Conference Coverage of 54th Annual Meeting of the American Academy of Neurology
Mark S. Freedman, MD
Professor of Neurology, University of Ottawa, Canada, and Director, Multiple Sclerosis Clinic, Ottawa Hospital, Canada
This year's AAN meeting was packed with new and updated information concerning the management of multiple sclerosis (MS). The following review touches on some of the more important highlights regarding advances in treatment, including several promising future approaches, as well as some advances in scientific research.
Long Awaited: Direct Comparisons of Available Interferons
Currently, 4 disease-modifying or immunomodulatory treatments have been approved: 3 interferons (IFN) and glatiramer acetate (GA). Each agent has demonstrated evidence of efficacy against placebo; but with 3 different IFNs to choose from, physicians and patients have been anxious to see results of direct comparative studies of the drugs. For this reason, one of the most important and eagerly awaited presentations was the report of a 48-week study comparing IFN-beta-1a, 30 mcg intramuscularly once weekly, with 44 mcg subcutaneously thrice weekly. Known as the European-North American Comparative Efficacy (EVIDENCE) study, this head-to-head single blinded trial involving some 677 patients was originally designed as a 24-week study, which demonstrated that higher, more frequent doses of IFN-beta-1a were superior. Because of concerns that these results would not be sustained in the long term, the study was extended to 48 weeks. The results of the 48-week study verified the earlier outcomes.
The primary outcome measure -- the proportion of patients who were relapse-free -- was 62% in the higher, more frequent-dose group vs 52% in the lower-dose group (P = .009). Those in the higher-dose group were 18% to 19% more likely to be free of relapses, with a 30% lower risk of experiencing a relapse during the 48-week period.
The 48-week MRI results were also similar to those at 24 weeks, with nearly 40% less MRI activity in the higher, more-frequent-dose group (1.8 active T2 lesions/patient/scan in the higher-dose group vs 2.9 in the lower-dose group, P < .001). These significant differences held true even when accounting for the presence of higher neutralizing antibodies (nearly 25%, higher titer only) in the higher-dose group, levels that were more elevated than previously reported in other studies (approximately 15%).
Similar results of high-dose vs low-dose therapies were presented by Italian researchers. The Independent Comparison of Interferon (INCOMIN) study compared IFN-beta 1b 250 mcg subcutaneously every other day with IFN-beta-1a 30 mcg intramuscularly once weekly. The proportion of patients free of relapse was 51% in the IFN-beta-1b group vs 36% in the IFN-beta-1a group (P = .036), a 42% higher probability of being free of relapse. In addition, the mean annualized relapse rate was lower in the IFN-beta-1b (0.47) than in the IFN-beta-1a group (0.73) (P < .03). A relative risk reduction of nearly 56% in expanded disability status scale (EDSS) progression was seen in the IFN-beta-1b group; 14% of patients in the IFN-beta-1b group worsened compared with 30% in the IFN-beta-1a group (P = .005).
This study was weakened because clinical measures were only singly blinded. Analysis of MRI data was double-blinded, however, and nearly 55% of IFN-beta-1b-treated patients were free of new T2 lesions over 24 months, compared with 26% in the IFN-beta-1a group (P < .0003). T2 lesion burden was reduced by 2.8% in the IFN-beta-1b group, but rose by 11.7% in the IFN-beta-1a group (P < .0001). The relative difference observed between the 2 treatments actually increased with time, being higher in the second year of treatment compared with the first.
Taken together, these direct comparative studies demonstrate clearly that higher, more frequent doses (3 or more per week) of IFN-beta yield better results compared with low doses given infrequently (once weekly).
"When Can I Stop All Those Shots?"
The same Italian group, led by Dr. Luca Durelli of the University of Turin, Italy, conducted another study to address the questions that come up so frequently when a patient appears to be doing well with high, frequent-dose IFN: "Doctor, do I really need to keep taking all these injections?" "If my MRIs look good and I haven't had a relapse in a couple of years, how about at least reducing the dose so that I don't get so many skin reactions?"
To address these issues, Dr. Durelli performed a prospective 1-year follow-up study of 27 relapsing remitting multiple sclerosis (RRMS) patients with low-grade disease (EDSS 1-3.5) who were randomized to either gradually switch from alternate-day IFN-beta-1b to once-weekly IFN-beta-1a (n = 13), or to continue IFN-beta-1b (n = 14) as before. Strikingly different from most previous studies, which required patients to have fairly active disease (eg, 2 attacks in 2 years), this inclusion cohort had to have received IFN-beta-1b for at least 3 years, and was required to be stable, with no clinical disease activity in the previous 2 years or MRI activity in the previous year.
There were no baseline differences between these groups. At the 1-year follow-up investigators found a substantially higher relapse rate (0.9 vs 0.2; P = .04), a lower number who were relapse-free (3/13 [23%] vs 11/14 [79%]; P = .006), and a higher number of patients with sustained EDSS worsening (3/13 [23%] vs 0/14, P = NS) for patients switching to IFN-beta-1a than for those continuing IFN-beta-1b. Similarly, 85% of the group that switched to IFN-beta-1a demonstrated MRI activity compared with only 36% (P = .03) of those who continued on IFN-beta-1b, and the T2 lesion load was higher (+6.7% compared with baseline, P = .002) in the switched group relative to a net reduction (-0.9% compared with baseline) in patients continuing IFN-beta-1b therapy.
These results strongly suggest that patients responding to higher, more frequent-dose IFN therapy should remain on this regimen. The other very important (but also subtler) message from this study is that a period of observed "stability" is no guarantee that it will continue. This means that patients with MS cannot be taken for granted and require close follow-up even when seemingly responding well to disease-modifying drugs.
IFN Plus Glatiramer Acetate
Other studies[5,6] examined the benefit of combining medications with an IFN to perhaps address the concern of patients who have more rapidly advancing disease or those seeming not to respond to IFN alone. Fred Lublin, from the Mount Sinai School of Medicine, New York, NY, reported the results of a multicenter study of the longer-term safety of combining GA with IFN-beta-1a. This was a 6-month extension of a 6-month study to assess the safety of the GA/IFN combination. Previously, some had wondered whether GA might block the action of IFN. At 12 months, investigators found no increase in MRI activity (which would have suggested that GA was interfering with the action of IFN) and no new safety issues, prompting a call for a properly controlled study to look at improved efficacy of the combination over either agent alone.
Although both drugs seem compatible when given simultaneously, this author wonders about the rationale for doing so, given 2 perhaps nonmiscible mechanisms of action. Given that IFN-beta-1a probably acts to reduce lymphocyte trafficking into the CNS, and GA is proposed to stimulate the production of special regulatory cells in the periphery that need to get to the CNS to function, it would seem that administering these 2 agents together would be counterproductive -- the IFN may well block the penetration of the GA-stimulated cells.
Just which cells these are was called into question with some exciting work on the immunologic front by Mike Racke, of the University of Texas Southwestern in Dallas. He presented his recently published data showing that GA might not operate as hypothesized, through altering the function of CD4+ cells, but rather through the restoration of a proliferative defect in MS CD8+ regulatory cells.
IFN Plus Azathioprine
In another combination study reported from the National Institutes of Health (NIH), along with a similar one from the Czech Republic, IFN-beta-1a was combined with an old but gentle chemotherapeutic agent, azathioprine (AZA). The NIH group studied 6 RRMS patients taking IFN-beta-1b for 3-35 months who nonetheless continued to develop a very high number of enhancing lesions on MRI and experienced a high yearly exacerbation rate (1.69), and therefore were deemed to be having a suboptimal IFN response. They found that adding AZA led to a significant reduction in MRI activity compared with the prior period of IFN therapy alone. A modest reduction in relapse rate was also seen in 4 of the patients.
The Czech study was an interim analysis that looked at adding 50 mg a day of AZA, with or without alternate days of prednisone (10 mg), to IFN-beta-1a 30 mcg once weekly. Though the study is ongoing and still blinded, the researchers have found a much higher relapse rate reduction overall (up to 72% by 2 years) than has ever been reported in any trial of IFN alone. These studies do suggest that we haven't heard the end of AZA as a potential treatment for MS, especially in combination with IFN.
Though we still await the publication of the largest study using the chemotherapeutic agent mitoxantrone (MX), many presentations at the Academy meeting examined the use of this agent in several phases of disease. In particular, it was of interest to see that some neurologists are using MX to transform IFN nonresponders into responders. Doug Jeffrey and colleagues from Wake Forest University in Winston-Salem, North Carolina, were able to reduce the appearance of new enhancing MRI lesions by 81% with the addition of MX to neutralizing antibody-negative patients found to have high MRI activity despite receiving IFN-beta-1b.
A French group led by Gilles Edan looked at induction therapy with MX followed by routine administration of disease-modifying agents. Although the number of patients was small, the reduction in disease activity was so dramatically reduced by MX alone that maintenance therapy with either IFN-beta-1a or GA following MX induction kept most disease activity to a bare minimum. This would seem a reasonable approach to take with patients who have demonstrated more aggressive disease at the start, but the potential toxicity of MX still raises questions as to whether it could be used for all patients with RRMS. A US registry called RENEW (Registry to Evaluate Mitoxantrone Effects in Worsening MS) has now been set up to follow at least 500 patients receiving treatment with MX for worsening disease.
Autologous Bone Marrow Transplants
The most intensive treatment of MS to date involves various degrees of immunoablation and restoration of the immune system using autologous bone marrow-derived stem cells. Dr. George Kraft presented the data from his Seattle, Washington-based group that enrolled 26 patients (median age, 41 years) with severe MS, including 8 with primary progressive MS (PPMS), 16 with secondary progressive MS (SPMS), and 1 with RRMS. Their median EDSS was 7.0 (range, 5.0-8.0). Most (24) had failed single or multiple previous therapies with immunomodulatory or immunosuppressive agents. Participants received high-dose immunosuppressive therapy followed by autologous stem cell transplantation. The median follow-up was 12 (range, 3-36) months.
With this treatment, 9 patients remained neurologically stable, 6 actually improved (including 3 patients with PPMS), but 10 deteriorated, using the definition of an EDSS 0.5-point change. Two patients with enhancing lesions on MRI at baseline still had these at 1 year following the transplant, 1 of whom reportedly had a flare of MS associated with the administration of granulocyte colony-stimulating factor (G-CSF). Two others with no baseline enhancement developed enhancing lesions. One death was reported due to a rare complication of Epstein-Barr virus infection believed to be due to use of rabbit-derived antithymocyte globulin.
Together with European researchers, who have also performed similar treatments on patients with advanced disease, Kraft's group agreed that this therapy needs to be given earlier in the course of disease when patients are less disabled. This is precisely the cohort targeted by the Canadian MS BMT Study Group, who reported on the safety of their regimen with data from the first 4 of their patients. Because of reported exacerbations using the stem-cell mobilizer G-CSF (as was seen in the Seattle-based study) the University of Ottawa researchers used cyclophosphamide alongside this agent and noted no exacerbation of either clinical or MRI activity. Their longest follow-up was only 6 months, but their initial safety data were encouraging. They plan to treat 24 patients over the next 3 years.
Further results were reported using a new agent, a monoclonal antibody to the VLA-4 adhesion molecule, which is currently in testing by itself and in combination with once-weekly IFN-beta-1a. This agent was already reported to result in a significant reduction in relapses (50%) and MRI activity (90%) at 6 months of treatment, so it was of interest to observe what happened in the subsequent 6-month washout period. At the 9- and 12-month time points, nearly all the treatment effect had vanished with a return to placebo levels of active MRI lesions using either 3- or 6-mg/kg monthly infusions of the agent. A similar loss of relapse benefit was noted, but with a slightly higher relapse rate seen in the higher-dose group.
This agent presumably works by stemming the flow of lymphocyte traffic across the blood brain barrier. Given alone, it would appear that the cells capable of causing disease simply pile up and enter the brain upon drug cessation. This raises concern over a possible "rebound" effect when the drug is stopped, and speaks for the need to use a concurrent immunomodulatory agent, such as an IFN, to act upon potential disease-causing cells in the periphery.
One of the most intriguing possible future therapies for MS is the use of statin agents. Animal work by Scott Zamvil and colleagues from the University of California, San Francisco, and in vitro human work from a German and Austrian group demonstrated the possible mechanism of action of statins in animal models of disease (EAE) and in manipulating lymphocytes and cytokines. Atorvastatin, initiated at the onset of induction of chronic EAE, reversed paralysis and could ameliorate relapses in a relapsing EAE model. Dr. Zamvil's elegant work histologically examined the brains and spinal cords of treated animals, finding significant reductions in both the number of perivascular lesions and the extent of infiltration. He also showed that lymphocytes from atorvastatin-treated mice demonstrated decreased IFN-beta and increased interleukin (IL)-4 and IL-10 secretion, thus promoting a Th2 bias, thought to be protective of disease.
In vitro, various statins were added to lymphocytes obtained from untreated MS patients or those treated with IFN-beta-1b, and statin effects were seen on all cells regardless of their source: reduced expression of lymphocyte activation markers; increased production of IL-4 (ie, driving a protective Th2-type immunologic response); and downregulated expression of chemokine receptors on both B and T cells. In some cases, particularly the inhibitory effects of IFN-beta-1b, statins were additive, suggesting that they may be used either singly or as add-on therapy for MS.
These are mere tidbits of the nearly 170 abstracts and posters concerning MS presented at this year's AAN meeting. The ongoing efforts and seemingly ever-expanding research in this area should reassure the many patients suffering with this disease that headway is surely being made towards a better understanding of this condition and the development of effective treatments.
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