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First-Year Disease Activity on Fingolimod Predicts Long-Term Outcomes, Study Finds

ARTICLE IN BRIEF

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DR. PAVLE REPOVIC: “With interferon, there is now a huge literature pinpointing what constitutes a failure one year into therapy. This study is the first time someone has looked in the same way at fingolimod. When you have a patient who relapses in the first year on therapy, do you just ignore it and say that some breakthrough activity is to be expected, or does this mean you should consider switching to another therapy? Our study says that patients who show continued disease activity are at significantly increased risk of more disease activity and disability progression down the road.”

A post-hoc analysis of follow-up data from the TRANSFORMS trial suggests that early disease activity during a patient's first year on fingolimod predicts longer-term outcomes in multiple sclerosis.

INDIANAPOLIS—Early disease activity during a patient's first year on fingolimod, whether seen on magnetic resonance imaging (MRI) or as relapses, predicts longer-term outcomes in multiple sclerosis (MS), according to a post-hoc analysis of follow-up data from the trial known as TRANSFORMS.

The study, presented here at the annual meeting of the Consortium of MS Centers in June, found that only 4.9 percent of patients given fingolimod showed early disease activity, compared with 12.9 percent of those given intramuscular interferon beta-1a (IFN beta-1a). But those who did break through were at significantly increased risk of confirmed disability progression in their second, third, and fourth years on the drug.

Left unanswered were the larger questions that clinicians are grappling with, namely, whether early disease activity while on fingolimod means that a patient should be promptly switched to another medication — and if so, which one.

“The implication is that in those cases, you should probably consider changing therapy,” said Jeffrey M. Cohen, MD, a professor of neurology and director of experimental therapeutics at the Cleveland Clinic's Mellen Center for Multiple Sclerosis Treatment and Research. “What you should change to, however, is unclear. Those studies are just starting to emerge now.”

Although Dr. Cohen was first author of the original TRANSFORMS paper, which was published in 2010 in the New England Journal of Medicine, he was not involved in the latest analysis presented by Pavle Repovic, MD, PhD, a neurologist at the Swedish Neurosciences Institute in Seattle.

Dr. Repovic told Neurology Today that the study provides clinicians with the kind of data on fingolimod that is already amply available for IFN beta-1a.

“With interferon, there is now a huge literature pinpointing what constitutes a failure one year into therapy,” he said. “This study is the first time someone has looked in the same way at fingolimod. When you have a patient who relapses in the first year on therapy, do you just ignore it and say that some breakthrough activity is to be expected, or does this mean you should consider switching to another therapy? Our study says that patients who show continued disease activity are at significantly increased risk of more disease activity and disability progression down the road.”

THE DATA

The study, which was supported by Novartis and co-authored by one of its scientists, analyzed the 36-month follow-up data from TRANFORMS. The original trial compared fingolimod (0.5 mg or 1.25 mg daily) against intraumuscular IFN beta-1a (30 μg weekly). On entering the three-year extension, patients who had previously been randomized to intramuscular IFN beta-1a were re-randomized to either fingolimod 0.5 mg or 1.25 mg.

Dr. Repovic and his coauthors assessed, post-hoc, whether MRI activity (defined as one or more T1 gadolinum-enhancing lesions or two or more T2 lesions) and/or one or more relapses during the first year of treatment predicted relapses or six-month confirmed disability progression as measured by the Expanded Disability Status Scale in the second, third, and fourth years.

A total of 1,292 patients were randomized in the core phase, with 1,030 (79.7 percent) entering the extension phase. Among the patients in the extension phase, the first year on fingolimod greatly reduced the risk of either MRI activity or relapses during months zero to 12 compared with IFN beta-1a: 4.9 percent vs. 12.9 percent.

Still, those few who did show breakthrough activity on fingolimod in the first year were found to be at continued risk of poorer outcomes in the years following. First-year relapses put patients at greater risk than did first-year MRI activity, but the two combined resulted in the greatest increased risk. [For more data, see “Findings from TRANFORMS.”]

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DR. JEFFREY M. COHEN: “Where things stand now — and the data are still emerging — it seems that early activity while on fingolimod should lead to a switch in therapy. The thinking is that you should switch to at least something of comparable efficacy: dimethyl fumarate, which has roughly the same potency, or perhaps natalizumab or alemtuzumab, which are considered somewhat more potent. But these drugs have not been compared yet in head-to-head trials, so for now these decisions need to be made carefully by clinicians and their patients.”

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DR. TIMOTHY L. VOLLMER: “We have about 400 patients on fingolimod, and I dont really see patients who are true treatment failures. As this study clearly demonstrates, the vast majority of patients are responders. Yes, disease activity is a bad prognostic finding. The question is: will the patient do better on another drug? Are they true biological failures? Im not sure.”

TO SWITCH OR NOT TO SWITCH?

Dr. Cohen said the paper should be seen as part of a broader effort to determine whether there are early indications that an MS drug may not be working as well as hoped, and whether that means the patient should then be switched to another drug.

“Where things stand now — and the data are still emerging — it seems that early activity while on fingolimod should lead to a switch in therapy,” he said. “The thinking is that you should switch to at least something of comparable efficacy: dimethyl fumarate, which has roughly the same potency, or perhaps natalizumab or alemtuzumab, which are considered somewhat more potent. But these drugs have not been compared yet in head-to-head trials, so for now these decisions need to be made carefully by clinicians and their patients.”

Not all neurologists who specialize in treating MS are convinced of the need to switch if continued disease activity is seen in the first year, however.

“It doesn't cause me to switch therapy just because they're having some disease activity,” said Timothy L. Vollmer, MD, FAAN, a professor and vice chair of research in the department of neurology at the University of Colorado School of Medicine. “We have about 400 patients on fingolimod, and I don't really see patients who are true treatment failures. As this study clearly demonstrates, the vast majority of patients are responders. Yes, disease activity is a bad prognostic finding. The question is: will the patient do better on another drug? Are they true biological failures? I'm not sure.”

FINDINGS FROM TRANSFORMS

  • MRI activity in year one increased the likelihood of relapses or chronic disease progression (CDP) in the second year by an odds ratio (OR) of 1.359 (95% confidence interval [CI], 0.958-1.926; p=0.0851), and in the third and fourth years by an OR of 1.701 (95% CI, 1.246-2.322; p=0.0008).
  • Relapses in the first year were even more strongly predictive of relapses or CDP in the second year (OR 2.096 [95% CI, 1.654-2.655; p<0.0001]) and in years three and four (OR 2.008 [95% CI, 1.541-2.616; p<0.0001]).
  • Patients who had both MRI activity and relapses in their first year on fingolimod had an OR for relapses or CDP of 2.695 (95% CI, 1.643-4.420; p<0.0001). In their third and fourth years, these patients had a three-fold higher OR for continuing decline (OR 3.030 [95% CI, 1.761-5.212; p< 0.0001]).

LINK UP FOR MORE INFORMATION:

•. Repovic P, Burton E, Meng X, et al.. Disease activity during the first year predicts clinical long-term outcomes in patients with multiple sclerosis: fingolimod treatment benefit https://cmsc.confex.com/cmsc/2015/webprogram/Paper3507.html. Presentation DX13, CMSC 2015.
    •. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis http://www.nejm.org/doi/full/10.1056/NEJMoa0907839. N Engl J Med 2010;362(5):402–415. Epub 2010 Jan 20.