Peg-Interferon Beta-1a Reduces MS Relapses and Progression

Daniel M. Keller, PhD

May 05, 2014

PHILADELPHIA, Pennsylvania — Three analyses from the phase 3 ADVANCE trial help to establish the efficacy and safety of pegylated interferon β-1a (pegIFN β-1a; Pelgridy, Biogen Idec) in the treatment of relapsing-remitting multiple sclerosis (MS).

The trial results show that this investigational drug — in clinical development for subcutaneous use with a less frequent dosing schedule than current injectable therapies — had positive effects on reducing relapse rates and disease progression over 2 years. Efficacy was better with dosing every 2 weeks (Q2W) compared with once every 4 weeks (Q4W). Safety and immunogenicity were good after 2 years.

"There was a 39% reduction in the proportion of patients relapsing [with] Q2 week dosing, which was highly significant and a 19% reduction in the proportion of patients relapsed in the Q4 week [dosing] group, which was significant," reported Peter Calabresi, MD, professor of neurology and director of the Division of Neuroimmunology at Johns Hopkins University in Baltimore, Maryland.

Another paper hints at a possible improvement in recovery from relapses with pegIFN β-1a treatment.

The additional data from the ADVANCE trial were presented here at the American Academy of Neurology (AAN) 66th Annual Meeting.

ADVANCE

ADVANCE was a multicenter, international, double-blind, parallel-group, phase 3 study involving 1516 patients randomly assigned 1:1:1 to pegIFN β-1a, 125 μg subcutaneously every 2 weeks or every 4 weeks or to placebo (with a dose escalation period for the initial 4 weeks). The primary endpoint was the determination of relapse rates after 1 year.

Thereafter, patients receiving placebo were re-randomly assigned to 1 of the pegIFN β-1a groups for the second year of the study. Patients initially in one of the pegIFN β-1a groups stayed in that group for the second year. Among patients who completed year 1 of the trial (n = 1332), there were similar retention rates (86% to 94%) among all the study groups.

In year 1 of the trial, pegIFN β-1a significantly reduced the risk for 12-week confirmed disability progression by 38% in both dosing groups compared with placebo, with an annualized relapse rate of 36% with Q2W dosing and 28% with Q4W dosing.

Improved Recovery?

During the same session at the meeting, Bernd Kieseier, MD, professor in the Department of Neurology at the Heinrich-Heine-University in Düsseldorf, Germany, presented year-1 data showing the superiority of pegIFN β-1a over placebo and investigating whether the drug improved recovery after relapses.

Fifty-five patients had confirmed disability progression associated with relapses, and 57 had confirmed disability progression not associated with relapses. The baseline Expanded Disability Status Scale scores and the degree of relapse severity did not differ between the 2 groups.

Among patients receiving placebo (n = 500), for those experiencing a relapse, 19.6% had confirmed disability progression compared with 15.2% for patients on the Q4W schedule (n = 500) and 13.6% for patients on Q2W dosing (n = 512).

Confirmed disability progression from incomplete recovery after relapse occurred in 27% of those who experienced relapse while receiving placebo, 16% of those who relapsed while receiving Q4W dosing (PP = .012 vs placebo).

In interpreting these results, Dr. Kieseier said, "The first [point] is that approximately half of the patients in this patient cohort studied for a year had an associated relapse that was driving the disability progression, and the effect on the relapse recovery was definitely in favor of the treatment with pegylated interferon β-1a."

On the other hand, half of the patients with the confirmed disability progression in year 1 did not have any associated relapses, he noted.

"So this implies that, at least in this group of patients the disability progression is only partially explainable by the accumulation of disability due to a relapse, so independent effects are happening," Dr. Kieseier said.

"So the combination of the overall reduction in risk of relapses plus higher chance of avoiding disease progression from experiencing any relapse resulted in an overall reduction in risk of experiencing disability progression caused by a relapse in the range of 56% in favor of treatment with pegylated interferon given twice monthly compared to placebo," he concluded.

Two-Year Data

Dr. Calabresi then presented 2-year clinical safety and efficacy data from ADVANCE. Patients who received continuous pegIFN β-1a for 2 years had better annualized relapse rates than patients who received placebo during the first year. PegIFN β-1a maintained its efficacy from year 1 through year 2.

In terms of sustained efficacy, the Q2W group had superior outcomes compared with Q4W dosing, "suggesting no loss of efficacy. If one looks at the same kind of comparison with MRI...you see the same effect [in] the Q2 week arm, certainly sustained or even improved efficacy in the second year compared to the first year," Dr. Calabresi reported.

Table. Maintenance of Efficacy of PegIFN β-1

Endpoint Placebo-to-pegIFN Group PegIFN Q2W PegIFN Q4W
Annualized relapse rate: year 1 (%) 23 28.6
Annualized relapse rate: year 2 (%) 17.8 29.1
Annualized relapse rate over 2 years (%) 35.1 22.1 (P < .001 vs placebo-to-pegIFN group) 29.1 (P = .09 vs placebo- to-pegIFN)
New or newly enlarged T2 lesions: year 1 (%) 4.2 9.4
New or newly enlarged T2 lesions: year 2 (%) 1.9 5.6

The 2 dosing groups differed little in adverse effects over 2 years. The most common ones were injection site erythema (59% to 64%), influenza-like illness (about 50%), pyrexia (41% to 43%), and headache (25% to 30%).

Any serious adverse effects occurred in 21% and 16% of the Q4W and Q2W groups, respectively. Deaths were less than 1% in each group. Almost all patients experienced elevations of liver aminotransferase, but most were less than 3 times the upper limit of normal and returned to normal after drug discontinuation.

Almost all patients had some form of hematologic laboratory abnormality, generally cytopenias, but no more than 10% had any 1 form of abnormality. For most participants, values returned to normal after discontinuation of the study drug.

"Importantly, immunogenicity with this product appears to be extremely low.... Interferon neutralizing antibodies were detected at less than 1%, keeping with the known effects of pegylation reducing immunogenicity of molecules," Dr. Calabresi noted. Binding antibodies occurred at a rate of 8% and 6% of anti-peg antibodies, "but these do not appear to have any effect on efficacy."

Imaging Results

Finally, in a third presentation on the ADVANCE trial, Douglas Arnold, MD, professor in the McConnell Brain Imaging Centre at the Montreal Neurological Institute and Hospital of McGill University in Montreal, Quebec, Canada, assessed clinical and MRI freedom from measured disease activity (FMDA) in the periods of baseline to week 48 and week 24 to 48 using a post hoc analysis.

He found that significantly higher proportions of patients receiving Q2W dosing had FMDA for both periods compared with patients receiving Q4W dosing or placebo. Similarly, the Q2W group had better MRI-FMDA for both periods compared with Q4W dosing or the placebo group. The Q2W group had superior clinical FMDA compared with the placebo group for the 2 periods (P < .01 for both periods).

"The FMDA analyses of results from year 1 of the ADVANCE study taken together with the evidence for clinical efficacy support peg-interferon β-1a Q2 weekly as a potential effective treatment for patients with relapsing-remitting MS with, of course, the benefit of less frequent subcutaneous administration over the currently available therapy," Dr. Arnold concluded.

Dr. Kieseier predicted that pegIFN β-1a may be available "hopefully by the end of this year."

Incremental Advantage

Session moderator Bruce Cree, MD, PhD, MCR, associate professor of clinical neurology at the University of California, San Francisco, commented to Medscape Medical News that the presentations of the ADVANCE trial showed both clinical and radiographic efficacy of both dosing regimens of pegIFN β-1a but that the Q2W dosing was superior to the Q4W regimen.

"So if we do see this drug come to market, I imagine we're going to see it as a Q2-week version. This represents an incremental advantage over the Q-week[ly] current version of IM [intramuscular] interferon," he said. "The injection is no longer an intramuscular injection. It's a subcutaneous injection, and it's administered once every 2 weeks instead of every week."

He noted that the overall levels of efficacy appear quite similar to what has previously been reported with intramuscular interferon. However, "the 1 presentation that caught my attention was one that described improved recovery following relapses, and I think that is interesting."

He said he is still trying to rationalize exactly the mechanism of action for that observed effect. The severity of relapses was similar but recovery was superior in the actively treated group.

 
[Peg-interferon beta-1a] may be available hopefully by the end of this year. Dr. Bernd Kieseier
 

ADVANCE was sponsored by Biogen Idec. Dr. Calabresi has received personal compensation for activities with Teva, Biogen Idec, Novartis, Genzyme, Johnson & Johnson, and Vertex and research support from Biogen Idec, Teva, EMD Serono, Vertex, Genentech, Abbott, and Bayer. Dr. Kieseier has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono, Novartis, Roche Diagnostics, Sanofi-Aventis Pharmaceuticals, and TEVA Neurosciences as speaker and research support from Bayer Pharmaceuticals, Biogen Idec, Merck Serono, and Teva Neurosciences. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono Inc, and Teva Neuroscience; has received research support from Bayer Healthcare, Biogen Idec, Genentech, NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono Inc, and Teva Neuroscience; has received honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, Coronado Biosciences, EMD Serono, Genentech, Genzyme, GSK, MedImmune, NeuroRx Research, Novartis, Opexa Therapeutics, Roche, Merck Serono, Teva, Mitsubishi, StemCells, Inc., and XenoPort;and has received salary from and owns stock in NeurRx Therapuetics. Dr. Cree has received personal compensation from AbbVie, Biogen Idec, EMD Serono, Genzyme/Sanofi Aventis, MedImmune, Novartis, and Teva Neurosciences and has conducted clinical trials with many of those companies plus Hoffmann-La Roche.

American Academy of Neurology (AAN) 66th Annual Meeting. Abstract S4.003. Presented April 29, 2014.

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