and TRANFORMS (Trial Assessing Injectable Interferon vs. FTY720 Oral in RRMS) — presented in 3 posters at the recent 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). 

Another poster reported on 5-year follow-up of patients taking open-label fingolimod, showing a sustained effect on relapse rate and disability progression.

Commenting on the brain volume findings for Medscape Medical News, Jeffrey Cohen, MD, Cleveland Clinic, Ohio, who was a coauthor on some of the analyses, said, "All 3 studies are complementary, and together they weave a story about brain volume/atrophy and make a case for the significance of brain volume as a measurement to monitor important MS disease processes."

He noted: "The data show that brain volume loss is worse in patients with more active disease, more relapses, and those who have an active MRI at study entry."

Dr. Cohen explained that the purpose of therapy is to reduce disability, but disability takes many years to develop. "We are looking for measures that can predict disability and brain volume seems to do this. A short-term weak association became more clear-cut over the longer term, 3 to 4 years."

But brain volume measurement requires specialized software. Dr. Cohen noted that images used are standard images taken on MRI, but the changes are subtle and cannot be discerned on standard MRI equipment at present. However, brain volume loss is widely used in clinical trials and will probably become available in the commercial MRI in the not-too-distant future, he said.

He also reported that fingolimod treatment was beneficial on brain volume loss vs placebo and versus interferon β. "If treatment was delayed and switched to fingolimod in the extension phase of the studies, there was more brain volume loss in the long-term compared to patients taking fingolimod from the beginning."

In addition, if the disease was not completely controlled, then patients did not do as well.

Dr. Cohen suggested that of all the MS drugs, fingolimod seems to be the most straightforward in terms of brain volume data. "It has shown a reduction in brain volume loss most convincingly and this does not appear to be associated with pseudo-atrophy — where brain volume loss appears to accelerate initially then slows — as with some of the other drugs."

LONGTERMS Study

The long-term clinical data with fingolimod is being assessed in the LONGTERMS study — an open-label extension study of the FREEDOMS and TRANSFORMS phase 3 clinical trials of fingolimod. LONGTERMS started in 2010 and will continue, with annual interim analyses, until 2016.

The current analysis evaluated relapse and disability outcomes in 757 patients who had completed the FREEDOMS trial and 698 patients who had completed the TRANSFORMS trial who went on to receive open-label fingolimod. Median duration of exposure was 4.95 years in FREEDOMS and 4.78 years in TRANSFORMS.

Results showed that annual relapse remained low in both studies.

Table 1. LONGTERMS: Annual Relapse Rate With Fingolimod

Time FREEDOM TRANSFORMS
Year 1 0.17 0.20
Year 2 0.15 0.14
Year 3 0.13 0.13
Year 4 0.16 0.14
Year 5 0.15 0.12

 

Disability also remained stable for up to 5 years in both studies

Table 2. LONGTERM: Expanded Disability Status Scale Scores at Baseline and Year 5 With Fingolimod

Time FREEDOM TRANSFORMS
Baseline 2.39 2.12
Year 5 2.45 2.12

 

Dr. Cohen has received research support from Biogen Idec, Genzyme, Lilly, Novartis, Merck Serono, and Teva.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Poster #518, #525, #1043, and #1052.

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