Interferon-ß-1a (Avonex TM): Clinical And MRI Impacts
Rev Neurol (Paris) 1999;155 Suppl 2:S13-9
Clinique Neurologique, CHU de Lille
PMID# 10367320; UI# 99295396
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.
MRI Results Of The PRISMS Trial: A Study Of Interferon-ß-1a In R/R Multiple Sclerosis
Li DK, Paty DW
Ann Neurol 1999 Aug;46(2):197-206
UBC Hospital, Vancouver, Dept of Radiology, BC, Canada
PMID# 10443885; UI# 99371485
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 And Multiple Sclerosis: Relation With Disease Course And Therapy
Prat A, Al-Asmi A, Duquette P, Antel JP
Ann Neurol 1999 Aug;46(2):253-6
McGill University, Montreal Neurological Institute, Quebec, Canada
PMID# 10443892; UI# 99371492
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.
Treatment Of Multiple Sclerosis - 1. New Drugs May Be Effective But There Still Are Frequent Relapses
Svenningsson A, Andersson M, Olsson T
Lakartidningen 1998 Dec 2;95(49):5623-7, 5630
Karolinska sjukhuset, Neurologiska kliniken, Stockholm
PMID# 9863300; UI# 99080668
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.