Multiple sclerosis drug pipeline

This page describes the process and status of pharmaceuticals for treating multiple sclerosis (MS).

From the moment a theoretical model of MS is hypothesized, until a drug that interferes with one of its pathways appears on the market, several phases must be gone through.

First, an animal model of the pathway to be studied is developed, and the drugs that are hypothesised to interfere with that pathway are trialled. After that, three phases of testing on humans begins. If the three phases work as hypothesised, the drug can apply to regulators.

Approved medication

Usually the regulatory agencies approve a medicatio for a specific clinical course. Most of the times for RRMS (relapsing-remitting), SPMS (secondary progressive) or PPMS (primary progressive). Some times they approve it for a subtype, like Highly-Active MS (HAMS, inside RRMS), Rapidly-Worsening MS (RWMS, inside PPMS) or "active SPMS" (previous progressive-relapsing)[1]

Approved for Relapsing-Remitting

As of 2020, the approved drugs for relapsing-remitting MS (RRMS) are:

There are few reports comparing these treatments in front of each other. Restricting the research only to relapses, it seems that alemtuzumab is the most cost effective[18] while anti-CD20 monoclonal antibodies (Rituxan, Ocrevus) have the better safety vs. efficacy profileF[19]

Approved for special courses

The courses primary progressive (PPMS) and secondary progressive (SPMS) are normally treated apart from RRMS. Besides, the regulatory agencies treat sometimes apart the cases aSPMS (Active Secondary progressive), nSPMS(non-active SPMS), HAMS (highly active) and RPMS (rapidly progressive)

  • Primary progressive: Ocrelizumab and Mitoxantrone are the only approved drugs for PPMS. The last with restrictions.
  • Secondary progressive: Ozanimod, Cladribine and Mitoxantrone are approved for SPMS. The last with restrictions. Though approved for SPMS its profile is considered dangerous and is not always risk worthy[20]
  • Active SPMS (formerly Progressive-Relapsing): The US the approval of cladribine includes active SPMS (SPMS with relapses) in its approval and also Siponimod is approved for this special course "active SPMS"[1]
  • Highly active RRMS:[21] As of 2020, Cladribine is the only drug specifically approved for this special course. It was approved also for SPMS (secondary progressive) in Europe in 2017 [22] and by FDA in April 2019[23] with the name Mavenclad.
  • Rapidly progressive PPMS: For aggressive PPMS or rapidly progressive multiple sclerosis only Mitoxantrone is approved[24][25]

Withdrawn medication
  • Daclizumab[26][27] Finally, after some reported deaths, it has been withdrawn by the regulatory agencies that had it previously approved.[28]

Submitted for approval, cleared for review and fast track

When a company considers that there is enough information from a clinical trial to fill an application, they submit a request for approval to the regulatory agencies (or New Drug Application, NDA). When the agency considers that the request is worthy to be evaluated they grant the state "under review" (cleared for review) to the drug. Some regulatory agencies have special workflows for drugs that cover something uncovered, like the FDA fast track.

  • 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[29] In March 2016 Ibudilast was designated a FDA fast track candidate for progressive MS[30]
  • Ponesimod - As of March 2020, it was submitted to the U.S. Food and Drug Administration (FDA)[31] and to the European Medicines Agency (EMA)[32]
  • Ofatumumab is another anti-CD20 monoclonal antibody. It is also in phase III for MS and has already been approved for others autoimmune diseases under the trade name Arzerra.[33][34] Submitted to the FDA on Feb. 2020.[35]

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 (EMA) 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 two years per patient.

  • Masitinib, anticancer drug that blocks cell replication and immune responses,[36] It targets the innate immune system (mast cells and microglia) and has shown efficacy in the progressive courses. The appropriate pathway to put forward masitinib through the regulatory agencies, for the treatment of progressive forms of multiple sclerosis, is under study[37]
  • Ublituximab has had good results on phase II studies.[38] As of 2020 was still on Phase 3 clinical trials for multiple sclerosis.[39]
  • Evobrutinib is a selective oral Bruton's tyrosine kinase (BTK) inhibitor that has been shown to inhibit B-cell activation both in vitro and in vivo.[40][41] Currently in phase III.[42]

Phase II

Phase II studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug works 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.

  • Amiselimod, S1P modulator[43]
  • Amiloride (Midamor) - Midamor is a sodium channel blocker. It can stop sodium from entering the nerve cells, which in turn reduces the release of calcium. Therefore, Midamor could have a neuroprotective function in MS patients
  • 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.[44]
  • Clemastine fumarate, also known as meclastin, is an antihistamine and anticholinergic drug. Between Jan 1, 2014, and April 11, 2015 it performed well in a Phase II clinical trial[45]
  • Estradiol, estriol, and estrogen receptors(ER): Estrogens have been shown to be anti-inflammatory and neuroprotective in a variety of neurological disease models and it is known that they work also in presence of inflammation.[46][47] Research in this area has focused on the efficacy of estriol as a treatment to reduce symptoms of relapse-remitting multiple sclerosis in non-pregnant women.[48][49][50]
  • Inosine: Inosine is a compound that has shown interesting preliminary results in Phase I and II clinical trials.[51][52] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion,[53] which is a natural antioxidant;[54] second, it has been shown to induce axonal rewiring in laboratory animals with stroke,[55] and spinal cord injury.[56] However it can cause health problems in a long-term treatment,[57] mainly kidney stones.[58] It seems that its mechanism of action is peroxynitrite inactivation[58] Other reports point to an immune modulation[59]
  • 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.[60] Earlier studies in the secondary-progressive stage of MS have failed to shown reversal of neurological symptoms.
  • Temelimab or Geneuro GNbAC1 - Monoclonal antibody against the viral The HERV-W envelope glycoprotein, which is supposed to be somehow pathogenic. It has passed a Phase IIb and a high dosis safety profile study[61] Currently in Phase IIb[62]
  • Tcelna (previously Tovaxin) A vaccine against self T-Cells, which consist of attenuated autoreactive T cells. It was developed by Opexa Therapeutics, (previously known as PharmaFrontiers), and finished a Phase IIb September 2008,[63] failing its primary target, though, in March 2008 was still performing well.[64] A Phase III trial was in 2011[65] but as of 2016 it was still in phase II.[66]
  • Fluoxetine (Prozac)
  • Riluzole (Rilutek)[67]

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)."[68][69][70]
  • Bosentan, endothelin-1 antagonist, has been proposed to lower the ET1 levels, which are involved in brain hypoperfusion[71]
  • Carnosol, a natural compound found in Rosemary, which has been found to prevent microglia activation[72]
  • Metformin - A drug that reverses age-related (but also injury-related) changes in olegodendrocytes, making OPCs respond to differentiation factors.[73]

First and second lines

Because of the side effects and dangers of some medications, they are classified into first and second line. First line includes the safest but less effective compounds, i.e. interferons and glatimer acetate.[74] The second line includes the rest of the compounds and is usually a stronger medication.

Some MS organizations separate medications into three lines:[75]

  • Moderately effective: Aubagio (Teriflunomide), Beta Interferons (1a and 1b) and Copaxone.
  • More effective: Mavenclad (Cladribine), Tecfidera (Dymethyl fumrate) and Fingolimod[19]
  • Highly effective: Ocrevus (Ocrelizumab) and Tysabri (Natalizumab).

Off and Open label

Some compounds have passed Phase III tests and are widely assumed to be safe and effective, however, they do not become approved. This may be because of lack of funding to go through the approval process. Some doctors prescribe them anyway off-label or under the schema of open label research. Examples of MS drugs used off label include:

  • Rituximab - Monoclonal antibody against CD20. According to some sources it has the a better efficacy vs. safety profile that most approved drugs.[76]
  • Cyclophosfamide - Strong immunosuppressor with conflicting evidence.[77]
  • Low-Dose Naltrexone (LDN).

Research into progressive variants

Progressive variants are more difficult to treat than the Relapsing-Remitting course. Normally research for PPMS and SPMS go together, being more difficult to treat PPMS. This section presents research on SPMS, with mentions of PPMS where applicable.

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 most of the previous pipeline drugs have been or will be tried on it at some point. At this moment several therapies are under research:

  • Cyclophosphamide (trade name Revimmune) is currently in Phase III for secondary progressive MS.[78] 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[79] Later, a 2007 open label study found it equivalent to Mitoxantrone[80] and in 2008 evidence appeared that it can reverse disability.[81]
  • Simvastatin, a cholesterol-lowering statin, Simvastatin (Zocor), has shown good results in progressive variants[82] This has shown brain atrophy reduction in secondary progressive MS.[82] This drug is under research for PPMS and SPMS.

Some PPMS patients with a special biomarker (Immunoglobulin M oligoclonal bands) have been shown to respond to standard RRMS medications, though there is only preliminary evidence waiting to be confirmed[83]

Other possible treatments under research
  • 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.[84] 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).[85]
  • Antioxidants, available as supplements, are reported to reduce the blood–brain barrier permeability.[86] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant,[87] and has been observed that raising uric acid levels protects against blood–brain barrier destruction (through peroxynitrite scavenging ).[88] 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[89] It is also known that uric acid levels decrease during the course of the disease[90]
  • Bilirubin has been found to have immunomodulatory properties, apart from the already known antioxidant properties and it is a possible future treatment.[91]
  • Use of drugs to suppress myelin-reactive effector memory T cells by blocking voltage-gated Kv1.3 channels in these cells.[92][93][94][95][96]
  • 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).[97]
  • Helminthic therapy: A study showed a negative association between MS and infection with intestinal parasites, such as hookworm, indicating that parasites may protect against multiple sclerosis.[98][99] 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.[100]
  • BCG vaccine: The common, live, attenuated vaccine against tuberculosis, has substantially reduced recurrence of symptoms in multiple sclerosis patients.[101] 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.[102] 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.[101][103]
  • 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[104] 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.[105] However, no compelling efficacy results for LDN in MS therapy have been published. LDN is available to MS patients in the US 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.[106][107][108]
  • 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.[109]
  • Plasmapheresis. Pattern II MS lesions have been reported to respond to plasmapheresis,[110] which points to something pathogenic into the blood serum, and the percentage reported of pattern II is very close to the 47% reported in Kir4.1 MS cases,[111] 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.[112] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.[113]
  • Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS.[114] 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[115]
  • Testosterone has been studied for its potential benefits in men with Multiple Sclerosis, but the results are preliminary.[116]
  • 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.[117] A new study on this in the same sense was published in 2013[118]
  • Omega-3 fatty acid: One study found that Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis[119]

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.

As of 2016, there are 10 active principles approved which are: Two interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, mitoxantrone, fingolimod, teriflunomide,[2] dimethyl fumarate[3] and finally three monoclonal antibodies (natalizumab, alemtuzumab[16] and since May 2016 daclizumab[26][27])

Combination of approved drugs
  • Mitoxantrone and 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.[120] 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.[121][122]
  • Natalizumab and copaxone: This combination has been found to be safe and well tolerated after six months.[123]
  • Mitoxantrone and Beta-interferon: This combination has worked in some cases but not in others[124]
  • Beta-interferon and Copaxone: Currently in Phase III, with good results published[125]
  • Interferon beta 1a and Natalizumab: Dangerous but effective.[126] 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.[127]
  • Interferon beta 1a and glatimer acetate: No additional benefits found[128]
  • Alemtuzumab and Copaxone: A combination trial of Alemtuzumab with glatiramer acetate (Copaxone) is being considered, and is expected to work synergistically.[129]
  • Laquinimod and Fampridine, with good results, subject to patent where applicable[130]
  • Mitoxantrone and rituximab: Human anti-chimeric antibodies (HACA) appear in patients treated with Rituximab. MTX reduces them. A safety analysis of RA patients treated with rituximab in combination with MTX in clinical trials showed that 11% of patients developed a positive titer for HACA's at least once during treatment with rituximab.[131]
  • Laquinimod and Dimethyl Fumarate: (Patented by Teva Pharmaceutical Industries Ltd): It has been tested and looks promising.[132]

Approved and experimental drugs combined
  • Copaxone and minocycline. Good results[133]
  • Avonex and atorvastatin: Avonex (beta-1a) has also been combined with Atorvastatin in a clinical trial showing that is safe in its conditions,[134] even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term.[135] Other clinical trials have found problems combining IFN beta with Atorvastatin[136]
  • Interferon beta-1b and 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.[137]
  • Cyclophosphamide and Beta-Interferon has been tried on IFNbeta-unresponsive patients with success, but it is still under study.[138]
  • Avonex and 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.[139][140] 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.[141]
  • Avonex and lipoic acid: Lipoic Acid is another common antioxidant[142]
  • Siponimod and Laquinimod: Patent pending[143]
  • Ponesimod and Tecfidera: Under study[144]

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[128] NO — — — — — — —
Mitoxantrone NO NO YES[121][122] — — — — — —
Natalizumab (Tysabri) YES (linked to PML) NO YES[123] 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)[145] NO NO NO NO NO NO NO NO —
Atorvastatin (Lipitor) YES YES[137] NO NO NO NO NO NO NO
Cyclophosphamide NO YES NO NO NO NO NO NO NO
Inosine YES[139][140] NO NO NO NO NO NO NO NO

Biomarkers for the expected response

Personalized treatment or theranostics in MS is an active field or research. Currently is trying to predict the response to the different known medications.

Interferons

Beta-interferons are contraindicated in cases of anti-AQP4 or anti-MOG seropositivity. Interferon injections can induce neutralising antibodies against them, turning the medication ineffective. IFN-β 1b is more immunogenic than IFN-β 1a, and the subcutaneous administration has a higher risk than the intramuscular administration[146] Both interferons should induce MxA (myxovirus protein A) mRNA, being its absence a negative indicator[147]

There is heterogeneity in the immunologic pathways even restricted to RRMS population, and it correlates with IFN-β response. In a small study patients were clustered into 6 distinct subsets by baseline cytokine profiles. Two subsets were associated with patients who responded poorly to therapy. Two other subsets showed a significant reduction in relapse rates and no worsening of disability.[148]

Glatimer Acetate

For Glatimer Acetate, the biomarkers for response are interleukins. IL-27 is a biomarker for response, and IL-18 and IL-4 are also possible good biomarkers[149][150]

It also seems that phosphorylated SIRT1 expression in mRNA is also a biomarker for response.[151]

Mitoxantrone

The best predictive biomarker for Mitoxantrone available is the number of relapses in separate areas within the past 24 months before treatment.[152]

Natalizumab

Natalizumab can also induce neutralising antibodies 4 to 6 months after treatment initiation. Fetuin-A (alpha-2-HS-glycoprotein) and circulating CD49 expression are emerging biomarkers for the therapeutic efficacy of natalizumab.[146]

Fingolimod

Lymphocyte subpopulations in peripheral blood is a promising tool to select RRMS candidate for fingolimod treatment.[153]

Rituximab and anti-CD20

Gadolinium enhancement before treatment initiation as a predictor of anti-CD20 response in MS.[154]

gollark: Are they providing significant value over non-green threads or, say, asynchronous IO? Are libraries in other languages not working for you?
gollark: ***p i c a l c u l u s***
gollark: Garbage collection, sure, that might be useful.
gollark: You won't use the green threads half the time and libraries exist.
gollark: And?

References
  1. Novartis press release about the approval
  2. "FDA approves new multiple sclerosis treatment Aubagio" (Press release). US FDA. 12 September 2012. Archived from the original on 16 January 2013. Retrieved 21 January 2013.
  3. "Biogen Idec's Tecfidera (Dimethyl Fumarate) Approved in US as a First-Line Oral Treatment for Multiple Sclerosis" (Press release). Biogen Idec. 27 March 2013. Archived from the original on 12 May 2013. Retrieved 4 June 2013.
  4. "Drug Approval Package: Tecfidera (dimethyl fumarate) Delayed-Release Capsules NDA #204063". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 30 June 2020.
  5. Matthew Dodson et al., Modulating NRF2 in Disease: Timing Is Everything, Annual Review of Pharmacology and Toxicology, Vol. 59, January 2019, Review in Advance first posted online on September 26, 2018, https://doi.org/10.1146/annurev-pharmtox-010818-021856
  6. "Vumerity (Previously BIIB098 and ALKS 8700)". Multiple Sclerosis News Today. 1 November 2019. Retrieved 21 February 2020.
  7. "Biogen and Alkermes Announce FDA Approval of Vumerity (diroximel fumarate) for Multiple Sclerosis". Biogen. Retrieved 2020-02-21.
  8. "Vumerity- diroximel fumarate capsule". DailyMed. 30 March 2020. Retrieved 30 June 2020.
  9. "Drug Approval Package: Vumerity". U.S. Food and Drug Administration (FDA). 21 April 2020. Retrieved 30 June 2020.
  10. "Bafiertam: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 April 2020.
  11. FDA approves new oral drug to treat multiple sclerosis in the US, Press release,
  12. Novartis receives FDA approval for Mayzent (siponimod), the first oral drug to treat SPMS with active disease, Press Release,
  13. "Zeposia: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 27 March 2020.
  14. "Drug Trials Snapshots: Zeposia". U.S. Food and Drug Administration (FDA). 25 March 2020. Retrieved 1 April 2020. This article incorporates text from this source, which is in the public domain.
  15. "U.S. Food and Drug Administration Approves Bristol Myers Squibb's ZEPOSIA (ozanimod), a New Oral Treatment for Relapsing Forms of Multiple Sclerosis". Bristol-Myers Squibb Company (Press release). 26 March 2020. Retrieved 26 March 2020.
  16. "FDA Approves Lemtrada" (Press release). Biogen Idec Press Release. 14 November 2013.
  17. "FDA Ocrevus approval" (Press release). U.S. Food and Drug Administration. March 29, 2017. Retrieved 24 August 2017.
  18. Jorissen W, Vanmierlo T, Wens I, Somers V, Van Wijmeersch B, Bogie JF, Remaley AT, Eijnde BO, Hendriks JJ (January 2018). "Twelve Weeks of Medium-Intensity Exercise Therapy Affects the Lipoprotein Profile of Multiple Sclerosis Patients". International Journal of Molecular Sciences. 19 (1): 88–105. doi:10.3390/ijms19010193. PMC 5755648. PMID 29316715.
  19. Stephen L. Hauser, Jonah R. Chan, Jorge R. Oksenberg, Multiple sclerosis: Prospects and promise, Annals of Neur. 16 August 2013,
  20. Wawrzyniak S, Rzepinski L (2020). "Is there a new place for mitoxantrone in the treatment of multiple sclerosis?". Neurol Neurochir Pol. 54 (1): 54–61. doi:10.5603/PJNNS.a2019.0069. PMID 31922582.
  21. Sørensen, Per Soelberg; Centonze, Diego; Giovannoni, Gavin; Montalban, Xavier; Selchen, Daniel; Vermersch, Patrick; Wiendl, Heinz; Yamout, Bassem; Salloukh, Hashem; Rieckmann, Peter (24 June 2020). "Expert opinion on the use of cladribine tablets in clinical practice". Therapeutic Advances in Neurological Disorders. 13: 175628642093501. doi:10.1177/1756286420935019.
  22. "European Commission Grants Approval for Mavenclad (Cladribine Tablets)". www.merckgroup.com.
  23. FDA press release, April 2019
  24. Saida T (Nov 2004). "Multiple sclerosis: treatment and prevention of relapses and progression in multiple sclerosis". Rinsho Shinkeigaku. 44 (11): 796–8. PMID 15651294.
  25. Gonsette RE, Dubois B (August 2004). "Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity". Journal of the Neurological Sciences. 223 (1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
  26. "FDA BLA Approval letter" (PDF). May 27, 2016. Retrieved 24 August 2017.
  27. "FDA approves Zinbryta to treat multiple sclerosis" (Press release). U.S. Food and Drug Administration. May 27, 2016. Retrieved 24 August 2017.
  28. The Lancet (March 2018). "End of the road for daclizumab in multiple sclerosis". Lancet. 391 (10125): 1000. doi:10.1016/S0140-6736(18)30565-8. PMID 29565004.
  29. Barkhof F, Hulst HE, Drulovic J, Uitdehaag BM, Matsuda K, Landin R (March 2010). "Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant?". Neurology. 74 (13): 1033–40. doi:10.1212/WNL.0b013e3181d7d651. PMID 20200338.
  30. "Potential Progressive MS Treatment, Ibudilast, Approved for Fast Track Development by FDA - Multiple Sclerosis News Today". 23 March 2016.
  31. "Janssen Submits Ponesimod New Drug Application to the U.S. FDA for Treatment of Adults with Relapsing Multiple Sclerosis" (Press release). Janssen Pharmaceutical. 18 March 2020. Retrieved 23 July 2020 – via PR Newswire.
  32. "Janssen Asks EMA to Approve Oral Ponesimod to Treat Relapsing MS". Multiple Sclerosis News Today Home. 4 March 2020. Retrieved 23 July 2020.
  33. Press rel. about chronic lymphocytic leukemia
  34. Troy Kish, Promising Multiple Sclerosis Agents In Late-Stage Development, PIPELINE PLUS, Vol. 43 No. 12, Dec 2018, url:
  35. Novartis press release
  36. "Masitinib - Multiple Sclerosis Society UK". www.mssociety.org.uk.
  37. AB Science Press release
  38. Congress Report
  39. https://clinicaltrials.gov/ct2/show/NCT03277261
  40. Montalban X, Arnold D, Weber M, Staikov I, Piasecka-Stryczynska K, Willmer J, Martin EC, Dangond F, Syed S, and Wolinsky JS (May 2019). "Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis". NEJM. 380 (25): 2406–2417. doi:10.1056/NEJMoa1901981. PMID 31075187.
  41. Montalban X, et al. (2019). "Placebo-Controlled Trial of an Oral BTK Inhibitor in Multiple Sclerosis". N Engl J Med. 380 (25): 2406–2417. doi:10.1056/NEJMoa1901981. PMID 31075187.
  42. Press release
  43. Kappos L, Arnold DL, Bar-Or A, Camm J, Derfuss T, Kieseier BC, Sprenger T, Greenough K, Ni P, Harada T (October 2016). "Safety and efficacy of amiselimod in relapsing multiple sclerosis (MOMENTUM): a randomised, double-blind, placebo-controlled phase 2 trial". The Lancet. Neurology. 15 (11): 1148–59. doi:10.1016/S1474-4422(16)30192-2. PMID 27543447.
  44. clinicaltrial.gov CDP323 Phase II Study. Archived 2011-07-21 at the Wayback Machine Retrieved on 25 November 2007.
  45. Green AJ, Gelfand JM, Cree BA, Bevan C, Boscardin WJ, Mei F, Inman J, Arnow S, Devereux M, Abounasr A, Nobuta H, Zhu A, Friessen M, Gerona R, von Büdingen HC, Henry RG, Hauser SL, Chan JR (December 2017). "Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial". Lancet. 390 (10111): 2481–2489. doi:10.1016/S0140-6736(17)32346-2. PMID 29029896.
  46. Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR (September 2007). "Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment". Proceedings of the National Academy of Sciences of the United States of America. 104 (37): 14813–8. Bibcode:2007PNAS..10414813T. doi:10.1073/pnas.0703783104. PMC 1976208. PMID 17785421.
  47. Palaszynski KM, Liu H, Loo KK, Voskuhl RR (April 2004). "Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis". Journal of Neuroimmunology. 149 (1–2): 84–9. doi:10.1016/j.jneuroim.2003.12.015. PMID 15020068.
  48. Sicotte NL, Liva SM, Klutch R, Pfeiffer P, Bouvier S, Odesa S, Wu TC, Voskuhl RR (October 2002). "Treatment of multiple sclerosis with the pregnancy hormone estriol". Annals of Neurology. 52 (4): 421–8. doi:10.1002/ana.10301. PMID 12325070.
  49. Gold SM, Voskuhl RR (November 2009). "Estrogen treatment in multiple sclerosis". Journal of the Neurological Sciences. 286 (1–2): 99–103. doi:10.1016/j.jns.2009.05.028. PMC 2760629. PMID 19539954.
  50. Voskuhl RR, Wang H, Wu TC, Sicotte NL, Nakamura K, Kurth F, Itoh N, Bardens J, Bernard JT, Corboy JR, Cross AH, Dhib-Jalbut S, Ford CC, Frohman EM, Giesser B, Jacobs D, Kasper LH, Lynch S, Parry G, Racke MK, Reder AT, Rose J, Wingerchuk DM, MacKenzie-Graham AJ, Arnold DL, Tseng CH, Elashoff R (January 2016). "Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial" (PDF). The Lancet. Neurology. 15 (1): 35–46. doi:10.1016/s1474-4422(15)00322-1. PMID 26621682.
  51. Clinical trial number NCT00067327 for "Treatment of Multiple Sclerosis Using Over the Counter Inosine" at ClinicalTrials.gov
  52. Toncev G (October 2006). "Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis". Vojnosanitetski Pregled. 63 (10): 879–82. doi:10.2298/VSP0610879T. PMID 17121380.
  53. Koch M, De Keyser J (April 2006). "Uric acid in multiple sclerosis". Neurological Research. 28 (3): 316–9. doi:10.1179/016164106X98215. PMID 16687059.
  54. Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M, Vassilopoulos D (September 2006). "Serum uric acid and multiple sclerosis". Clinical Neurology and Neurosurgery. 108 (6): 527–31. doi:10.1016/j.clineuro.2005.08.004. PMID 16202511.
  55. Chen P, Goldberg DE, Kolb B, Lanser M, Benowitz LI (June 2002). "Inosine induces axonal rewiring and improves behavioral outcome after stroke". Proceedings of the National Academy of Sciences of the United States of America. 99 (13): 9031–6. Bibcode:2002PNAS...99.9031C. doi:10.1073/pnas.132076299. PMC 124418. PMID 12084941.
  56. Liu F, You SW, Yao LP, Liu HL, Jiao XY, Shi M, Zhao QB, Ju G (July 2006). "Secondary degeneration reduced by inosine after spinal cord injury in rats". Spinal Cord. 44 (7): 421–6. doi:10.1038/sj.sc.3101878. PMID 16317421.
  57. McNaughton L, Dalton B, Tarr J (December 1999). "Inosine supplementation has no effect on aerobic or anaerobic cycling performance". International Journal of Sport Nutrition. 9 (4): 333–44. doi:10.1123/ijsn.9.4.333. PMID 10660865.
  58. Markowitz CE, Spitsin S, Zimmerman V, Jacobs D, Udupa JK, Hooper DC, Koprowski H (June 2009). "The treatment of multiple sclerosis with inosine". Journal of Alternative and Complementary Medicine. 15 (6): 619–25. doi:10.1089/acm.2008.0513. PMC 3189001. PMID 19425822.
  59. Junqueira SC, Dos Santos Coelho I, Lieberknecht V, Cunha MP, Calixto JB, Rodrigues AL, Santos AR, Dutra RC (July 2017). "Inosine, an Endogenous Purine Nucleoside, Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis: a Role for A2A Adenosine Receptor". Molecular Neurobiology. 54 (5): 3271–3285. doi:10.1007/s12035-016-9893-3. PMID 27130268.
  60. Burt RK, Loh Y, Cohen B, Stefoski D, Stefosky D, Balabanov R, Katsamakis G, Oyama Y, Russell EJ, Stern J, Muraro P, Rose J, Testori A, Bucha J, Jovanovic B, Milanetti F, Storek J, Voltarelli JC, Burns WH (March 2009). "Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: a phase I/II study" (PDF). The Lancet. Neurology. 8 (3): 244–53. doi:10.1016/S1474-4422(09)70017-1. hdl:10044/1/21144. PMID 19186105.
  61. GeNeuro Announces Positive Results from Temelimab (GNbAC1) Phase 1 High-dose Clinical Trial, Press Release,
  62. ANGEL-MS Phase 2b extension study confirms and extends the neuroprotective effects of temelimab in MS, Press release,
  63. "Opexa shares lose most of value on study data".
  64. "Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin For Treatment Of Multiple Sclerosis".
  65. Tovaxin phase III announced http://www.opexatherapeutics.com/?page=release&section=news&article=010511
  66. Shirani, Afsaneh; Okuda, Darin T.; Stüve, Olaf (4 January 2016). "Therapeutic Advances and Future Prospects in Progressive Forms of Multiple Sclerosis". Neurotherapeutics. 13 (1): 58–69. doi:10.1007/s13311-015-0409-z. PMC 4720678. PMID 26729332.
  67. MS society o Canada, press release https://mssociety.ca/research-news/treatments-in-development/amiloride-fluoxetine-riluzole
  68. "McGill/JGH researchers successfully reverse multiple sclerosis in animals New immune-suppressing treatment forces the disease into remission in mice". McGill University. August 11, 2009. Retrieved 2009-08-12.
  69. "Multiple Sclerosis Successfully Reversed In Mice: New Immune-suppressing Treatment Forces The Disease Into Remission". Science Daily. August 12, 2009.
  70. Rafei M, Hsieh J, Zehntner S, Li M, Forner K, Birman E, Boivin MN, Young YK, Perreault C, Galipeau J (September 2009). "A granulocyte-macrophage colony-stimulating factor and interleukin-15 fusokine induces a regulatory B cell population with immune suppressive properties". Nature Medicine. 15 (9): 1038–45. doi:10.1038/nm.2003. PMID 19668193.
  71. D'haeseleer M, Beelen R, Fierens Y, Cambron M, Vanbinst AM, Verborgh C, Demey J, De Keyser J (April 2013). "Cerebral hypoperfusion in multiple sclerosis is reversible and mediated by endothelin-1". Proceedings of the National Academy of Sciences of the United States of America. 110 (14): 5654–8. Bibcode:2013PNAS..110.5654D. doi:10.1073/pnas.1222560110. PMC 3619305. PMID 23509249.
  72. Li X, et al. (2018). "Carnosol modulates Th17 cell differentiation and microglia switch in experimental autoimmune encephalomyelitis". Front. Immunol. 9: 1807. doi:10.3389/fimmu.2018.01807. PMC 6100297. PMID 30150982.
  73. Neumann B, et al. (2019). "Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells". Cell Stem Cell. 25 (4): 473–485.e8. doi:10.1016/j.stem.2019.08.015. PMC 6863391. PMID 31585093.
  74. UK Great Ormond Street Hospital
  75. Choices - Disease Modifying Therapies, web online publication
  76. Stephen L. Hauser, Jonah R. Chan, Jorge R. Oksenberg, Multiple sclerosis: Prospects and promise, Annals Neurol. Volume74, Issue3, Pages 317-327, September 2013,
  77. Awad A, Stüve O (Nov 2009). "Cyclophosphamide in Multiple Sclerosis: Scientific Rationale, History and Novel Treatment Paradigms". Ther Adv Neurol Disord. 2 (6): 50–61. doi:10.1177/1756285609344375. PMC 3002608. PMID 21180630.
  78. Significant Advances in Multiple Sclerosis Treatment http://www.pharmacytimes.com/publications/specialty-pt/2011/February-2011/SPT-NPP-0211 Archived 2016-08-19 at the Wayback Machine
  79. Gladstone DE, Zamkoff KW, Krupp L, Peyster R, Sibony P, Christodoulou C, Locher E, Coyle PK (October 2006). "High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis". Archives of Neurology. 63 (10): 1388–93. doi:10.1001/archneur.63.10.noc60076. PMID 16908728.
  80. Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Amato MP (March 2008). "Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: an open-label comparative study of efficacy and safety". Journal of the Neurological Sciences. 266 (1–2): 25–30. doi:10.1016/j.jns.2007.08.023. PMID 17870094.
  81. Krishnan C, Kaplin AI, Brodsky RA, Drachman DB, Jones RJ, Pham DL, Richert ND, Pardo CA, Yousem DM, Hammond E, Quigg M, Trecker C, McArthur JC, Nath A, Greenberg BM, Calabresi PA, Kerr DA (August 2008). "Reduction of disease activity and disability with high-dose cyclophosphamide in patients with aggressive multiple sclerosis". Archives of Neurology. 65 (8): 1044–51. doi:10.1001/archneurol.65.8.noc80042. PMC 2574697. PMID 18541787.
  82. Chataway J, Schuerer N, Alsanousi A, Chan D, MacManus D, Hunter K, Anderson V, Bangham CR, Clegg S, Nielsen C, Fox NC, Wilkie D, Nicholas JM, Calder VL, Greenwood J, Frost C, Nicholas R (June 2014). "Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial". Lancet. 383 (9936): 2213–21. doi:10.1016/S0140-6736(13)62242-4. PMID 24655729.
  83. Villar LM, Casanova B, Ouamara N, Comabella M, Jalili F, Leppert D, de Andrés C, Izquierdo G, Arroyo R, Avşar T, Lapin SV, Johnson T, Montalbán X, Fernández O, Álvarez-Lafuente R, Masterman D, García-Sánchez MI, Coret F, Siva A, Evdoshenko E, Álvarez-Cermeño JC, Bar-Or A (August 2014). "Immunoglobulin M oligoclonal bands: biomarker of targetable inflammation in primary progressive multiple sclerosis". Annals of Neurology. 76 (2): 231–40. doi:10.1002/ana.24190. PMID 24909126.
  84. Bagos PG, Nikolopoulos G, Ioannidis A (August 2006). "Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis". Multiple Sclerosis. 12 (4): 397–411. doi:10.1191/1352458506ms1291oa. PMID 16900753.
  85. Sriram S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS (July 2005). "Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS". Journal of the Neurological Sciences. 234 (1–2): 87–91. doi:10.1016/j.jns.2005.03.042. PMID 15935383.
  86. Oztaş B, Kiliç S, Dural E, Ispir T (November 2001). "Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures". Journal of Neuroscience Research. 66 (4): 674–8. doi:10.1002/jnr.10023. PMID 11746387.
  87. "Uric Acid In Multiple Sclerosis". 1997–2005. Archived from the original on 2005-05-07. Retrieved 2006-05-10.
  88. Kean RB, Spitsin SV, Mikheeva T, Scott GS, Hooper DC (December 2000). "The peroxynitrite scavenger uric acid prevents inflammatory cell invasion into the central nervous system in experimental allergic encephalomyelitis through maintenance of blood-central nervous system barrier integrity". Journal of Immunology. 165 (11): 6511–8. doi:10.4049/jimmunol.165.11.6511. PMID 11086092.
  89. Schreibelt G, van Horssen J, van Rossum S, Dijkstra CD, Drukarch B, de Vries HE (December 2007). "Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology". Brain Research Reviews. 56 (2): 322–30. doi:10.1016/j.brainresrev.2007.07.005. PMID 17761296.
  90. Moccia M, Lanzillo R, Costabile T, Russo C, Carotenuto A, Sasso G, Postiglione E, De Luca Picione C, Vastola M, Maniscalco GT, Palladino R, Brescia Morra V (2015). "Uric acid in relapsing-remitting multiple sclerosis: a 2-year longitudinal study". Journal of Neurology. 262 (4): 961–7. doi:10.1007/s00415-015-7666-y. PMID 25673130.
  91. Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M (August 2008). "Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis". Journal of Immunology. 181 (3): 1887–97. doi:10.4049/jimmunol.181.3.1887. PMID 18641326.
  92. Beeton C, Wulff H, Barbaria J, Clot-Faybesse O, Pennington M, Bernard D, Cahalan MD, Chandy KG, Béraud E (November 2001). "Selective blockade of T lymphocyte K(+) channels ameliorates experimental autoimmune encephalomyelitis, a model for multiple sclerosis". Proceedings of the National Academy of Sciences of the United States of America. 98 (24): 13942–7. Bibcode:2001PNAS...9813942B. doi:10.1073/pnas.241497298. PMC 61146. PMID 11717451.
  93. Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, Chandy KG (June 2003). "The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS". The Journal of Clinical Investigation. 111 (11): 1703–13. doi:10.1172/JCI16921. PMC 156104. PMID 12782673.
  94. Vennekamp J, Wulff H, Beeton C, Calabresi PA, Grissmer S, Hänsel W, Chandy KG (June 2004). "Kv1.3-blocking 5-phenylalkoxypsoralens: a new class of immunomodulators". Molecular Pharmacology. 65 (6): 1364–74. doi:10.1124/mol.65.6.1364. PMID 15155830.
  95. Rus H, Pardo CA, Hu L, Darrah E, Cudrici C, Niculescu T, Niculescu F, Mullen KM, Allie R, Guo L, Wulff H, Beeton C, Judge SI, Kerr DA, Knaus HG, Chandy KG, Calabresi PA (August 2005). "The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain". Proceedings of the National Academy of Sciences of the United States of America. 102 (31): 11094–9. Bibcode:2005PNAS..10211094R. doi:10.1073/pnas.0501770102. PMC 1182417. PMID 16043714.
  96. Matheu MP, Beeton C, Garcia A, Chi V, Rangaraju S, Safrina O, Monaghan K, Uemura MI, Li D, Pal S, de la Maza LM, Monuki E, Flügel A, Pennington MW, Parker I, Chandy KG, Cahalan MD (October 2008). "Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block". Immunity. 29 (4): 602–14. doi:10.1016/j.immuni.2008.07.015. PMC 2732399. PMID 18835197.
  97. Leung G, Sun W, Zheng L, Brookes S, Tully M, Shi R (January 2011). "Anti-acrolein treatment improves behavioral outcome and alleviates myelin damage in experimental autoimmune encephalomyelitis mouse". Neuroscience. 173: 150–5. doi:10.1016/j.neuroscience.2010.11.018. PMC 3034379. PMID 21081153.
  98. Correale J, Farez M (February 2007). "Association between parasite infection and immune responses in multiple sclerosis". Annals of Neurology. 61 (2): 97–108. doi:10.1002/ana.21067. PMID 17230481.
  99. Correale J, Farez M, Razzitte G (August 2008). "Helminth infections associated with multiple sclerosis induce regulatory B cells". Annals of Neurology. 64 (2): 187–99. doi:10.1002/ana.21438. PMID 18655096.
  100. Fleming JO, Isaak A, Lee JE, Luzzio CC, Carrithers MD, Cook TD, Field AS, Boland J, Fabry Z (June 2011). "Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study". Multiple Sclerosis. 17 (6): 743–54. doi:10.1177/1352458511398054. PMC 3894910. PMID 21372112.
  101. Ristori G, Buzzi MG, Sabatini U, Giugni E, Bastianello S, Viselli F, Buttinelli C, Ruggieri S, Colonnese C, Pozzilli C, Salvetti M (October 1999). "Use of Bacille Calmette-Guèrin (BCG) in multiple sclerosis". Neurology. 53 (7): 1588–9. doi:10.1212/wnl.53.7.1588. PMID 10534275.
  102. Paolillo A, Buzzi MG, Giugni E, Sabatini U, Bastianello S, Pozzilli C, Salvetti M, Ristori G (February 2003). "The effect of Bacille Calmette-Guérin on the evolution of new enhancing lesions to hypointense T1 lesions in relapsing remitting MS". Journal of Neurology. 250 (2): 247–8. doi:10.1007/s00415-003-0967-6. PMID 12622098.
  103. Rutschmann OT, McCrory DC, Matchar DB (December 2002). "Immunization and MS: a summary of published evidence and recommendations". Neurology. 59 (12): 1837–43. doi:10.1212/wnl.59.12.1837. PMID 12499473.
  104. Clinical trial number NCT00501696 for "A Randomized Placebo-Controlled, Crossover-Design Study of the Effects of Low Dose Naltrexone" at ClinicalTrials.gov
  105. Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G (September 2008). "A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis". Multiple Sclerosis. 14 (8): 1076–83. doi:10.1177/1352458508095828. PMID 18728058.
  106. Zabad RK, Metz LM, Todoruk TR, Zhang Y, Mitchell JR, Yeung M, Patry DG, Bell RB, Yong VW (May 2007). "The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study". Multiple Sclerosis. 13 (4): 517–26. doi:10.1177/1352458506070319. PMID 17463074."It has been available for over 30 years and, in the United Kingdom alone, more than 6.5 million people have been treated with minocycline for an average of 9 months, mostly for acne." Minocycline is probably the most cost effective, and effective treatment available for MS, but its low cost, means that large pharmaceutical companies will fight to prevent its introduction as an MS treatment.
  107. "May 2003 Emerging Therapies for MS".
  108. Tilley BC, Alarcón GS, Heyse SP, Trentham DE, Neuner R, Kaplan DA, Clegg DO, Leisen JC, Buckley L, Cooper SM, Duncan H, Pillemer SR, Tuttleman M, Fowler SE (January 1995). "Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group". Annals of Internal Medicine. 122 (2): 81–9. doi:10.1001/archinte.122.1.81. PMID 7993000.
  109. Gonsette RE, Dubois B (August 2004). "Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity". Journal of the Neurological Sciences. 223 (1): 81–6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
  110. Wilner AN, Goodman (March 2000). "Some MS patients have "Dramatic" responses to Plasma Exchange". Neurology Reviews. 8 (3). Archived from the original on 2009-08-07. Retrieved 2016-07-26.
  111. Srivastava R, Aslam M, Kalluri SR, Schirmer L, Buck D, Tackenberg B, Rothhammer V, Chan A, Gold R, Berthele A, Bennett JL, Korn T, Hemmer B (July 2012). "Potassium channel KIR4.1 as an immune target in multiple sclerosis". The New England Journal of Medicine. 367 (2): 115–23. doi:10.1056/NEJMoa1110740. PMC 5131800. PMID 22784115.
  112. Gregg C, Shikar V, Larsen P, Mak G, Chojnacki A, Yong VW, Weiss S (February 2007). "White matter plasticity and enhanced remyelination in the maternal CNS". The Journal of Neuroscience. 27 (8): 1812–23. doi:10.1523/JNEUROSCI.4441-06.2007. PMC 6673564. PMID 17314279.
  113. Vukusic S, Confavreux C (March 2006). "[Multiple sclerosis and pregnancy]" [Multiple sclerosis and pregnancy]. Revue Neurologique (in French). 162 (3): 299–309. doi:10.1016/S0035-3787(06)75016-0. PMID 16585885.
  114. Weber MS, Prod'homme T, Steinman L, Zamvil SS (December 2005). "Drug Insight: using statins to treat neuroinflammatory disease". Nature Clinical Practice Neurology. 1 (2): 106–12. doi:10.1038/ncpneuro0047. PMID 16932506.
  115. "Statin may slow progressive MS".
  116. Sicotte NL, Giesser BS, Tandon V, Klutch R, Steiner B, Drain AE, Shattuck DW, Hull L, Wang HJ, Elashoff RM, Swerdloff RS, Voskuhl RR (May 2007). "Testosterone treatment in multiple sclerosis: a pilot study". Archives of Neurology. 64 (5): 683–8. doi:10.1001/archneur.64.5.683. PMID 17502467.
  117. Munger KL, Zhang SM, O'Reilly E, Hernán MA, Olek MJ, Willett WC, Ascherio A (January 2004). "Vitamin D intake and incidence of multiple sclerosis". Neurology. 62 (1): 60–5. doi:10.1212/01.wnl.0000101723.79681.38. PMID 14718698.
  118. Mowry EM, Waubant E, McCulloch CE, Okuda DT, Evangelista AA, Lincoln RR, Gourraud PA, Brenneman D, Owen MC, Qualley P, Bucci M, Hauser SL, Pelletier D., Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis
  119. Shinto L, Marracci G, Baldauf-Wagner S, Strehlow A, Yadav V, Stuber L, Bourdette D (2009). "Omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 80 (2–3): 131–6. doi:10.1016/j.plefa.2008.12.001. PMC 2692605. PMID 19171471.
  120. "United Kingdom early Mitoxantrone Copaxone trial". Archived from the original on 2015-06-01. Retrieved 2020-04-09.
  121. Vollmer T, Panitch H, Bar-Or A, Dunn J, Freedman MS, Gazda SK, Campagnolo D, Deutsch F, Arnold DL (June 2008). "Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis". Multiple Sclerosis. 14 (5): 663–70. doi:10.1177/1352458507085759. PMID 18424479.
  122. Arnold DL, Campagnolo D, Panitch H, Bar-Or A, Dunn J, Freedman MS, Gazda SK, Vollmer T (October 2008). "Glatiramer acetate after mitoxantrone induction improves MRI markers of lesion volume and permanent tissue injury in MS". Journal of Neurology. 255 (10): 1473–8. doi:10.1007/s00415-008-0911-x. PMID 18854910.
  123. Goodman AD, Rossman H, Bar-Or A, Miller A, Miller DH, Schmierer K, Lublin F, Khan O, Bormann NM, Yang M, Panzara MA, Sandrock AW (March 2009). "GLANCE: results of a phase 2, randomized, double-blind, placebo-controlled study". Neurology. 72 (9): 806–12. doi:10.1212/01.wnl.0000343880.13764.69. PMC 2821836. PMID 19255407.
  124. Zaffaroni M, Rizzo A, Baldini SM, Ghezzi A, Comi G (September 2008). "Induction and add-on therapy with mitoxantrone and interferon beta in multiple sclerosis". Neurological Sciences. 29 Suppl 2 (Suppl 2): S230-2. doi:10.1007/s10072-008-0946-x. PMID 18690501.
  125. "NIH Deepens Investment In Combination Study Of MS Drugs".
  126. Radue EW, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Rudick RA, Lublin FD, Weinstock-Guttman B, Wynn DR, Fisher E, Papadopoulou A, Lynn F, Panzara MA, Sandrock AW (May 2010). "Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis". Journal of the Neurological Sciences. 292 (1–2): 28–35. doi:10.1016/j.jns.2010.02.012. PMID 20236661.
  128. "Common MS Drugs Taken Together Do Not Reduce Relapse Risk".
  129. "Sanofi and Genzyme Report New Positive Data from First Phase III Study with MS Drug". 24 October 2011.
  130. Treatment of multiple sclerosis with combination of laquinimod and fampridine, US Patent US 20160235735 A1
  131. Du FH, Mills EA, Mao-Draayer Y (November 2017). "Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment". Auto- Immunity Highlights. 8 (1): 12. doi:10.1007/s13317-017-0100-y. PMC 5688039. PMID 29143151.
  132. US patent US20180050031A1
  133. Metz LM, Li D, Traboulsee A, Myles ML, Duquette P, Godin J, Constantin M, Yong VW (October 2009). "Glatiramer acetate in combination with minocycline in patients with relapsing--remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial". Multiple Sclerosis. 15 (10): 1183–94. doi:10.1177/1352458509106779. PMID 19776092.
  134. Paul F, Waiczies S, Wuerfel J, Bellmann-Strobl J, Dörr J, Waiczies H, Haertle M, Wernecke KD, Volk HD, Aktas O, Zipp F (April 2008). Gwinn K (ed.). "Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis". PLOS ONE. 3 (4): e1928. Bibcode:2008PLoSO...3.1928P. doi:10.1371/journal.pone.0001928. PMC 2276246. PMID 18398457.
  135. Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman
  136. Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT (October 2008). "Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis". Neurology. 71 (18): 1390–5. doi:10.1212/01.wnl.0000319698.40024.1c. PMID 18525027.
  137. Kamm CP, El-Koussy M, Humpert S, Findling O, Burren Y, Schwegler G, Donati F, Müller M, Müller F, Slotboom J, Kappos L, Naegelin Y, Mattle HP (2014). "Atorvastatin added to interferon beta for relapsing multiple sclerosis: 12-month treatment extension of the randomized multicenter SWABIMS trial". PLOS ONE. 9 (1): e86663. Bibcode:2014PLoSO...986663K. doi:10.1371/journal.pone.0086663. PMC 3907426. PMID 24497963.
  138. Perini P, Calabrese M, Rinaldi L, Gallo P (September 2008). "Cyclophosphamide-based combination therapies for autoimmunity". Neurological Sciences. 29. 29 Suppl 2 (S2): S233-4. doi:10.1007/s10072-008-0947-9. PMID 18690502.
  139. Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman
  140. Gonsette RE, Sindic C, D'hooghe MB, De Deyn PP, Medaer R, Michotte A, Seeldrayers P, Guillaume D (April 2010). "Boosting endogenous neuroprotection in multiple sclerosis: the ASsociation of Inosine and Interferon beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial". Multiple Sclerosis. 16 (4): 455–62. doi:10.1177/1352458509360547. PMID 20200198.
  141. Muñoz García D, Midaglia L, Martinez Vilela J, Marín Sánchez M, López González FJ, Arias Gómez M, Dapena Bolaño D, Iglesias Castañón A, Alonso Alonso M, Romero López J (June 2015). "Associated Inosine to interferon: results of a clinical trial in multiple sclerosis". Acta Neurologica Scandinavica. 131 (6): 405–10. doi:10.1111/ane.12333. PMID 25313094.
  142. Valentina Durastanti et al. ALPHA LIPOIC ACID AS ADD-ON THERAPY TO SUBCUTANEOUS INTERFERON Β-1A FOR RELAPSING-REMITTING MULTIPLE SCLEROSIS: A PILOT STUDY, International Journal of Applied Biology and Pharmaceutical Technology Page: 336
  143. United States Patent Application 20170304289, Smith, Paul Alfred (Saint Louis-Strasse, CH)Application Number: 15/517280
  144. Global Phase 3 Trial of Oral Ponesimod Plus Tecfidera Enrolling Relapsing MS Patients
  145. FDA approves Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis
  146. Del Boccio P, Rossi C, di Ioia M, Cicalini I, Sacchetta P, Pieragostino D (April 2016). "Integration of metabolomics and proteomics in multiple sclerosis: From biomarkers discovery to personalized medicine". Proteomics. Clinical Applications. 10 (4): 470–84. doi:10.1002/prca.201500083. PMID 27061322.
  147. Tomas Uher et al. Absence of MxA induction is related to a poor clinical response to interferon beta treatment in multiple sclerosis patients, Neurology 2016; vol. 86 no. 16 Supplement P3.019
  148. Hegen H, et al. (Apr 2016). "Cytokine profiles show heterogeneity of interferon-β response in multiple sclerosis patients". Neurol Neuroimmunol Neuroinflamm. 3 (2): e202. doi:10.1212/NXI.0000000000000202. PMC 4747480. PMID 26894205.
  149. Mindur JE, Valenzuela RM, Yadav SK, Boppana S, Dhib-Jalbut S, Ito K (March 2017). "IL-27: a potential biomarker for responders to glatiramer acetate therapy". Journal of Neuroimmunology. 304: 21–28. doi:10.1016/j.jneuroim.2016.07.004. PMID 27449853.
  150. Valenzuela RM, Kaufman M, Balashov KE, Ito K, Buyske S, Dhib-Jalbut S (November 2016). "Predictive cytokine biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis". Journal of Neuroimmunology. 300: 59–65. doi:10.1016/j.jneuroim.2016.06.005. PMID 27390072.
  151. Ciriello J, et al. (2018). "Phosphorylated SIRT1 as a biomarker of relapse and response to treatment with glatiramer acetate in multiple sclerosis". Experimental and Molecular Pathology. 105 (2): 175–180. doi:10.1016/j.yexmp.2018.07.008. PMID 30028960.
  152. Debouverie M, Vandenberghe N, Morrissey SP, Anxionnat R, Pittion-Vouyovitch S, Vespignani H, Edan G (August 2004). "Predictive parameters of mitoxantrone effectiveness in the treatment of multiple sclerosis". Multiple Sclerosis. 10 (4): 407–12. doi:10.1191/1352458504ms1066oa. PMID 15327038.
  153. Bibiana Quirant‐Sánchez et al, Predicting therapeutic response to fingolimod treatment in multiple sclerosis patients, 15 April 2018, doi=https://doi.org/10.1111/cns.12851
  154. R Hoepner1, A Miclea1, J Popovic1, 2, N Kamber1, A Chan1, A Salmen1, Immunoglobulin levels may aid in the prediction of treatment response in anti-CD20 treatment of multiple sclerosis, March 22, 2018; Issue published: June 1, 2018, https://doi.org/10.1177/2514183X18764792
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.