Rebif Treatments In Multiple Sclerosis

Background
The EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study was an international, randomized, open-label, assessor-blinded, parallel-group study.

Assessing the efficacy and tolerability of Interferon-beta-1a (IFN-ß-1a), 44 mcg subcutaneously (sc) three times weekly (tiw), and IFN-ß-1a, 30 mcg intramuscularly (im) once weekly (qw), in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

The aim of this analysis was to assess whether reductions in T₂ Burden Of Disease (BOD) were greater for patients receiving IFN-ß-1a, 44 mcg sc tiw.

Than for those treated with IFN-ß-1a, 30 mcg im qw, and to assess the impact of Neutralizing AntiBodies (NABs).

Methods
A post-hoc analysis was performed on Magnetic Resonance Imaging (MRI) data collected prospectively from the EVIDENCE study.

The analysis included all patients with evaluable T₂ MRI scans at the start of dosing and at week 48, and those who received at least one drug dose (n = 553).

Lesions were identified by a radiologist blinded to treatment codes and the Total Volume Of T₂ Lesions (BOD) was reported in mm3.

Results
Both median percentage decreases and absolute reduction in BOD were greater in the IFN-ß-1a, 44 mcg sc tiw, treatment group.

The adjusted mean treatment difference in percentage change in BOD from baseline to week 48 showed a significant treatment benefit.

For patients treated with IFN-ß-1a, 44 mcg sc tiw, over those treated with IFN-ß-1a, 30 mcg im qw (-4.6%; standard error: 2.6%; p = 0.002).

The presence of NABs reduced the effect of IFN-ß-1a 44, mcg sc tiw, on BOD, but BOD changes were still similar to those seen with IFN-ß-1a, 30 mcg im qw.

Conclusion
Patients with RRMS treated with IFN-ß-1a, 44 mcg sc tiw, had greater reduction in T₂ BOD:

After 48 weeks than those treated with IFN-ß-1a, 30 mcg im qw, which is consistent with other clinical and MRI outcome measures in the EVIDENCE study.

In patients testing positive for NABs (NAB⁺) to IFN-ß-1a 44 mcg sc tiw, changes in BOD were smaller than in NAB negative (NAB-) patients, but similar to those receiving IFN-ß-1a, 30 mcg im qw.

Objective
Benefits from Interferon-beta (IFN-ß treatment in patients with Multiple Sclerosis are affected by many factors.

Including sustained clinical efficacy, acceptable tolerability, adherence to therapy, and the development of Neutralizing AntiBodies (NABs).

The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF) was designed to compare the relative efficacy and tolerability of the two IFN-ß-1a products for up to 5 years.

Methods
PROOF compared the relative efficacy and tolerability of IntraMuscular (IM) IFN-ß-1a (Avonex) 30 microg once weekly (n = 69) and SubCutaneous (SC) IFN-ß-1a (Rebif) 44 microg three times per week (n = 67).

The duration of the retrospective portion of the study was 12-24 months. Due to slow enrollment, PROOF ended earlier than planned and the final duration of the prospective portion of the study was 6 months.

Therefore, between 18 and 30 months of efficacy and tolerability data were available for analysis.

Results
After controlling for baseline disability level, Expanded Disability Status Scale (EDSS) scores revealed no statistically significant differences between the treatment groups.

During the prospective portion of the study, with sustained disability progression similar in both groups (25.8% IM IFN-ß-1a 30 mug once weekly vs. 26.7% SC IFN-ß-1a 44 mug three times per week).

Relapse rates were similar in the groups, as were MRI endpoints of Brain Parenchymal Fraction, T₁ lesion volume, T₂ lesion volume, number of new/enlarging T₂ lesions, and Gadolinium-enhancing (Gd⁺) lesion volume and count.

Treatment groups differed in frequency of NABs, with 19% of patients treated with SC IFN-ß-1a 44 microg three times per week NAb⁺ compared with none treated with IM IFN-ß-1a 30 microg once weekly.

More NAb⁺ patients compared with NAB^- patients had disability progression (40.0% vs. 27.8%, p = NS), new or enlarging T₂ lesions at the end of treatment (63.6% vs. 40.7%, p = 0.003), and Gd⁺ lesions after 12-24 months of treatment (36.4% vs. 15%, p = 0.001).

The IFN-ß-1a products had comparable tolerability. However, fewer patients treated with IM IFN-ß-1a 30 microg once weekly had injection-site reactions (2.9% vs. 6.0%).

Limitations of this study include its design and sample size, both of which hinder detection of differences in efficacy between IFN-ß-1a treatments.

Conclusions
The results of the present study show that the two IFN-ß-1a products have comparable efficacy and differing Immunogenicity.

Subcutaneous recombinant Interferon-beta-1a (Rebif) 22 or 44 microg three times weekly is a valuable option in the first-line treatment in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

It has shown benefits on outcome measures related to relapses, progression of disability and Magnetic Resonance Imaging (MRI) in clinical trials.

A significant efficacy advantage for subcutaneous Interferon-beta-1a three times weekly over intramuscular Interferon-beta-1a 30 microg once weekly was shown at 24 and 48 weeks.

The most common adverse events are generally mild and clinically manageable.

Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous Interferon-beta-1a 44 microg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS.

Recent clinical trials with Interferon-beta (IFN-ß) in Relapsing/Remitting Multiple Sclerosis (RRMS) have clearly demonstrated that the IFN-ß dosing regimen affects the clinical efficacy.

Thereby highlighting the importance of determining the relative biologic activities of the IFN-ß products currently available.

Although studies have been published that examine the biologic activities of the two structurally different forms of recombinant IFN-ß, IFN-ß-1a (Rebif), Serono, Geneva, Switzerland) and IFN-ß-1b (Betaseron)/Betaferon), Berlex [Montville, NJ]/Schering [Berlin, Germany]), there have been few direct comparative studies.

Therefore, to obtain a more accurate estimate of the relative biologic activities of Rebif and Betaseron, this study examined the AntiViral activities of these two products within the same assay system and against the same natural human IFN-ß standard.

Whereas the manufacturers' information suggests that the BioActivity of Betaseron is only about 8.7-fold less than that of Rebif:

The results of the present direct, comparative study show that Rebif has an AntiViral activity 14 times greater than that of Betaseron.

This may have important clinical implications, because on the basis of the results reported here, Rebif at 44 microg t.i.w. is approximately double the maximal licensed weekly dose for Betaseron.