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Title: Interferon Beta-1a New Formulation Has Benefits in Patients With Relapsing Multiple Sclerosis: Presented at ECTRIMS

"Interferon Beta-1a New Formulation Has Benefits in Patients With Relapsing Multiple Sclerosis: Presented at ECTRIMS"

By Chris Berrie PRAGUE, CZECH REPUBLIC -- October 16, 2007 -- A new formulation of subcutaneous interferon beta-1a (IFNbeta-1a) that is free from human- and animal-derived albumin (NF-IFNbeta-1a) shows an improved immunogenic profile that is accompanied by improvements in key aspects of the standard IFNbeta-1a safety profile for patients with relapsing multiple sclerosis (MS). Florence Casset-Semanaz, MSc, Statistician and Associate Director, Biostatistics, Merck Serono International S.A., Geneva, Switzerland, presented a multicenter, historically controlled, open-label, single-arm, phase 3B study here at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Treatment of patients with MS using various recombinant proteins can be associated with the development of neutralizing antibodies (NAbs). At high titers, these can potentially reduce the therapeutic effects of interferon. "We therefore tested a new formulation of IFNbeta-1a that is free from human- and animal-derived albumin, with the aim of improving injection tolerability and reducing immunogenicity," Casset-Semanaz said during her presentation on October 12. The study enrolled 260 patients aged 18 to 60 years who were interferon-naive and had an expanded disability status score (EDSS) no greater than 6.0 with a diagnosis of relapsing MS confirmed by McDonald criteria. Treatment with NF-IFNbeta-1a was administered by self-injection at 44 mcg three times per week after a standard titration period of 4 weeks. During her presentation, Casset-Semanaz reported on the results at 96 weeks, and compared these with the 96-week results from the European-North American Comparative Efficacy (EVIDENCE) trial and the 48-week results from the Rebif versus Glatiramer Acetate in Relapsing MS Disease (REGARD) trial. Presence of binding antibodies and NAbs against interferon in blood samples from these patients was assessed at baseline and at weeks 12, 24, 36, 48, 60, 72, and 96. NAb positivity was defined as titers of 20 or more neutralizing units (NU)/mL on the initial measurement. The primary objective of the study was to compare the immunogenicity of NF-IFNbeta-1a with the historical data based on the proportion of patients who were NAb-positive at week 96, according to a last observation carried forward (LOCF) analysis. Casset-Semanaz and colleagues also looked at changes in the time course of NAb development in patients who were newly exposed to NF-IFNbeta-1a, and evaluated overall safety of NF-IFNbeta-1a as compared with the standard IFNbeta-1a formulation. The NF-IFNbeta-1a efficacy was also assessed as an exploratory analysis according to the number of relapses and patients' EDSS scores. Patients enrolled in the NF-IFN-1a study had a mean age of 34.0 years (male, 28.5%). Their median duration of MS was 5.5 years; they had a median of 1 relapse in the 12 months prior to study, and their median EDSS score was 2.0. A direct comparison was thus made with the proportions of NAb-positive patients from the REGARD (n = 374; mean age, 36.7 years; male, 28.8%) and EVIDENCE (n = 336; mean age, 39.0 years; male, 25.1%) trials. Results of the analysis show that in the NF-IFNbeta-1a population, binding antibodies were seen in 29.7% and 28.6% of patients by weeks 48 and 96, respectively. In the EVIDENCE study these stood at 49.1% and 36.9%, respectively. The percentages of NAbs present in the REGARD trial, the EVIDENCE trial, and the NF-IFNbeta-1a study at 48 weeks, respectively, were 25.7%, 24.4%, and 13.9%. At 96 weeks, the percentages of patients with NAbs were 27.3%, 21.4%, and 17.4%. In addition, Casset-Semanaz and colleagues conducted a meta-analysis of the percentages of "anytime" patients with NAbs, and obtained the following: 33.7%, 27.1%, and 18.9%, respectively. While this evaluation looked at data across different trials and should be looked at with caution, as a monitor of the efficacy of NF-IFNbeta-1a this analysis did show that 53.3% of patients treated with NF-IFNbeta-1a were relapse-free at 96 weeks compared with 34.8% in the EVIDENCE study. The researchers also found that there were fewer mean relapses per patient in the 96 weeks of NF-IFNbeta-1a treatment compared with the 2 years prior to study entry (1.8% vs 0.7%, respectively). Furthermore, a significant trend was seen when the on-study 96-week data were portioned according to patients with fewer, equal, or more relapses than in the 2 years prior to study entry (54.1% vs 33.6% vs 12.4%, [P <.0001).

In contrast, the EDSS scores remained constant throughout the 96 weeks of treatment with NF-IFNbeta-1a, with median EDSS scores of 2.0 at baseline and 0.0 at 96 weeks.

Again, comparisons were made across the different studies for safety analysis. With NF-IFNbeta-1a, the incidence of patients reporting injection-site reactions was 3-fold lower than in the EVIDENCE study. Similarly, lower or similar proportions were reported here between the NF-IFNbeta-1a data and the EVIDENCE study for hepatic disorders, cytopenia, depression and suicide ideation, skin rashes, hypersensitivity reactions, and thyroid disorders.

Alternatively, while the majority of patients who experienced adverse events reported them as being mild or moderate in severity, the rate of serious adverse events with NF-IFNbeta-1a was 5.8%, while in the EVIDENCE study, the rate was 8.6%.

Therefore, overall, these results support the further use of NF-IFNbeta-1a as it provides a more favorable immunogenicity profile, as compared with the patients in the EVIDENCE and REGARD studies. Similarly, NF-IFNbeta-1a showed confirmed efficacy at 96 weeks, with 53% of patients remaining relapse free, while showing stable EDSS scores throughout this study.

Funding for this study was provided by Merck Serono International S.A.

[Presentation title: Safety and Immunogenicity of Interferon Beta-1a (Rebif® New Formulation) in a Phase 3B Study in Patients With Relapsing Multiple Sclerosis: 48- and 96-Week Results. Abstract P193]

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