Daniel M. Keller, PhD

June 06, 2014

ISTANBUL, Turkey — Combined results of 2 pivotal trials of the oral drug fingolimod (Gilenya, Novartis) show that it can slow the annual rates of brain volume loss (BVL) in patients with relapsing-remitting multiple sclerosis (MS) to levels observed in healthy adults.

Study investigator Nicola De Stefano, MD, PhD, associate professor in the Department of Medicine, Surgery, and Neuroscience at the University of Siena, Italy, found that proportionately more patients who received fingolimod had BVL less than both a 0.2%/year and a 0.4%/year loss threshold compared with patients who received placebo.

The usual rate of BVL in relapsing-remitting MS ranges from 0.5% to 1.35% annually compared with 0% to 0.2%/year for healthy adults younger than age 35 years to 0.2% to 0.35%/year for those aged 35 years or older, depending on the study or series of studies, with accelerating losses as age increases.

The study was presented here at the 24th Meeting of the European Neurological Society (ENS).

The accelerated changes in brain volume in MS are evident from the earliest stages, reflecting both diffuse and focal (lesional) damage, said Dr. De Stefano. Several studies have shown that the volume losses correlate with worsening disability over time, more frequent relapses, and declining cognitive function.

Results of the 2 pivotal phase 3, randomized, placebo-controlled FTY720 Research Evaluating Effects of Daily Oral therapy in MS I and II (FREEDOMS I and II) trials were pooled. Study patients were 17 to 60 years old and received placebo or fingolimod, 0.5 mg or 1.25 mg daily, for 24 months.

Two-year data were analyzed by age categories, as well as for the drug or placebo groups as a whole to compute annual brain volume changes from baseline using Structural Image Evaluation using Normalisation of Atrophy (SIENA) criteria. Results were expressed as the proportions of patients not exceeding a BVL of 0.2%/year or 0.4%/year.

"Annual rates of brain volume loss similar to those expected in healthy adults were achieved in proportionately more patients with MS who received fingolimod than those who received placebo," said Dr. De Stefano. "The results were consistent across age categories and at both thresholds."

Table. Proportion of Patients With BVL Less Than 0.2%/Year or Less Than 0.4%/Year

Group Age 17 - 30 yr (%/%) Age 31 - 40 yr (%/%) Age 41 - 50 yr (%/%) Age 51 - 60 yr (%/%) Age 17 - 60 yr (%/%)
Placebo 21.6/31.5 (n = 111) 18.3/26.8 (n = 224) 21.3/23.9 (n = 197) 18.8/27.1 (n = 48) 20.0/26.7 (n = 580)
Fingolimod, 0.5 mg 32.8/40.0 (n = 125) 26.7/37.3 (n = 225) 27.2/35.3 (n =224) 38.8/38.8 (n = 49) 29.1a/37.2a (n = 623)
Fingolimod, 1.25 mg 34.5/40.5 (n = 116) 33.5/39.9 (n = 188) 32.6/41.7 (n = 218) 28.8/35.6 (n = 59) 32.9a/40.3a (n = 581)

a P<.001 vs placebo.


Considering that brain volume loss is increased in patients with MS and that it correlates with clinical outcomes, he said it is important for the neurology community to consider applying BVL thresholds to these patients across age groups. He suggested incorporating BVL in excess of the threshold into a composite measure of disease activity, which could aid in assessment of a patient's overall disease status in clinical trials as well as in clinical practice.

Kjell-Morten Myhr, MD, PhD, professor of neurology at the University of Bergen, Norway, said that evidence of BVL was previously presented in the original fingolimod trial data.

"But this is some kind of a new stratification, setting a threshold similar to the normal aging, so that's an interesting way of making the analysis," he told Medscape Medical News. "It may be a new analysis to include in the definition of disease-free activity."

BVL "may be simpler for people to understand if it's compared to normal aging than as a certain percentage or a certain amount of milliliters. So perhaps it's easier to understand for both the doctor and the patient," he said, adding that BVL should be compared in an age-matched healthy population.

Dr. Myhr noted that these trials were initiated at a time when a placebo control would be acceptable. Now that several effective therapies are available for MS, anything less than an active control would be unethical.

The studies were supported by Novartis. Dr. De Stefano has received honoraria from Schering, Biogen-Dompè, Teva, and Merck Serono S.A. for consulting services, speaking, and travel support. He serves on advisory boards for Merck Serono S.A. He has received research grant support from the Italian MS Society. Other authors have received research support from Biogen Idec, Merck-Serono, Novartis, and Actelion; have consulted for Mitsubishi Pharma, Eli Lilly, Genzyme, Novartis, ATI, Biogen Idec, and Allergan; or have received institutional research support from Actelion, Allozyne, Bayer Health Care Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, CLC Behring, Elan, GeNeuro SA, Genzyme, GlaxoSmithKline, Lilly, Merck Serono, Mitsubishi, Novartis, Sanofi-Aventis, Santhera, Roche, and Teva. Several authors are Novartis employees. Dr. Myhr has received honoraria for lecturing, participation in advisory boards or pharmaceutical company-sponsored clinical trials, and travel support from Allergan, Almiral, Bayer Schering, Biogen Idec, Novartis, Merck-Serono, Roche, and Sanofi-Aventis.

24th Meeting of the European Neurological Society (ENS). Abstract OS1114. Presented May 31, 2014.


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