Introduction

William H. Stuart, MD, Medical Director, MS Center of Atlanta

Carefully designed randomized trials have now been completed in which all patterns exclusive of primary progressive MS have been responsive to immunomodulatory treatment. Primary progressive MS is an uncommon pattern that may have a different mix of pathology from the more common patterns of MS. Clinical trials are currently in process regarding treatment in this pattern. Dr. Jeff Cohen has reported on this recent trial in secondary progressive MS using interferon beta-1a (Avonex, Biogen Inc.), 60 µg intramuscularly once a week, with statistically significant results in the three principal outcome measures: the progression of disability as determined by the MS functional composite outcome measure, magnetic resonance imaging, and relapse rates. Interferon beta-1a was well tolerated by the study patients.

It is a time-consuming effort for both patients and neurologists to engage in long-term treatment with immunomodulatory drugs for MS. The start-up issues are not an easy undertaking. Office overhead issues and patient compliance monitoring can present formidable obstacles to this effort. It is, however, personally rewarding to the patient and the neurologist when these drugs are used and success is realized. Interferon beta-1a given once a week can become the "foundation" treatment of a more complex multidrug regimen. The regimens currently under study can allow greater degrees of control of this progressive illness. It should be remembered that percentage changes in clinical trials, even at 2 and 3 years, do not always reflect the benefits of these drugs. Many patients realize improved quality of life within a disability scale, and these percentage changes do not always reflect time to disability when plotted on a life scale.

The "dismal" failure of the "MS community," both patients and neurologists, to recognize this is reflected in another presentation by Dr. Larry Jacobs. Dr. Jacobs summarized a Harris Interactive poll on immunomodulatory usage and compliance. It is clear from this poll that the rapidly accumulating information regarding MS pathology and its clinical course, as well as the results of clinical trials during early treatment, have not yet filtered down to the predominant number of neurologists and patients making treatment decisions. Furthermore, most patients rely heavily on their physicians for advice regarding treatment decisions, rather than self-analysis of available drug data, as is too commonly employed. The solution seems obvious. It is now time to begin a major patient and physician education effort. With this effort, hopefully we can move on to the more important task at hand, which is finding newer and better treatment modalities and combinations.

Secondary Progressive MS

Treatment with interferon beta-1a (Avonex), 60 µg intramuscularly once a week, was effective in slowing the progression of disability by 40.4% as determined by the MS functional composite (MSFC) outcome measure, reducing the relapse rate by a mean of 33% and magnetic resonance imaging (MRI) disease-related activity in patients with secondary progressive MS (SPMS), according to results of a phase III multicenter, randomized, placebo-controlled, double-blind trial. Although previous trials have shown that interferon beta-1a slows the progression of disability, reduces relapse rate, and suppresses MRI activity in relapsing-remitting MS (RRMS), an earlier form of the disease, this study is one of the first to show a benefit for disease-modifying therapy in SPMS.

"Previous studies of other interferon beta preparations have yielded conflicting results in SPMS," said Jeffrey A. Cohen, MD, The Cleveland Clinic Foundation, The Mellen Center, Cleveland. "This study shows that Avonex had a significant effect on the primary end point, as well as on measures of quality of life, patient perception of benefit, and MRI parameters in SPMS."

The study included 436 subjects with active disease over the previous 12 months. Patients' ages ranged from 18 to 60 years, and baseline EDSS was 3.5 to 6.5. Patients were randomized to receive treatment with either interferon beta-1a (Avonex) 60 µg or placebo by weekly injection. Progression of disability from baseline to 24 months was assessed using the MSFC, a new instrument that includes a measure of leg function (time to walk 25 feet), arm function and coordination (9-hole peg test), and cognition (Paced Auditory Serial Addition Test [PASAT]), while the EDSS measures primarily lower-limb function and ambulation.

"Interestingly, no benefit was seen on measures of ambulation for Avonex in this study [i.e., the EDSS and the time to walk 25 feet test]," Dr. Cohen told listeners. "The benefit seen on the MSFC was driven primarily by the 9-hole peg test and the PASAT results, which are not measures of ambulation," he emphasized.

At baseline, the two treatment groups were well matched for demographic, clinical, and disease characteristics, as well as MRI findings. At 2 years, the mean reduction in MS progression, as measured by the change in z scores on the MSFC components, was 27% in the group receiving interferon beta-1a (Avonex) compared with placebo. The median reduction for these measures was 40% in the treated group.

No difference was found in subgroup analysis performed according to higher and lower EDSS scores, presence or absence of relapses during the study, and presence or absence of gadolinium-enhancing lesions on MRI scans.

Interferon beta-1a (Avonex) treatment achieved a statistically significant difference compared to placebo on eight of 11 scales of the MS Quality of Life Inventory (MSQLI), and a trend was observed in favor of Avonex on the other three scales. MRI data revealed highly statistically significant changes in favor of Avonex for the number of gadolinium-enhancing lesions and the number of new and enlarging T2 lesions compared with placebo (p < 0.001 for both). "These results support the benefit of treatment with interferon beta-1a in SPMS," said Dr. Cohen.

A similar number of patients discontinued the study treatment: 25 in the placebo group and 28 in the active treatment group. More patients discontinued treatment due to side effects in the active treatment group, while more patients in the placebo group discontinued treatment due to perceived worsening of disease. Avonex-treated patients had a very low incidence of positive neutralizing antibodies (3.3%) at 2 years.

"Therapy was well tolerated by these patients with SPMS, and the results validate the MSFC as a measure of disability. Short-term changes in the MSFC are highly predictive of the course of disease," said Dr. Cohen.

Survey of Neurologists and MS Patients

Despite the wealth of evidence supporting early treatment, results of two surveys of neurologists and patients reported at this meeting showed that only 42% of MS patients are currently being treated with interferon beta-1a (Avonex), interferon beta-1b (Betaseron, Berlex Laboratories), or glatiramer acetate (Copaxone, Teva Neuroscience), the three drugs currently approved for relapsing forms of MS in the United States.

The Harris Interactive pollsters concluded that a major obstacle to moving patients onto treatment is the lack of awareness among both physicians and patients about treatment options and potential benefits. The obstacle to beneficial treatment may have its foundation in surprising data revealed by the Harris survey. Nearly 40% of patients with MS have hidden the fact that they have the disease, 50% are afraid to be socially excluded, and more than half are worried about losing their job. Understandably, the patients' self-perceptions and hesitancy to discuss their disease must be addressed before beneficial treatment can begin.

Both surveys included questions related to the clinical and social aspects of MS. One was conducted with a nationally representative sample of 251 neurologists who treat patients with MS, and the other was conducted among 562 MS patients drawn from the Harris Interactive chronic illness panel who reported having either RRMS or SPMS.

Older patients and those diagnosed with MS at least 5 years ago were less likely to be taking these drugs compared with their younger, more recently diagnosed counterparts. The three most frequently cited reasons by patients for not being treated were not having experienced a relapse in a while (42%); drug reimbursement issues (32%); and the physician not believing the treatment would provide benefit (31%).

Studies have also shown that initiation of treatment in high-risk patients who have not yet developed clinically definite MS slows the progression of disease. Eighty-two percent of neurologists said that the ability to delay the onset of clinically definite MS after one demyelinating event is extremely or very important, but only 26% of neurologists reported beginning disease-modifying treatment at the first demyelinating event. This suggests that results of recent studies in high-risk patients have not yet filtered down to clinical practice. Overall, 92% of neurologists in the survey reported treating patients either at the first or second demyelinating event or at the time of diagnosis, which is more consistent with older evidence.

Regardless of when treatment is initiated, 81% of neurologists and 87% of MS patients believe that when treating the disease, it is more important to slow the overall progression of MS in terms of the accumulation of physical disability than it is to reduce the number and severity of relapses experienced each year.

Eighty-eight percent of patients who are being treated said that physician advice was extremely or very influential in their decision to start treatment. This suggests that physicians play an important role in encouraging patients to go on treatment with disease-modifying therapy and that more education of physicians and patients is needed about the evidence for early initiation of treatment.

More information about the survey can be obtained online at http://www.harrisinteractive.com/news/allnewsbydate.asp?NewsID=287.