Interferon beta-1a (Avonex®, Biogen, Inc.), which is effective in preventing relapses and slowing disability progression in relapsing-remitting multiple sclerosis, also slows cognitive decline, according to an article by Fischer et al. recently published in the Annals of Neurology.№*

"This is the first multicenter clinical trial in MS to prospectively assess NP outcomes across a wide range of cognitive functions. Relapsing MS patients treated with Avonex® for 2 years performed significantly better than placebo patients on a composite of information processing and learning/recent memory measures. A similar trend was observed on a composite measure of visuospatial abilities and executive functions but not on the verbal abilities and attention span [that are usually not affected by multiple sclerosis]. Thus, beneficial treatment effects were most apparent in cognitive domains commonly disrupted by MS." №

"IFNЯ-1a [Avonex®] also significantly lengthened time to sustained deterioration on a different Brief NP Battery measure, the PASAT processing rate: only 19.5% of INFЯ-1a patients had a sustained worsening in their PASAT processing rate by week 104 compared with 36.6% of placebo patients, reflecting a 46.7% reduction in the risk of cognitive deterioration. These NP findings are consistent with the main outcome of the trial, namely, that IFNЯ-1a significantly lengthened time to sustained disability progression as assessed by the EDSS."№, І "We believe that [Avonex®] exerts its beneficial effects on cognitive function via both anti-inflammatory mediators and prevention of central nervous system tissue injury," said Dr. Fischer.

Two previous trials in relapsing-remitting MS assessed neuropsychological outcomes in a limited fashion. In the glatiramer acetate (Copaxone®, Teva Marion) trial,і no statistically significant treatment effects were observed. In the interferon beta-1b (Betaseron®, Berlex) study,(4) a beneficial treatment effect was only reported on visual memory measures out of the 13 neuropsychological outcomes measured in the study.

The current interferon beta-1a study was part of the pivotal trial2, which found that Avonex® favorably impacts the clinical course of MS. The study included 276 patients who had relapsing-remitting MS symptoms for 1 year or more but who were clinically stable for at least 2 months. The primary endpoint was time to sustained EDSS progression; thus, patients were treated and followed for varying lengths of time. Treatment was either Avonex® (30 µg weekly IM) or placebo once weekly for 2 years.

Neuropsychological Assessments

This study employed the Comprehensive NP Battery, a broad-spectrum cognitive assessment instrument consisting of 10 independent factors. For the study purpose, the 10 factors were grouped into 3 sets. Set A Composite consisted of learning/recent memory and information processing, which are cognitive functions most often impaired in MS. The Set B Composite consisted of visuospatial abilities and executive functions, which are often moderately impaired, and Set C Composite included verbal abilities and attention span that are infrequently impaired.

Secondary Neuropsychological (NP) Outcome results consisted of change on selected brief assessment measures. These measures were 1) Brief NP Battery of three variable composite of functions frequently or moderately impaired in MS and 2) the Pace Auditory Serial Addition Test (PASAT).

Results

Set A Composite results showed that "INFЯ-1a significantly improved performance on measures of information processing and memory relative to placebo (p = 0.036). The treatment effect was accentuated when baseline performance was included as a covariate (p = 0.011). Examination of the 2-year change on individual set A variables revealed that the between-group difference was most pronounced on a measure of verbal learning."№

The "effect of INFЯ-1a on measures of visuospatial abilities and executive functions [Set B Composite] was statistically significant (p = 0.005). The treatment effect was attenuated when baseline differences were taken into account, however, a trend towards a treatment effect was noticed (p = 0.085). Group differences in 2-year change on individual set B variables were in the predicted direction on four of five variables (p = 0.032 with baseline adjustment) and attained statistical significance on a measure of planning ability."№

As expected because there is no known MS impact on verbal abilities and attention span [Set C Composite], there were no apparent treatment effects.№

In the Secondary NP Outcome Analysis, less INFЯ-1a patients (17.7%) than placebo patients (29.7%) had sustained deterioration and a longer time to its onset. Furthermore, in the INFЯ-1a-treated group, fewer patients than placebo met criteria for sustained PASAT deterioration (p = 0.023).№

"These neuropsychological findings are consistent with the main outcome of the trial, namely, that interferon beta-1a significantly lengthened time to sustained disability progression as assessed by the EDSS," Dr. Fischer said.

Implications for Treatment

MS-related cognitive dysfunction can have a devastating impact on employment, social functioning, and domestic responsibilities. Extensive and irreversible cognitive impairment is most likely attributable to cerebral plaque accumulation and brain atrophy, both of which have been shown to be favorably affected by Avonex®, the authors pointed out.

Proactive treatment with disease-modifying therapy as recommended by the National Multiple Sclerosis Society may forestall the development or worsening of MS-related cognitive dysfunction, even when physical disability is mild, Dr. Fischer said. "The results of this study suggest that even patients with minimal physical disability can have cognitive dysfunction related to their MS, and that interferon beta-1a (Avonex®) can produce measurable neuropsychological benefits in these patients. Data from natural history studies suggest that, once present, MS-related cognitive deficits rarely remit, so early identification of cognitive deficits and early treatment of these patients are critical."

* Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Fischer JS, Priore RL, Jacobs LD, et al. Ann Neurol. Copyright (c) 2000 Wiley-Liss, Inc. Reprinted by permission of John Wiley & Sons, Inc.

References:

1. Fischer JS, Priore RL, Jacobs LD, et al. Neuropsychological effects of interferonЯ-1a in relapsing multiple sclerosis. Ann Neurol 2000; 48:885-92.

2. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing/remitting multiple sclerosis. Ann Neurol 1996; 39:285-294.

3. Weinstein A, Schwid SR, Schiffer RB, et al. Neuropsychological status in multiple sclerosis after treatment with glatiramer acetate (Copaxone). Arch Neurol 1999; 56:319-324.

4. Pliskin NH, Hamer DP, Goldstein DS, et al. Improved delayed visual reproduction test performance in multiple sclerosis patients receiving interferon Я-1b. Neurology 1996; 47:1463-1468.