Interferons In Multiple Sclerosis

Several Phase III studies have proven that the ß-Interferons have positive effects on the number and severity of acute exacerbations of Relapsing/Remitting Multiple Sclerosis.

Recently the first study on the effectiveness of Interferon-ß-1b in Secondary/Progressive Multiple Sclerosis was published.

In a multicenter, double-blind, randomized, Placebo-controlled study 718 patients with Secondary/Progressive Multiple Sclerosis and an Expanded Disability Status Scale (EDSS) value between 3.0 and 6.5 were treated with either 8 MIU Interferon-ß-1b or Placebo subcutaneously every second day for two to three years.

The primary study end-point was the time until confirmed progression of the disease as signified by a one point increase of the EDSS value (for initial EDSS values between 3.0 and 5.5) or 0.5 point increase when the initial EDSS value was between 6.0 and 6.5.

After two years an interim analysis showed a highly significant difference in delay of disease progression by nine to twelve months for the treatment group (p = 0.0008).

This means that Interferon-ß-1b is the first recombinant Interferon-ß to be shown effective in the treatment of Secondary/Progressive Multiple Sclerosis.

Recently, a placebo-controlled multicenter randomized clinical trial was published on the efficacy of Interferon-ß-Ib in the treatment of Secondary/Progressive Multiple Sclerosis.

The study was stopped after the interim analysis because evidence of efficacy was already clear. However, the results appear to be considerably less convincing.

The decision to prematurely stop the clinical trial was based more on an overestimate of the p-values than on the clinical relevance of the treatment effects.

The efficacy of Interferon should be investigated in relation to other treatment options, such as ImmunoGlobulin, Copolymer-I, Azathioprine and Methotrexate.

• Comment in: Ned Tijdschr Geneeskd 1999 Apr 10;143(15):815-7

Objectives
To evaluate clinical and MRI effects of natural Interferon-ß treatment in both Relapsing/Remitting (RR) and Secondary/Progressive (SP) Multiple Sclerosis patients.

Material And Methods
A double-blind, randomized trial of natural Interferon beta (nIFN-ß) in 58 ambulatory patients with RR and 40 with SP Multiple Sclerosis.

Forty-nine patients (29 RR and 20 SP) were treated with intramuscular nIFN-ß 6 MIU three times a week for 24 months and 49 control patients were treated with placebo.

Results
Primary clinical endpoints were differences in exacerbation rates and proportion of patients remaining exacerbation-free.

There were no significant baseline differences between the treated and placebo groups.

In the treated RR group a significant reduction in exacerbation rate, an increase in the probability of remaining exacerbation-free, and an improvement in mean EDSS were found at 24 months.

MRI activity and total lesion burden were significantly reduced in treated RR patients.

In the SP group, nIFN-ß produced a significant reduction in EDSS score, a significant reduction in active Lesion number, a marginally significant favorable difference in total Lesion Burden but no significant effect on the number of Gadolinium-enhancing lesions. Side effects were transient and mild in treated patients.

Conclusions
These observations confirm that nIFN-ß is a promising and well-tolerated treatment for either RR or SP MS patients.

A randomized placebo-controlled trial of Interferon-ß-1b was performed on 718 patients with Secondary/Progressive Multiple Sclerosis with follow-up of up to 3 years.

In addition to clinical variables, serial Magnetic Resonance Imaging (MRI) studies were performed to determine the effect of treatment on the pathological evolution of the disease.

All patients eligible for MRI had annual Proton Density/T₂-weighted Brain scans from which total lesion volume was measured and the number of new and enlarging lesions noted.

A subgroup of 125 patients also underwent monthly Gadolinium-enhanced and Proton Density/T₂-weighted Brain MRI from months 0 to 6 and 18 to 24 to determine the effect of treatment on the frequency of new lesion activity, defined as new enhancing lesions and new/enlarging T2 lesions not enhancing with Gadolinium.

The difference in total lesion volume between treatment groups was highly significant. In the placebo group, there was an increase of 15% from baseline to last scan, whereas in the Interferon-ß-1b group, a reduction of 2% was seen.

Within the placebo group, there was a significant year-on-year increase in total lesion volume, with a mean increase of 16% at year 3 compared with baseline.

In the treated group, there was a significant reduction at year 1 (4%) and year 2 (5%) compared with baseline; the 2% decrease at year 3 was not significant.

The number of new or enlarging Proton Density/T2 Lesions was also significantly reduced by treatment. In the frequent MRI subgroup, treatment was associated with a significant 65% reduction in new lesion activity between months 1 and 6, and 78% reduction from months 19 to 24.

Interferon-ß-1b has a substantial and sustained effect on reducing the accumulation of new Inflammatory Disease Foci in Secondary/Progressive MS.

This therapeutic mechanism may contribute to the positive clinical benefits of treatment on the progression of sustained Neurological Disability and relapse activity that were also identified in this trial.

The use of Interferon-ß in the Relapsing/Remitting phase of Multiple Sclerosis is a new though fairly established therapy.

The beneficial effect of this treatment is thought to be due to Immune modulation, with inhibitory action on proliferation of Leukocytes and Antigen Presentation, an increased amount of InterLeukins, but no change in the ProInflammatory Cytokine Interferon-gamma.

In Norway, one Interferon-ß 1b and two Interferon-ß 1a products have recently been introduced for administration by either subcutaneous or intramuscular injection.

Approximately 30% reduction in the Relapse Rate is reported for both products,but differences appear in the effect on the Disability Progression, and also with regard to adverse reactions. Patients less strongly affected by the illness seem to have the best outcome.

Neutralizing AntiBodies are often produced during this treatment, but the significance of this is still unclear.

Results from international studies on Interferon therapy of Multiple Sclerosis are discussed. Initial results from studies on Interferon treatment of Secondary/Progressive Multiple Sclerosis are now available.

A further expansion, also in Norway, of the indications for Interferon-ß therapy of Multiple Sclerosis is expected in the near future.

This article presents critical aspects of the pivotal Phase III study that led to approval of Interferon-ß-1a (Avonex) as treatment for Relapsing/Remitting Multiple Sclerosis (MS).

An update on data from the pivotal study or other open studies, further demonstrating the practical clinical impact of Avonex, are also presented.

The purpose of the pivotal study was to determine whether Avonex could slow the progressive irreversible Neurological Disability of Relapsing-MS.

301 patients were randomized into a double-blind placebo-controlled, multicentric trial of Avonex. Avonex 6.0 MUI (30 micrograms) was administered by intramuscular injection weekly.

The primary outcome variable was time to sustained physical disability at 6 months progression of at least 1.0 point on the EDSS. Avonex produced a significant delay in time to sustained EDSS progression (p = 0.02).

The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9 p. 100 in the placebo group and 21.9 p. 100 in the Avonex treated group, representing a 37 p. 100 reduction in the risk of accumulating disability.

Further analysis showed that the clinical efficacy related to disability did not depend on the definition of disability progression. Significantly fewer Avonex recipients progressed to EDSS milestones of 4.0 or 6.0.

The exacerbation frequency was decreased by 32 p. 100 in the Avonex group. Patients treated with Avonex had also a significantly lower number and volume of Gadolinium-enhanced Lesions on MRI.

There was no major adverse events related to treatment. Injection site reactions were rare and no reports of skin Necrosis have been recorded. There was no significant and clinically relevant biological disturbances due to Avonex.

The PRISMS (Prevention of Relapses and Disability by Interferon-ß-1a Subcutaneously in Multiple Sclerosis) trial was a double-blind, randomized, multicenter, Phase III, placebo-controlled study of Interferon-ß-1a in 560 patients from 22 centers in 9 countries with Clinically Definite or Laboratory-Supported Relapsing/Remitting Multiple Sclerosis.

The patients were randomized to receive recombinant Interferon-ß-1a (Rebif), 22 microg (6 mIU), 44 microg (12 mIU), or placebo, given subcutaneously, three times weekly for 2 years.

All patients underwent biannual Proton Density/T₂-weighted MRI scans to determine the overall MRI disease activity and Burden Of Disease, and a cohort of 205 patients had 11 initial monthly Proton Density/T₂-weighted and Gadolinium-enhanced T₁-weighted MRI scans.

Over the 2 years, the placebo group showed a progressive median increase in burden of disease of 10.9%, whereas the 22-microg group and 44-microg group showed median decreases of 1.2% and 3.8%, respectively.

The number of T2 active Lesions and percentage of scans showing T2 activity on the biannual scans were also significantly reduced in both treatment groups compared with placebo, with a clear dose-effect favoring the 44-microg dose over the 22-microg dose.

In the subgroup undergoing initial monthly scanning, this reduction in activity became statistically significant 2 months after the start of treatment.

These results provide strong, objective evidence to support the positive clinical results of reduction in relapses and delay in disease progression. In addition, they also demonstrate a significant dosage effect, favoring the 44-microg dose.

Lymphocyte migration into the Central Nervous System is a central event in lesion formation in Multiple Sclerosis.

By using a Fibronectin-coated membrane Boyden chamber assay, we observed that migration rates of immediately ex vivo Lymphocytes from patients with Relapsing/Remitting, with or without concurrent clinical relapse, or with Secondary/Progressive Disease, were increased compared with healthy donors.

Migration rates of Lymphocytes from Relapsing/Remitting Multiple Sclerosis patients receiving either Glatiramer Acetate (Copaxone 20 mg daily) or Interferon-ß-1b (Betaseron 8 MIU, three times per week) were significantly reduced compared with untreated Relapsing/Remitting patients.

In vitro treatment with Interferon-ß-1b (1,000 U/ml), but not Glatiramer Acetate (20 microg/ml), significantly reduced Lymphocyte-migration rates, suggesting that the effects of these two therapeutic agents on migration result from different mechanisms of actions.

Interferon-ß-1b acts, at least in part, by a direct effect on this cell property, whereas Glatiramer Acetate effects are indirect.

Multiple Sclerosis (MS) is a DeMyelinating, Central Nervous System Disease, of putative AutoImmune PathoGenesis.

Although no effective pharmacological therapy has been available for this often disabling disease until recently, several studies have now confirmed that subcutaneous or intramuscular administration of Interferon-ß may reduce the frequency and severity of relapses in Relapsing MS, and may also inhibit Disease Progression.

Studies are under way to determine the possible efficacy of Interferon-ß during the Progressive phase of the disease.

Three Interferon-ß formulations are currently available in Sweden. Another drug, Glatiramer Acetate, also shown to have some effect on the disease course, is expected to be registered for use in Sweden shortly.

Interferon-beta (IFN-ß) has beneficial effects on the clinical symptoms of Multiple Sclerosis (MS) patients, but its exact mechanism of action is yet unknown.

We here suggest that IFN-ß directly modulates inflammatory events at the level of Cerebral Endothelium.

IFN-ß treatment resulted in a marked reduction of PeriVascular infiltrates in acute Experimental Allergic Encephalomyelitis (EAE), the rat model for MS, which was coupled to a major decrease in the expression of the Adhesion Molecules ICAM-1 and VCAM-1 on Brain Capillaries.

In vitro, IFN-ß reduced the mRNA levels and protein expression of Adhesion Molecules of Brain Endothelial Cell cultures and diminished Monocyte TransEndothelial migration.

Monocyte adhesion and subsequent migration was found to be predominantly regulated by VCAM-1.

These data indicate that IFN-ß exerts direct AntiInflammatory effects on Brain Endothelial Cells thereby contributing to reduced lesion formation as observed in MS patients.

Background
The three Interferon-ß preparations approved for treatment of Relapsing/Remitting Multiple Sclerosis (MS) differ in dose and frequency of administration.

Interferon-ß-1a 30 microg is administered once a week, Interferon-ß-1a 22 microg or 44 microg is given three times a week, and Interferon-ß-1b 250 microg is administered on alternate days.

No clinical study directly comparing the different regimens has been published.

The INCOMIN study was designed to compare the clinical and Magnetic Resonance Imaging (MRI) benefits of on-alternate-day Interferon-ß-1b 250 microg with once-weekly Interferon-ß-1a 30 microg.

Methods
INCOMIN was a 2-year, prospective, randomized, multicenter study. 188 patients with Relapsing/Remitting MS were assigned to Interferon-ß-1b (n=96) or Interferon-ß-1a (n=92).

Primary outcome measures were the proportion of patients free from relapses and that of patients free from new Proton Density/T₂ lesions at MRI assessment.

Several secondary outcome measures were also assessed. Analysis was by intention to treat.

Findings
Over 2 years, 49 (51%) individuals administered Interferon-ß-1b remained relapse-free compared with 33 (36%) given Interferon-ß-1a relative risk of relapse 0.76; 95% CI 0.59-0.9; p=0.03).

And, 42 (55%) compared with 19 (26%), respectively, remained free from new T₂ lesions at MRI (relative risk of new T₂ lesion 0.6; 0.45-0.8; p<0.0003).

In both groups, the differences between the two treatments increased during the second year. There were also significant differences in favor of Interferon-ß-1b in most of the secondary outcome measures, including delay of confirmed disease progression.

Interpretation
High-dose Interferon-ß-1b administered every other day is more effective than Interferon-ß-1a given once a week.

MS is an Immunologically mediated disease, as determined by observation of the response to ImmunoTherapy and the existence of an animal model, Experimental AutoImmune Encephalitis.

Interferon-beta-1b (IFN-ß), IFN-ß-1a, and Glatiramer Acetate, the therapies used for Relapsing or Remitting MS, have mechanisms of action that address the Immunologic PathoPhysiology of MS.

The IFNs bind to Cell Surface-Specific Receptors, initiating a cascade of signaling pathways that end with the secretion of AntiViral, AntiProliferative, and ImmunoModulatory gene products.

Glatiramer Acetate, a synthetic molecule, inhibits the activation of Myelin Basic Protein-Reactive T-Cells and induces a T-Cell repertoire characterized by AntiInflammatory effects.

Although the two classes of drugs have some overlapping mechanisms of action, the IFNs rapidly block Blood-Brain Barrier leakage and Gadolinium (Gd) enhancement within 2 weeks, whereas Glatiramer Acetate produces less rapid resolution of Gd-enhanced MRI activity.

IFN-ß has no direct effects in the CNS, but Glatiramer Acetate-Specific T-Cells are believed to have access to the CNS, where they can exert AntiInflammatory and possibly NeuroProtective effects.