We compared the ability of the Kurtzke Expanded Disability Status Scale (EDSS) and a composite outcome of non-physician based measures of Time to Ambulate 25 feet (TA) and Manual Dexterity (the Box and Block Test [BBT], and 9-Hole Peg Test [9HPT]) to discriminate treatment effects in the Phase III study of Interferon-ß-1a.

A log-rank comparison of Kaplan-Meier curves by treatment group showed the non-physician based composite of BBT, 9HPT, and TA was of comparable sensitivity (P = 0.013) in discriminating sustained treatment failure as the EDSS alone (P = 0.029).

The composite of BBT, 9HPT, TA, and EDSS was more sensitive (P = 0.009) in discriminating sustained treatment failure than the EDSS alone.

Compositive outcomes of the EDSS and non-physician based measures of Manual Dexterity and Timed Ambulation provide an appealing strategy to reduce the number of patients required to discriminate treatment effects in MS clinical trials.

Background
Interferon-ß is an effective treatment for Relapsing Multiple Sclerosis (MS). As with other protein drugs, Neutralizing AntiBodies (NAB) can develop that reduce the effectiveness of treatment.

Objectives
To determine the incidence and biological significance of NAB to Interferon beta-la (IFN-ß-1a; Avonex; Biogen, Cambridge, MA) in MS patients.

Methods
A two-step assay for NAB to IFN-ß-1a was developed and used to assay Serum samples from participants in the Phase III clinical trial of IFN-ß-1a, and from patients in an ongoing open-label study of IFN-ß-1a.

The biological significance of NAB to IFN-ß-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules Neopterin and ß-2 MicroGlobulin.

The clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-ß-1a therapy in patients who were NAB⁺ and NAB^-.

The incidence of NAB was compared in MS patients who had used only IFN-ß-1a with the incidence in MS patients who had used only IFN-ß-1b.

Results
In patients in the open-label study, development of NAB to IFN-ß-1a resulted in a titer-dependent reduction in Neopterin induction after Interferon injections.

In patients in the Phase III study, development of NAB was associated with a reduction in ß-2 MicroGlobulin induction.

In the Phase III study, a trend toward reduced benefit of IFN-ß-1a on MRI activity in NAB⁺ versus NAB^- patients was observed.

The incidence of NAB to IFN-ß-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-ß-1a therapy.

But was four- to sixfold higher using the same assay for patients exposed only to IFN-ß-1b for a similar duration.

There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB.

Conclusions
NAB directed against IFN-ß have in vivo biological consequences in patients with MS.

The frequency with which MS patients develop NAB against IFN-ß is significantly greater with IFN-ß-1b therapy compared with IFN-ß-1a therapy.

Treatment decisions in MS patients treated with IFN-ß should take into account development of NAB.

• Comment in: Neurology 1998 May;50(5):1206-8

The Multiple Sclerosis Collaborative Research Group trial was a double-blind, randomized, multicenter, Phase III, placebo-controlled study of Interferon-ß-1a (IFN-ß -1a; Avonex) in Relapsing forms of Multiple Sclerosis.

Initial Magnetic Resonance Imaging results have been published; this report provides additional results.

Treatment with IFN-ß-1a, 30 microg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T₂ lesions over 2 years.

The median increase in T₂ lesion volume in placebo and IFN-ß-1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance.

For active patients, defined as those with Gadolinium enhancement at baseline, the median change in T₂ lesion volume in placebo and IFN-ß-1a patients was 1,578 and -12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively.

Except for a minimal correlation of 0.30 between relapse rate and the number of Gadolinium-enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor.

Once weekly intramuscular IFN-ß-1a appears to impede the development of Multiple Sclerosis lesions at an early stage and has a favorable impact on the long-term sequelae of these inflammatory events as indicated by the slowed accumulation of T₂ lesions.

• Comment in: Ann Neurol 1998 Sep;44(3):424-5

Background And Objective
A Phase III double-blind, placebo-controlled clinical trial demonstrated that Interferon-ß-1a (IFN-ß-1a) (Avonex, Biogen) significantly delayed progression of Disability in Relapsing MS patients.

The primary clinical outcome was time from study entry until Disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months.

The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance.

Methods
Post hoc analyzes related to Disability outcomes using data collected during the double-blind, placebo-controlled Phase III clinical trial.

Results

1. Clinical efficacy related to Disability did not depend on the definition of Disability progression.

2. A significant benefit in favor of IFN-ß-1a was observed:
   • When > or = 2.0 point worsening from baseline EDSS was required, Or
   • When worsening was required to persist for > or = 1.0 year.

3. Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN-ß-1a recipients who reached the primary study outcome.

4. Significantly fewer IFN-ß-1a recipients progressed to EDSS milestones of:
   • 4.0 (relatively severe impairment), Or
   • 6.0 (unilateral assistance needed to walk)

5. Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to Disability progression was IFN-ß-1a treatment.

Conclusions
The primary clinical outcome for the IFN-ß-1a clinical trial underestimated clinical benefits of treatment.

Results in this report demonstrate that IFN-ß-1a treatment is associated with robust, clinically important beneficial effects on Disability progression in Relapsing MS patients.

We compared the number of new Gadolinium-enhancing (Gd⁺) and T₂-weighted (T₂W) lesions on 6-monthly MRI scans before and after initiating weekly intramuscular injections of Interferon-ß-1a (Avonex) 30 mcg.

The mean number of new focal Gd⁺ lesions detected during the 6 monthly on-treatment scanning sessions was:

1. 58 per cent less per MRI scan
2. 62.5 per cent less per patient than during the 6 monthly pre-treatment scanning sessions (p = 0.016, Wilcoxon signed rank test)

The results are similar for new focal Gd⁺ and T₂W lesions.

The reduction in disease activity detected by monthly Gd⁺ enhanced MRI scans after initiating weekly intramuscular IFN-ß-1a 30 mcg is consistent with benefits observed with:

1. thrice weekly subcutaneous IFN-ß-1a 10 mcg
2. thrice weekly subcutaneous IFN-ß-1a 30 mcg
3. alternate day subcutaneous IFN-ß-1b 8.0 MIU

Objective
Interferon-beta (IFN-ß) has repeatedly shown benefit in Multiple Sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with Magnetic Resonance Imaging and, to some degree, the progression of disability;

However, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage.

This multicenter, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN-ß-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with Secondary/Progressive MS.

Methods
A total of 371 patients with Clinically Definite SPMS were randomized to receive either placebo or subcutaneous IFN-ß-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months.

The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate.

Results
Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67).

Other disability measures were also not significantly affected by treatment.

Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted.

Conclusions
This patient population was less clinically active than SPMS populations studied in other trials.

Treatment with low dose, IFN-ß-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses.

These results add a point at one extreme of the dose-response spectrum of IFN-ß therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

Background
Interferon-beta-1a (IFN-ß-1a), Avonex is efficacious in Relapsing forms of MS. Studies of other IFN-ß preparations in Secondary/Progressive MS (SPMS) yielded conflicting results.

This study was undertaken to determine whether IFN-ß-1a slowed disease progression in SP-MS.

Methods
A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFN-ß-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years.

The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of Ambulation (Timed 25-Foot Walk), Arm Function (Nine-Hole Peg Test [9HPT]), and Cognition (Paced Auditory Serial Addition Test [PASAT]).

Results
Median MSFC Z-score change was reduced 40.4% in IFN-ß-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT.

There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFN-ß-1a subjects had 33% fewer relapses (p = 0.008).

There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T₂-HyperIntense Brain MRI lesions and Gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001).

IFN-ß-1a was well tolerated by the majority of subjects. Neutralizing AntiBodies developed in 3.3% of IFN-ß-1a-treated subjects.

Conclusions
IFN-ß-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.