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Immunomodulatory Agents for the Treatment of Relapsing Multiple Sclerosis
A Systematic Review
Steven L. Galetta, MD;
Clyde Markowitz, MD;
Andrew G. Lee, MD
Arch Intern Med. 2002;162:2161-2169.
ABSTRACT
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Background Within the past 10 years, several immunomodulatory agents (IMAs) have
become available for the treatment of relapsing multiple sclerosis (MS), making
therapeutic decisions more complex. We performed a systematic review of the
literature to assess the efficacy and safety of these agents on physical,
inflammatory, and cognitive measures of disease activity.
Methods We identified relevant studies by searching electronic databases (MEDLINE
and Current Contents) from January 1, 1993, through August 31, 2001. We included
English-language reports of data from phase 3 trials of interferon beta-1b
(Betaseron), 2 preparations of interferon beta-1a (Avonex and Rebif), or glatiramer
acetate (Copaxone) for the treatment of relapsing MS.
Results Twenty-one studies met explicit inclusion criteria. Comparison of study
results indicated no differences among IMAs regarding their efficacy on relapse-related
measures. Interferon beta-1a significantly reduced disability progression,
whereas no significant effect of glatiramer acetate or interferon beta-1b
on disability progression was seen. On inflammatory measures, all of the IMAs
showed reductions in the burden of disease (T2-weighted lesions) to varying
degrees. Interferon beta and glatiramer acetate reduced new lesion activity;
however, interferon beta had a more profound effect. One interferon beta-1a
preparation (Avonex) appeared to reduce brain atrophy, whereas glatiramer
acetate showed an effect in 1 of 2 studies. Only Avonex demonstrated efficacy
in slowing progression of cognitive dysfunction.
Conclusions Data show that the IMAs have similar effects on several physical and
inflammatory measures. In addition, Avonex has demonstrated efficacy in slowing
cognitive progression in relapsing MS. One disadvantage of interferon beta
is the possibility of immunogenicity, which may occur more often with subcutaneous
administration. The IMAs have similar safety and tolerability profiles.
INTRODUCTION
MULTIPLE SCLEROSIS (MS) is a multifocal, demyelinating disease of the
central nervous system (CNS) that is characterized by recurrent or chronically
progressive neurologic dysfunction. Multiple sclerosis is first recognized
by clinicians as relapsing-remitting MS (RRMS) in most patients.1 Relapsing-remitting
MS is characterized by well-defined disease relapses followed by periods of
full recovery or with residual deficit on recovery. Although a lack of disease
progression between relapses is seen, RRMS may be ongoing subclinically before
clinical manifestations. Secondary-progressive MS starts as RRMS and is characterized
by gradual disease progression with or without relapses, minor remissions,
and plateaus.2 Natural history data suggest
that of patients with RRMS at onset, the disease will transform to progressive
MS after 10 years in more than 50% and after 25 years in approximately 90%.1
Multiple sclerosis is a heterogeneous disease, with high intrapatient
and interpatient variability in the clinical course and manifestations. The
disease is manifested in physical symptoms (relapses and disability progression),
CNS inflammation, brain atrophy, and cognitive dysfunction. Hence, the ideal
therapy for MS would be effective against multiple aspects of the disease
(ie, physical, inflammatory, and cognitive). Since 1993, the following 2 types
of immunomodulatory agents (IMAs) have been available as first-line therapies
for the treatment of relapsing MS in the United States: interferon beta-1b
(Betaseron; Berlex Laboratories, Montville, NJ), interferon beta-1a (Avonex;
Biogen, Inc, Cambridge, Mass), and synthetic glatiramer acetate (Copaxone;
Teva Neuroscience, Kansas City, Mo). Another form of interferon beta-1a (Rebif;
Serono, Inc, Norwell, Mass) is available in Europe, Canada, and Australia,
and recently in the United States. In 1998, a consensus statement issued by
the National Multiple Sclerosis Society recommended that therapy with an approved
disease-modifying agent should be initiated as soon as possible after a definite
diagnosis of MS and determination of a relapsing course.3
Although clinicians have effective agents to choose from, selecting
the appropriate treatment can be challenging because of the wide intrapatient
and interpatient variability observed in the clinical course and symptoms
of MS. In addition, differences in study design, patient population, and clinical
end points make it difficult to compare trials. The purpose of this report
is to summarize data regarding the efficacy and safety of each IMA from phase
3 clinical trials. Since no single outcome measure captures all aspects of
the disease, MS therapies are evaluated according to their efficacy on physical,
inflammatory, and cognitive measures of disease activity.
STUDY SELECTION AND INCLUSION CRITERIA
Data were obtained from published clinical trials of IMAs (interferon
beta products and glatiramer acetate) as first-line therapy for the treatment
of RRMS or other relapsing forms of MS. Relevant studies were identified by
searching electronic databases (MEDLINE and Current Contents) from January
1, 1993, through August 31, 2001, using the terms multiple
sclerosis, interferon beta, and glatiramer acetate. To be included in this review, reports were required to be written
in English, and the data had to be from (or part of) a phase 3 trial of an
IMA used as first-line therapy for the treatment of relapsing MS. Phase 3
trials were defined as large ( 100 patients per treatment arm), randomized,
double-blind studies designed to evaluate the efficacy and safety of a drug
on the basis of clinical outcomes; small open-label trials were not included.
In addition, trials were excluded if they pertained to MS treatments for more
progressive forms of relapsing disease or secondary progressive MS (eg, mitoxantrone
hydrochloride therapy).
We assessed the study design, clinical characteristics of the patients,
outcome measures, comparison groups, and drug doses. Efficacy data were summarized
according to physical (relapse-related measures and disability), inflammatory
(magnetic resonance imaging [MRI] measures of disease activity and brain atrophy),
or cognitive measures of disease activity. Safety outcomes assessed included
the severity and incidence of treatment-related adverse events and the development
of neutralizing antibodies (NABs) to interferon beta.
PHASE 3 TRIALS IN RRMS
We identified a total of 45 articles. We included 21 in the review of
efficacy after initial screening of the abstracts. Four of the 21 selected
articles reported the primary clinical results of the pivotal phase 3 trials
for each agent. The remaining 17 articles reported the results of secondary
outcomes (eg, MRI results) or post hoc analyses of the pivotal phase 3 trials
or of additional phase 3 studies. Studies were excluded if they were small-scale
(n<100 patients per treatment group), nonrandomized, nonmasked, or non–phase
3 clinical trials.
Study Design and Patients
The study designs and patients in each phase 3 trial are summarized
in Table 1. All phase 3 trials
were randomized, placebo-controlled, double-blind, multicenter, 2-year studies.
The interferon beta-1b phase 3 trial included 372 patients with baseline Expanded
Disability Status Scale (EDSS) scores ranging from 0 to 5.5 (mean, 2.9) and
at least 2 relapses during the 2 years before enrollment.4 Patients
were randomized to receive subcutaneous (SC) interferon beta-1b, 8 mIU (250
µg) or 1.6 mIU (50 µg), or placebo every other day for 2 years.
The primary end points were the annual relapse rate and the proportion of
relapse-free patients. Secondary end points included the number of days to
first relapse, relapse duration and severity, change from the baseline EDSS
and Scripps Neurologic Rating Scale scores, and quantitative disease burden
as measured by means of T2 lesion activity on annual MRI scans.4
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Table 1. Study Designs of Pivotal Phase 3 Trials*
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In the phase 3 trial of Avonex, 301 patients with relapsing MS were
randomized to receive 30 µg of the study drug (n = 158) or placebo (n
= 143) intramuscularly once weekly for 2 years.5 Patients
with a baseline EDSS score of 1.0 to 3.5 (mean, 2.4) who experienced at least
2 relapses during the 3 years before enrollment (mean, 1.2) were enrolled
in the study. The primary outcome variable was time to onset of sustained
worsening in disability, defined as deterioration from baseline by at least
1.0 point on the EDSS that was sustained for at least 6 months. Secondary
outcome variables included relapse rate, the number and volume of lesions
with contrast enhancement on T1-weighted MRI after administration of gadolinium
(Gd-positive lesions), and the number and volume of T2 lesions.
In the phase 3 trial of Rebif, the Prevention of Relapses and Disability
by Interferon  -1a Subcutaneously in Multiple Sclerosis (PRISMS) study,
560 patients with RRMS were randomized to receive SC interferon beta-1a, 22
or 44 µg, or placebo 3 times weekly for 2 years.6 Patients
were included in the study if they had had at least 2 relapses during the
2 years before enrollment and an EDSS score of 0 to 5.0 (mean, 2.5). The primary
outcome measure was the relapse rate. Secondary outcome measures included
the proportion of relapse-free patients, times to first and second relapses,
time to sustained disability progression, findings on an ambulation index 8 and an arm-function index,9 need
for corticosteroids and hospitalization due to MS, and MRI measures of disease
burden and T2 active lesions.
In the phase 3 trial of glatiramer acetate, 251 patients with RRMS were
randomized to receive 20 mg of the study drug or placebo SC once daily for
2 years.7 Patients who had had at least 2 relapses
during the 2 years before enrollment and an EDSS score of 0 to 5.0 (mean,
2.6) were enrolled in the study. The primary outcome variable was the mean
number of relapses during 2 years. Secondary outcome variables included the
proportion of relapse-free patients, time to first relapse, proportion of
patients with sustained disease progression, and mean change in the EDSS score
and an ambulation index.
All of these phase 3 trials were randomized, placebo-controlled, double-blind
multicenter studies with similar patient populations. The mean baseline EDSS
score was slightly higher in the interferon beta-1b trial (mean, 2.9) compared
with the other trials (mean EDSS scores, 2.4-2.6). Three of 4 studies used
the relapse rate as the primary outcome measure4, 6-7;
in the Avonex trial, the time to sustained progression in disability was the
primary end point.
Physical Measures
The physical category includes measures of relapse (eg, annual relapse
rate and proportion of relapse-free patients) and progression in neurologic
disability. Relapses are defined as the appearance of new neurologic symptoms
or the worsening of a preexisting neurologic symptom in a patient who had
been stable or improving for a period (eg, 30 days) before the relapse. Studies
differ in the amount of time the symptoms are required to last (24 vs 48 hours)
and the amount of time allowed for the examining neurologist (masked to treatment
assignments) to verify the relapse. Progression in neurologic disability is
most often assessed using the EDSS.10 The EDSS
assesses cerebellar, pyramidal, brainstem, sensory, bowel, bladder, visual,
and mental functional systems on an ordinal scale, with scores ranging from
0 (normal neurologic examination findings) to 10 (death due to MS) in half-point
increments. Scores that range from 0 to 3.5 indicate the number of functional
symptom scores and the severity of dysfunction for each functional system,
whereas scores of greater than 4.0 are based primarily on the effect of the
disease on ambulation.10
A summary of the effects of each agent on relapses and disability progression
is shown in Table 2. A significant
effect of interferon beta-1b was observed on the primary outcome variable,
the annual relapse rate.4 The annual relapse
rate was 1.17 (95% confidence interval, 1.03-1.33) in patients treated with
1.6 mIU of the study drug, 0.84 (95% confidence interval, 0.72-0.97) in patients
treated with 8 mIU of the study drug, and 1.27 (95% confidence interval, 1.12-1.43)
in patients treated with placebo (P = .01 for 1.6
mIU; P<.001 for 8 mIU), representing a 34% reduction
in relapses with 8 mIU of interferon beta-1b (Table 2). The number of relapse-free patients after 2 years was
not significantly different between the group receiving 1.6 mIU of interferon
beta-1b and the placebo group (P = .07), but it was
significantly higher in the group receiving 8 mIU of interferon beta-1b compared
with the placebo group (36 vs 18; P = .007). Treatment
with 8 mIU of interferon beta-1b significantly prolonged the median time to
first relapse (295 days) compared with placebo (P =
.02). No statistically significant treatment effect on confirmed disability
progression was observed (defined as a 1.0-point increase in EDSS score)
in any of the 3 study years with either dose of interferon beta-1b. The 8-mIU
dose, but not the 1.6-mIU dose, was approved for the treatment of RRMS on
the basis of the results of this trial. The findings of this study suggest
that a dose-response curve for interferon beta-1b exists.
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Table 2. Summary of Results on Physical Measures of Disease Activity
From Pivotal Phase 3 Trials*
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In the phase 3 trial of Avonex, time to sustained progression of disability,
the primary outcome variable, was significantly greater in patients treated
with interferon beta-1a compared with placebo (P =
.02).5 The proportion of patients with progression
of disability by 2 years based on results of Kaplan-Meier analysis was 21.9%
for interferon beta-1a and 34.9% for placebo, representing a 37% reduction
in the risk for disability progression with interferon beta-1a. Annual relapse
rates for patients who completed 2 years of treatment were 0.90 for placebo-treated
patients and 0.61 for interferon beta-1a–treated patients (P = .002), representing a 32% reduction in relapse rate with interferon
beta-1a (Table 2). The reduction
in the relapse rate was 18% for all patients, regardless of time in the study.
Analysis of all patients using all time in the study also showed that interferon
beta-1a significantly reduced the annual relapse rate compared with placebo
(0.67 vs 0.82; P = .04). Patients treated with interferon
beta-1a were significantly less likely than those treated with placebo to
experience multiple relapses (P = .03); 38% of the
interferon beta-1a–treated patients were relapse free compared with
26% of the placebo-treated patients. Interferon beta-1a increased the median
time to first relapse (331 days) compared with placebo; however, the between-group
difference failed to reach statistical significance.5
The mean number of relapses was significantly lower during the 2 years
of treatment with both doses of Rebif compared with placebo (P<.005); the mean number of relapses was 1.82 for the 22-µg
group, 1.73 for the 44-µg group, and 2.56 for the placebo group.6 The reductions in the relapse rate were 29% for the
22- and 32% for the 44-µg groups (Table 2). In addition, the proportion of relapse-free patients was
significantly higher (P<.005), and the mean number
of moderate-to-severe relapses was significantly lower (P<.005) in the 2 interferon beta-1a groups compared with the placebo
group; no significant differences were observed between the 2 interferon beta-1a
doses. The time to sustained disability progression was significantly longer
(P<.05) in both interferon beta-1a treatment groups
compared with the placebo group. Based on estimations of published Kaplan-Meier
curves, reductions in disease progression were 23% for the group receiving
22 µg of the study drug and 31% for the group receiving 44 µg.
In the phase 3 trial, glatiramer acetate had a significant effect on
the primary end point, relapse rate.7 The mean
relapse rate at year 2 was 1.19 for glatiramer acetate–treated patients
compared with 1.68 for placebo-treated patients (P =
.007), representing a 29% reduction in favor of glatiramer acetate (Table 2). There were no significant effects
of glatiramer acetate on the proportion of relapse-free patients or the median
time to first relapse compared with placebo. Although there was a trend in
slowing disability progression, glatiramer acetate had no effect on progression
to sustained disability (defined as an increase of at least 1.0 points on
the EDSS that was maintained for at least 3 months); 78% of patients receiving
glatiramer acetate were free of progression compared with 75% of those receiving
placebo. However, a higher proportion of glatiramer acetate–treated
patients showed significant improvement on the EDSS, and a lower proportion
of glatiramer acetate–treated patients showed worse EDSS scores compared
with placebo-treated patients (P = .04).7
As shown in Table 2, we
found no major differences among IMAs with regard to their effects on relapse-related
measures; all agents reduced the number of relapses by approximately 30%.
Both preparations of interferon beta-1a (Avonex and Rebif) significantly reduced
disability progression, whereas no significant effect of glatiramer acetate
or interferon beta-1b (1.6 or 8 mIU) on disability progression was seen. However,
neither study used disability progression as their primary end point.
Inflammatory Measures
Disease activity and inflammation in the CNS are assessed using MRI.
Gadolinium-positive lesions indicate breakdown of the blood-brain barrier
and acute inflammatory changes.12-13 New
Gd-positive lesions are thought to have predictive value regarding the short-term
course of MS, with a higher number of Gd-positive lesions associated with
increased T2 lesion burden, relapse rate, and disability progression.14-18 Areas
of high signal abnormality on T2-weighted MRI (eg, the number of new or enlarged
T2 lesions [T2 lesion load]) are thought to provide a measure of past disease
activity and are frequently referred to as the "burden of disease."19 The T1 hypointense lesions ("black holes") reflect
axonal loss, gliosis, loss of the intracellular matrix, and demyelination
and are thought to be markers for areas of more destructive focal CNS damage
in patients with MS.20-22 Phase
3 trials of IMAs have evaluated the number and volume of Gd-positive lesions,5, 23-25 the
number and volume of T2 lesions,5, 23-27 the
number of new or enlarging T2 lesions,25-27 and
the volume of T1 hypointense lesions.23, 28 These
imaging studies have limited intraobserver and interobserver variability by
using standard protocols, single reading centers, and a small number of trained
technicians and neuroradiologists.
Serial MRI scans of patients treated with 8 mIU of interferon beta-1b
showed a significant reduction in the disease burden on T2-weighted images
compared with those of placebo-treated patients (P =
.001). Patients who received 8 mIU of interferon beta-1b showed no increase
in total MRI lesion area, whereas the placebo group showed a 20% increase
in lesion area after 2 years (P<.001).4, 26 Paty et al26 reported
a detailed analysis of MRI scans from 327 of 372 patients from the phase 3
study. Serial cranial MRI scans also were performed at 6-week intervals in
a subgroup of 52 patients. The group receiving 8 mIU showed an 80% reduction
in new, recurrent, or enlarging T2 lesions compared with the placebo group
(P = .008).26
In the phase 3 trial of Avonex, the mean ± SEM number of Gd-positive
lesions in all patients receiving the study drug was significantly reduced
compared with that in placebo-treated patients at 1 year (1.04 ± 0.28
vs 1.59 ± 0.31; P = .02); these differences
were maintained at 2 years (0.80 ± 0.22 vs 1.65 ± 0.48; P = .05).5 In patients with
enhancement at baseline, interferon beta-1a produced an 89% reduction from
baseline in the number of Gd-positive lesions. There also were significant
differences in volume (P = .03) of Gd-positive lesions
in favor of interferon beta-1a treatment. Interferon beta-1a produced a significant
reduction in T2 lesion volume after 1 year, but not 2 years of treatment.
This lack of effect on T2 lesion volume may have been due to the small number
of patient scans available at 2 years and the large variability of T2 lesion
volume observed in the study. Interferon beta-1a treatment significantly reduced
the number of new (P = .006), enlarging (P = .02), and new plus enlarging T2 lesions (P =
.002) during 2 years compared with placebo.27
The MRI scans of T1 hypointense lesions were examined in 80 patients
treated with interferon beta-1a and 80 treated with placebo from the Avonex
phase 3 trial.28 Placebo-treated patients showed
a 29% increase from baseline in mean T1 lesion volume during the 2-year study
(P<.001 vs baseline) compared with an 11.8% increase
(not significant vs baseline) in interferon beta-1a–treated patients.
The median increase in T1 lesion volume at 2 years was 124.5 mm3 in
the placebo group and 40 mm3 in the interferon beta-1a group, which
represented a 68% reduction in T1 lesion volume with interferon beta-1a treatment;
the difference between groups was not statistically significant (P = .07).28 Analyses of MRI scans were
conducted to determine the effects of interferon beta-1a on whole-brain atrophy
as measured by brain parenchymal fraction (BPF).29 The
BPF is defined as the ratio of brain parenchymal volume to the total volume
within the brain surface contour. A total of 140 patients had MRI scans available
from baseline, year 1, and year 2. Results showed that interferon beta-1a
reduced the rate of brain atrophy by 55% compared with placebo during the
second year of treatment (P = .03).29
The MRI data from the phase 3 trial of Rebif showed that interferon
beta-1a produced a reduction in the burden of disease as measured by proton
density on T2-weighted MRI.6, 25 The
T2 burden of disease showed a median decrease of 1.2% in the group receiving
22 µg of interferon beta-1a and a median decrease of 3.8% in the group
receiving 44 µg of interferon beta-1a, but a median increase of 10.9%
in the placebo group (P<.001 for both doses).
Both interferon beta-1a doses also produced a significant reduction in the
number of T2 active lesions compared with placebo (P<.001),
with a significant dose effect in favor of the 44-µg dose (P<.001).6, 25 In a cohort
of 205 patients who underwent monthly scans, an analysis of combined unique
lesions (Gd-enhanced T1/T2 lesions) showed significant reductions in the median
number of combined unique active lesions and the percentage of combined unique
active lesions on scans at 9 months in both interferon beta-1a treatment groups
compared with the placebo group (P<.001). In addition,
within the monthly MRI cohort, interferon beta-1a significantly reduced the
median number of Gd-enhanced lesions at 9 months; an 82% reduction was observed
in the 22-µg group and an 84% reduction was observed in the 44-µg
group compared with the placebo group (P<.001).25 Data from the PRISMS study showed no effect of Rebif
on brain atrophy.23
The effects of glatiramer acetate on MRI measures of disease activity
were evaluated in a subset of patients (n = 27) enrolled in the phase 3 study
of glatiramer acetate.7, 24 The
primary outcome variables were the number and volume of Gd-positive lesions,
the number and volume of T2 lesions, and brain atrophy as measured by BPV.
Significant reductions from baseline in the number of Gd-positive lesions
(P = .03) and in brain atrophy (P = .008) were observed in glatiramer acetate–treated patients
compared with placebo-treated patients. Glatiramer acetate did not affect
the number or the volume of T2 lesions. Some of these disparate findings may
be explained by the number of patients studied (N = 27).24
A European and Canadian placebo-controlled, double-blind phase 3 trial
has been conducted to evaluate the effects of glatiramer acetate on MRI measures.23 This study included 239 patients with RRMS who had
an EDSS score of 0 to 5.0 (mean, 2.4), at least 1 relapse in the 2 years before
enrollment, and at least 1 Gd-positive lesion at the time of enrollment. Patients
were randomized to receive SC glatiramer acetate, 20 mg (n = 119), or placebo
(n = 120) once daily for 9 months. At 9 months, glatiramer acetate treatment
produced a 29% to 35% reduction in the total number of enhancing lesions compared
with placebo (P = .003).23 Significant
reductions in the number of new Gd-positive lesions (P<.003),
in the monthly change in Gd-positive lesion volume (P =
.01), and in the volume and number of new T2 lesions (P = .006 and P<.003, respectively) were
observed compared with placebo. Glatiramer acetate produced a 37% reduction
in T1 hypointense lesion volume compared with placebo; however, this effect
was not statistically significant.23 The data
from this study were reanalyzed to determine the effect of glatiramer acetate
on T1 black holes. Results, which were reported in a separate paper by Filippi
et al,30 showed that the percentage of new
lesions that evolved into black holes was 28% lower at 7 months (P = .04) and 50% lower at 8 months (P = .002)
in the glatiramer acetate group compared with the placebo group. The same
study showed no significant effect of glatiramer acetate on brain atrophy.31
Although interferon beta and glatiramer acetate reduce the number of
Gd-positive lesions, interferon beta seems to have a more profound effect.
An 89% reduction in Gd-positive lesions was observed in patients treated with
Avonex5 with enhancement at baseline (P = .001). Furthermore, Rebif produced an 82% to 84% reduction
in the median number of Gd-positive lesions (P<.001).25 A 29% to 35% reduction in Gd-positive lesions has
been observed with glatiramer acetate at 9 months.23 Table 3 summarizes MRI data from phase
3 trials of the IMAs. All agents significantly reduced T2 hyperintense lesions.
For example, interferon beta-1b showed an 80% reduction in new, recurrent,
or enlarging T2 lesions compared with placebo. Avonex reduced brain atrophy
and the volume of T1 hypointense lesions. Glatiramer acetate also reduced
brain atrophy in a small substudy from a phase 3 trial. A larger but short-term
study of glatiramer acetate showed a positive effect on T1 hypointense lesions,
but no effect on brain atrophy.30-31
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Table 3. Summary of Results on Inflammatory Measures of Disease Activity
From Phase 3 Trials*
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Cognitive Measures
Although the patterns of cognitive deficits vary considerably among
patients with MS,33 certain cognitive domains
appear to be more susceptible than others. The cognitive domains most commonly
affected in MS are information processing (eg, distractibility, slowing of
mental process and difficulty performing multiple tasks) and verbal and visual
memory (eg, forgetfulness and especially delayed recall of recently learned
information).34 Traditional outcome measures
used in MS clinical trials do not measure cognitive function.35 In
addition, currently available neuropsychological (NP) tests cannot detect
all of the cognitive deficits in MS. Hence, the best approach to measuring
cognitive deficits in patients with MS is to select NP tests that measure
information processing, verbal memory, and visual memory, which are the cognitive
domains most affected by MS.36 For information
processing, such tests include the following: the Paced Auditory Serial Addition
Test, Trail-Making Tests A and B, Stroop test, Symbol-Digit Modalities Test,
and the California Computerized Assessment Package. For verbal learning and
memory, tests include the Buschke Selective Reminding Test, the Rey Auditory
Verbal Learning Test, and the California Verbal Learning Test. For visual
learning and memory, tests include the Wechsler Memory Scale–Revised
Visual Reproduction, the 10/36 Spatial Learning Test, and the Ruff Figural
Fluency Test.36
Neuropsychological function was assessed in 30 patients with MS who
participated in the phase 3 trial of interferon beta-1b.37 These
patients were administered a battery of tests that measured immediate and
delayed memory recall, visual reproduction, attention/mental speed, and motor
function and a depression inventory scale.37 Significant
improvement was observed on 1 of 13 measures (delayed visual reproduction; P<.003 vs the placebo group) in patients who received
the 8-mIU dose of interferon beta-1b. The clinical significance of this isolated
improvement in 1 domain in the treated group remains uncertain, given the
small number of patients studied.
The effects of Avonex on cognitive function were evaluated in patients
who participated in the phase 3 trial.38 Two
hundred seventy-six patients were administered a comprehensive NP battery
on study entry, and 166 patients also completed the comprehensive NP battery
at year 2. The primary outcome measure was the 2-year change in performance
on the comprehensive NP battery, grouped into domains of information processing
and learning/memory (most often impaired in MS), visuospatial abilities and
problem solving (moderately impaired), and verbal abilities and attention
span (rarely impaired). Results showed that interferon beta-1a significantly
improved performance on measures of the cognitive domains most vulnerable
to MS, ie, information processing and learning/memory (P = .01). In addition, interferon beta-1a slowed the progression of
cognitive deterioration by 47% compared with placebo, based on a commonly
used NP measure (the Paced Auditory Serial Addition Test processing rate)
(P = .02).38
As part of the phase 3 trial of glatiramer acetate, 248 patients were
randomized to receive SC glatiramer acetate, 20 mg, or placebo once daily.39 At baseline and after 12 and 24 months of treatment,
patients were administered the Brief Repeatable Battery of Neuropsychological
Tests, which includes measures of sustained attention and concentration, verbal
learning and delayed recall, visuospatial learning and delayed recall, and
semantic retrieval. No significant treatment effects were observed on any
of the NP outcome measures.39 The active-treatment
and placebo groups showed improvement in their cognitive function in this
2-year study.
To date, Avonex is the only treatment that has shown significant beneficial
effects on the cognitive domains most affected by MS (Table 4). In their respective phase 3 trials, interferon beta-1b
showed a significant effect on only 1 of 13 NP tests and glatiramer acetate
demonstrated no effect. No reports on the effects of Rebif on cognitive function
in MS have been made.
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Table 4. Summary of Studies on Cognitive Measures of Disease Activity*
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Safety
Adverse events produced by interferon beta-1b were dose related, including
injection-site reactions, fever, chills, myalgia, sweating, and malaise significantly
associated with the 8-mIU dosage of interferon beta-1b (P = .05); injection-site reactions occurred in 69% of patients receiving
8 mIU compared with 6% of those receiving placebo. These adverse events decreased
to placebo levels across the first year of treatment, although injection-site
reactions remained common in the interferon beta-1b groups.
The incidence of flulike symptoms, muscle aches, fever, and chills was
significantly higher in the Avonex group compared with the placebo group (P<.05). Interferon beta-1a therapy was well tolerated,
with 93% of patients completing treatment as scheduled. Injection-site reactions,
depression, and menstrual disorders were reported by 10% to 15% of patients.5
In the phase 3 trial of Rebif, significantly higher incidences of injection-site
reactions, lymphopenia, leukopenia, granulocytopenia, and increased alanine
aminotransferase levels were observed in patients who received interferon
beta-1a compared with placebo (P .05). All of
these adverse events except injection-site reactions were observed more frequently
with the 44-µg than the 22-µg dose. The most common adverse event
associated with glatiramer acetate treatment was a localized injection-site
reaction consisting of erythema and induration, which occurred at least once
in 90% of glatiramer acetate–treated patients and 69% of placebo-treated
patients. Another adverse event associated with glatiramer acetate treatment
was a transient, unpredictable, systemic postinjection reaction, consisting
of flushing, chest tightness, dyspnea, palpitations, and anxiety. This systemic
reaction was reported in 15% of glatiramer acetate–treated patients
and 3% of placebo-treated patients.7
Neutralizing Antibodies
Neutralizing antibodies can develop during long-term administration
of interferon beta products; however, there are differences in the incidence
of NABs among the interferon beta products. The incidence of NABs reported
for interferon beta-1b and Rebif has ranged from 38% to 47% and 12% to 24%,
respectively,4, 6, 40 whereas
the incidence of NABs to Avonex has ranged from 5% to 22%.5, 41-42 The
development of NABs has been shown to reduce the efficacy of interferon beta.
In the phase 3 study of interferon beta-1b, patients with NAB-positive findings
showed a significant increase in exacerbations (P<.05),
a significant increase in enlarging lesions (P<.05),
and an increase in new lesion formation (P = .07)
after 18 months compared with patients with NAB-negative findings.43 Recent data from the 4-year extension phase of the
PRISMS study showed that NABs were associated with significant reductions
in the efficacy of Rebif.44 Similar to findings
with interferon beta-1b, patients in whom NABs developed during treatment
with Rebif showed significantly higher relapse rates (P = .002), numbers of T2 active lesions, and burden of disease (P<.001) compared with patients with NAB-negative findings.
In this study, the effects of NABs on efficacy were observed after 2 years
of treatment.44 In the phase 3 trial of Avonex,
no correlation was found between NAB status and disability progression or
relapse rate. The lack of correlation is most likely due to the small number
of patients who had NABs and the short 2-year follow-up.
Neutralizing antibodies can develop and significantly reduce the efficacy
of interferon beta. The incidence of NABs is higher with interferon beta-1b
than with the interferon beta-1a preparations. The clinical effects of NABs
were observed after 18 to 24 months of administration, indicating that short-term
studies cannot adequately assess the efficacy of interferon beta. The occurrence
of NABs may relate to structural differences between interferon beta-1b and
interferon beta-1a. Other important variables could include the frequency
and route of administration of the interferon preparation.
COMMENT
To date, well-controlled head-to-head comparison studies to assess the
relative efficacy of MS treatments have not been reported. Therefore, physicians
must make treatment decisions based on a critical review of available data
across clinical trials of each IMA. A major challenge in comparing the efficacy
of MS agents is the variety of outcome measures used in clinical studies.
The goal of the present review was to summarize data from randomized, double-blind,
placebo-controlled, multicenter phase 3 trials to evaluate the efficacy of
IMAs on physical, inflammatory, and cognitive measures of disease activity.
On physical measures of disease activity, no differences are found among
the agents regarding their efficacy on relapse-related measures. However,
only Avonex and Rebif have shown significant beneficial effects on disability
progression. On inflammatory measures of disease activity, all IMAs have shown
reductions in T2 hyperintense lesions to varying degrees. Interferon beta
and glatiramer acetate reduce Gd-positive lesions; however, interferon beta
products (82% to 89% reductions) appear to have a more profound effect than
glatiramer acetate (29% to 35% reductions). Avonex has been shown to reduce
brain atrophy as assessed by a 3-dimensional measure, BPF in year 2 of therapy;
glatiramer acetate was shown to reduce brain atrophy in 1 of 2 studies. Regarding
cognitive measures of disease activity, only Avonex has shown beneficial effects
on the cognitive domains most affected by MS in a large, well-controlled clinical
trial. Although more clinical trial evidence of the efficacy of interferon
beta exists compared with glatiramer acetate, NABs to interferon beta can
develop over time and potentially diminish their efficacy.
In general, interferon beta and glatiramer acetate are well tolerated.
The most common adverse events associated with interferon beta treatment are
flulike symptoms, which decrease during the first year of treatment. Subcutaneous
administration of interferon beta produces a higher incidence of injection-site
reactions than does intramuscular administration; injection-site reactions
are also commonly observed with glatiramer acetate treatment. The most common
adverse event associated with glatiramer acetate treatment was a self-limited
systemic reaction consisting of flushing, chest tightness, dyspnea, palpitations,
and anxiety.
AUTHOR INFORMATION
Accepted for publication March 26, 2002.
Corresponding author and reprints: Steven L. Galetta, MD, Department
of Neurology, University of Pennsylvania Hospital, 3400 Spruce St, 3W Gates
Bldg, Philadelphia, PA 19104 (e-mail: galetta{at}mail.med.upenn.edu).
From the Departments of Neurology (Drs Galetta and Markowitz) and Ophthalmology
(Dr Galetta), University of Pennsylvania Hospital, Philadelphia; and the Departments
of Ophthalmology, Neurology, and Neurosurgery, University of Iowa Hospitals
and Clinics, Iowa City (Dr Lee). Drs Galetta and Markowitz have received research
funding and speaking honoraria from Biogen, Inc, Cambridge, Mass, and Teva
Neuroscience, Kansas City, Mo. Dr Markowitz has received research funding
from Serono, Inc, Norwell, Mass.
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