May 10, 2004
Multiple sclerosis (MS) is the most common cause of neurologic disability in young adults, and it exhibits significant clinical, radiologic, and pathologic heterogeneity. MS remains a complex disease to manage, and no curative therapy exists. Furthermore, much debate remains about what few, available treatments should be enlisted, as well as when and for how long. Some issues, such as neutralizing antibodies to interferon-beta, one of the mainstays of MS treatment, have emerged as a clinical controversy in the field. Scott Williams, Senior Editor, Medscape Neurology & Neurosurgery, interviewed Barry Singer, MD, Assistant Professor of Clinical Neurology at Washington University School of Medicine in St. Louis, Missouri, to discuss these and other important issues in the management of patients with MS, including new research presented at the 56th Annual Meeting of the American Academy of Neurology.
Medscape: For patients with newly diagnosed relapsing-remitting multiple sclerosis (MS), how do you choose the most appropriate treatment?
Dr. Singer: I determine the goals for therapy with each individual patient. Efficacy, in terms of reducing relapses, MRI lesions, and most importantly progression of disability, drives my decision-making process. Route of administration, dosing frequency, tolerability, and potential risks are secondary.
Medscape: What are the most pressing controversies or unresolved questions currently facing clinicians who treat patients with MS?
Dr. Singer: The most challenging problem I face with my patients is how to treat progressive disease. Interferons have been successful for patients with secondary progressive disease, but only when the patients are actively relapsing. Novantrone (mitoxantrone) is another option for secondary progressive disease. Of course, treatment for primary progressive disease is desperately needed. Data presented at this year's AAN Meeting showed no significant benefit from either Copaxone (glatiramer acetate) or Novantrone for patients with primary progressive MS. The focus for treatment development of progressive patients will likely have to shift from anti-inflammatory to neuroprotective therapies.
Medscape: The clinical significance of neutralizing antibodies to interferons in the context of MS treatment is obviously a controversial topic. How would you characterize the differing views of investigators in this area of research, and what implications does that have for the clinician specializing in MS?
Dr. Singer: The spectrum of views regarding neutralizing antibodies is extreme. Some MS specialists never check for antibodies and deem them irrelevant. Others insist that the development of neutralizing antibodies to interferon makes the agent as good as placebo. On the basis of data from the Prevention of Relapses and Disability by Interferon-beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial, the relapse rate over 4 years was not statistically different, whether patients were neutralizing-antibody-positive or -negative. The relapse rate was higher over the course of years 3-4 in the presence of neutralizing antibodies, but the difference disappeared at the end of year 4. At 64 weeks in the EVIDENCE trial, neutralizing-antibody-positive patients receiving subcutaneous Rebif (interferon-beta-1a) had more relapses and MRI activity than the neutralizing-antibody-negative patients receiving the same drug, but had fewer relapses and MRI activity than patients receiving Avonex (intramuscular interferon-beta-1a formulation). My initial selection of interferon is primarily based on overall efficacy rather than the risk of developing neutralizing antibodies. If a patient is doing poorly on interferon, I will check neutralizing antibody status to help determine the next treatment options.
Medscape: In your opinion, what were the most compelling data on neutralizing antibodies at AAN?
Dr. Singer: Only limited data were presented about neutralizing antibodies. Dr. Susan Goelz of Biogen Idec presented a poster of a study of 49 patients who were switched to Avonex after developing neutralizing antibody titers >/= 5 while on Betaseron (interferon-beta-1b). Of the 39 patients with initial titers of 5-99, 90% were neutralizing-antibody-negative at the end of 6 years. Of the 10 patients with titers >/= 100, 5 patients became neutralizing-antibody-negative at the end of 6 years. The median time to become neutralizing-antibody-negative was 6 months.
An open-label study from Torino, Italy, looked at the incidence of neutralizing antibodies and its effect on relapse rate and disability in 78 patients. The trial enrolled only 13 neutralizing-antibody-positive patients in total on Avonex, Betaseron, or Rebif 22 mcg 3 times weekly. Patients who were neutralizing-antibody-negative had a greater reduction in relapses as compared with neutralizing-antibody-positive patients. A higher percentage of neutralizing-antibody-positive patients vs neutralizing-antibody-negative had worsening of the Expanded Disability Status Scale (EDSS) of >/= 1 point over the course of 3 years.
Medscape: Although there is evidence that disease-modifying therapies reduce the relapse rate and are beneficial in the short term, what types of studies will need to be done to determine whether long-term disability related to MS is being reduced?
Dr. Singer: The pivotal trial using Avonex did demonstrate a 36% reduction in the progression of disability over 2 years as compared with placebo, but long-term data are lacking. The PRISMS 7-8 year follow-up data demonstrated the least disability progression in the group of patients randomized to the high-dose (44 mcg 3 times weekly) Rebif from the treatment onset. Although years 4-8 were open-label with retrospective data collection, the results are fairly compelling because 68% of all the patients receiving this formulation and 74% of the high-dose patients were included in the final analysis. The 3-year trial of Betaseron for relapsing-remitting MS did not show a significant reduction in disability, but the European trial of this agent for patients with secondary progressive disease did show significant benefit. Eight-year data on disability are being collected from the European study.
Copaxone did not provide a significant impact on confirmed disability in the pivotal 2-year clinical trial. Open-label results at 10 years showed lower disability in patients still receiving Copaxone monotherapy, but most patients were no longer on this regimen. A long-term trial of relapsing-remitting patients randomized blindly to placebo vs active drug to prove reduction of disability over a period of years is unlikely to occur at this point, primarily because placing patients on placebo for a period of years would be considered unethical.
Medscape: At AAN, there were long-term follow-up reports of patients treated with disease-modifying therapies. What did the longer-term data show in that regard?
Dr. Singer: The long-term PRISMS follow-up (7-8 years) showed strong beneficial effects of using high-dose Rebif (44 mcg 3 times weekly) from the onset. The increase in the burden of disease seen on T2 MRI for these patients was only 5.0%. Those patients initially placed on 22 mcg 3 times weekly or placebo demonstrated a 17.4% and 24.5% increase, respectively, on burden of disease. The 5-year CHAMPIONS Study showed a 47% reduction in relapse rate for patients who were begun on Avonex immediately after a monophasic demyelinating event. Only 36% of patients treated immediately developed clinically definite MS at 5 years in contrast to 49% in the delayed-treatment group. The 10-year open-label Copaxone trial demonstrated less disability in 108 patients receiving ongoing Copaxone monotherapy than the 47 patients who withdrew from the study and were reached for long-term follow-up. An additional 77 patients withdrew, but long-term follow-up was not available. More disability in the withdrawal group may reflect treatment failure since 29% of patients withdrew to switch or combine therapies and 26% withdrew because the patient was perceived as clinically worsening. From the original EUSPMS trial of 718 patients, 222 entered a long-term follow-up study ongoing to 8 years. Preliminary data indicate less disability in the cohort of patients who initially received Betaseron instead of placebo.
Medscape: What are your insights about data at AAN concerning experimental immunomodulatory therapies, such as daclizumab and laquinimod, and the potential therapeutic benefit of supplements, such as alpha-lipoic acid?
Zenapax (daclizumab) is a monoclonal antibody specific for the interleukin-2 receptor that inhibits lymphocyte activation. In an open-label trial of 20 patients, 10 patients had a reduction in disability, 9 patients had stable disability, and 1 dropped out because of paresthesias. The percentage of active MRI scans decreased significantly from 39% to 13% with treatment. This monthly infusion therapy seems very promising, but double-blind trials will be needed.
Laquinimod, an oral immunomodulatory agent, demonstrated a 44% reduction in the mean number of cumulative active MRI lesions. However, the result only had marginal statistical significance (P = .0498) despite triple-dose gadolinium administration. As a previous Linomide (roquinimex) clinical trial investigator, I have concerns about the similarities of laquinimod to Linomide because cases of myocardial infarctions occurred in MS patients on Linomide.
Finally, the antioxidant alpha-lipoic acid was given orally to 29 patients for 14 days. Levels of serum matrix metalloproteinase-9 were reduced, which might inhibit migration of activated autoreactive T cells in the brain. The results are interesting, but more clinical parameters, such as MRI, will need to be studied to assess therapeutic benefit.
Disclosure: Barry A. Singer, MD, has disclosed that he has received grants for clinical research from Pfizer/Serono as well as served as an advisor or consultant for Pfizer/Serono, Biogen, and Teva Neuroscience. Dr. Singer has reported that he does not discuss any investigational or unlabeled uses of commercial products in this activity.
Disclosure: Scott Williams has no significant financial interests
or relationships to disclose.
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