Pauline Anderson

April 20, 2012

April 20, 2012 — Emerging research adds more weight to the theory that in multiple sclerosis (MS), the earlier the treatment, the better the outcome.

A new study, an extension of the previously reported phase 3 REbif FLEXible dosing in early Multiple Sclerosis (REFLEX) trial shows that patients who received injections of interferon β-1a (IFNβ-1a, Rebif, Merck Serono SA) soon after their first clinical demyelinating event were less likely to progress to clinically definite MS (CDMS) at 3 years than those who switched to this drug from placebo.

Results of this study also suggest that in some respects, a thrice-weekly regimen with this drug is superior to once-weekly administration.

Full findings from the phase 3 study will be released at the American Academy of Neurology's 64th Annual Meeting later this month. The study was supported by Merck Serono SA, Geneva, Switzerland, a branch of Merck Serono SA, Coinsins, Switzerland, and an affiliate of Merck KGaA, Darmstadt, Germany.

"At issue here is whether you are losing anything by waiting for these patients to have further attacks before administering the drug," said lead investigator Mark Freedman, MD, professor, neurology, University of Ottawa, Ontario, Canada; director of the MS Research Unit, Ottawa Hospital, General Campus, and senior scientist, Ottawa Hospital Research Institute. "I think we've seen it several times now, that the early time period is really important to jump in with a therapy, when you have the best opportunity to do something."

Dr. Mark Freedman

Important to "Jump in"

The multicenter REFLEX trial included 517 patients who had experienced a first clinical episode suggestive of a demyelinating event, such as tingling, numbness, muscle weakness, or problems with balance, along with at least 2 clinically silent brain lesions detected by brain magnetic resonance imaging. These patients were randomly assigned to receive 44 μg of subcutaneous IFNβ-1a 3 times a week, 44 μg of the drug once a week, or placebo for 24 months or until a second clinical episode.

The trial was conducted by using a formulation of IFNβ-1a that is free of human serum albumin; although this formulation is available in other countries, including those in the European Union, Switzerland, Canada, Australia, and several countries in Asia, Africa, Latin America, and the Middle East, it is currently not available in the United States.

The REFLEX results showed that early treatment — thrice or once weekly — significantly delayed CDMS compared with placebo. Both doses were also associated with a reduced risk of meeting McDonald criteria for MS, which include active lesions on MRI, with a significant benefit for thrice-weekly over once-weekly treatment.

At the end of 2 years, all patients were eligible for the extension study (REFLEXION). Those originally receiving placebo who were not reaching CDMS were switched to the thrice-weekly dose, and once-weekly and thrice-weekly patients not reaching CDMS continued their initial regimen.

Of the original 517 patients, 402 (77.8%) were entered into the REFLEXION study (delayed treatment, n = 133; thrice weekly, n = 127; once weekly, n = 142). The study was double-blind, with all patients taking 3 injections of placebo or active drug each week.

At 36 months, the cumulative probabilities of CDMS were 41.3% for the delayed-treatment group (those who had switched from placebo to thrice-weekly treatment), 27.6% for the group receiving once-weekly treatment for 3 years (P = .006 vs delayed therapy), and 27.1% for those receiving thrice-weekly treatment for 3 years (P = .002 vs delayed treatment).

Study patients who had taken the treatment drug for 3 years were also less likely to meet McDonald criteria for MS. In the delayed-treatment group, 86.5% met the criteria compared with 79.1% in the once-weekly group and 66.8% in the thrice-weekly group.

"It's very clear" that the extension study clarifies that the delay to a second event continues to even out to year 3, said Dr. Freedman.

Clear-Cut Dose Response

There was also a "very clear-cut" dose response, noted Dr. Freedman. "The MRI data shows that the 3 times weekly dose is significantly better than the once weekly dose, and it was statistically significant and stayed statistically significant even out to 3 years."

The study results prompt the question of whether clinicians should ever wait to initiate treatment if MS is suspected. "The argument has been that these patients only had a first event, that we have to wait for a second event to make sure they really have MS," said Dr. Freedman.

Such a "wait and see" approach would not be used for other patients, he said. "If a patient had a stroke or a transient ischemic attack, would you wait for them to come back with a second one before you offered them something to protect them? That doesn't make any sense."

He added that a second event in MS "can be devastating."

Cost of the treatment could be a factor in the treatment decision, he said. "If this was a little aspirin, nobody would question it."

"Slight Advantage"

Thrice-weekly administration of the drug has a "slight advantage" in that patients adapt to it more quickly, said Dr. Freedman. "You get flu-like reactions in response to the drug when you inject it; the more often you inject it, the faster your body acclimatizes to the drug and flu like reactions disappear. When you take it less often, you almost never really adapt."

The drawbacks to more frequent injections include possible dose-dependent lab-related changes, such as reductions in white blood cell count and liver function elevations, although none in this trial were significant, said Dr. Freedman.

The REFLEXION trial is ongoing and will provide long-term data out to 5 years.

Reached for comment, Lily Jung Henson, MD, Swedish Neuroscience Institute, medical director, Eastside Neurology Services, Seattle, Washington, agreed that early treatment is key.

"The study shows that using this drug as currently available (3 times a week) is more effective than using placebo in preventing the development of MS after having presented with a single attack suggestive of MS," Dr. Jung Henson told Medscape Medical News.

"It tells us what we already know, which is that early treatment is critical to preventing the development of the full-blown condition."

Dr. Freedman reports that in the last 2 years, he has received research or educational grants from Bayer Healthcare and Genzyme and honoraria or consultation fees from Bayer Healthcare, Biogen Idec, EMD Canada, Novartis, sanofi-aventis, and Teva Canada Innovation; he is a member of a company advisory board, board of directors, or other similar group for Bayer Healthcare, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, Celgene.

American Academy of Neurology 64th Annual Meeting. April 21-28, 2012. New Orleans, Louisiana.

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