Tuesday, October 31, 2006

Canadian Local Thought Leader Perspectives in Neurology & Neurosurgery

From Medscape Neurology & Neurosurgery

Editor's Note:
Multiple sclerosis (MS) is a chronic and often progressive inflammatory disorder of the central nervous system (CNS), and characterizing patient response to various treatments for this disease and monitoring its progression are key to patient management. Medical Editor Penelope Gray-Allan, on behalf of Medscape, discussed patient management and treatment approaches -- presented at the recent meeting of the American Academy of Neurology (AAN) -- with Mark S. Freedman, MD, Professor of Medicine (Neurology), at the University of Ottawa, in Ottawa, Ontario, Canada.

Medscape: What are the primary indicators to look for in a patient who is entering into a more progressive form of MS?

Dr. Freedman: Generally speaking, the disease is almost always progressing, but one of our primary concerns is to identify those patients before they experience rapid progression.

The primary indicators to look for include changes in physical exams, cognitive abilities, magnetic resonance images, and electrophysiology. Progression is usually indicated by relapses with a slower recovery time, a shorter time period between relapses, a reduction in the effectiveness of steroids in reducing the inflammation and leading to near complete recovery, loss of endurance, and greater difficulty doing the same tasks. A physical exam might show that there has been some accumulation of a deficit, and, if the Expanded Disability Status Scale (EDSS) is used, it will move in the absence of attacks. These indicators strongly suggest that the patient is entering into a progressive phase.

Medscape: There were a number of studies presented at the recent AAN annual meeting that looked at combination therapies, such as interferon (IFN) beta-1a and inosine,[1] IFN beta-1a and atorvastatin,[2] and IFN beta-1a and natalizumab.[3] Are these combinations showing greater promise for relapsing-remitting MS than IFN beta alone?

Dr. Freedman: Inosine and IFN beta-1a were combined in a small randomized, placebo-controlled study with 36 patients to determine the safety and tolerability of this combination as well as the effects on disease activity and progression.[1] The data suggested that this combination is safe and well tolerated with a low incidence of adverse events.

Atorvastatin is very interesting. In general, it has a different mechanism of action than IFN beta, which could complement the IFN beta activity and create synergy between the 2. However, atorvastatin requires very high doses in order to be effective, and one of its biggest side effects is hepatic problems. Side effects attributed to IFN also include liver complications, so when these therapies are combined, there may be more hepatic problems than anticipated. The other issue with high doses of statins is that they can cause muscle disease, which would be an unwanted obstacle for an individual who already has MS.

While the results of the natalizumab-IFN combination were very good,[3] 2 patients developed progressive multifocal leukoencephalopathy (PML), which is a fatal demyelinating disease of the CNS. Research is ongoing to determine the role of natalizumab but in the meantime, natalizumab has been removed from the marketplace.

There are many drugs that can potentially be added to IFN beta and to glatiramer acetate that might lead to synergy. But they're still all very much in the experimental testing phase, and no one has really been able to show definitively that combining drugs is more beneficial.

Medscape: Based on the available therapeutic agents, what do you consider to be the optimal treatment regimen for MS?

Dr. Freedman: That is a difficult question, because MS can manifest itself very differently in different people, and what may be optimal therapy for one person may not be optimal therapy for another. The clinician must tailor the treatment to the needs and the overall clinical picture of the individual patient, considering all aspects: treatment regimen, patient adherence, cost, and other complicating features, such as being realistic about the disease and the fact that the individual will need to use this medication on a regular basis.

In general, the high-dose IFNs do seem to offer more in terms of efficacy. Currently, there are ongoing studies comparing high-dose IFNs with glatiramer acetate. In 1.5-2 years, we'll know more about how they compare.

Medscape: What factors do you look for when assessing a patient for treatment failure?

Dr. Freedman: Treatment failure is so hard to define. There are very few physicians, when asked, who will define it in the same way. It seems better to define what to expect as a good response and easier to say that a patient didn't reach that optimal response. So, we prefer the term suboptimal response, which we define as a minimal amount of disease activity as determined by monitoring the relapse rate, neurologic progression, and magnetic resonance imaging (MRI) activity. Some breakthrough is normal and to be expected because the drugs are not curative.

As a member of the Canadian Multiple Sclerosis Working Group, we recently developed practical recommendations on how neurologists can assess the status of patients on disease-modifying therapies and decide when it may be necessary to modify treatment in order to optimize outcomes.[4] We fell short in that paper of actually identifying that critical number, but we provided an analog model of 3 gauges -- 1 for relapse, 1 for progression, and 1 for MRI activity. The model ranks outcomes as "low," "medium," or "high" in terms of levels of concern. If any 1 gauge reads "high," any 2 "medium," or all 3 "low," then it is likely that treatment response is suboptimal and that strategies to optimize treatment response need to be implemented. That's our hypothesis, but we need to validate it.

Medscape: At the 2005 AAN meeting, Harold Moses, MD,[5] presented results of a post hoc analysis comparing the efficacy of high-dose, high-frequency IFN beta-1a with low-dose, low-frequency IFN beta-1a among a small subgroup of patients from the EVIDENCE study. What were some of the highlights from that study?

Dr. Freedman: Physicians used to believe that patients with earlier disease might not need as much IFN. Clinicians thought that for patients with early MS, there might be a closer relationship between high-dose, high-frequency IFN beta-1a and low-dose, low-frequency IFN beta-1a, and that patients in later stages of MS might be in greater need of high-dose IFN. The study presented by Dr. Moses[5] compared IFN beta-1a 44 mcg 3 times weekly with IFN beta-1a 30 mcg once weekly, ie, 132 mcg vs 30 mcg per week, a dose that is more than 4 times greater than the low dose of IFN. There were approximately 70 early MS patients in each group. Over the entire comparative phase, 66.2% of patients who received the high dose and 53.7% of patients who received the low dose remained free from relapses. This result was not significant (P = .205). However, this favorable trend is consistent with the statistically significant results achieved during the comparative phase of the entire EVIDENCE cohort (P = .023). During the comparative phase, MRI scans showed that the mean number of T2-active lesions per patient per scan was significantly lower in the high-dose group, ie, .6 vs 1.7 in the low-dose group (P < .001).

Results from this study strongly suggest that patients in the early stages of disease do not get the full benefit of treatment if they receive low-dose IFN; there is still something to be gained by administering high-dose IFN. Remember, though, that this study was an ad hoc analysis, ie, it generates a hypothesis, but does not present proof.

Medscape: In a study you presented at the recent AAN meeting,[6] you applied treatment optimization recommendations (TOR) to the 4-year data from the PRISMS study to evaluate whether TOR disease status assessments, based on a combined evaluation of relapses and disease progression during years 1 and 2, can predict clinical outcomes during years 3-4. What were some of the highlights of that study?

Dr. Freedman: We took a database of patients who had been followed for 4 years in the PRISMS study and applied our treatment optimization recommendation tables in order to determine if we could accurately predict which of those patients would have progression or relapse. We knew that in the first 2 years they had a certain number of events, and what those events were, so we applied TOR in the first 2 years to determine how accurate we would have been at predicting which individuals would progress in years 3 and 4. We found that if we combined the progression and the relapse concerns (we didn't have the MRI data, so we left it out of the equation), we were able to predict with about 80% to 85% certainty all the individuals who either progressed or relapsed in years 3 and 4. A retrospective study like this cannot prove whether the hypothesis is true, but it does allow one to conceive of a study to test this hypothesis.

Medscape: How important are TOR for assessing MS progression?

Dr. Freedman: I think they're very useful, especially for clinicians who are not as familiar with MS and want some guidance for managing their MS patients. It's a logical approach for dealing with disease treatments that are not cures, and allows clinicians to determine just how much breakthrough is considered acceptable.

It's important to remember that patients receiving these treatments must be monitored. It's not enough to just prescribe a drug to a patient and say, "adios." Not everybody has a response to therapy that would be considered optimal. We don't have a huge armamentarium of drugs from which to choose; we have 4 drugs, 3 of which are similar, so a good rationale, such as using TOR, is necessary in order to be able to choose among them and make switches.

There are opportunities to be gained from switching from one therapy to another, and TOR can help determine when it might be appropriate to make a change. When to change the treatment is a key question. The window of opportunity for maximal benefit of treatment from the current drugs that we have is small, and recognizing that fact means that treatment is required early. Clinicians need to know how to monitor patients and to be able to determine how much breakthrough disease is too much. They also need to know how much progression will warrant moving from one therapy to another.

What drug do you switch to? What drug do you switch from? There are studies that look at just that. For example, in the ABOVE trial patients with "breakthrough" on low-dose IFN beta-1a are randomized to continue with low-dose IFN beta-1a, or switch to IFN beta-1b. The patients will be followed for 2 years. A similar study called ACHIEVE is also ongoing wherein patients with breakthrough on high-dose IFN beta-1a are randomized to either continue with their current therapy or switch to glatiramer acetate. The question is whether patients who are failing any of the disease-modifying drugs are apt to continue to fail when switched to a different one, ie, a "class" effect of failure. Alternatively, suboptimal responses to one disease-modifying drug might not necessarily mean suboptimal responses to all, and a switch to a different disease-modifying drug might lead to a successful response. MS has become a very complex disease that has become treatable; understanding the drugs and how to use them effectively and understanding how to monitor patients is a real art.

Medscape: How important is the use of MRI as a TOR tool?

Dr. Freedman: If there was a standardized MRI protocol for MS patients that was always followed, then it's possible that MRI would become much more useful as a TOR tool. All the same, that would only be true if there was enough access, and access to MRI in Canada for the most part is very limited.


Garcia DM, Marin M, Coruna A, et al. Safety and tolerability of inosine + subcutaneous interferon beta-1a (IFN beta-1a) in multiple sclerosis: could inosine protect from IFN beta -1a related adverse effects? Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida. Abstract P06.157.
Birnbaum G, Altafullah I. A double blind, placebo controlled combination trial of interferon beta-1a (Rebif) and atorvastatin (Lipitor) in patients with relapsing remitting multiple sclerosis. Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida. Abstract P06.158.
Rudick R, Stuart W, Calabresi P, et al. SENTINEL: a randomized, double-blind, placebo-controlled, multicenter trial to determine the efficacy and safety of natalizumab, when added to intramuscular interferon beta-1a, in patients with relapsing multiple sclerosis (MS). One year clinical and MRI results. Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida. Abstract S36.001.
Freedman MS, Patry DG, Grand'Maison F, et al. Treatment optimization in multiple sclerosis. Can J Neurol Sci. 2004;31:157-168.
Moses H. Benefits of high-dose, high frequency interferon beta-1a in early MS: comparative results from the EVIDENCE trial. Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida. Abstract P05.130.
Freedman MS, Forrestal FG. Treatment optimization recommendations (TOR) can predict relapse rates in patients with MS: analysis of the PRISMS study data. Program and abstracts of the American Academy of Neurology 57th Annual Meeting; April 9-16, 2005; Miami Beach, Florida. Abstract P05.128.
Funding Information
Supported by an independent educational grant from Serono Canada, Inc.

Mark S. Freedman, MD, Professor of Medicine (Neurology), University of Ottawa, Ottawa, Ontario, Canada

Disclosure: Penelope Gray-Allan has disclosed no relevant financial relationships.

Disclosure: Mark S. Freedman, MD, has disclosed that he has received grants for educational activities from Serono. Dr. Freedman has also disclosed that he has served as an advisor or consultant to Biogen Idec, Berlex, Serono, Teva, Bayer, Schering, and Pfizer.

Medscape Neurology & Neurosurgery. 2005;7(2) ©2005 Medscape