Biweekly Dosing of Pegylated Interferon Reduces MS Relapses

Daniel M. Keller, PhD

June 11, 2013

BARCELONA, Spain — Pegylated interferon β-1a (pegIFN β-1a; Plegridy, Biogen Idec) given every 2 or 4 weeks to patients with relapsing multiple sclerosis (MS) significantly reduced annualized relapse rates. Biweekly administration consistently showed significant superiority compared with placebo for all clinical and radiologic outcome measures, 1-year results from the ADVANCE pivotal trial of the drug show.

Bernd Kieseier, MD, from the Department of Neurology at Heinrich-Heine University in Düsseldorf, Germany, said the study results suggest that pegIFN β-1a may offer patients with relapsing MS efficacy and safety equivalent to those of currently available interferon agents but with the added benefit of reduced frequency of dosing.

β-interferons are established first-line treatments for MS. Adding polyethylene glycol (peg) to the molecules increases their half-life and may reduce immunogenicity. Patient benefits may include less frequent dosing and potentially better adherence to therapy.

Dr. Kieseier presented the first-year results here at the 23rd Meeting of the European Neurological Society (ENS). Biogen Idec, the developer of pegIFN β-1a, submitted a Biologics License Application to the US Food and Drug Administration on May 21 for approval of the drug.

ADVANCE is a 2-year, multicenter, randomized, double-blind, parallel-group, phase 3 study with an initial 1-year placebo-controlled period. The study randomly assigned 1516 patients 1:1:1 to pegIFN β-1a,125 μg subcutaneously, every 2 weeks or every 4 weeks or to placebo for the first year. There was a 4-week dose escalation period for the groups receiving active drug. At the beginning of year 2, patients in the placebo group were randomly assigned to either dosing regimen of pegIFN β-1a.

Study patients were men and women aged 18 to 65 years with relapsing MS, a baseline Expanded Disability Status Scale (EDSS) of 5.0 or less, and 2 or more relapses in the past 3 years with 1 or more relapses in the year before the initial randomization. Patients were excluded if they had progressive forms of MS, had prior interferon treatment exceeding 4 weeks, or discontinued interferon treatment less than 6 months before baseline.

Average age in each of the 3 study groups was about 36 years, 70% of participants were women, about 82% were white, and 71% lived in Eastern Europe. Only 11% were from Western Europe or North America because it is difficult to recruit patients with MS to a placebo-controlled trial if they already have effective drugs available to them. Patients averaged about 1.6 relapses in the previous 12 months. Across the 3 groups, 86% to 91% of patients completed the first year of the trial.

Fewer Relapses, Fewer Lesions With PegIFN β-1a

Compared with placebo, pegIFN β-1a every 4 weeks reduced the annualized relapse rate by 27.5%. Dosing every 2 weeks reduced the rate by 35.6%. PegIFN β-1a treatment every 2 or 4 weeks reduced the proportion of patients relapsing within 1 year, with reductions in risk for relapse of 39% and 26%, respectively (biweekly dosing hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.47 - 0.80; P < .001; HR with dosing every 4 week, 0.74; 95% CI, 0.57 - 0.95; P = .02).

The number of new or newly enlarging T2 lesions was reduced by 28% vs placebo with dosing every 4 weeks and by 67% with biweekly dosing. The number of gadolinium-positive lesions compared with placebo was reduced by 36% and 86%, respectively.

Table. Disease Activity at 1 Year With PegIFN β-1a vs Placebo

Endpoint Placebo PegIFN β-1a Every 4 Weeks P Value vs Placebo PegIFN β-1a Every 2 Weeks P Value vs Placebo
Annualized relapse rate* 0.397 0.288 .0114 0.256 <.001
New or newly enlarging T2 lesions (n) 10.9 7.9 <.001 3.6 <.001
Gadolinium-positive lesions at 1 year (n) 1.4 0.9 .0738 0.2 <.001

* Adjusted for baseline EDSS and baseline relapse rate.

The rates of antibody formation against peg or against interferon were low in both the biweekly and the every-4-weeks dosing groups but higher than in the placebo group. In no case were more than 9% of patients positive for interferon-binding, interferon-neutralizing, or anti-peg antibodies.

The 3 groups were similar in their rates of adverse events (AEs), which were common but mild to moderate in severity. The highest rate of serious AEs (15%) was in the placebo group, although the rate of severe AE was highest in the biweekly group (18% vs 16% in the every-4-weeks group and 11% in the placebo group). Five percent of patients discontinued the study in each of the pegIFN β-1a groups vs 1% in the placebo group.

More than half the patients in the pegIFN β-1a groups had injection site reactions, 47% in each active drug group had influenza-like illness, and about 45% had pyrexia (vs 15% with pyrexia for placebo). Four patients died: 2 in the placebo group and 1 in each of the active drug groups. Very few patients had elevations of liver aminotransferase levels 3 or more times the upper limit of normal, and all groups were equivalent in this regard.

Dr. Kieseier concluded that pegIFN β-1a at 125 μg subcutaneously every 2 or 4 weeks for 1 year, compared with placebo, reduced the relapse rate, the risk for relapse, and the number of new or newly enlarging T2 lesions, with the greatest benefits seen with biweekly dosing. Biweekly dosing also resulted in fewer gadolinium-enhancing lesions.

Session co-chair Ludwig Kappos, MD, professor of neurology and clinical neuroimmunology at the University of Basel in Switzerland, commented to Medscape Medical News that the results were "quite straightforward" and showed efficacy, especially with biweekly dosing.

"It is of course a pity that we don't have a direct comparison to the current treatment with interferon β-1a once weekly, which of course might have provided an impression about where to place the absolute effect in the spectrum of available options," he pointed out.

In light of the availability of newer chemical entities to treat MS, some of them oral, the question arose of whether physicians may choose them instead of an interferon, even a newer one. But Dr. Kappos said the interferons have a long track record, and their known safety is still an advantage.

"We have data of 20 or more years of treatment, and there seem to be patients who respond to this treatment, and why should I take a risk if I can go with something where the risk is sufficiently low?" he emphasized. "I think it was well tolerated, and it seems to be a good option for patients who remain [on] or start interferon treatment."

The study was funded by Biogen Idec. Dr. Kieseier has received compensation for activities with Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi Aventis, and Teva Neuroscience as a lecturer. He has received research support from Bayer Schering, Biogen Idec, Merck Serono, and Teva Neuroscience. Dr. Kappos has disclosed no relevant financial relationships.

23rd Meeting of the European Neurological Society (ENS). Abstract O227. Presented June 9, 2013.

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