Multiple sclerosis research

Research in multiple sclerosis may find new pathways to interact with the disease, 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]

Regarding neuroprotective and 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]

Finally, regarding the ethiological research, it is considered that current diagnostic methods are confusing several disease entities into the same clinical entity "multiple sclerosis". For example, neuromyelitis optica, formerly considered a kind of MS, was separated in 2006 with the discovery of AQP4-IgG, and currently a second variant has been separated, antiMOG associated encephalomyelitis. Many other conditions are expected to be distinguished from MS following the discovery of specific pathogens.[10]

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.[11] 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.[11]

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. [12]

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.[13] This study may presumably identify all the common genetic variants involved in MS.[13] Further studies will probably involve full genome sequencing of large samples, or the study of structural genetic variants such as insertions, deletions or polymorphisms.[13]

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.[14] Some genetic mutations have been associated with an increased risk to develop MS, like STK11-SNP.[15] The chronic demyelination may cause axons to be notably vulnerable to repetitive and increasing injury and destruction.[16]

Research into pathogenesis

Research into pathogenesis focuses in explaining the ultimate causes of MS onset and progression, and explaining the heterogeneous behaviour[1]

Pathological research tries to obtain correlations for the observable biomarkers. Several important areas of study have been delimited, like Normal Appearing White Matter areas, which are the source of the lesions and under special MRI techniques like Magnetic Resonance Spectroscopy have been found to have a similar molecular composition.[17]

Also some external agents can modify the disease course. Smoking is known to modify (for worse) the course of the disease, and recently this effect has been seen via MRI.[18] An explanation of this effect could shed some light into the pathogenesis.

Research into new disease-modifying drugs

main: Multiple sclerosis drug pipeline

Disease-modifying drugs represent possible interventions able to modify the natural course of the disease instead of targeting the symptoms or the recovery from relapses.[19] Over a dozen clinical trials testing potential therapies are underway, and additional new treatments are being devised and tested in animal models.

New drugs must pass several clinical trials in order to get approved by regulatory agencies. Phase III is normally the last testing phase and when results are as expected a formal approval request is submitted to the regulator. 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 United States, Therapeutic Goods Administration (TGA) for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.

Relapsing-Remitting MS

Currently there are several ongoing phase III trials, and there are also some drugs that are waiting for approval after finishing theirs.

For example, Cladribine (under development by Merck Serono; anticipated brand name: Movectro) is a antineoplastic oral drug with immunosuppressive effects. It is already currently used as an intravenous infusion to treat hairy cell leukemia (leukemic reticuloendotheliosis). An oral version of cladribine is in phase III.[20] The completion of the phase III program took place in early 2009 meeting its main endpoint with 58% relative reduction in annualized relapse rates with respect to placebo.[21] Formal submission to European EMEA took place in middle 2009. In January 2010, researchers published in NEJM significant results of cladribine use in reducing relapsing course of multiple sclerosis.[22] This drug was expected to be in the market in 2011 for use in multiple sclerosis patients.,[23][24] but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.[25] Nevertheless, it seems that approval process continued in Europe and the EMEA has accepted a review process[26]

Also are in phase III at least the following drugs (for a complete list see Multiple sclerosis drug pipeline):

Research into treatment for secondary progressive variants

Relapsing-Onset variants (RO), even when they turn into progressive, have proved easier to treat than Progressive-Onset variants. Though difficult to treat, Secondary progressive and Progressive-Relapsing are easier to treat than PPMS. Only Mitoxantrone has been approved for them, but there is nothing for PPMS. At this moment several therapies are under research:

Treatment for Primary Progressive variants

Most Progressive-Onset variants does not have any approved disease-modifying treatment currently. Some possible treatments have been published, such as methylprednisolone pulses[39] or riluzole,[40] and some reduction of spasticity was reported in a pilot Italian study on low dose naltrexone[41] but there is nothing conclusive still.

Currently, good results using the monoclonal antibody Ocrelizumab in primary progressive MS (PPMS)[42] have put the focus into depleting B cells targeting CD20 proteins[43]

A Statin, Simvastatin (Zocor), has shown good results in progressive variants[44] Also Masitinib and Ibudilast, mainly targeted to SPMS have recruited PPMS patients in their clinical trials with good results.

Respect the etiological research, a special genetic variant named rapidly progressive multiple sclerosis[45] has been described. It is due to a mutation inside the gene NR1H3, an arginine to glutamine mutation in the position p.Arg415Gln, in an area that codifies the protein LXRA.

Highly active relapsing remitting variant

Highly Active Relapsing Remitting, sometimes called Rapidly Worsening relapsing remitting, is a clinical form considered distinct from standard RRMS 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.[46] Cyclophosphamide is currently used off-label for Rapidly Worsening MS (RWMS).[47]

Research into biomarkers

Biomarkers for diagnosis

Apart from its possible involvement in disease pathogenesis, vitamin D has been proposed as a biomarker of the disease evolution.[48]

Diagnosis of MS has always been made by clinical examination, supported by MRI or CSF tests. According with both the pure autoimmune hypothesis and the immune-mediated hypothesis,[49] researchers expect to find biomarkers able to yield a better diagnosis, and able to predict the response to the different available treatments.[50]

As of 2016 no specific biomarker for MS has been found,[51] but several studies are trying to find one. Some researchers are focusing also in specific diagnosis for each of the clinical courses[52]

Some people focus on blood tests, given the easy availability for diagnosis. Among the studies for blood tests, the highest sensitivity and specificity reported to date is testing circulating erythrocytes[53] (s=98.3%, e=89.5%). Also a good result was obtained using methylation patterns of circulating cell debris are specific for a number of conditions, including RRMS[54] There are ongoing efforts to be able to diagnose MS by analysing myelin debris into the blood stream.

As of 2014, the only fully specific biomarkers found were four proteins in the CSF: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signalling glycoprotein), and autotaxin-T (a phosphodiesterase)[55] This list was expanded on 2016, with three CSF proteins (Immunoglobulins) reported specific for MS. They are the following immunoglobulins: Ig γ-1 (chain C region), Ig heavy chain V-III (region BRO) and Ig-κ-chain (C region)[56]

Biomarkers are expected to play an important role in the near future[57]

Biomarkers for existing damage and disease evolution

During a clinical trial for one of the main MS drugs, a catheter was inserted into the brain's ventricles of the patients. Existing damage was evaluated and correlated with body fluids. Thanks to the courage of these volunteers, now we know that in PPMS, neurofilament light chain (NF-L) level, in CSF and serum, is a sensitive and specific marker for white matter axonal injury[58]

About biomarkers for MRI images, Radial Diffusivity has been suggested as a biomarker associated with the level of myelination in MS lesions. However, it is affected also by tissue destruction, which may lead to exaggeration of diffusivity measures. Diffusivity can be more accurate. Distinct patterns of diffusivity in MS lesions suggest that axonal loss dominates in the T1 hypointense core and that the effects of de/remyelination may be better detected in the "T2-rim", where there is relative preservation of structural integrity.[59]

Biomarkers for tailored treatments and response to therapy

Currently the only clear biomarker that predicts a response to therapy is the presence of anti-MOG autoantibodies in blood. Anti-MOG seropositive patients do not respond to approved MS medications.[60] In fact, it seems that MS patients with anti-MOG positivity could be considered a different disease in the near future.

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[61]

But the ideal target is to find subtypes of the disease that respond better to a specific treatment. A good example could be the discovery that the presence of a gene called SLC9A9 appears in people who fail to respond to interferon β therapy[62] or that the disregulation of some transcription factors define molecular subtypes of the disease[63] Other good example could be the Hellberg-Eklund score for predicting the response to Natalizumab.[64]

Though biomarkers are normally assumed to be chemical compounds in body fluids, image can also be considered a biomarker. For an example about research in this area, it has been found that fingolimod is specially suitable for patients with frequently relapsing spinal cord lesions with open-ring enhancement[65] Anyway, patients with spinal cord lesions could have different T-helper cells patterns that those with brain lesions[66][67]

Biomarkers are also important for the expected response to therapy. As a example of the current research, in 2000 was noticed that patients with pattern II lesions were dramatically responsive to plasmapheresis,[68] and in February 2016, it was granted the first patent to test the lesion pattern of a patient without biopsy.[69]

Other examples could be the proposal for protein SLC9A9 (gen Solute carrier family 9) as biomarker for the response to interferon beta,[70] as it happens for serum cytokine profiles[71] The same was proposed to MxA protein mRNA.[72] The presence of anti-MOG, even with CDMS diagnosis, can be considered as a biomarker against MS disease modifying therapies like fingolimod[73]

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  68. ↑ while others were irresponsive
  69. ↑ United States patent US9267945
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