Multiple Sclerosis Forum Report
Toulouse, France

The Latest Evidence-Based Medicine Presented on Multiple Sclerosis Treatment

This report was reviewed for medical and scientific accuracy by Andrew Goodman, MD , Department of Neurology, University of Rochester Medical Center, New York.


Timothy Vartanian MD, PhD, Director, Multiple Sclerosis Treatment Center, Beth Israel Deacones Medical Center, Boston, Massachusetts

Multiple sclerosis disables young adults at great personal, social, and economic costs. The evidence that MS is most often a relentlessly disabling disease stems not only from the observations of the concerned neurologist, but also from well-conducted longitudinal studies (Weinshanker ref, and British/Irish longitudinal study). It stands to reason then, that if we are to make a meaningful impact on the lives of individuals with MS, a clear and definitive diagnosis should be made early, and disease-modifying therapies initiated promptly. Two major clinical studies have recently been completed that address the latter issue and beg the question of the former. The CHAMPS and ETOMS studies have asked: if we begin a disease-modifying therapy, proven to slow disease progression in definitive MS (Poser and Paty criteria), in a population of patients currently deemed at high risk for developing MS, then what is the probability that we can postpone the development of clinically definitive MS (traditional Poser and Paty criteria)? Both studies were well conducted, appropriately randomized and blinded, and looked at a similar series of end points. The CHAMPS study reported that, at any point in time, there was a 44 percent reduction in the risk of developing clinically definitive MS for patients receiving Avonex® compared to placebo (p = 0.002). The ETOMS study reported a 31 percent reduction in the risk of developing clinically definitive MS for patients receiving Rebif® compared to placebo (p = 0.047). While the magnitude of effectiveness in reducing the probability of developing clinically definitive MS favored Avonex®, the important message is that early intervention works.

Most clinicians caring for individuals with MS recognize that the diagnostic criteria for MS require modification. For instance, my definition of clinically definite MS at initial presentation would require: 1. An initial presentation of a CNS demyelinating event

2. Exclusion of masquerading genetic, metabolic, vascular, collagen-vascular, infectious, and nepotistic diseases

3. MRI of the brain and cervical spine showing lesions (in additional to the lesion presumed responsible for presenting event) that are characteristic of MS

By implementing such criteria, we can be certain that patients receive therapy in a timely fashion. The abstracts below underscore this notion and highlight the enthusiasm for understanding the molecular and cellular basis of MS in order to devise strategies for more effective therapeutic interventions.


Final Results of the CHAMPS Study

R. Philip Kinkel, MD, Medical Director, Mellen Center, Cleveland Clinic, Ohio

The first report of the final results of CHAMPS (Controlled High Risk Avonex® Multiple Sclerosis Prevention Study) confirms the encouraging interim results, which were presented at the Annual Meeting of the American Academy of Neurology in San Diego, April, 2000. The final results of CHAMPS, taken together with results of another recent study, ETOMS (Early Treatment of MS), firmly support early treatment of MS with disease-modifying therapy following a first attack of MS with MRI evidence of disease activity.

CHAMPS showed that Avonex® (interferon beta-1a, Biogen, Inc.) reduced the rate of conversion from a clinically isolated syndrome (CIS) to clinically definite MS (CDMS) by 44 percent compared to placebo (rate ratio = 0.56, confidence interval 95 percent, p = 0.002). This treatment effect was observed on all secondary MRI outcome measures, including a 91 percent reduction in T2 lesion volume accumulation, a 67 percent reduction in the number of enhancing lesions, and a 57 percent reduction in new and enlarging T2 lesions at the end of 18 months (p values < 0.001).

"CHAMPS suggests that patients with a first demyelinating event and MRI evidence of MS should receive early treatment with Avonex®. At the Cleveland Clinic, we consider starting Avonex® in a person with a first attack and one or more symptomatic MRI lesions," stated R. Philip Kinkel, MD.

Dr. Kinkel continued that a person with a first attack and normal MRI who has oligoclonal bands (OCB) in the cerebral spinal fluid (CSF) should be monitored with an annual MRI, and Avonex® should be considered at any sign of worsening. However, a person with the first attack and normal MRI who is OCB-negative does not require MRI monitoring.

The CHAMPS Study

CHAMPS was a randomized, double-blind, placebo-controlled multicenter trial conducted at 50 centers in North America. The study enrolled 383 subjects between April 1996-April 1998 and randomized them to either placebo or Avonex® 30 mcg once a week IM injections. Patients' ages ranged from 18-50 years. To be included, patients had to have experienced a first, isolated, well-defined, demyelinating event, representing optic neuritis, spinal cord syndrome, or brainstem syndrome. About 50 percent of the study group had < 4 Gd+ lesions. All patients were treated with intravenous (IV) methylprednisolone for up to 14 days after onset of symptoms, and then were switched to oral prednisone. Baseline MRI was conducted four days after IV methylprednisolone. Then patients were withdrawn from oral steroids and followed for one month, during which time those who developed CDMS were excluded.

Relative Risk of Clinically Definite MS (CDMS)

AVONEX ® Placebo Relative Month n %CDMS n %CDMS Risk 6 164 8% 146 17% 0.48 12 143 15% 131 23% 0.65 18 109 19% 94 32% 0.60 24 69 21% 56 38% 0.56

A rapid treatment effect was seen for Avonex®, and this effect continued throughout the study, said Dr. Kinkel. Patients with lower T2 lesion loads experienced the same benefits as those with higher loads. At 24 months, there was a 44 percent risk reduction of progressing to CDMS in the Avonex® treated group.

MRI Results

MRI scans were conducted at baseline, six, 12, and 18 months. Dr. Kinkel explained that as patients developed CDMS, they were withdrawn from the study (in both groups), so that the results of the MRI scans represent relatively stable patients.

At baseline, patients in the Avonex® group had more Gd+ lesions than those in the placebo group, which could have biased against observing a treatment effect. Nevertheless, a robust treatment effect was seen on MRI. At each time point (six, 12, and 18 months), the number of new and enlarging T2 lesions increased in the placebo group but remained stable in the Avonex® group. "At 18 months, the MRI comparison was between patients who remained clinically stable on interferon beta-1a (Avonex®) and placebo," Dr. Kinkel emphasized.

Magnitude of Treatment Effects at 18 Months on Brain MRI

MRI Lesions Avonex® Placebo % Reduction p value Group Group Comparing Avonex® (n=135) (n=119) to Placebo Group

Mean number of 2.1 5.0 57% p<0.0001 new or enlarging T2 lesions

Change in T2 lesion 28 313 91% p<0.0001 volume [median mm3]

Mean number of 0.5 1.4 67% p<0.0001 enhancing lesions

Volume of 37 108 66% p<0.0001 enhancing lesions [median mm3]

"This study demonstrates the importance of obtaining cranial MRI in patients experiencing the first symptom of MS. MRI has helped us identify patients likely to develop CDMS who can be selected for early therapy. Over the course of the study, we learned more about MRI, in particular, that subclinical Gadolinium enhancement (Gd+) and T2 disease activity occurred on serial MRI following a single demyelinating event. We also know that neuronal damage occurs following a single event," Dr. Kinkel told listeners.

Flu-like symptoms occurred in 39 percent of Avonex®-treated patients versus 22 percent of the placebo group. Depression (but not suicidal thoughts or suicide) was present in 20 percent versus 12 percent, respectively. Neutralizing antibodies (NABs) virtually did not occur, said Dr. Kinkel. Less than 2 percent of patients treated with Avonex® developed NABs at a titer of greater than 1/20.

Pending Questions

Although Dr. Kinkel was enthusiastic about the results of CHAMPS, he pointed out that there are some unanswered questions. In particular, it is not yet clear whether early treatment will prevent the development of disability over the long term, continue to decrease the T2 and Gd+ lesions over time, prevent the development of secondary progressive MS, and prevent the development of permanent brain tissue injury as seen on MRI.

The CHAMPIONS (CHAMPS In Ongoing Neurologic Surveillance) study has been initiated to answer these questions, he continued. All the original CHAMPS patients will be included in this open-label prospective study of the CHAMPS cohort followed for five years. CHAMPIONS will assess conversion to CDMS, relapse rate, EDSS, MRI, and quality of life.

In Support of Early Treatment

Dr. Kinkel supports early treatment in selected patients. He presented some common misinterpretations about early treatment, then gave reasons to negate them:

Claim Denial

Patients may have a different diagnosis than MS This is unlikely with well-chosen MRI criteria

Patients with an isolated clinical event may remain Only 18 percent of untreated stable patients in CHAMPS showed no evidence asymptomatic for many years. of MRI disease activity over an 18-month period

The patient may have benign disease Benign disease is a myth. The vast majority of MS patients have symptoms that are compromising, including fatigue and/or cognitive problems

Relatively unimpaired patients may not tolerate injections Less than 2 percent of patients treated with Avonex® in the CHAMPS study discontinued therapy

Patients can develop NABs, which will compromise In the CHAMPS study, NABs were not a problem. Less than 2 percent of patients developed NABs therapy

In summary, Dr. Kinkel stated that the evidence in favor of early treatment is much more convincing than arguments against it. He encouraged neurologists in the audience to consider early treatment with Avonex® in patients who fulfill the entry criteria for CHAMPS, i.e., an isolated demyelinating event and MRI evidence of one or more active lesions.

Rebif® (Interferon Beta-1a) in Patients with Acute Neurological Syndromes Suggestive of MS

Giancarlo Comi, MD, Professor of Neurology, University of Milan, Italy, and the ETOMS Study Group

Early treatment with Rebif® (interferon beta-1a) 22 mcg administered subcutaneously once a week, reduced disease activity, both clinically and by MRI parameters, in a randomized Phase III trial reported by Giancarlo Comi, MD, on behalf of the Early Treatment of Multiple Sclerosis (ETOMS) study.1

This multicenter study aimed to evaluate efficacy of interferon beta-1a in preventing progression to clinically definite MS after the first suggestive neurological episode. The population included 308 patients who were less than three months from their first attack and whose MRI was strongly suggestive of MS. Baseline parameters were similar between patients receiving interferon beta-1a and those receiving placebo. Eighty two percent of patients originally randomized to interferon beta-1a completed two years of therapy, compared to 74 percent of placebo-treated patients.

Of the placebo-treated patients, 45 percent converted to CDMS, compared to 34 percent of the Rebif®-treated group. This corresponds to a 24 percent (p = 0.047) reduction in risk of conversion to CDMS. Furthermore, time to conversion was significantly longer in the interferon group: 533 days versus 251 for placebo (p = 0.034), he said.

Treatment with Rebif® also reduced the annual relapse rate by 23 percent (p = 0.045), from 0.43 to 0.33. Furthermore, the relative reduction in T2 activity was 44 percent in year one (p < 0.001), 27 percent in year two (p < 0.05), and 38 percent overall (p < 0.001).

To conclude, Dr. Comi stressed the importance of early treatment in suspected MS. "Almost all patients converted. 'Benign' cases are much in the minority," he remarked.

The results of the study are less pronounced than the CHAMPS results. The results do, however, indicate the importance of early interferon beta treatment in patients with high risk from developing MS. The effect of 22 µg Rebif® used in ETOMS strongly contradicts the lack of effect seen with the same dose administered once a week subcutaneously in the OWIMS study.

Interferon Beta-1a in Primary Progressive MS (PPMS): Results of a Phase II, Double-Blind, Placebo-Controlled Trial

Siobhan M. Leary, MD, University College, Institute of Neurology, NMR Research Unit, Queen Square, London, United Kingdom

Preliminary results of the randomized controlled trial of interferon beta-1a (Avonex®, Biogen, Inc.) in primary progressive multiple sclerosis (PPMS) were not conclusive but suggest a beneficial effect for Avonex® 30 mcg once weekly IM injections on T2 lesion load. Although these are modestly encouraging results, they should be viewed in the context of PPMS being the most challenging form of MS to treat, and that currently there is no effective treatment.

Results of this study have been awaited eagerly by the MS community, because most clinical trials have excluded patients with PPMS. Although these results were somewhat inconclusive, final analysis may provide stronger evidence of treatment benefit.

The single-center study included 50 subjects with PPMS of at least two years' duration and a history of progression over the two years prior to entry. EDSS scores ranged from 2.0-7.0, and all subjects had at least two lesions in the brain and/or spinal cord. The double-blind, placebo-controlled trial randomized subjects to one of three arms: weekly intramuscular (IM) injections of Avonex® 30 mcg IM, Avonex® 60 mcg IM once weekly, or IM placebo injections once weekly. There were 15 patients in each of the active treatment groups and 20 patients in the placebo group.

The primary clinical endpoint of the trial was time to sustained disability progression, as reflected by an increase of at least one point on the EDSS for patients with an EDSS score of < 5, or a 0.5-point increase for patients with an EDSS score of = 5. A number of other clinical and MRI secondary endpoints were included, such as T2 lesion load, spinal cord atrophy, and brain atrophy. Patients were also given a timed ten-meter walk test and a nine-hole peg test, but preliminary results of these two tests were not available, said Siobhan M. Leary, MD.

In an intent-to-treat analysis, 49 patients completed two years of follow-up and 43 completed two years of treatment. There were seven patient withdrawals, four due to flu-like symptoms in the 60 mcg arm. The majority of dose reductions occurred in the 60 mcg arm as well.

"Nine patients in the interferon beta-1a 60 mcg arm had either the dose reduced or withdrew, so the data from this very small arm must be cautiously interpreted," Dr. Leary told the audience.

Although baseline clinical characteristics were similar in the three arms, MRI characteristics differed in that the high-dose Avonex® arm included patients with higher T2 and T1 lesion loads, thus biasing against a treatment effect.

The preliminary results indicate that no significant differences were seen in the three groups for EDSS progression. However, when the MRI data were analyzed, a significantly lower rate of T2 lesion load accumulation was seen in the Avonex® 30 mcg arm compared to the other two in the study (p = 0.025), noted Dr. Leary.

Flu-like symptoms occurred in 87 percent of patients in the 30 mcg arm and virtually all of those in the 60 mcg arm. However, as Dr. Leary pointed out, 55 percent of placebo patients also experienced these symptoms. "Only 58 percent of the whole study group could correctly identify the treatment they were assigned to," she added, indicating adequate blinding of the study.

"This was a small trial that included only 50 patients and these results should be considered preliminary. It is difficult to draw conclusions from this small study. Further analysis using more sophisticated MRI techniques may reveal stronger data or data that leads in a specific direction. We need to wait for the final analysis," said Dr. Leary.

Avonex® 30 mcg once weekly IM was well tolerated and showed an effect on decreasing T2 lesion load by brain MRI. This is the first drug to show this effect in people with PPMS.

Cognitive Dysfunction in Multiple Sclerosis

Stephen M. Rao, PhD, Professor of Neurology, Section of Neuropsychology, Medical College of Wisconsin, Milwaukee

Contrary to past assumptions, researchers now know that cognitive dysfunction is common in MS, occurring in 43-65 percent of patients. Even though these cognitive deficits can be viewed as mild in many cases, they nevertheless interfere with employment, socializing, and general functioning.

The types of cognitive dysfunction that occur in MS are not uniform, explained Stephen M. Rao, PhD. Declines are commonly observed on measures of sustained attention, recent memory, executive functions, and information processing speed, with language and intellectual skills being relatively spared. Studies at Dr. Rao's institution show that more than 20 percent of MS patients have deficits in information processing and memory, eight to nine percent have language deficits, and 12-19 percent have compromised visuospatial skills.

"Cognitively impaired MS patients are less likely to work and socialize, and they need more personal assistance than cognitively intact persons, even with the same EDSS," he told attendees.

Tests such as the Wisconsin Card Sort, the 12-Word List, and the PASAT (Paced Auditory Serial Addition Test) are used to detect cognitive impairment. The Wisconsin Card Sort Test requires patients to shift from one organizing concept (i.e., color) to another (shape). Many patients who take this test have trouble shifting to a new organizing principle (perseveration), which has negative implications for work performance. The 12-Word Sort List selectively reminds subjects to recall words, and the test identifies problems in learning and memory. "Patients with MS usually have no trouble . . . getting the information in; it's the retrieval of information that is faulty," explained Dr. Rao. PASAT is a sensitive test for information processing, and many MS patients have trouble performing the serial addition required by the test.

Results of neuropsychological tests (i.e., cognitive dysfunction) are highly correlated with total cerebral lesion load (T2-weighted MRI), but the correlations between MRI lesion load and EDSS have been somewhat disappointing, observed Dr. Rao. Correlates of cognitive dysfunction in MS patients include emotional factors, medications, severity of physical disability, duration of illness, and extent of brain involvement.

A natural history study of 77 community-based MS patients, conducted by Dr. Rao and colleagues, showed that over a three-year period, 62 patients had no change in cognitive function but 15 got worse (Rao et al. Neurology, 1991 May; 41(5): 685-91; Rao et al. Neurology, 1989 Feb; 39(2 Pt 1):161-6). In the group that worsened, a greater total T2 lesion load was seen on MRI: an increase of nearly 15 cm2 compared to less than a 5 cm2 increase in the cognitively stable group (p < 0.003). The increase in EDSS in the two groups was roughly equivalent.

"This suggests that preventing new lesions with immunomodulatory treatment can prevent cognitive deterioration, whereas untreated groups with increased lesion burden and brain atrophy should demonstrate a worsening of cognitive function," he stated.

Positive Effects of Avonex® (Interferon Beta-1a) on Cognitive Function

Patients enrolled in the pivotal Avonex® (interferon beta-1a, Biogen, Inc.) trial underwent a comprehensive neuropsychological battery of tests at baseline and two years thereafter, including a brief battery of neuropsychological tests every six months. Results of these tests show that Avonex® favorably influenced cognitive function in patients with RRMS (Fischer J. Ann Neurol, in press). At baseline, 64 percent of patients had evidence of cognitive impairment-most frequently, in memory, information processing, and speed of information processing. Some patients exhibited visuospatial and executive function impairment, and verbal impairment was rare. Avonex® significantly improved function in those with impaired information processing and memory problems (p = 0.011) and a 47 percent reduction in impairment on the PASAT was also noted for Avonex® versus placebo (p = 0.023). There was a trend suggesting that Avonex® improved the visuospatial and executive function (p = 0.085) compared to placebo.

In summary, Avonex® had a statistically significant effect on cognitive function of RRMS patients included in the pivotal trial. The treatment effect was most evident in vulnerable domains, such as memory and information processing. Cognitive dysfunction due to MS should be considered when selecting a therapy for patients with RRMS, and the evidence suggests that early therapy will help preserve cognitive function.

A Longitudinal Study of Brain Atrophy and Cognitive Disturbances in the Early Phase of RRMS

Robert Zivadinov, MD, Department of Neurology, Clinica Neurologica Ospedale Di Trieste, University of Trieste, Italy

The first longitudinal study of brain atrophy and cognitive performance in relapsing-remitting multiple sclerosis (RRMS) showed that over a two-year period, there was a striking increase in the number of patients with cognitive dysfunction that was independently associated with brain parenchymal atrophy. Loss of brain volume was the only MRI abnormality significantly associated with cognitive decline in this study-neither T2 lesion load nor T1 lesion load correlated with cognitive worsening. In a previous study, two years of treatment with Avonex® (interferon beta-1a, Biogen, Inc.) was shown to reduce the progression of brain atrophy (Rudick RA et al. Neurology, 1999; 53:1698-1704), suggesting that early treatment with disease-modifying therapy can prevent cognitive decline.

"Our study shows that in the early phase of RRMS, cognitive decline relies predominantly on the development of brain atrophy, rather than disease severity. Brain atrophy probably underlies the progressive accumulation of physical disability, since it is initiated during the initial phase of the disease. Our data contribute to the evidence for early use of disease-modifying therapy in patients without overt clinical symptoms and are in agreement with the recent CHAMPS and ETOMS study supporting early treatment in patients with a first episode of MS," stated Robert Zivadinov, MD.

The study presented by Dr. Zivadinov was singled out for an award as best oral presentation by the ECTRIMS scientific committee. Dr. Zivadinov was praised for this important research, which represents a collaboration between researchers in Trieste, Italy, and Rijeka, Croatia.

Explaining the rationale for the study, Dr. Zivadinov said, "Cognitive dysfunction can be present in early MS. Recent studies suggest that cognitive impairment depends not only on the extent and severity of disease, but also on microscopic changes in normal-appearing white matter (NAWM). New MRI techniques show that progressive pathological changes can develop in the brain. Longitudinal studies are the most sensitive in determining which MRI parameters can predict the development of cognitive impairment."

Previous studies show that loss of brain parenchymal volume ranges between 0.8 percent and one percent per year in RRMS. Reduction in this parameter becomes more severe with ongoing disease activity, ranging from one to three percent per year.

The present study included 53 patients with RRMS, ages 18-60, with an EDSS of less than or equal to 5.0, and a mean duration of disease of one to five years. Patients were excluded from the study if their score on the Mini Mental Status Exam was less than 24, if they had concomitant disorders, and if they were currently taking immunosuppressive, steroid, and/or psychoactive drugs.

Within 48 hours of enrollment, patients had an MRI scan and a standard battery of 18 neuropsychological tests. Patients were considered cognitively impaired if they had abnormal results in two or more domains. Fourteen patients were cognitively impaired at baseline, and at the end of the two-year study, 28 had evidence of cognitive impairment. Five patients showed cognitive improvement, 33 remained stable, and 15 worsened. T2 and T1 lesion load increased over the two-year study, but this was not significant. A significant decrease in brain parenchymal volume from baseline was seen in those subjects with cognitive impairment-a decrease of 66 ml (5.4 percent, p = 0.0031). The ten patients who worsened at least one point on the EDSS during the course of the study had a decrease of 99 ml in brain parenchymal volume (8 percent, p = 0.005).

"A remarkable percentage of patients with early RRMS presented with cognitive worsening at the end of the study: 28 versus 14 at baseline. Cognitive performance was independently predicted by a reduction in brain parenchymal volume," stated Dr. Zivadinov.

Mean EDSS increased from 1.0 to 1.5 over two years (p = 0.007). A robust relationship was seen between brain parenchymal volume and EDSS changes during the study, he continued. Other studies have shown a lack of correlation between MRI lesion load and the EDSS (see summary of Dr. Rao's presentation above).

Dose-Comparison Study of Avonex® (Interferon Beta-1a)

Professor Michel Clanet, Federation of Neurology, CHU Purpan Hospital, Toulouse, France

A dose-comparison study of interferon beta-1a (Avonex®, Biogen, Inc.) was initiated to compare 60 mcg versus 30 mcg of Avonex® injected IM once weekly in patients with relapsing-remitting MS (RRMS).

The double-blind, randomized, multicenter study is being conducted at 38 European sites and includes 802 patients with RRMS, EDSS scores of 2.0-5.5, and at least two relapses within three years prior to enrollment. Part 1 of the study will explore the safety and efficacy of the higher dose over a three-year period, explained Professor Michel Clanet. Part 2 is a double-blind extension phase lasting up to one year during which patients who completed part 1 will be offered the study drug. Enrollment for part 1 has been recently completed.

EDSS will be assessed every three months, and patients will have periodic MRI scans: 138 patients will have frequent MRI scans every few months, 248 will have annual MRIs, and 416 will not undergo MRI. The primary endpoint of the study is time to sustained progression of disability as measured by deterioration in EDSS lasting for at least six months.

Baseline characteristics of the two treatment groups are similar-mean age is 36 years, 68 percent are female, and mean EDSS is 3.6.

"More than 30 percent of patients had an EDSS of four or higher, which will be important when we consider the results," noted Prof. Clanet. This may indicate if there will be a dose effect in this special group.

Exacerbations within three years of entering the study were similar between groups, with a mean of 1.3. Baseline MRI data showed no significant difference in the number of active lesions or in the mean T2 lesion area.

Interim results of part 1 should be available early in 2001. "These results should answer the question of whether there is a dose effect of Avonex® [in patients with RRMS]," observed Prof. Clanet.

MRI As an Early Course Predictor of MS

Massimo Filippi, MD, Scientific Institute Ospedale San Raffaele, Neuroimaging Research Unit, Department of Neuroscience, Milan, Italy

MRI studies suggest that the amount of T2 lesions is the best predictor of conversion from clinically isolated syndrome (CIS) to clinically definite MS (CDMS), explained Massimo Filippi, MD. The evidence from his imaging studies and those of other experts suggests that early treatment with disease-modifying agents, which prevent inflammation, may represent a strategy to prevent neurodegeneration due to MS in early disease.

"Our studies show that the activity in CIS is not just inflammation. Tissue damage is occurring at early stages. There is continual progression of tissue destruction in RRMS and in secondary progressive MS (SPMS) as well," Dr. Filippi told listeners.

The spectrum of disease ranges from CIS to RRMS to SPMS. At the early end of the spectrum, inflammation is predominant, but as the disease progresses to RRMS and then to SPMS, neurodegeneration becomes more prominent than inflammation. This dissociation between inflammation and neurodegeneration as RRMS progresses is not well understood, he added. However, MRI studies show larger numbers of Gd+ lesions are present in earlier stages of disease. These studies contribute to the rationale for early treatment with disease-modifying agents that reduce the inflammatory component of the disease.

MRI scans of patients with CIS reveal several defects suggesting the presence of lesions. MRI can help identify dissemination of lesions in space. Several MRI studies have characterized the number, size, location, and shape of lesions in CIS. The ETOMS (Early Treatment of MS) study showed that a higher T2 lesion load predicted the evolution of CIS to CDMS. ETOMS also showed that early treatment with interferon beta-1a (Rebif®) significantly reduced MRI activity (p < 0.001) and the T2 lesion burden (p = 0.002). Other recent studies have also confirmed that a high lesion volume predicts evolution from CIS to CDMS.

"We have strong evidence that the presence of more lesions predicts the progression of disease and an increase in disability," stated Dr. Filippi.

Serial MRI studies at Dr. Filippi's institution demonstrate that disease pathology is present early in the course of MS and continues to progress rapidly, even in asymptomatic patients. In 31 patients with CIS who underwent monthly MRI scans, 58 percent had at least one Gd+ lesion during the first three months, and by the end of the first six months, 68 percent had at least one Gd+ lesion.

Factors that predict the conversion from CIS to CDMS include the amount of lesions, the amount of enhancing lesions, and the location of lesions (juxtacortical lesions, infratentorial lesions, and periventricular lesions are associated with disease evolution). Black holes are evident even in CIS, which reflect tissue destruction. Also, magnetic transfer ratio (MTR) imaging demonstrates changes in NAWM.

Conventional MRI has poor predictive value in RRMS because of the dissociation between inflammation and neurodegeneration, he continued. MTR shows that tissue destruction is increased in SPMS compared to RRMS. The T2 lesion load (which reflects inflammation) correlates with disease severity in RRMS, but not in SPMS.

"In the future, new techniques may be able to measure the effectiveness of repair. We are doing small studies with new techniques to measure different parameters and to build models for understanding brain and spinal cord activity in specific disability scenarios," he concluded.


Treatment of Relapsing-Remitting MS (RRMS) Patients with Avonex® (Interferon Beta-1a): A Phase IV, Open-Label, Multicenter Study of Two Years' Duration

Oscar Fernandez, MD, Department of Neurology, Complejo Hospitalario Carlos Haya, Malaga, Spain

A prospective, Phase IV study has demonstrated that Avonex® (interferon beta-1a, Biogen, Inc.) is as safe and effective in clinical practice as it was in the pivotal trial.

"Although this Phase IV, open-label study is susceptible to important biases and does not take into account the phenomenon of regression to the mean, we consider that this prospective design with a common multicenter protocol verifies that interferon beta-1a (Avonex®) has been able to reproduce in a daily clinical setting the results of efficacy and safety obtained in the pivotal Phase III studies," stated Oscar Fernandez, MD.

The study included 96 patients with RRMS treated with Avonex® 30 mcg (6 MIU) IM once a week over a two-year period. The mean follow-up during the first year of treatment was 10.2 months, and during the second year, 23.7 months.

The annualized rate of exacerbation showed a reduction of 65 percent (Confidence Interval [CI] 95 percent: 55-73). The percentage of exacerbation-free patients was 33 percent (CI 95 percent: 21-45).

At two years, 34 (35.4 percent) of patients showed improvement, 27 (28.1 percent) remained stable, and 35 (36.5 percent) deteriorated.

Treatment was well tolerated. Three patients withdrew from treatment.

Tolerability of Avonex® (Interferon Beta-1a) in Children with Multiple Sclerosis

Emmanuelle Waubant, MD, University of California San Francisco, Mt. Zion MS Center, San Francisco

There are few data on the tolerability of Avonex® (interferon beta-1a, Biogen, Inc.) in the pediatric population. A recent study, one of the few conducted in children, suggests that weekly Avonex® 30 mcg IM is well tolerated in youngsters under the age of 16, with a similar safety and tolerability profile compared to that of adults.

The study was a retrospective review based on physicians' responses to a questionnaire about pediatric MS patients treated with interferon beta-1a. A standardized questionnaire was sent to 200 neurologists in the U.S. in January of 1999, in an attempt to identify patients under 16 years who were taking weekly Avonex® for RRMS. The questionnaires were sent to MS centers and neurological practices that participated in multicenter trials of agents for MS. Also, local neurologists were recruited from the San Francisco area.

Of the 184 neurologists who responded, 29 were treating a total of 62 children with MS using disease-modifying agents: 33 on interferon beta-1a (Avonex®), 15 on glatiramer acetate (Copaxone®, Teva Marion Partners), and 14 on interferon beta-1b (Betaseron®, Berlex).

Nine questionnaires completed for Avonex®-treated children were obtained and formed the basis of the study. All nine patients were under the age of 16 and had clinically definite MS. Mean age of onset of MS was 11 years (range, six to 14 years). Mean age of initiation of treatment was 12.7 years (range, eight to 15 years). Mean time on Avonex® was 17 months (five to 36 months). Adverse events included flu-like symptoms (N = 3), headaches (N = 4), fever (N = 2), and muscle aches (N = 1). In nine of ten events, the effects were mild to moderate, and severe in one case.

No patient discontinued therapy due to side effects. In two patients, one child was treated with intravenous methylprednisolone and subsequently switched to azathioprine, and a second child was continued with interferon beta-1a plus glatiramer acetate (Copaxone®), which was well tolerated.

"In this study, Avonex® was well tolerated in children under 16 for a relatively short time. Further study with longer follow-up should be undertaken in children to confirm the safety of the drug over the long term," said Emmanuelle Waubant, MD.

Safety, Pharmacokinetic, and Pharmacodynamic Drug Interaction Study of Antegren® and Interferon beta-1a (Avonex®) in Patients with Relapsing-Remitting MS

Timothy Vollmer, MD, Associate Professor of Neurology, Yale University School of Medicine, Director, Yale MS Research Center, New Haven, Connecticut

This Phase II study showed that the combination of Antegren® (natalizumab, Elan Corporation), a monoclonal antibody, and Avonex® (interferon beta-1a, Biogen, Inc.) was safe and well tolerated. The addition of Antegren® to Avonex® did not result in untoward drug-drug interactions or interference with the kinetics, activity, or usefulness of Avonex®. Results of this study suggest that the two drugs can be safely combined and studied.

Antegren® is a recombinant humanized antibody that binds to alpha integrin on lymphocytes and monocytes and inhibits interaction with VCAM-1 on endothelial cells. The drug is currently under study as a monotherapy for patients with MS, explained Timothy Vollmer, MD.

"Antegren® is being studied because of its ability to block the migration of inflammatory cells to the brain, which is one of the pivotal steps leading to demyelination and cerebral injury. There are reliable animal and human data to suggest Antegren® might be an effective therapeutic option for patients with MS. Looking ahead, the next opportunity would be to see if the effect of Antegren® could be enhanced by currently available therapy, or vice-versa," he explained.

The study sought to determine the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of Avonex® 30 mcg once week IM in MS patients following a single intravenous (IV) dose of Antegren®. During the 14-week study, patients on stable doses of Avonex® received Antegren® 3.0 mg/kg (N = 15) or 6.0 mg/kg (N = 22). PK and PD of Avonex® were assessed, including serum neopterin and beta-2 microglobulin, PK of Antegren®, and the immunogenicity of both agents. Safety assessments included physical examination, laboratory tests, ECG, SNRS, and adverse events.

Following Antegren® (3.0 mg/kg dose), mean pre- to post-dose comparisons were:

Pre-Dose Values Post-Dose Values Avonex® AUC 3482 3521 Neopterin 425 413 Beta-2 microglobulin 223 213

Three exacerbations of MS occurred during the course of the study, one of which required hospitalization. No other serious adverse events were found.

A multicenter, multiple-dose, Phase II study of Antegren® monotherapy is currently in progress. Results of this study are not yet available.

"Although the currently available disease-modifying agents slow disease progression, the majority of patients will continue to progress and accumulate disability. Researchers are now beginning to test more novel therapies and to look at drug combinations to see if we can improve efficacy. The combination of Antegren® and Avonex® appears to be a worthwhile strategy to pursue in trials," stated Dr. Vollmer.

Interferon Neutralizing Antibodies Reduce Clinical and MRI Efficacy in MS Patients Treated with Rebif® (Interferon Beta-1a): Observations from the PRISMS 4-Year Extension Study

George P. A. Rice, MD, University Hospital, Ontario, Canada

A two-year, open-label extension of the two-year-long PRISMS study showed that the development of neutralizing antibodies (NABs) on treatment with Rebif® was associated with significantly higher relapse rates and more disease activity on MRI for MS patients. Compared to the placebo group, NAB-negative patients had significantly better outcomes.

"The presence of NABs can have a negative impact on relapse rates and MRI activity, and this effect can be missed by short-term studies. In the PRISMS study, the impact of NAB-positivity was not seen during the first two years and only became evident during the two-year extension phase of the study," stated G. P. A. Rice, MD.

In the pivotal PRISMS study of patients with relapsing MS, neutralizing antibodies developed in 12.5 percent of patients taking Rebif® 44 mcg x 3 per week and in 23.7 percent of those taking Rebif® 22 mcg x 3 per week during the first two years. These antibodies were generally found within the first 24 months of treatment and rarely thereafter, said Dr. Rice.

During a two-year extension phase of the pivotal trial, persistent NAB-positive were demonstrated in 14 percent of the Rebif® 44 mcg group and in 23.7 percent of the Rebif® 22 mcg group. During the third and fourth year, relapse rate was significantly higher in the NAB-positive patients in both treatment groups (p = 0.002 for the 44 mcg group and p = 0.096 for the 22 mcg group). Patients with NAB positive also had by MRI a significantly higher burden of disease and T2 lesions. The effect of NAB may be missed in a short study. Interferon beta-1a 44 mcg seems to be associated with less NAB-positive patients, said Dr. Rice.


1. Rebif® is not approved by the US Food and Drug Administration for use in the United States.

© 2000 Millennium Medical Communications, Inc.

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