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MS Forum workshop: looking ahead--advances in multiple sclerosis in the next decade: Athens, Greece, 22 October 2008.

This brings us to the question of what the next 5 to 10 years will hold in terms of our understanding of the disease, our ability to manage patients with MS, and the prospects for new and more effective therapies with which to reduce the burden of this disease on patients and society. It was in this context that the members of the MS Forum Executive Committee convened at the end of 2008 to consider anticipated developments in the MS field, to understand how those developments would affect patient management and to identify educational needs and opportunities for the programme.

Current Disease-modifying Therapies for the Treatment of Relapsing--Remitting MS

The four main treatments for MS, interferon beta-1b (IFNB-1b; Betaferon[R]), IFNB-1a (Rebif[R]; Avonex[R]) and glatiramer acetate (GA; Copaxone[R]), have become well established with proven and demonstrable effectiveness across the spectrum of the disease course over the past 16 years. Their benefits include reduction in relapse rates, decreased magnetic resonance imaging (MRI) activity and lesion load, and potential improvements in long-term disability. Nevertheless, there remain a number of open questions, the answers to which would provide valuable information to further patient management. With current therapies there is limited long-term efficacy and safety data and few head-to-head comparisons. This is also especially true for the new MS therapies likely to be approved in the future. Lessons from the recent introduction of natalizumab (Tysabri[R]), and more complete monitoring of mitoxantrone, indicate that while these therapies offer apparently greater efficacy there are necessarily even fewer data available on long-term efficacy and no data on long-term hard outcomes. Since these therapies come with a cost of potential unknown risks, safety concerns must rank high among considerations as products currently in clinical testing eventually reach the pharmacists' shelves and can be prescribed for patients with MS.

Current disease-modifying therapies (DMTs) have favourable safety profiles and are demonstrably well tolerated in general. There are, however, some recognized and quantified tolerability issues. Classification of MS patients using the new McDonald criteria has been widely adopted. This allows for more definite MS diagnosis early in the disease course although there remains no evidence that diagnostic accuracy is increased. The recognition of subgroups of those with a clinically isolated syndrome (CIS), or first presentation relapsing--remitting MS (FP-RRMS) having a more active course has led some investigators to believe that treatment can and should be initiated earlier. Clinical trial results from long-term follow-up studies such as for IFNB-1b suggest that such early treatment may be important in the management of MS, thus possibly making efficacy gains from recent trials appear greater due to the timing of treatment initiation.

There is now better understanding that T-cells alone cannot explain all the aspects of MS pathology. In RRMS B-cells have been shown to have a role in the pathogenesis of MS through B-cell activating factor BAFF (BlyS/TALL-1/zTNF). The role of B-cells is not limited to antibody production as suggested by rituximab clinical trials, where immune changes were evident so early that they could not be explained by antibody responses alone. B-cells are now recognized as a target for intervention in MS, with both rituximab and alemtuzumab showing promising results. However, more research is needed on new MS therapies in order to determine their relative efficacy and long-term safety. The rare but potentially severe safety risks associated with some of them need to be complemented by cumulative follow-up data, including the risk of opportunistic infections and malignancies in the longer term.

DMTs for Secondary Progressive MS

Data on the effectiveness of current DMTs in secondary progressive MS (SPMS) are limited, with evidence for effects on inflammatory activity but without apparent changes in progression of disability. There is an evolving understanding of the differences between RRMS and SPMS, which may guide future intervention. Over the past few years, early permanent axonal damage, rather than demyelination, has been identified as the substrate for progression of disease.

Currently no therapies have shown convincing efficacy in SPMS, and despite continuing research, no new therapies effective in treating SPMS are expected to be licensed in the next 5--10 years. The main aim of all MS trials might well be the prevention of the progressive course and the only thing preventing this from being the primary outcome is the impractically long latent period which defies maintaining randomization and blinding.

Strategies of Neuroprotection

No current immunomodulatory therapy, available or in development, can be expected to prevent every single attack or lesion. Accordingly, it may be critical to prevent damage and protect against whatever insult remains in order to preserve neuronal function. Although there are no therapies that convincingly show neuroprotection, future MS management should include both immunomodulation and neuroprotective strategies, together with drugs to stimulate remyelination and repair of damaged neurons. A neuroprotective therapy may be available within the next decade. Furthermore, MS will be an important disease to study neuroprotection since neural degeneration occurs over many years.

Monitoring Patients

Even small changes in conventional MRI (cMRI) methodology have been shown to potentially alter the observed MS lesion profile in significant ways. Thus, cMRI methodology needs better standardization in order to directly compare cMRI results from different trials, or even to compare different cMRI results from a single patient. In addition, we still need to examine the relationship between the accumulation of disability in MS, gadolinium lesions and scanning technology in general. New technologies, such as magnetic resonance spectroscopy (MRS) or magnetization transfer ratio (MTR) are unlikely to become routine in either MS clinics or clinical research in the near future due to their complexity and the length of time required to validate them as surrogates. However, new understanding in the analysis of existing MRI technologies should occur in the next decade.

Cause and Outcome of MS

Interaction of specific genes with environmental factors, such as insufficient exposure to ultraviolet radiation at certain times in the life of an individual can increase the risk of MS. Research in genetics is facilitating a better understanding of the cause of MS, which may lead to new strategies for its prevention. Although primary prevention is the ultimate goal, there will remain the need to manage patients who have or are likely to get MS. In the near future, a new central nervous system pathway for pathogenesis and outcome may be elucidated with the presence of an association of MS with Kif1b, a gene involved in axonal transport. In addition, the localization of the first epigenetic effect for MS may ultimately lead to the identification of environmental factors key to prevention.

Future Considerations for MS Management

Although new MS therapies such as cladribine (Mylinax[R]) and FTY-720 (fingolimod) are likely to be licensed in the next few years, their role in MS management is uncertain at this point for a variety of reasons (Figures 1 and 2). We still lack long-term safety profiles and measures of relative efficacy versus the established therapies. In addition, monitoring patient adherence to oral drugs may be more difficult than once-yearly or once-monthly infusions or injectable therapies. It has been shown that even oral cancer medications can have problems with patient adherence, despite the gravity of that disease reinforcing the necessities of treatment. Given that MS can be asymptomatic between relapses, nonadherence may be a greater issue for oral MS medications. Although convenient for the patient, MS drugs administered by infusion currently have a high risk profile. An important issue is the ability to monitor adherence so that failure to adhere is not mistaken for lack of efficacy. Infusions have an adherence advantage in that they are controlled by the treating physicians. Furthermore, next-generation infusion therapies might be more effective and, despite potential safety issues, their greater convenience should make them attractive options for patients.

[FIGURE 1 OMITTED]

Risk--benefit profiles of new therapies need to be carefully considered when initiating treatment. Clinically useful definitions of treatment failure are essential, together with an understanding of the methods available to measure treatment benefit, in order to adequately evaluate the efficacy and treatment-related risks associated with these new therapies. However, future clinical trials that will address the core disease management questions will be complex to plan, implement and fund. In addition, as more trials are initiated, fewer eligible patients will be available, and the evidence from comparing contemporary with historical trials indicates that patient characteristics are likely to be different.

[FIGURE 2 OMITTED]

As our understanding of MS increases there will be implications from prognostic markers. For example, the use of genetics to determine MS susceptibility, new biomarkers such as antibodies, MRI refinements that may help in determining MS severity, and the use of pharmacogenomics should lead to refinements in benefit--risk ratios for treatment decisions, for tracking treatment progress and inform the wisdom of earlier MS treatment.

The current measures of disease progression and therapeutic benefits are limited. The future challenge will be to use new MRI information, improved strategies to obtain long-term data and better methods to assess MS pathology, to improve our understanding of how we can intervene most appropriately and identify the patients at risk of a worse disease course. It is essential to select outcome measures in an MS trial that fit both the duration of the trial and the population enrolled. Although the Kurtzke Expanded Disability Status Scale (EDSS) has proven value in determining disease stage, it has limitations such as the lack of a cognitive component. Other ranking scales such as the Multiple Sclerosis Functional Composite (MSFC) are unlikely to replace the EDSS, but may make EDSS measurements more reliable by providing a scale of reference. New biological markers for MS diagnosis or prognosis are unlikely to be developed for clinical use in the next 10 years, making disability scales such as EDSS a necessity in determining both disease progression and treatment benefit.

As a result of the discussions, developments that may occur over the next 5--10 years were identified (Table 1). Developments in MS are occurring rapidly. However, new treatments, biomarkers and a better understanding of MS disease processes are necessary for the further advancement of patient diagnosis, treatment and management. It was considered that follow-up of early MS drug trials could help neurologists to understand the treatment effect of a drug in the original population for which it was approved. MS diagnosis and monitoring the disease course in the clinic and in trials should improve in the next 5--10 years and new treatments are expected to add to the options currently available to patients.

M Clanet Toulouse, France and GC Ebers Oxford, UK
Table 1: Potential developments in MS over the next 5-10 years

Therapies            Trend towards long-term studies to evaluate
                     safety and efficacy of DMTs Active comparators
                     likely to become the norm in clinical trials
                     Developments in therapies for neuroprotection
                     and/or repair

Biology of disease   Key advances in genetics of MS and the role of
                     environmental factors in prevention

Patient management   Improved clinical scales likely to be developed
                     Health economics and treatment efficiency will
                     play an increasing role in therapeutic
                     decision-making

Biomarkers           Increased role of MRI, genetics and antibodies in
                     diagnosis and as surrogate markers in clinical
                     trials Developments in discovery and validity of
                     surrogate markers to measure treatment effects in
                     clinical trials
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Title Annotation:Meeting Report
Author:Clanet, M.; Ebers, G.C
Publication:The International MS Journal
Article Type:Conference news
Geographic Code:4EUGR
Date:Jul 1, 2009
Words:1866
Previous Article:The 61st annual meeting of the American Academy Of Neurology: Seattle, USA, 25 April-2 May 2009.
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