Fingolimod Reduces Disease Activity, Brain Atrophy in MS

Megan Brooks

July 10, 2012

July 10, 2012 — Fingolimod (Gilenya, Novartis) reduced inflammatory lesion activity and reduced brain volume loss in patients with multiple sclerosis who participated in the pivotal FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) trial, according to magnetic resonance imaging (MRI) results from the trial.

"These analyses from the 2-year FREEDOMS study confirm that the efficacy of fingolimod therapy is robust across all MRI end points," first author Ernst-Wilhelm Radue, MD, of the Medical Image Analysis Center, University Hospital, Basel, Switzerland, and the FREEDOMS study team write.

"These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution," they add.

The study was published online July 2 in Archives of Neurology.

Neuroprotective Effect?

Reached for comment, Lily Jung Henson, MD, from the Swedish Neuroscience Institute, and medical director at Eastside Neurology Services, Seattle, Washington, said, "The key issue here is that not only did fingolimod reduce inflammation, it reduced brain atrophy, which suggests that there may be some neuroprotective effect of the drug."

"Since we recognize that MS is in fact a neurodegenerative disease, the use of fingolimod might allow us to delay the neurodegeneration we see in our patients over the long term. That is a real positive for MS patients," added Dr. Jung Henson. She was not involved in the study.

Fingolimod was approved by the US Food and Drug Administration (FDA) in September 2010 and is a first-in-class sphingosine-1 phosphate receptor modulator approved for treating MS. It was the first oral disease-modifying drug approved to reduce relapses and delay disability progression in patients with relapsing forms of MS.

Approval was based on 2 pivotal phase 3 studies, FREEDOMS and TRANSFORMS (TRial Assessing injectable interferoN vS FTY702 Oral in RrMS), both of which were published in the New England Journal of Medicine and were reported by Medscape Medical News at that time.

The FREEDOMS trial was a double-blind trial of 1272 patients with relapsing-remitting MS with scores of 0 to 5.5 on the Expanded Disability Status Scale, who had had 1 or more relapses in the previous year or 2 or more in the previous 2 years. They were randomly allocated to once-daily fingolimod capsules (0.5 or 1.25 mg) or matching placebo for 24 months.

After 24 months, the annualized relapse rate, the primary endpoint, was significantly reduced with both doses of fingolimod vs placebo (P < .001), as was the risk of disability progression (P = .02).

"Rapid and Sustained" Effects

As part of the study, standardized MRI scans were obtained at screening and at 6, 12, and 24 months. Across treatment groups, evaluable MRI scans and brain volume data were available for the vast majority of study subjects at all time points.

According to the new analysis, fingolimod led to "rapid and sustained" reductions in inflammatory lesion activity as assessed by gadolinium-enhancing and new or newly enlarged T2 lesions after 6, 12, and 24 months of treatment (P < .001 for all comparisons vs placebo).

Roughly half the patients on fingolimod were free from any new inflammatory lesions throughout the 24-month treatment period compared with only 21% of patients receiving placebo, the investigators note.

Changes in T2 hyperintense and T1 hypointense lesion volume also significantly favored fingolimod (P < .05 for all comparisons), they write.

In addition, fingolimod 0.5 mg (the licensed dose) significantly reduced brain volume loss over the course of the study (P < .05) compared with placebo, irrespective of the presence or absence of Gd-enhancing lesions, T2 lesion load, previous treatment status, or level of disability.

The investigators point out in their paper that brain atrophy is thought to be a better MRI predictor of future disability than T2 lesion load or T1 hypointense lesion load. "Therefore, the significant reduction in brain atrophy over 2 years with fingolimod therapy complements the reported reductions in relapse rate and disability vs placebo," they say.

The brain volume data in FREEDOMS are consistent with the results of the companion 1-year TRANSFORMS study comparing fingolimod with intramuscular interferon beta-1a.

In TRANSFORMS, "fingolimod reduced brain volume loss relative to intramuscular interferon beta-1a during the controlled phase of the study, while patients switching from intramuscular interferon beta-1a to fingolimod in the 1-year extension experienced marked slowing of brain atrophy," the study team notes.

The FREEDOMS study was funded by Novartis Pharma AG, Basel, Switzerland. Dr. Radue has received personal compensation from Bayer Schering, Biogen Idec, Novartis, and Merck Serono for consulting and speaking services and financial support for research activities from Actelion, Basilea Pharmaceutica Ltd, Biogen Idec, Merck Serono, and Novartis. A complete list of author disclosures is listed with the original article. Dr. Jung Henson receives research funding from Sanofi-Aventis, Genzyme, Novartis, and Biogen and is a speaker for Novartis.

Arch Neurol. 2012. Published online July 2, 2012. Abstract.

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