From Medscape Neurology & Neurosurgery
New Perspectives in Multiple Sclerosis: An Expert Interview With Mark S. Freedman, HBSc, MSc, MD
The 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) was held from September 27 to 30, 2006 in Madrid, Spain. During this meeting, new information about the diagnosis and management of multiple sclerosis (MS) was presented. Marni Kelman, MSc, Medscape Neurology & Neurosurgery Editorial Director, discussed results presented at this year's meeting and their implications with Mark S. Freedman, HBSc, MSc, MD, Professor of Neurology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Medscape: In your opinion, what were the most important research findings presented at this year's meeting?
Dr. Freedman: One topic that received a lot of emphasis is what we call gray matter disease. Multiple sclerosis has long been known as a white matter disease, but that's only because we've been missing a lot of what goes on in the gray matter. Gray matter is concentrated in 2 areas -- the cortex and in the deeper areas referred to as the "deep gray matter" or basal ganglia -- and is made up mostly of neurons. White matter represents most of the connecting myelinated tracts coming from the gray matter structures, but there are white matter projections right up into the gray matter that have been hard to see on imaging studies, but are easily seen pathologically. Now we've got some confirmation about this, by looking at both pathology and high-resolution MRI images. There are now some startling MRI images taken with higher resolution MRI machines. One example of a study on this topic was by Calabrese and colleagues. They showed that cortical lesions appear early and are a relevant pathologic phenomenon that correlate with white matter pathology, disability, and the presence of oligoclonal IgG [immunoglobulinG] bands (IgGOB) in the CSF [cerebrospinal fluid]. Another study by Durastanti and colleagues investigated in more detail the differences between cortical and subcortical gray matter pathology in MS patients with high-field-strength MRI and healthy volunteers as a reference. They found some interesting differences between the cortical and basal ganglia gray matter, suggesting that the deep gray matter is affected differently from the cortical gray matter.
In addition, there was a whole session on spinal fluid, a topic that is dear to my heart, because we've been pushing spinal fluid analysis in patients with MS and trying to get people to pay attention to it more instead of just relying on imaging. So, I was glad to see an entire symposium devoted to looking at spinal fluid. One of the big questions is: Are these studies still useful and should we be doing them? Tintoré and colleagues evaluated whether the presence of oligoclonal bands adds additional risk to baseline MRI in predicting the conversion of clinically isolated syndromes (CIS) to clinically definite multiple sclerosis (CDMS) in more than 500 subjects from 1995 to the present date. They found that the risk of having a second relapse is almost 2-fold when the oligoclonal bands are positive in patients with low, medium, or high risk to CDMS on the basis of baseline MRI. I believe that a spinal fluid exam should be part of the work-up in most patients with CIS, not so much to rule in MS, but to rule out other entities, and to assess the risk of developing CDMS, which means that they will have a second episode over the ensuing years. A higher risk for CDMS usually will stir physicians into considering treatment at the CIS stage.
I thought that this study was useful because we published an article on an international consensus for CSF analysis in patients suspected of having MS, and this was soon established by the FDA [US Food and Drug Administration] as the way in which CSF should be examined in the United States. It's the only approved CSF test, yet Americans are still resistant to do this exam, probably stemming from a time when standards were not established and many labs were inconsistent in their reporting. There is still quite a bit that we can learn from studying the brain's "soup." It really helps because some CIS patients only have a few small lesions on their brains, and you say to yourself: "Shall I treat; should I not treat; what's the chance that they're going to convert; maybe I can wait?" The goal of treatment is to treat early when current medications have their greatest effect. However, you don't want to treat everybody at the CIS stage because some patients may not even have MS, or if they do, they might be on track for a mild (benign) type of illness. You do want to treat those who have the highest risk of going on and having more attacks. The study that I described by Tintoré and colleagues confirmed that you should consider that the patients they deem as "high-risk" really do have MS, and you might want to initiate therapy for them.
So, let me jump ahead to studies on current treatments. One interesting study investigated how long the effects of natalizumab might last after you discontinue it. O'Connor and colleagues determined the annualized relapse rate and the number of gadolinium-enhancing lesions over time following suspension of natalizumab dosing. They found that within 3 months the relapse rate went up. In fact, it went up every month after stopping the drug. In the group of patients in whom natalizumab was making a difference, within 3 months the relapse rate and the level of gadolinium activity matched what was observed in the placebo group in the second year of the study. Although the study authors correctly concluded that patients didn't rebound beyond the placebo/Avonex control relapse rate during the second year of the AFFIRM and SENTINEL studies, I think the important message is that after only a month or so after stopping natalizumab there were already signs that the treatment had not changed the underlying disease and it redeclared itself. To compare, other NIH [National Institute of Health] studies have shown that if you stop interferons the effect of treatment will last about 6 months before you start to see gadolinium-enhancing lesions reappearing.
Another interesting study with regard to current therapies is by Vollmer and colleagues on combining mitoxantrone and glatiramer acetate. The purpose of this study was to determine whether short-term induction of immunosuppression with mitoxantrone accelerates the onset and enhances the efficacy of long-term treatment with glatiramer acetate. The end result of the combination was pretty good; the group that received upfront dosing of mitoxantrone had a marked reduction in the number of enhancing lesions after the end of the study and outward to at least 2 years. This short-term induction almost produced a 90% reduction in MRI activity that was sustained well to the end of the study, which went as far as 15 months. Unfortunately, what is missing from this study is a third arm with mitoxantrone alone to compare with the other 2 groups in order to know whether mitoxantrone in the absence of further treatment with glatiramer acetate would fare the same. However, this shows that people are starting to think about combining medicines.
Medscape: Were there other findings that you think are important to mention?
Dr. Freedman: Yes. I couldn't believe the number of presentations at this meeting that dealt with neutralizing antibodies. For example, we conducted a study that described 5 patients with high-titer neutralizing antibodies who had relapsing-remitting MS and were experiencing disease breakthrough after a relatively stable period of disease control on standard high-dose IFN-beta [interferon-beta] therapy. Patients were taking standard doses of interferon beta-1a 44 mcg [micrograms] 3 times a week or interferon beta-1b 250 mcg every other day. Neutralizing antibodies were assessed with both the CPE assay (S. Grossberg, Milwaukee, Wisconsin) and the MX protein assay (LabCorp, San Leandro, California). Each patient was given the opportunity to take a double dose of interferon beta-1b (500 mcg) every other day. The rationale for this change was that a higher dose would induce tolerance, similar to what was seen with Rebif when you looked at the difference between 22 and 44 mcg 3 times a week; in that case, the 44-mcg higher dose had a lower incidence of neutralizing antibodies. The other rationale is that in some patients, even current high doses of IFN-beta are not high enough to fully control their disease. What we observed was that in just about every case, we were able to drive the antibody level down with a switch to double-dose IFN-beta therapy; however, that depended on which lab you used. Clearly, these different laboratory methods do not correlate, despite the claims by many that they do. The second point was that in many cases, we were able to see a positive response to the higher dose IFN-beta, in that it was controlling the disease, but still there were others that continued to break through with new attacks. That leads to the third important point that we observed, which was that patients who are breaking through with new disease activity do so despite high or low neutralizing antibodies and may be in need of something beyond IFN-beta treatment. So, a nonresponder with high neutralizing antibody activity is probably not a nonresponder because of the neutralizing antibodies but is a nonresponder because the disease is evolving beyond the ability of first-line treatments to contain it. In other words, high-neutralizing-antibody titers do not necessarily correlate with a poor response to treatment.
Another interesting study by Grossberg and colleagues assessed the distribution and frequency of neutralizing antibody levels in more than 2700 unselected, treated MS patients across all Canadian provinces over 3 years. Seven hundred forty patients who were tested had detectable neutralizing antibodies; the distribution according to treatment was as follows: Avonex, 9.8%; Rebif, 34%; and Betaseron, 25%. These results are very different from what was reported by the companies.
The last study that I would like to describe on the topic of neutralizing antibodies is by Goodin and colleagues. The rates of neutralizing antibody-positive titers were investigated in 6698 patients in North America, Europe, and Australia receiving IFNB-1b [interferon beta-1b]. In North America and Europe, patients were largely selected for testing because of a poor clinical response according to the treating physician, suspecting neutralizing antibodies as the cause of this poor response. In contrast, testing is mandatory in Australia because you cannot get reimbursement for your interferon unless you are shown to be negative for neutralizing antibodies at 1 year and 2 years. So, all patients in Australia must be tested, and it has nothing to do with whether they're perceived to be doing well or not; it has only to do with whether they're on interferon and whether they want to stay on interferon.
If you thought that neutralizing antibodies were responsible for breakthrough disease, which group do you think would have the highest titers and which group would have the highest incidence of neutralizing antibodies? You would think the group from Europe and North America; however, completely the opposite was observed. Neutralizing antibodies were found in 37% of Australians vs 21.3% in North Americans and 27.6% in Europeans (P < 10-11 for both comparisons). This P value is certainly the largest that I've ever seen reported in a clinical trial. Morever, that difference was significant at every titer of neutralizing antibody measured. So how could that possibly be? They went through a series of possible explanations for such an outstanding result and seemed to be able to explain away all of these. If anything, all of the things that you would think of would still have favored the Australian group to have lower titers and a lower incidence of neutralizing antibodies, but the opposite was true. So, the question here remains: Do neutralizing antibodies matter? If so, then how can you explain this overwhelming finding that suggests otherwise?
Medscape: While we are on the topic of neutralizing antibodies, can you please comment on the phase 3b study that compared the antigenicity and tolerability profile of the new Rebif formulation ?
Dr. Freedman: If in fact neutralizing antibodies are important, then the new Rebif formulation that was designed to not only reduce some of the injection-site reactions and problems concerning pain, but also to reduce the immunogenicity of the drug, may be beneficial. Giovannoni and colleagues presented results comparing the antigenicity and tolerability of the new formulation with historical data on the current formulation. In total, 2.7% of patients taking the new formulation were positive for neutralizing antibodies at 24 weeks compared with 15.1% of patients with the current formulation at the same time point on the basis of historical data. So, these results showed that the company was successful at formulating a new type of drug that's better tolerated. They are now going to look at efficacy to ensure that although they've altered properties of the formulation to make it better tolerated, it doesn't lose anything in terms of efficacy.
Medscape: What about data presented on new drugs in development?
Dr. Freedman: The one drug that everybody talked about and that had a lot of data and interest is FTY720, the oral sphingosine 1-phosphate receptor modulator that is now called fingolimod. Kappos and colleagues and Radue and colleagues showed that the 12-month data from the phase 2 trial are the same as the 6-month data, and that there's a very prolonged effect of reducing relapses and MRI activity. The startling thing was that the phase 2 trial was completely underpowered to look at a clinical effect, yet it showed a very dramatic clinical effect of reducing relapses, and a very potent effect on MRIs. Some scientific data suggested that the drug can cross into the brain, and actually generate the kind of signals that may be necessary for repair and maintenance of myelin through the recruitment or survival of oligodendrocytes. One agent that can do both would be a magical agent for the treatment of MS disease. Of course, it first needs to be shown to be safe as well as effective in a proper longer term phase 3 trial, which is now under way. Nevertheless, these early safety studies are very supportive and encouraging.
One other oral therapy that was curious is the novel agent called oral fumarate, deemed BG00012 by the company developing it. This agent evolves from the psoriasis world where it has been tested for some time.
Kappos and colleagues did a standard 24-week study in patients who had early disease; they had to have at least 1 attack in the last year, and at least 1 or more enhancing lesions. They tested placebo and 3 different drug levels: 120 mg once a day, 120 mg 3 times a day, or 240 mg 3 times a day. Then, all patients received BG00012 during a 24-week dose-blinded safety-extension period. Patients had a 69% reduction in the total number of gadolinium-enhancing lesions at weeks 12-24 and a reduction in the number of new and enlarging T2-hyperintense and T1-hypointense lesions. The largest effect was seen with the 240-mg 3 times a day dose. It appears that these results are encouraging enough to proceed into phase 3 testing.
Therefore, BG00012, teriflunomide, fingolimod, and cladribine are now in phase 3 trials. This means that we now have 4 oral therapies in phase 3 trials, so potentially by the end of this first decade of the millennium, we may have a number of oral therapies for MS, if they all prove to be successful.
Medscape: You presented a talk entitled "Treat Early, Treat Right, Optimizing MS Therapy." Can you please summarize some of the key points discussed and their implications for clinical practice?
Dr. Freedman: As I alluded to at the beginning with the discussion about CSF testing, it is important to ascertain the true "risk" for a patient developing active disease after CIS in order to take advantage of this early-warning sign of MS and initiate treatment.
I think the point of making an early diagnosis is so that you can judge which patients you think need to be treated now as opposed to those you might want to wait to treat for 6 months or a year. There was nothing presented at this meeting that certainly refuted what I'm about to tell you. Essentially, you can identify patients who are at higher risk of early attacks and progression. Those with higher risk are usually people who present with more silent disease; when you do that first MRI, you see lots of evidence that they've had disease beforehand, or if they present with optic neuritis and you examine them, you find evidence that they've actually got more ongoing than just optic neuritis. If the person's attack actually shows dissemination in space, if there's evidence that there has to be more than 1 lesion in the nervous system to account for not only all the patient's symptoms, but all the patient's signs, then that fact itself (termed a "multifocal" attack) carries the highest risk of having another attack in the next 2 years. This was actually shown in the BENEFIT study by looking at patients who presented with a monofocal or multifocal first attack of CIS and looking at what further information could be gained from looking at their MRI studies. For patients presenting with a monofocal first attack, having more T2 lesions or at least 1 enhancing lesion on their MRI conferred a nearly double risk of having another clinical attack within 2 years. However, patients presenting with a multifocal attack had the same risk for further attacks in 2 years regardless of what was seen on their MRI.
There were other features about CIS patients to consider, and these include being CSF-positive for oligoclonal bands as well as being younger (age < 30). Because you can identify patients who have a much higher risk of going on to develop second attacks and maybe even worsening disease earlier than others, those are the patients who probably needed treatment yesterday. So if you don't want to treat everyone, at least treat these individuals. Although it's often said that if you delay therapy you can still get a response when you initiate it, the patients never do as well as those who started out earlier. In essence, what you lose by delaying therapy, you never regain. To steal a phrase from our stroke colleagues, "time is brain," although our time scale is measured in months to years vs seconds to minutes.
Medscape: An important consideration for MS patients is the balance between the benefits of treatment and the risks. Can you provide some insight into your thoughts on this topic?
Dr. Freedman: Well, I presented another talk on benefits and risks, and in that presentation we compared benefits and risks among the first-line agents. In general, the risks are very low for interferons and glatiramer and the benefits relatively high; therefore, the benefit:risk ratio is relatively high. All of the agents act to stave off progression, likely via reducing relapses and MRI activity. The cost for doing that in terms of patient side effects is extremely low. On the other hand, when you look at the benefit for a drug such as natalizumab, or for mitoxantrone, the risks are much higher. With natalizumab, you get about the same absolute reduction in relapse rate, disease progression, or even MRI activity, but now you need to consider a whole new set of potential side effects by dealing with the risk of getting PML [progressive multifocal leukoencephalopathy]. The risk is a stated 1:1000 in 2 years, but you also need to consider what the lifetime risk will be. So theoretically, if you were treated for 4 years, that would be a risk of 2:1000; that's a 1:500 risk, and that risk just keeps getting higher the longer you treat. The question is whether you want to treat people with natalizumab for a long time. In terms of mitoxantrone, you can only use it for 2 years. With mitoxantrone, the risk for leukemia would be about the same, 1:1000 in around 2-3 years. Leukemia is at least "the devil we know," and we can treat it. With PML, once you get PML there is little that anyone can do for this condition.
Medscape: What are some of the largest outstanding challenges in the treatment of MS that need to be addressed in the future?
Dr. Freedman: There's a general belief that we're lacking in not only clinical trials to help us see repair or regenerative capacity, but in agents capable of doing so. The challenge is going to be to design clinical trials and methodologies that will allow us to test agents, see the ability of treatments to bolster the person's own endogenous ability to repair, and to investigate agents that we think act to stimulate repair.
In that regard, one of the up and coming technologies is something called OCT, optical coherence tomography. There were several posters and presentations on this topic; one was by my own group (Costello and colleagues), in which we're looking at OCT as a possible window to examine the integrity of axons in the brain by looking at the retina. In a nutshell, this is a fancy ultrasound that uses infrared technology, and it can measure the thickness of the retinal nerve fiber layer, made up exclusively of unmyelinated axons. So the real question is this: Will measuring the thickness of the nerve fiber layer, which is sort of a surrogate marker for axonal density, be indicative of what's going on in the brain? Theoretically, if you can make the axons look better in the eye, maybe they'll look better in the brain.
Calabrese M, Bernardi V, Atzori M, et al. Cortical lesions appear early, are frequent and clinically relevant in multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 9.
Durastanti V, Pellegrini S, Ostuni J, et al. Grey matter disease in patients with multiple sclerosis imaged at high field: correlation between cortical and subcrotical pathology. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 189.
Tintoré M, Pelayo R, Rovira Á, et al. Do oligoclonal bands add information to baseline MRI in first attacks of multiple sclerosis? Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 74.
Freedman MS, Thompson EJ, Deisenhammer F, et al. Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol. 2005;62:865-870.
O'Connor PW, Goodman A, Kappos L, et al. Sandrock for the AFFIRM and SENTINEL Investigators. Results of clinical and magnetic resonance imaging analyses following cessation of natalizumab dosing in patients with multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 84.
Vollmer T, Panitch H, Freedman MS, Gasda SK, Bar-Or A, Arnold DL. Short-term induction with mitoxantrone preceding treatment with glatiramer acetate offers early and pronounced effects on MRI-disease activity in patients with relapsing forms of multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 62.
Soucy N, Cardinal K, Theoret G, MacLean H, Freedman MS. Double dose interferon-beta-1b (500 mcg) re-establishes efficacy and lowers neutralising antibodies in patients with breakthrough of multiple sclerosis disease on standard high-dose interferon-beta therapy. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 679.
Francis GS, Rice GPA, Alsop JC; PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology. 2005;65:48-55.
Grossberg SE, Gehshan A, Long C, Chuppa SL, Nicholson K, Grossberg LD. Interferon-beta neutralising antibodies in Canadian multiple sclerosis patients treated with different interferon-beta products. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 726.
Goodin DS, Noronha A, Hurwitz BJ. Neutralising antibodies to interferon-beta-1b have no impact on clinical response in multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 719.
Giovannoni G, Barbarash OL, Jaber A, et al; RNF Study Group. Reduced immunogenicity with a new formulation of interferon-beta-1a (Rebif): 24-week results of a phase IIIb study. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 675.
Kappos L, Antel JP, Comi G, et al; FTY720D2201 Study Group. Oral fingolimod (FTY720) in relapsing multiple sclerosis: 24-month results of the phase II study. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 376.
Radue E-W, O'Connor P, Antel JP, et al;FTY720D2201 Study Group. Oral fingolimod (FTY720) in relapsing multiple sclerosis: MRI results of a placebo-controlled phase II study and active drug extension. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 377.
Kappos L, Miller DH, MacManus DG, et al. BG00012, a novel oral fumarate, is effective in patients with relapsing-remitting multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 325.
Costello F, Eggenberger E, Demeulemeester C, et al. Comparison of retinal nerve fibre layer measurements and visual function among patients with multiple sclerosis. Program and abstracts of the 22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis; September 27-30, 2006; Madrid, Spain. Abstract 349.
Supported by an independent educational grant from Serono/Pfizer
Mark S. Freedman, HBSc, MSc, MD, Professor of Neurology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
Disclosure: Marni Kelman, MSc, has disclosed no relevant financial relationships.
Disclosure: Mark S. Freedman, HBSc, MSc, MD, has disclosed that he has received grants for clinical research and educational activities from Serono Canada. Dr. Freedman has also disclosed that he has served as an advisor or consultant to, and that he has received honoraria from, Bayer, Berlex, Pfizer, Serono Canada, Novartis, and Teva.
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