Multiple sclerosis research

Treatments under investigation for multiple sclerosis may improve function, curtail attacks, or limit the progression of the underlying disease. Many treatments already in clinical trials involve drugs that are used in other diseases or medications that have not been designed specifically for multiple sclerosis. There are also trials involving the combination of drugs that are already in use for multiple sclerosis. Finally, there are also many basic investigations that try to understand better the disease and in the future may help to find new treatments.

Research directions

Research directions on MS treatments include investigations of MS pathogenesis and heterogeneity; research of more effective, convenient, or tolerable new treatments for RRMS; creation of therapies for the progressive subtypes; neuroprotection strategies; and the search for effective symptomatic treatments.[1]

Advancements during the last decades have led to the recent approval of several oral drugs. These drugs are expected to gain in popularity and frequency of use at the expense of previously existing therapies.[2] Further oral drugs are still under investigation, the most notable example being laquinimod, which was announced in August 2012 to be the focus of a third phase III trial after mixed results in the previous ones.[3] Similarly, several other studies are aimed to improve efficacy and ease of use of already existing therapies through the use of novel preparations.[4] Such is the case the PEGylated version of interferon-β-1a, that has a longer life than normal interferon and therefore it is being studied if given at less frequent doses has a similar efficacy than the existing product.[5][6] Request for approval of peginterferon beta-1a is expected during 2013.[6]

Monoclonal antibodies, which are drugs of the same family as natalizumab, have also raised high levels of interest and research. Alemtuzumab, daclizumab and CD20 monoclonal antibodies such as rituximab, ocrelizumab and ofatumumab have all shown some benefit and are under study as potential treatments for MS.[7] Nevertheless, their use has also been accompanied by the appearance of potentially dangerous adverse effects, most importantly opportunistic infections.[2] Related to these investigations is the recent development of a test against JC virus antibodies which might help to predict what patients are at a greater risk of developing progressive multifocal leukoencephalopathy when taking natalizumab.[2] While monoclonal antibodies are probably going to have some role in the treatment of the disease in the future, it is believed that it will be small due to the risks associated to them.[2]

Another research strategy is to evaluate the combined effectiveness of two or more drugs.[8] The main rationale for polytherapy in MS is that the involved treatments target different mechanisms of the disease and therefore, their use is not necessarily exclusive.[8] Moreover, synergies, in which a drug potentiates the effect of another are also possible. Nevertheless, there can also appear important drawbacks such as antagonizing mechanisms of action or potentiation of deleterious secondary effects.[8] While there have been several clinical trials of combined therapy none has shown positive enough effects to merit the consideration as a viable treatment for MS.[8]

Finally, regarding neuroprotective and specially regenerative treatments such as stem cell therapy, while their research is considered of high importance at the moment they are only a promise of future therapeutic approaches.[9] Likewise, there are not any effective treatments for the progressive variants of the disease. Many of the newest drugs as well as those under development are probably going to be evaluated as therapies for PPMS or SPMS, and their improved effectiveness when compared with previously existing drugs may eventually lead to a positive result in these groups of patients.[2]

Clinical measures of evolution

The main measure of evolution of symptoms, specially important as an endpoint in MS trials, is the EDSS. However, this and other measures used in clinical studies are far from perfect and suffer from insensitivity or inadequate validation.[10] In this sense there is ongoing research to improve the EDSS and other measures such as the multiple sclerosis functional composite. This is important as the greater efficacy of existing medications force functional measures in clinical trials to be highly sensitive in order to adequately measure disease changes.[10]

Geographical Causes

Extensive research on multiple sclerosis is being done on what parts of the world have higher rates of MS compared to other regions. Researchers have studied MS mortality statistics in various latitudes of the earth and the pattern shows that MS mortality rates are lowest in equatorial regions, which contain the countries, Ethiopia and Jamaica. It increases towards the north and south showing that the highest MS rate is at a latitude of around 60 degrees, which are the countries Orkney, Shetland Islands, and Oslo, Norway. The next step for researchers would be to consider what factors are different at the latitudes of 60 degrees and the equatorial regions and continue to narrow down their theories for the exact cause of MS. [11]

Genetics

Advances in genetic testing techniques have led to a greater understanding of the genetics of MS. However, it is hard to predict how these future discoveries will impact clinical practice or research for new drugs and treatments.[2]

An example of a soon-to-be finished study is the Wellcome Trust case control consortium, a collaboration study including 120,000 genetic samples, of which 8000 are from individuals with MS.[12] This study may presumably identify all the common genetic variants involved in MS.[12] Further studies will probably involve full genome sequencing of large samples, or the study of structural genetic variants such as insertions, deletions or polymorphisms.[12]

Genetic factors are the primary cause to the more rapid progression and frequency of the disease. Although genetics is linked to multiple sclerosis, most of the prime perceptivity of the linkage has not been fully characterized as there has not been a big enough sample size available for the research needed.[13] Some genetic mutations have been associated with an increased risk to develop MS, like STK11-SNP.[14] The chronic demyelination may cause axons to be notably vulnerable to repetitive and increasing injury and destruction.[15]

Disease-modifying drugs and procedures

Disease-modifying drugs and procedures represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses.[16] Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.

Phase III

Phase III programs consist of studies on large patient groups (300 to 3,000 or more) and are aimed at being the definitive assessment of how effective and safe a test drug will be. It is the last stage of drug development and is followed by a submission to the appropriate regulatory agencies (e.g., European Medicines Agency (EMEA) for the European Union, the Food and Drug Administration (FDA) for the USA, Therapeutic Goods Administration (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.

A phase III trial should run from Dec 2012 to Dec 2016.[28]

Phase II

Phase II studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug may work in the targeted disease area, as well as to continue earlier safety assessments obtained in healthy volunteers. Treatment in MS phase II studies is with 4–12 months usually shorter than in phase III studies.

Phase I and animal models

Phase I and medicaments used in animal models would make a huge list. Here only some of them with special interest are listed.

Other possible treatments

Combined therapies

Several combinations of drugs have been tested. Some of them are couples of approved drugs. Other tests try one approved drug with one experimental substance. Finally, at some point there could appear some trials testing couples of non-approved drugs.

Combination of approved drugs

Approved and experimental drugs combined

Summary table

Summarizing in a table which combinations have been tried:

Interferon beta-1a Interferon beta-1b (Betaseron) Glatiramer acetate (Copaxone) Mitoxantrone Natalizumab (Tysabri) Fingolimod (Gilenya) Teriflunomide (Aubagio) Dimethyl fumarate BG12 (Tecfidera) Alemtuzumab (Lemtrada)
Interferon beta-1a
Interferon beta-1b (Betaseron) NO
Glatiramer acetate (Copaxone) YES[93] NO
Mitoxantrone NO NO YES[86][87]
Natalizumab (Tysabri) YES (linked to PML) NO YES[88] NO
Fingolimod (Gilenya) NO NO NO NO NO
Teriflunomide (Aubagio) NO NO NO NO NO NO
Dymetyl fumarate BG12 (Tecfidera) NO NO NO NO NO NO NO
Alemtuzumab (Lemtrada)[104] NO NO NO NO NO NO NO NO
Atorvastatin (Lipitor) YES YES[99] NO NO NO NO NO NO NO
Cyclophosphamide NO YES NO NO NO NO NO NO NO
Inosine YES[101][102] NO NO NO NO NO NO NO NO

Biomarkers and tailored treatments

Comparative Effectiveness Research (CER) is an emerging field in Multiple Sclerosis treatment. The response of the disease to the different available medications at this moment cannot be predicted, and would be desirable[105]

Research is on its way. For example, a biomarker recently proposed is vitamin D. Apart from its possible involvement in disease patogenesis, it has been proposed as a biomarker of the disease evolution[106]

But the ideal target is to find subtypes of the disease that respond better to a specific treatmet. A good example could be the discovery of the disregulation of some transcription factors,[107] or the promising report about autoantibodies against the potasium channel Kir4.1 appearing with high specificity in MS patients (they have shown to be pathogenic in models).

Aggressive variants

Progressive variants have proved more difficult to treat than RRMS. This is the status of the research into progressive variants.

Highly active relapsing remitting

Highly Active Relapsing Remitting, sometimes called Rapidly Worsening relapsing remitting, is a clinical form considered distinct from standard RR during clinical trials, being normally non responsive to standard medication.

As of 2011, fingolimod has been approved as the first disease modifying therapy for this clinical course.[108] Cyclophosphamide is currently used off-label for Rapidly Worsening MS (RWMS).[109]

Primary progressive

This variant does not have any approved treatment currently. Some possible treatments have been published, such as methylprednisolone pulses[110] or riluzole,[111] and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone[70] but there is nothing conclusive still.

A Statin, Simvastatin (Zocor), has shown good results in progressive variants[80]

Secondary progressive and progressive-relapsing

Only Mitoxantrone has been approved, but most of the previous pipeline drugs have been or will be tried on it at some point.

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