Talk:Research in multiple sclerosis

Drug pipeline
Hi, in the corrosponding article of the german wikipedia I have made a table with the substances in trials for MS (http://de.wikipedia.org/wiki/Liste_von_Multiple-Sklerose-Wirkstoffen_in_der_Erprobung). If you are interested to embed it in this article I could translate (as far as needed) it in englisch. --Garak76 —Preceding unsigned comment added by 87.176.117.79 (talk) 23:37, 25 October 2008 (UTC)

Recent reviews
Where possible wp:MEDRS calls for the use of secondary sources. Some recent reviews of relevance to this article:

LeadSongDog come howl!  18:19, 24 January 2011 (UTC)

Expanded article on Zamboni liberation procedure?
I've been reading in the news a lot about the Zamboni liberation procedure--in particular the controversy around it and whether it should be funded as a medical procedure (this is a big issue in the Canadian medical world at least). I would recommend an additional article is created on this topic to expand upon it as it appears to be provoking big debate within medical science.96.50.87.54 (talk) 08:12, 30 June 2011 (UTC)
 * As you can see in the article, there is a link to CCSVI where the Zamboni procedure is explained. I have updated the status of the clinical trial for angioplasties from "others" to the current phase-III in which it is now. --Juansempere (talk) 21:24, 5 August 2011 (UTC)

Recent research with promising results
Just read this and don't know enough about MS research to integrate the info, but thought those following this page would find it useful.[]

Announcement of Changes
My name is Florian Schaub from Merck KGaA. My aim is to make some changes in this article because we have found some misleading information. I've compiled the suggested changes which you can find herinafter. They all follow one pattern:

• Current text

• Suggested revision

• Reason

• Suggested reference

If someone has objections please let me know.

_Current text

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]

_Suggested revision

Replace current out of date reference with 2 new references (see suggested references)

_Reason

To provide more current information

_Suggested reference

[1] National Multiple Sclerosis Society. Stopping MS In Its Tracks. http://www.nationalmssociety.org/Research/Research-We-Fund/Stop-MS-In-Its-Tracks [Retrieved on 19 July 2017]

[2] National Multiple Sclerosis Society. Restoring What's Been Lost. http://www.nationalmssociety.org/Research/Research-We-Fund/Restoring-What-s-Been-Lost [Retrieved on 19 July 2017]

_Current text

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]

_Suggested revision

Treatments Advances during the past decades have led to the recent approval of several oral drugs (fingolimod, teriflunomide, dimethyl fumarate).[1] Further oral drugs, laquinimod, ozanimod, and ponesimod, are under investigation in phase III trials.[2] On 22 June 2017, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency issued a positive opinion for approval of Cladribine Tablets (proposed tradename MAVENCLAD) for the treatment of relapsing forms of MS (RMS) in patients with high disease activity.[3]

_Reason

Provide an updated ref for approved oral therapies. Remove second sentence with ref (i.e. “These drugs are expected to gain in popularity and frequency of use at the expense of previously existing therapies.[2]”): the ref doesn’t support the statement and there is no other supporting ref for this statement. Update copy on oral therapies in phase III trials and on EMA acceptance of the MAA for Cladribine Tablets with updated supporting refs

_Suggested reference

[1] National Multiple Sclerosis Society. Disease-Modifying Therapies for MS; p. 9. http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-The-MS-Disease-Modifying-Medications.pdf [Retrieved on 19 July 2017]

[2] MS Society. Treatments in the pipeline. https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline [Retrieved on 19 July 2017]

[3] Summary of opinion (initial authorisation). European Medicines Agency: Committee for Medicinal Products for Human Use (22 June 2017).

http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004230/WC500229786.pdf [Retrieved on 19 July 2017]

_Current text

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]

_Suggested revision

Delete text

_Reason

Delete these sentences because peginterferon has been approved

_Current text

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][8]

_Suggested revision

The CD20 monoclonal antibody ofatumumab has shown some benefit and is being evaluated in a phase III trial as a potential treatment for MS.[1]

_Reason

Update paragraph: remove first sentence and alemtuzumab, daclizumab and ocrelizumab as they are all now approved. Remove rituximab because further development has been halted (see https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline/rituximab). Suggest deleting rest of paragraph because it is not relevant to MS research, and is also inaccurate as monoclonal antibodies are being used for MS, different antibodies have different adverse effect profiles and it is based on two out-of-date refs (i.e. “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][8]”)

_Suggested reference

[1] MS Society. Treatments in the pipeline. https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline [Retrieved on 19 July 2017]

_Current text

Another research strategy is to evaluate the combined effectiveness of two or more drugs.[9] 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.[9] 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.[9] 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.[9]

_Suggested revision

Delete text

_Reason

Delete this section because this copy is based on an out-of-date reference and ongoing research is focused on developing new therapies (see https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline#RRMS

_Current text

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.[10]

_Suggested revision

Neuroprotective and regenerative treatments include stem cell therapy. Autologous hematopoietic stem cell transplantation involves replacing the harmful immune cells that attack the brain and spinal cord in MS with the individual’s own stem cells.[1] The MIST trial is a large international phase III clinical trial to investigate hematopoietic stem cell therapy for patients with inflammatory MS failing alternate approved therapy.[2]

_Reason

Update copy and references

_Suggested reference

[1] MS Society. HSCT. https://www.mssociety.org.uk/ms-research/emerging-areas/stem-cells/AHSCT#AHSCT research to date [Retrieved 19 July 2017]

[2] Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study. NCT00273364. https://clinicaltrials.gov/ct2/show/study/NCT00273364#contacts [Retrieved 19 July 2017]

_Current text

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]

_Suggested revision

As of January 2017, the Food and Drug Administration (FDA) has approved 15 medications with eight different mechanisms of action thought to address distinct components of the immune-mediated disease process to treat RRMS.[1] These medications differ in their route and frequency of administration and side effect and risk profiles.[1] None are curative and efficacy varies considerably between individuals and for any given individual at different points in time.[1] Currently one drug is approved for PPMS.[2] Many new drugs are being tried out in clinical trials for all variants of MS.[3]

_Reason

Update copy and references. Also move this section to the second paragraph in the “Research directions” section

_Suggested reference

[1] Multiple Sclerosis Coalition. The Use of Disease-Modifying Therapies in Multiple Sclerosis: Principles and Current Evidence. http://www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color  p.21 [Retrieved 19 July 2017]

[2] National Multiple Sclerosis Society. Ocrevus. http://www.nationalmssociety.org/Treating-MS/Medications/Ocrevus [Retrieved 19 July 2017]

[3] MS Society. Treatments in the pipeline: Potential treatments for relapsing MS. https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline#RRMS [Retrieved 19 July 2017]

_Current text

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.

_Suggested revision

Disease-modifying drugs New drugs must undergo rigorous assessment of efficacy and safety in a series of clinical trials to obtain approval from regulatory agencies. Phase III is normally the last testing phase, and if the prespecified endpoints are met a formal approval request is submitted to the regulator (e.g., the EMA for the European Union, the FDA for the United States, Therapeutic Goods Administration [TGA] for Australia). Phase III programs consist of studies on large patient groups (300 to >3,000 patients).[1]

_Reason

Add reference and update text for accuracy

_Suggested reference

[1] https://www.mssociety.org.uk/ms-research/how-we-decide-what-we-fund/research-process-timeline

_Current text

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.[23] 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.[24] 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.[25] This drug was expected to be in the market in 2011 for use in multiple sclerosis patients.,[26][27] but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.[28] Nevertheless, it seems that approval process continued in Europe and the EMEA has accepted a review process[29]

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

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,[30] failing its primary target though in March 2008 was still performing good.[31] After several financial troubles, a phase III trial has been granted in 2011[32] 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.[33]

_Suggested revision

Relapsing-remitting MS Currently, a number of medications are being investigated in ongoing or following completion of phase III trials[1]. For example, Cladribine Tablets (under development by Merck Serono; proposed tradename MAVENCLAD) is an oral drug that met its primary endpoint in the phase III CLARITY study in patients with active RRMS; 58% relative reduction in annualized relapse rates in patients treated with Cladribine Tablets compared with placebo [2]. Cladribine Tablets received a positive opinion from the CHMP of the EMA for the treatment of RMS in patients with high disease activity.[3]

_Reason

Update copy as indicated with updated refs and move updated copy on Tovaxin/Tcelna and siponimod, which are both indicated for progressive forms of MS to the secondary progressive MS section

_Suggested reference

[1] MS Society. Treatments in the pipeline: Potential treatments for relapsing MS. https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline#RRMS [Retrieved 19 July 2017]

[2] Pharmaceutical Business Review. Merck Serono's Phase III multiple sclerosis trial meets endpoint. http://drugdiscovery.pharmaceutical-business -review.com/news/merck_seronos_phase_iii_multiple_sclerosis_trial_meets_endpoint_300109 [Retrieved 19 July 2017]

[3] Summary of opinion (initial authorisation). European Medicines Agency: Committee for Medicinal Products for Human Use (22 June 2017). http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004230/WC500229786.pdf [Retrieved on 19 July 2017]

_Current text

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:

_Suggested revision

Secondary progressive variants Relapsing-onset variants, even when they turn into progressive disease, have proved easier to treat than progressive-onset variants. Though difficult to treat, secondary progressive and progressive-relapsing are easier to treat than PPMS. Mitoxantrone has been approved for secondary progressive MS (SPMS), progressive relapsing or worsening RRMS.[1] Ocrevus® has been approved for RMS and PPMS.[2,3]

Several other therapies are being investigated in phase II and III studies.[4]

_Reason

Factual correction (precise indication for use of mitoxantrone and indication for Ocrevus®) plus content suggestion to provide three up-to-date references

_Suggested reference

[1] Scott LJ, Figgit DP (2004). Mitoxantrone: a review of its use in multiple sclerosis. CNS Drugs. 18: 379–96.

[2] F. Hoffmann-La Roche Ltd. Media Release, 29 March 2017. http://www.roche.com/media/store/releases/med-cor-2017-03-29.htm [Retrieved 19 July 2017]

[3] http://www.nationalmssociety.org/Treating-MS/Medications/Ocrevus [Retrieved 19 July 2017]

[4] MS Society. Treatments in the pipeline: Potential treatments for relapsing MS. https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline#RRMS [Retrieved 19 July 2017]

_Current text

Cyclophosphamide (trade name Revimmune) is currently in Phase III for secondary progressive MS.[34] 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[35] Later, a 2007 open label study found it equivalent to Mitoxantrone[36] and in 2008 evidence appeared that it can reverse disability.[37] Simvastatin has shown brain atrophy reduction in secondary progressive MS.[38] Tcelna is currently under active research by Opexa, showing promising results.[39] Masitinib, a tyrosine kinase inhibitor, is in late-stage testing for the treatment of patients with secondary and primary progressive MS (PPMS). It is a twice-daily oral medication that targets mast cells and inhibits several biochemical processes.14 Ibudilast: MediciNova, Inc., announced that MN-166 (ibudilast) has been approved for "fast track" development by the U.S. Food and Drug Administration (FDA) as of 2016, as a potential treatment for progressive multiple sclerosis (MS). Progressive MS in this case means both the primary progressive (PPMS) and secondary progressive (SPMS) forms of the disease. [34] Significant Advances in Multiple Sclerosis Treatment http://www.pharmacytimes.com/publications/specialty-pt/2011/February-2011/SPT-NPP-0211 [35] Gladstone DE, Zamkoff KW, Krupp L, et al. (2006). "High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis". Arch. Neurol. 63 (10): 1388–93. doi:10.1001/archneur.63.10.noc60076. PMID 16908728. [36] Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Pia Amato M (2007). "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. [37] Krishnan C, Kaplin AI, Brodsky RA, et al. (June 2008). "Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis". Arch. Neurol. 65 (8): 1044–51. doi:10.1001/archneurol.65.8.noc80042. PMC 2574697Freely accessible. PMID 18541787. [38] Chataway, J (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". The Lancet. 383 (9936): 2213–2221. doi:10.1016/s0140-6736(13)62242-4. [39] Opexa Initiates Late Stage Clinical Study of Tcelna in Patients with Secondary Progressive Multiple Sclerosis [4]

_Suggested revision

Simvastatin has shown brain atrophy reduction in SPMS.[38] Tcelna® is an injectable treatment that uses a person’s own immune cells to alter the behavior of the immune system in MS.[1] It has been granted fast track status by the FDA for SPMS, and the manufacturer Opexa is currently conducting a phase IIb clinical trial.[2] Opexa has also completed formal end of phase II meetings with the FDA and received support to move forward with phase III clinical trials for RRMS.[2] Masitinib stops some cells from growing or dividing and is an oral treatment being developed by AB Science for progressive MS. It is currently in phase III trials.[1,3] In March 2016, MN-166 (ibudilast) received Fast Track Designation from the FDA as a potential treatment for progressive MS.[4] MN-166 for the treatment of MS is currently being assessed in phase II trials.[5]

_Reason

Delete copy and refs on cyclophosphamide because all refs are out of date and not mentioned by the MS Society as a pipeline product. Update original Tcelna®, masitinib and ibudilast copy and refs

_Suggested reference

[1] MS Society. Treatments in the pipeline: Potential treatments for relapsing MS. https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline#RRMS [Retrieved 19 July 2017]

[2] Opexa Therapeutics, Inc. Tcelna® (imilecleucel-T). http://www.opexatherapeutics.com/tcelna/tcelna-description/default.aspx [Retrieved 19 July 2017]

[3] https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline/masitinib [Retrieved 19 July 2017]

[4] MS Society. Masitinib. https://multiplesclerosisnewstoday.com/2016/03/23/please-work-on-this-one-first-fda-grants-fast-track-designation-for-medicinovas-mn-166-ibudilast-for-progressive-multiple-sclerosis/ [Retrieved 19 July 2017]

[5] Multiple Sclerosis News Today. Potential Progressive MS Treatment, Ibudilast, Approved for Fast Track Development by FDA, 23 March 2016. https://multiplesclerosisnewstoday.com/2016/03/23/please-work-on-this-one-first-fda-grants-fast-track-designation-for-medicinovas-mn-166-ibudilast-for-progressive-multiple-sclerosis/ [Retrieved 19 July 2017]

[38] Chataway, J (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". The Lancet. 383 (9936): 2213–2221. doi:10.1016/s0140-6736(13)62242-4.

_Current text

Currently, good results using the monoclonal antibody Ocrelizumab in primary progressive MS (PPMS)[43] have put the focus into depleting B cells targeting CD20 proteins[44]

_Suggested revision

After a successful phase III trial, the monoclonal antibody ocrelizumab (Ocrevus®) has recently received FDA approval for treatment of PPMS [1,2]

_Reason

Update copy as indicated with updated text and refs

_Suggested reference

[1] Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS; ORATORIO Clinical Investigators (2017). Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 376: 209–220.

[2] National Multiple Sclerosis Society. Ocrevus. http://www.nationalmssociety.org/Treating-MS/Medications/Ocrevus [Retrieved 19 July 2017]

--Florian Schaub at Merck KGaA (talk) 08:06, 17 October 2017 (UTC)

Start to edit the article - Merck
As nobody had any objections to my announcement of changes from the 17th October I will now start editing the article. --Florian Schaub at Merck KGaA (talk) 13:58, 30 October 2017 (UTC) --Florian Schaub at Merck KGaA (talk) 13:50, 6 November 2017 (UTC)
 * Did you do them all ? Most seem OK (it would have been helpful to number the proposals) but please be aware of possible conflict of interest since you seem to work for Merck. - Rod57 (talk) 12:57, 7 May 2018 (UTC)

Merge
This article should be merged in Multiple sclerosis drug pipeline Doc James  (talk · contribs · email) 16:46, 7 November 2017 (UTC)
 * Purely with respect to naming, would it be more appropriate to go the other way? That is, should we have all of the research into therapeutic options under multiple sclerosis research, rather than multiple sclerosis drug pipeline.  I mean, it's pretty obvious at this point that CCSVI and the Zamboni model are a bust, but it's certainly possible that other non-drug interventions (or even repurposed old drugs) will be part of legitimate future investigations.  In that vein, I would argue that we should retain the broader article title if we're planning to consolidate all the content. TenOfAllTrades(talk) 19:16, 7 November 2017 (UTC)
 * I would prefer to keep them apart because approval is more a burocratic task than a research task. But in case of merge, I prefer to put the pipeline into the research article.--Juansempere (talk) 13:27, 22 November 2017 (UTC)
 * Better kept apart (maybe with clarification of scope); but if merge then pipeline could be a section in research. (Can't have [all] research in pipeline eg research on epidemiology or lifestyle factors). "pipeline" is pharmaceutical industry jargon (for pre-approval drug candidates/development) - Could redirect pipeline to MS research. - Rod57 (talk) 12:51, 7 May 2018 (UTC)

No description of animal models
Article could discuss induced and non-induced animal models of MS. eg " macaque monkeys who carry a naturally occurring version of MS called Japanese macaque encephalomyelitis. The condition, which causes clinical symptoms similar to multiple sclerosis in people, is the only spontaneously occurring MS-like disease in nonhuman primates in the world." & source. - Rod57 (talk) 17:49, 9 September 2019 (UTC)

All MS meds are poisons
Living proof in cinemas has the evidence of. 86.27.107.137 (talk) 12:00, 1 September 2023 (UTC)