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.

• Angioplasty for chronic cerebrospinal venous insufficiency (the so-called Zamboni liberation procedure), currently in phase III.^[17] The treatment uses an inflatable balloon (instead of stenting) to open narrowed blood vessels in hopes of improving blood flow, based on the hypothesis that a compromised blood drainage system can debilitate the blood–brain barrier.^[18]
• Daclizumab (injectable. Brand name Zenapax; under development by Biogen and PDL) is an anti-IL2 monoclonal antibody and an immunosuppressant used to prevent rejection after organ transplantation. Results from two Phase II were reported in 2007.^[19][20] The phase III trial has already started^[21]
• Tovaxin (injectable) A vaccine against self T-Cells, which consist of attenuated autoreactive T cells. It is developed by Opexa Therapeutics, (previously known as PharmaFrontiers), and finished a phase IIb September 2008,^[22] failing its primary target though in March 2008 was still performing good.^[23] After several financial troubles, a phase III trial has been granted in 2011^[24]
• Peginterferon Beta-1a, also known as Plegridy, was recently approved by the FDA and is expected to be available by prescription in November 2014.^[25] It can be considered a pharmaceutical formulation of interferon beta-1a in which the molecules are pegylated to extend their half-life and to reduce dosing requirements. Plegridy is a long-acting form of the interferon beta-1a drug, Avonex. The mechanism of action of Peginterferon Beta-1a is not known but it is expected to work similarly to other drugs in the interferon beta class. Drugs in the interferon Beta class work by reducing neuron inflammation and reducing the inflammatory cells that cross the blood brain barrier. This is thought to improve the production of nerve growth factor and therefore improve neuron survival.^[26] The effectiveness of Plegridy compared to other interferon medications and MS treatments is unknown since they were not compared during clinical trials. However compared to placebo, the relapse rates were reduced by 35.6% during the first year of the trial. The reduction in relapse rate was similar to that of other interferon’s. Plegridy’s advantage is it only needs injecting once every two weeks.^[27]
• Siponimod, (BAF312) is a sphingosine-1-phosphate receptor modulator for oral use for MS.

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.

• ATL1102 (under development by Teva and Antisense therapeutics) is a second-generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4). Results of a Phase IIa have been reported.
• CDP323 (under development by UCB S.A. and Biogen) is a compound for oral intake acting against α4-integrin, i.e., it has the same mechanism of action as natalizumab. Phase II investigations started in 2007.^[29]
• Estradiol and estrogen receptors(ER): Both have been shown to be antiinflammatory and neuroprotective in a variety of neurological disease models and now is known that they work also in presence of inflammation^[30][31]
• Ibudilast: A phase II trial shows that Ibudilast does not reduce lesion rate, but prevents them to turn into black holes. They classify its action as class III evidence of delay on disease activity^[32]
• Inosine: Inosine is a compound that has shown interesting preliminary results in phases I and II clinical trials.^[33][34] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion,^[35] which is a natural antioxidant;^[36] second, it has been shown to induce axonal rewiring in laboratory animals with stroke,^[37] and spinal cord injury.^[38] However it can cause health problems in a long-term treatment,^[39] mainly kidney stones.^[40] It seems that its mechanism of action is peroxynitrite inactivation^[41] Other reports point to an immune modulation^[42]
• Ocrelizumab, Anti-CD20 humanized monoclonal antibody, whose mechanism of action targets B-Cells, like Rituximab, currently in phase II.^[43]
• Ofatumumab, other anti-CD20 monoclonal antibody, also in phase II for MS, and phase III for others autoimmune diseases
• Stem cell transplantation was found feasible in a phase I/II study in 21 patients with relapsing-remitting MS not responsive to interferon beta. It involves collecting some of the patient's own peripheral blood stem cells, giving low-intensity chemotherapy to eliminate auto-reactive lymphocytes, and then reinfusing the stem cells.^[44] Earlier studies in the secondary-progressive stage of MS have failed to shown reversal of neurological symptoms.

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.

• GIFT15 is a treatment which suppresses the immune system, and has been successfully used in the treatment of mice. The immune system attacks the central nervous system in Multiple Sclerosis patients. Specifically a "granulocyte-macrophage colony–stimulating factor (GM-CSF) and interleukin-15 (IL-15) 'fusokine]' (GIFT15) exerts immune suppression via aberrant signaling through the IL-15 receptor on lymphomyeloid cells. We show here that ex vivo GIFT15 treatment of mouse splenocytes generates suppressive regulatory cells of B cell ontogeny (hereafter called GIFT15 Breg cells)."^[45][46][47]

• Bosentan, endothelin-1 antagonist, has been proposed to lower the ET1 levels, which are involved in brain hypoperfusion^[48]

Other possible treatments

• Antimicrobial agents against Chlamydophila pneumoniae: MS patients are more likely to have detectable levels of Chlamydophila pneumoniae DNA in their cerebrospinal fluid, compared to other patients with neurological diseases; however these findings are insufficient to establish an etiologic relation.^[49] Anecdotal reports of the use of antimicrobial agents against Chlamydophila pneumoniae are favorable, but only one double-blind placebo-controlled trial has been published, in which the number of patients studied was too small (four in each arm of the trial) to reach statistical significance in the primary outcome measure (volume of gadolinium-enhancing lesions, as viewed on MRI).^[50]
• Antioxidants, available as supplements, are reported to reduce the blood–brain barrier permeability.^[51] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant,^[52] and has been observed that raising uric acid levels protects against blood–brain barrier destruction (through peroxynitrite scavenging ).^[53] Peroxynitrite has been correlated with the axons degeneration and its removal can protect neurons from further damage after an attack. They can also remove other reactive oxygen species^[54] It is also known that uric acid levels decrease during the course of the disease^[55]
• Bilirubin has been found to have immunomodulatory properties, apart from the already known antioxidant properties, and is a possible future treatment.^[56]
• Use of drugs to suppress myelin-reactive effector memory T cells by blocking voltage-gated Kv1.3 channels in these cells.^{[57][58][59][60][61]}
• Hydralazine Due to its ability to damage myelin nerve sheaths, acrolein may be a factor in the development of multiple sclerosis. The antihypertensive drug hydralazine, a known scavenger of acrolein, was found to reduce myelin damage and significantly improve behavioral outcomes in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis).^[62]
• Helminthic therapy: A study showed a negative association between multiple sclerosis and infection with intestinal parasites, such as hookworm indicating that parasites may protect against multiple sclerosis.^[63][64] Helminth therapy involves ingesting helminth eggs by the names of Trichuris suis, which are non parasitic worms. This is done in hopes that the body will redirect the immune response away from attacking the myelin, which produce lesions, and target the helminths. The study by Dr Fleming shows this is affective in reducing the extent of lesions seen through MRI’s taken before and after the study.^[65]
• BCG vaccine: The common, live, attenuated vaccine against tuberculosis, has substantially reduced recurrence of symptoms in multiple sclerosis patients.^[66] The frequency of new enhancing lesions as detected by Gd-enhanced MRI was reduced by more than half in 12 patients, comparing the six-month run-in phase to the six-month post BCG phase of the experiment. Persistence at subsequent MR scan was reduced from 18 to 1 lesion, and evolution to black holes was reduced from 28 to 6 lesions.^[67] The conventional explanation of such protection is that parasites (including bacteria) modulate the sensitivity of the immune system. BCG appears safe as a treatment for multiple sclerosis.^[66][68]

• Low dose naltrexone is also known as LDN. Naltrexone, a pure opiate antagonist, licensed by the FDA for the treatment of alcohol and opioid addictions, is currently being studied at a lower dosage for MS patients. A small, short-duration clinical trial^[69] with MS patients was recently conducted at the University of California, San Francisco. In October 2007 data was presented at the European Congress of MS in Prague regarding safety findings of a pilot study of low dose naltrexone therapy in multiple sclerosis by neurological researchers in Milan, Italy.^[70] However, no compelling efficacy results for LDN in MS therapy have been published. LDN is currently available to MS patients in the USA by off-label prescription.
• Minocycline: the antibiotic minocycline has shown an effect on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in MS patients over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment relapse rate in patients in the study prior to treatment, no relapses occurred between months 6 and 24. The only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Clinical and MRI outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in MS.^[71][72][73]
• Pixantrone: pixantrone (BBR2778) is an analogue of mitoxantrone devoid of toxic effects on cardiac tissue. It is as potent as mitoxantrone in animal models of MS; however results of human trials had not been published in 2007.^[74]
• Plasmapheresis. Pattern II MS lesions have been reported to respond to plasmapheresis,^[75] which points to something pathogenic into the blood serum, and the percentaje reported of pattern II is very close to the 47% reported in Kir4.1 MS cases,^[76] turning Kir4.1 patients into candidates for plasma exchange.
• Prolactin:In 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of MS.^[77] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.^[78]
• Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS.^[79] However, there is no evidence that statins are beneficial in the treatment of human MS patients, and concerns exist that, if ever shown to be effective, the high doses needed would prevent long-term use due to the potential for liver damage and muscle-wasting disease. One of them, Atorvastatin, has been tried in combination with several approved treatments, though with little success. Other, Simvastatin (Zocor) has shown good results in progressive variants^[80]
• Testosterone has been studied for its potential benefits in men with Multiple Sclerosis, but the results are preliminary.^[81]
• Vitamin D: a 2004 study found that women who took vitamin D supplements were 40% less likely to develop MS than women who did not take supplements. However, this study does not provide enough data to conclude that vitamin D has a beneficial influence on ongoing MS. Furthermore, it could not distinguish between a beneficial effect of vitamin D and that of multivitamin supplements including vitamin E and various B vitamins, which may also exert a protective effect.^[82] A new study in the same sense was published in 2013^[83]
• Omega-3 fatty acid: A study found that Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis^[84]

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

• Mitoxantrone & Copaxone: A recent study in the United Kingdom revealed interesting results when using a combination of mitoxantrone and copaxone. In an open-label study of 27 patients with RRMS, the results suggested a rapid and sustained suppression of relapses. A three-year controlled study of 60 patients is now being launched at 10 centres across the UK.^[85] In another clinical trial, glatiramer acetate (Copaxone) has been combined with Mitoxantrone in such a way that every course of Mitoxantrone is followed by GA treatment. It has yielded promising results twice, in a consistent way.^[86][87]
• Tysabri & Copaxone This combination has been found to be safe and well tolerated after six months.^[88]
• Mitoxantrone & beta-interferon: This combination has worked in some cases but not in others^[89]
• Avonex & Copaxone: Currently in phase III, with good results published^[90]
• Interferon beta 1a & Tysabri: Dangerous but effective.^[91] Linked with PML, but is remarkable that Natalizumab alone is also linked with it.
• Natalizumab and Fingolimod. No formal research has been done, but some problems have been reported.^[92]
• Interferon beta 1a & Glatimer acetate: No additional benefits found^[93]
• Alemtuzumab & Copaxone: A combination trial of Alemtuzumab with glatiramer acetate (Copaxone) is being considered, and is expected to work synergistically.^[94]

Approved and experimental drugs combined

• Copaxone & Minocycline. Good results^[95]
• Avonex & Atorvastatin: Avonex (beta-1a) has also been combined with Atorvastatin in a clinical trial showing that is safe in its conditions,^[96] even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term.^[97] Other clinical trials have found problems combining IFN beta with Atorvastatin^[98]
• Betaseron & Atorvastatin: Betaseron (beta-1b) has also been combined with Atorvastatin with good safety results but poor performance. The combined treatment did not have any beneficial effects on RRMS compared to IFNB-1b monotherapy.^[99]
• Cyclophosphamide & Beta-interferon has been tried on IFNbeta-unresponsive patients with success, but it is still under study.^[100]
• Avonex & Inosine: Avonex (interferon beta-1a) was combined with Inosine. Available data suggests that this combination is safe and well tolerated, though with no improvements respect interferon beta alone.^[101][102] Recently the lack of additional benefits respect Avonex have been confirmed, and it has been reported that 2gr/day should be considered as the maximum safe dosage.^[103]

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.

• Cyclophosphamide (trade name Revimmune) is currently in Phase III for secondary progressive MS.^[112] It was also studied for RRMS but the company does not pursue actively this path. After a 2006 study for refractory cases it showed good behaviour^[113] Later, a 2007 open label study found it equivalent to Mitoxantrone^[114] and in 2008 evidence appeared that it can reverse disability.^[115]
• Simvastatin has shown brain atrophy reduction in secondary progressive MS.^[116]
• Tcelna is currently under active research by Opexa, showing promising results.^[117]

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