Talk:Multiple sclerosis drug pipeline

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Approved drugs

  • Siponimod is a sphingosine-1-phosphate receptor modulator for oral use for MS. A phase III trial should run from Dec 2012 to Dec 2016.[1] The results were published in The Lancet in April 2018, showing good behaviour for the secondary progressive course.[2] On July 18, 2018, Vas Narashimhan, CEO of Novartis said that they had just completed the regulatory submission of BAF312 to FDA.[3]
Approved: Approved in USA by FDA in March 2019
  • Ozanimod:The manufacturer Celgene has applied for FDA approval after two phase III trials.[4] The application was rejected and the company is planning to apply again[5].
Approved: March 2020
  • Cladribine (under development by Merck Serono; anticipated brand name: Movectro) is a antineoplastic compound 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.[6] 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.[7] 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.[8] Drug is expected to be in the market in 2011 for use in multiple sclerosis patients.[9][10] but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.[11] Nevertheless, it seems that approval process continued in Europe and the EMEA has accepted a review process[12].
Removal. As of 2011 Merck decided to withdraw all marketing applications for cladribine tablets, and to stop selling it in Russia and Australia which had approved it.[13]
Reintroduction: It went further further in Europe[14]
Approved: It was approved in Europe in 2017 and in USA in 2019, both with restrictions.
  • Fingolimod (under development by Novartis, also known as FTY720, expected trade name Gilenya) is a sphingosine-1-phosphate receptor modulator for oral use. In 2006, it showed promising results in a phase II clinical trial for relapsing multiple sclerosis, with a relapse reduction of over 50% compared to placebo. Potential safety profile issues included lowering of heart rate upon dosing.[15] In January 2010, published results in NEJM from a phase III trial involving more than 1000 patients showed significant reduction in relapse rates compare to interferon therapy.,[16][17]
Approved: It makes no sense to have it in this article anymore.
"On September 22, 2010, fingolimod became the first oral disease-modifying drug approved by the Food and Drug Administration to reduce relapses and delay disability progression in patients with relapsing forms of multiple sclerosis.[9][10] Novartis announced on March 10, 2011 that it had received a notice of compliance from Health Canada and that the drug would be available April 1, 2011 at pharmacies.[11][12] On March 17, 2011, the European Medicines Agency approved the drug for use in the European Union.[13]. In July 2011, Sultanate of Oman has become first country among middle east to approve this drug as oral medicine for Multiple Sclerosis".
Approved: On 15 Sept 2012 it was approved by FDA[21]
  • BG00012 (oral). A fumarate ester under development by Biogen; whose anticipated brand name is Tecfidera.[22] It has completed Phase II investigations[23] and Phase III started Jan 2007 and plans to follow approx 1000 patients until Dec 2010.[24] As of October 2011 the trial results were published showing good results.[25] In September 2012 the study was extended to 1400 patients being the result again positive.[26].
Approved in April 2013 with name Tecfidera[27]


  • Alemtuzumab (injectable. brand names: Campath and Lemtrada; under development by Genzyme and Bayer Schering) is a monoclonal antibody currently already used in the treatment of chronic lymphocytic leukemia and T-cell lymphoma. Results from the phase II study comparing it to Rebif (interferon beta-1a) were published in May 2007 showing efficacy. However, the trial was halted after 3 cases [28] of immune thrombocytopenic purpura (ITP) were reported; later on, a further 3 more cases were found, and 1 patient died. This is a life-threatening side effect but is treatable if detected. Therefore, all patients receiving alemtuzumab should have their platelet count monitored.[29][30] Two phase 3 trials comparing with Rebif are due to end in 2011.[31][32] The results have been considered a success.[33] Though the drug has been submitted for approval on June 2012[34] under the name Lemtrada there are doubts about its approval.[35]
Approved by the FDA in 2014[36]
Approved on May 2016[40]


  • Peginterferon beta-1a, also known as Plegridy, was recently approved by the FDA and is expected to be available by prescription in November 2014.[41] 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.[42] 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.[43]
Approved on November 2014[15]

Removed drugs

Following Merck removal of Cladribine in June 2011 I have moved here the text in case it should be recovered some day, or somebody wants it for historical reasons. Later I have added all the phase III approved or witdrawn drugs.

Removed. On 27 July 2009, a statement was released, stating "BioMS Medical Corp. (TSX: MS) today announced that dirucotide did not meet the primary endpoint of delaying disease progression, as measured by the Expanded Disability Status Scale (EDSS), during the two-year MAESTRO-01 Phase III trial in patients with secondary progressive multiple sclerosis (SPMS). In addition, there were no statistically significant differences between dirucotide and placebo on the secondary endpoints of the study", this means that the MAESTRO-02 and MAESTRO-03 trials are discontinued. — Preceding unsigned comment added by 85.53.127.142 (talk) 19:42, 17 August 2011 (UTC)[reply]
  • Rituximab, trade names Rituxan and MabThera, is an anti-CD20 monoclonal antibody previously used against cancer, has shown damaging lesions reduction by 91% and relapses by 58%.[45] This drug has the particularity that it targets B Cells instead of T cells, which were supposed the main actors in MS. The behavior of this drug has made researchers to question the traditional model of the MS attacks.[46] Due to the side-effect profile and better anti-CD20 drugs,[47] Rituximab's further trials are limited to primary progressive MS only, where no treatment is currently available.
  • Removed: As of April 2008, Rituxan appears to have failed its first Phase 3 trial in PPMS, casting doubt upon its future in mainstream MS therapy.[48]. Besides, Ocrelizumab is a slightly modified version of Biogen/Genentech's existing therapy Rituxan/Rituximab. As Rituxan was approaching FDA approval for treatment of multiple sclerosis, it was simultaneously approaching the end of its patent. To avoid the profit loss of a new treatment that could have been available sooner and eventually in a generic form, Rituxan trials were halted and Ocrelizumab trials quickly began.[49]
  • Laquinimod (under development by Teva and Active Biotech) is an immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis. In a phase II study, oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis.[50] During 2009 was granted FDA fast-track status[51]
Removed: "In 2011 Teva announced that its clinical trials involving Laquinimod had failed, being unable to significantly reduce relapses into multiple sclerosis among patients beyond what a placebo was.[52]"
Removed: The trial did not succeed.
  • Tcelna (previously Tovaxin) A vaccine against self T-Cells, which consist of attenuated autoreactive T cells. It was under active research by Opexa Therapeutics (previously known as PharmaFrontiers), showing promising results.[55] After a failure in phase II the company is not pusuing its approval anymore[56] and finished a Phase IIb September 2008,[57] failing its primary target, though, in March 2008 was still performing well.[58] A Phase III trial was in 2011[59] but as of 2016 it was still in phase II.[60]
  • Biotin(MD1003, Qizenday, Cerenday) - As of 2020 was under study but that year the results were disappointing, casting doubts into the continuity of the studies.[61] In fact some reports point to Biotin making PPMS worse[62] and others point to Bioting responsiveness being a hint of MS misdiagnosis[63] As of 2020, the last trials were disappointing.[64] Discontinued on 2020.

References

  1. ^ Clinical trial number NCT01665144 for "Exploring the Efficacy and Safety of Siponimod in Patients With Secondary Progressive Multiple Sclerosis (EXPAND)" at ClinicalTrials.gov
  2. ^ Newspaper article, forextv.com
  3. ^ Novartis third quarter finantial results
  4. ^ MS-UK.org, New MS drug Ozanimod seeks FDA approval
  5. ^ Biospace.com, Celgene Plans To File Second NDA for Ozanimod in 2019 Following FDA Rejection in February [1]
  6. ^ clinicaltrial.gov CLARITY Study. Retrieved on 25 November 2007.
  7. ^ Merck Serono's Phase III multiple sclerosis trial meets endpoint
  8. ^ Giovannoni G, et al., NEJM 2010
  9. ^ Merck KGaA Submits Application For Cladribine Tablets As Multiple Sclerosis Therapy In Europe [2]
  10. ^ Hope for MS pill after cladribine and fingolimod trials, BBC News;Published 20-January-2010
  11. ^ http://www.genengnews.com/gen-news-highlights/merck-serono-gives-up-on-getting-drug-candidate-for-multiple-sclerosis-approved/81245334/
  12. ^ Press release
  13. ^ http://www.genengnews.com/gen-news-highlights/merck-serono-gives-up-on-getting-drug-candidate-for-multiple-sclerosis-approved/81245334/
  14. ^ Press release: [3]
  15. ^ Kappos L, Antel J, Comi G; et al. (2006). "Oral fingolimod (FTY720) for relapsing multiple sclerosis". N. Engl. J. Med. 355 (11): 1124–40. doi:10.1056/NEJMoa052643. PMID 16971719. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  16. ^ Cohen J, et al., NEJM 2010
  17. ^ Information on the phase III trial for fingolimod
  18. ^ ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  19. ^ "Sanofi-Aventis' Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial". 15 Oct 2010.
  20. ^ Investigational Oral Multiple Sclerosis Therapy Teriflunomide http://www.medicalnewstoday.com/releases/235702.php
  21. ^ Aubagio (teriflunomide), a once-daily tablet for adults with relapsing forms of MS (multiple sclerosis), has been approved by the US Food and Drug Administration (FDA) [4]
  22. ^ Tecfidera (dimethyl fumerate) Retrieved on 2013-03-16.
  23. ^ Kappos L, Miller DH, MacManus DG; et al. (2006). "BG00012, a novel fumarate is effective in patients with relapsing-remitting multiple sclerosis". Mult Scler. 12 (Suppl 1): S85. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  24. ^ Efficacy and Safety of BG00012 in Relapsing-Remitting Multiple Sclerosis. ClinicalTrials.gov (2007-09-1). Retrieved on 2007-11-12.
  25. ^ Dimethyl Fumarate Considerably Reduces MS Relapses And Disability Progression http://www.medicalnewstoday.com/articles/236427.php
  26. ^ Another oral drug coming soon - Data highlight safety profile of oral MS drug BG-12 [5]
  27. ^ http://ccsvi-ms.ning.com/profiles/blogs/biogen-bg12-the-twice-a-day-capsules-called-tecfidera-now?xg_source=msg_mes_network
  28. ^ Hader, Walter J., and Irene M. Yee. "The Prevalence of Familial Multiple Sclerosis in Saskatoon, Saskatchewan." Multiple Sclerosis International 2014 (2014).
  29. ^ Information from GenZyme on its clinical trial for Alemtuzumab
  30. ^ Coles AJ, Compston DA, Selmaj KW; et al. (October 2008). "Alemtuzumab vs. interferon beta-1a in early multiple sclerosis". N Engl J Med. 359 (17): 1786–801. doi:10.1056/NEJMoa0802670. PMID 18946064. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  31. ^ clinicaltrial.gov Phase III Alemtuzumab Study 1;vs Rebif. Enrollment: 81, Start Sept 2007, Est' end date May 2011
  32. ^ clinicaltrial.gov Phase III Alemtuzumab Study 2;vs Rebif Enrollment: 840, Start Date: Oct 2007, Est End Date: Sept 2011.
  33. ^ Sanofi Reports Positive Top-Line Results From First Phase 3 Study Of Alemtuzumab (Lemtrada™) In Multiple Sclerosis, [6] L
  34. ^ Lemtrada submitted for approval on June 2012
  35. ^ Sanofi’s Lemtrada Drug May Be Too Risky, FDA Staff Says
  36. ^ FDA approves Lemtrada (alemtuzumab) for the treatment of patients with relapsing forms of multiple sclerosis [7]
  37. ^ Montalban X, Wynn D, Kaufman M et al. Preliminary CHOICE results. ECTRIMS 2007
  38. ^ Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG (2007). "Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results". Neurology. 69 (8): 785–9. doi:10.1212/01.wnl.0000267662.41734.1f. PMID 17709711.
  39. ^ ClinicalTrials.gov: Identifier NCT01064401. Updated on 7. April 2011.
  40. ^ FDA Press Release, May 27, 2016 [8]
  41. ^ [9]
  42. ^ [10]
  43. ^ Peginterferon beta-1a description National Multiple Sclerosis Society (15 August 2014). Retrieved on 27 October 2014
  44. ^ Dirucotide fails phase III trials
  45. ^ MS therapy shows promise in test, By Thomas H. Maugh II, Los Angeles Times Staff Writer [11]
  46. ^ Hauser SL, Waubant E, Arnold DL; et al. (2008). "B-cell depletion with rituximab in relapsing-remitting multiple sclerosis". N Engl J Med. 358 (7): 676–88. doi:10.1056/NEJMoa0706383. PMID 18272891. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  47. ^ Castillo J, Milani C, Mendez-Allwood D (2009). "Ofatumumab, a second-generation anti-CD20 monoclonal antibody, for the treatment of lymphoproliferative and autoimmune disorders". Expert Opin Investig Drugs. 18 (4): 491–500. doi:10.1517/13543780902832679. PMID 19335277. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  48. ^ "Genentech: Newsroom: Press Releases: News Release April 14, 2008". Genentech. 2008-04-14. Retrieved 2008-04-14.
  49. ^ The shameful story of Rituximab in Multiple Sclerosis
  50. ^ Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T (2005). "Treatment with laquinimod reduces development of active MRI lesions in relapsing MS". Neurology. 64 (6): 987–91. doi:10.1212/01.WNL.0000154520.48391.69. PMID 15781813.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  51. ^ Laquinimod granted FDA fast track
  52. ^ Kresege, Naomi (1 August 2011). "Teva's Copaxone Successor Fails in Latest Clinical Trial". Bloomberg. Retrieved 2 August 2011. Teva Pharmaceutical Industries Ltd. (TEVA)'s experimental multiple sclerosis pill failed to reduce relapses more than placebo in a clinical trial, dealing a blow to the company's effort to find a successor to an older drug.
  53. ^ Clinical trial number NCT01371760 for "BRAVE-DREAMS (BRAin VEnous DRainage Exploited Against Multiple Sclerosis) (BRAVE-DREAMS)" at ClinicalTrials.gov
  54. ^ Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall'Ara S, Bartolomei I, Salvi F (April 2009). "Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis". Journal of Neurology, Neurosurgery, and Psychiatry. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024.
  55. ^ Opexa Initiates Late Stage Clinical Study of Tcelna in Patients with Secondary Progressive Multiple Sclerosis [12]
  56. ^ Opexa Press Release [13]
  57. ^ "Opexa shares lose most of value on study data".
  58. ^ "Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin For Treatment Of Multiple Sclerosis".
  59. ^ Tovaxin phase III announced http://www.opexatherapeutics.com/?page=release&section=news&article=010511
  60. ^ 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.
  61. ^ MedDay Press Release
  62. ^ Branger, Pierre; Parienti, Jean-Jacques; Derache, Nathalie; Kassis, Nizam; Assouad, Rana; Maillart, Elisabeth; Defer, Gilles (15 June 2020). "Relapses During High-Dose Biotin Treatment in Progressive Multiple Sclerosis: a Case-Crossover and Propensity Score-Adjusted Prospective Cohort". Neurotherapeutics. doi:10.1007/s13311-020-00880-z.
  63. ^ Wolf, Barry (29 April 2020). "Any individual with multiple sclerosis who markedly improves neurologically with high-doses of biotin should be evaluated for biotinidase deficiency". Multiple Sclerosis Journal - Experimental, Translational and Clinical. 6 (2): 205521732092313. doi:10.1177/2055217320923131.
  64. ^ MedDay Reports Top-Line Data from Phase III Trial “SPI2” for Treatment of Progressive Forms of Multiple Sclerosis, Press release, [14]

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

From the moment a theoretical model of multiple sclerosis is hypothesized until a drug appears that interferes with one of its pathways, several phases must be completed. First, an animal model of the pathway to be studied must be developed, and the possible drugs that will be tried to interfere with it must be tried out. After that, three phases of human testing begin, and if everything works as expected, finally the drug will reach the status of approved by the regulatory agencies.


_Suggested revision

From the moment a theoretical model of the disease is hypothesized, until a drug appears that interferes with one of its pathways, several phases must be completed. First an animal model of the pathway to be studied must be developed, and the possible drugs that will be tried to interfere with it must be tried out. After that, three phases of human testing begin, and if everything works as expected, finally the drug will reach the status of approved by the regulatory agencies.[1]


_Reason

To provide a reference


_Suggested references

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


_Current text

As of 2017, there are 11 active principles approved for RRMS, with one of them approved also for PPMS (Ocrelizumab), and another one (Mitoxantrone) for SPMS.


_Suggested revision

As of January 2017, the US 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 relapsing–remitting MS (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] One drug is approved for the treatment of primary progressive MS (PPMS).[2] Several new drugs are being tried out in clinical trials for PPMS.[3]


_Reason

To correct misleading information re. 11 active principles and to provide additional clarifying information provided by reference 1. References provided too


_Suggested references

[1] http://www.nationalmssociety.org/Treating-MS/Medications

[2] http://www.nationalmssociety.org/Treating-MS/Medications/Ocrevus

[3] https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline#PPMS


_Current text

The approved drugs for RRMS are: Two interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, mitoxantrone, teriflunomide,[1] dimethyl fumarate,[2] one S1P modulator (fingolimod) and finally three monoclonal antibodies (natalizumab, alemtuzumab [3], Daclizumab [4][5] and since March 2017 Ocrelizumab [6].


_Suggested revision

The approved medications for RRMS in the US and the UK are: four interferons (interferon beta-1a,[1][2] subcutaneous interferon beta-1a,[3][4] intramuscular interferon beta-1b,[5][6][7][8] peginterferon beta-1a,[9][10]), glatiramer acetate,[11][12][13] teriflunomide,[14][15] dimethyl fumarate,[16][17] one S1P modulator (fingolimod,[18][19]) and four monoclonal antibodies (natalizumab,[20][21] alemtuzumab,[22][23], daclizumab,[24][25] and, since March 2017 in the US, ocrelizumab[26]). Mitoxantrone is approved in the US and some countries in the EU.[27][28][29][30][31]


_Reason

To correct information and provide latest US Prescribing information and UK Summary of Product Characteristics references for each medication


_Suggested references

[1] https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103628s5258lbl.pdf

[2] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000102/WC500029425.pdf

[3] https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/103780s5178s5179lbl.pdf

[4] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000136/WC500048682.pdf

[5] https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103471s5186lbl.pdf

[6] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000081/WC500053086.pdf

[7] https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/extavia.pdf

[8] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000933/WC500034702.pdf

[9] https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125499s000lbl.pdf

[10] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002827/WC500170305.pdf

[11] https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020622s057lbl.pdf

[12] http://www.tevauk.com/mediafile/id/15860.pdf

[13] https://www.copaxonehcp.com/Content/pdfs/PrescribingInformation.pdf

[14] http://products.sanofi.us/aubagio/aubagio.pdf

[15] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002514/WC500148685.pdf

[16] https://www.tecfidera.com/content/dam/commercial/multiple-sclerosis/tecfidera/pat/en_us/pdf/full-prescribing-info.pdf

[17] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002601/WC500162072.pdf

[18] https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/gilenya.pdf

[19] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/002202/WC500104530.pdf

[20] https://www.tysabri.com/content/dam/commercial/multiple-sclerosis/tysabri/pat/en_us/pdfs/tysabri_prescribing_information.pdf

[21] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000603/WC500044688.pdf

[22] http://products.sanofi.us/lemtrada/lemtrada.pdf

[23] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003718/WC500150523.pdf

[24] https://www.zinbryta.com/content/dam/commercial/multiple-sclerosis/zinbryta/pat/en_us/pdfs/zinbryta-prescribing-information.pdf

[25] http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003862/WC500210600.pdf

[26] "FDA Ocrevus approval". FDA Press Release. 29 March 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm549325.htm

[27] http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126445.htm

[28] https://www.mstrust.org.uk/a-z/mitoxantrone

[29] https://www.medicines.org.uk/emc/medicine/29862

[30] http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Novantrone_30/WC500205581.pdf

[31] https://www.thepharmaletter.com/article/fda-approves-novantrone-for-secondary-progressive-multiple-sclerosis


_Current text

Only one of them, Mitoxantrone, has been approved for Secondary Progressive MS (SPMS) and for the special course of PPMS "rapidly progressive multiple sclerosis"[7] and also one of them (Ocrelizumab) is approved for Primary Progressive (PPMS).

7. Gonsette RE, Dubois B (2004). "Pixantrone (BBR2778) a new immunosuppressant in multiple sclerosis with a low cardiotoxicity". Journal of the Neurological Sciences. 223 (1): 81–86. doi:10.1016/j.jns.2004.04.024. PMID 15261566


_Suggested revision

Only one of these medications, mitoxantrone, has been approved for secondary progressive MS (SPMS), progressive relapsing or worsening RRMS[1][2][3] and one, ocrelizumab, is approved for PPMS.[4]


_Reason

To correct text and provide appropriate reference


_Suggested references

[1] https://www.medicines.org.uk/emc/medicine/29862

[2] http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Novantrone_30/WC500205581.pdf

[3] https://www.thepharmaletter.com/article/fda-approves-novantrone-for-secondary-progressive-multiple-sclerosis

[4] "FDA Ocrevus approval". FDA Press Release. 29 March 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm549325.htm


_Current text

Cladribine (under development by Merck Serono; anticipated brand name: Movectro) is an 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.[8] 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.[9]. 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.[10] This drug was expected to be in the market in 2011 for use in multiple sclerosis patients.,[11][12] but in 2011 the company decided to stop selling the tablets in Russia and Australia though it was already approved in this countries.[13] Nevertheless, it seems that approval process continued in Europe and the EMEA has accepted a review process[14]


_Suggested revision

Cladribine Tablets 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 with respect to placebo.[1] On 23 June 2017, Merck Serono Europe announced that the Committee for Medicinal Products for Human Use (CHMP) of the EMA has issued a positive opinion for approval of Cladribine Tablets for the treatment of relapsing forms of MS (RMS) in patients with high disease activity.[2]


_Reason

To update text and provide up-to-date references in line with Wikipedia style (i.e. no original research articles)


_Suggested references

[1] http://drugdiscovery.pharmaceutical-business -review.com/news/merck_seronos_phase_iii_multiple_sclerosis_trial_meets_endpoint_300109

[2] http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/004230/WC500229786.pdf


_Current text

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[15] In March 2016 Ibudilast was designated a FDA fast track candidate for progressive MS[16]


_Suggested revision

In March 2016, MN-166 (ibudilast) was awarded an FDA Fast Track Designation as a potential treatment for progressive MS.[1] MN-166 is a first-in-class, orally bioavailable, small-molecule phosphodiesterase (PDE)-4 and -10 inhibitor and a macrophage migration inhibitory factor (MIF) inhibitor that works by suppressing pro-inflammatory cytokines and promoting neurotrophic factors. It reduces activated glial cells, which play a significant role in a number of neurological conditions.[1] MN-166 for the treatment of MS is currently being assessed in phase II trials.[1]


_Reason

Updated information to reflect that in press release. Previous reference was 2010. Reference link doesn’t work so correct link provided


_Suggested references

[1] 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/


_Current text

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]


_Suggested revision

Angioplasty for chronic cerebrospinal venous insufficiency (the so-called Zamboni liberation procedure) has been investigated in a phase III study completed in December 2015.[1] 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.[2][3]

_Reason

Updated this copy as the study has now been completed but not yet published. Added in MS society reference about CCSVI for a balanced discussion of the technique


_Suggested references

[1] https://clinicaltrials.gov/ct2/show/NCT01371760

[2] Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall’Ara S, Bartolomei I, Salvi F (Apr 2009). Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry. 80 (4): 392–9. doi:10.1136/jnnp.2008.157164. PMC 2647682. PMID 19060024.

[3] https://www.mssociety.org.uk/ms-news-and-research/ms-research/potential-treatments/emerging-areas-of-research/ccsvi


_Suggested new text

Laquinimod is a carboxamide derivative believed to have an immunomodulatory effect.[1] Mixed results from two previous phase III trials have been reported.[2][3] Data from a third phase III study are anticipated in 2017.[4] Ozanimod and ponesimod are small molecule agonists that bind to S1P receptors with similar mechanisms of action to fingolimod.[5][6] After positive phase II results, several phase III trials in relapsing MS are currently underway with expected completion dates of 2019–2020.[7][8][9][10][11]

_Reason

Updated information to reflect new drugs


_Suggested references

[1] Thöne J, Linker RA (Mar 2016). Laquinimod in the treatment of multiple sclerosis: a review of the data so far. Drug Design, Development and Therapy. 10: 1111–8.

[2] Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M; ALLEGRO Study Group (Mar 2012). Placebo-controlled trial of oral laquinimod for multiple sclerosis. New England Journal of Medicine. 366 (11): 1000–9.

[3] Vollmer TL, Sorensen PS, Selmaj K, Zipp F, Havrdova E, Cohen JA, Sasson N, Gilgun-Sherki Y, Arnold DL; BRAVO Study Group (Apr 2014). A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. Journal of Neurology. 261 (4): 773–83.

[4] https://clinicaltrials.gov/ct2/show/NCT01707992

[5] Scott FL, Clemons B, Brooks J, Brahmachary E, Powell R, Dedman H, Desale HG, Timony GA, Martinborough E, Rosen H, Roberts E, Boehm MF, Peach RJ (Jun 2016). Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. British Journal of Pharmacology. 173 (11): 1778–92.

[6] D’Ambrosio D, Freedman MS, Prinz J (Jan 2016). Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Therapeutic Advances in Chronic Disease. 7 (1): 18–33.

[7] Cohen JA, Arnold DL, Comi G, Bar-Or A, Gujrathi S, Hartung JP, Cravets M, Olson A, Frohna PA, Selmaj KW; RADIANCE Study Group (Apr 2016). Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurology. 15 (4): 373–81.

[8] https://clinicaltrials.gov/ct2/show/NCT02576717

[9] Olsson T, Boster A, Fernández Ó, Freedman MS, Pozzilli C, Bach D, Berkani O, Mueller MS, Sidorenko T, Radue EW, Melanson M (Nov 2014). Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. Journal of Neurology, Neurosurgery & Psychiatry. 85 (11): 1198–208.

[10] https://clinicaltrials.gov/ct2/show/NCT02425644

[11] https://clinicaltrials.gov/ct2/show/NCT02907177


_Current text

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,[19] failing its primary target though in March 2008 was still performing good.[20] After several financial troubles, a phase III trial has been granted in 2011[21] [19] Opexa shares lose most of value on study data [20] Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin [21] Tovaxin phase III announced http://www.opexatherapeutics.com/?page=release&section=news&article=010511

Also under Phase I and animal models Tcelna is currently under active research by Opexa, showing promising results.[52] [52] Opexa Initiates Late Stage Clinical Study of Tcelna in Patients with Secondary Progressive Multiple Sclerosis


_Suggested revision

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 Designation 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]


_Reason

Replace original copy in phase III and phase I and animal model sections with this new updated copy and refs and move new copy to section on Fast Track


_Suggested referrences

[1] https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline#SPMS

[2] http://www.opexatherapeutics.com/tcelna/tcelna-description/default.aspx


_Current text

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.


_Suggested revision

ATL1102 (under development by Antisense Therapeutics) is a second-generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4).[1] Results of a phase IIa trial have been reported.[2]


_Reason

Remove ATL1102 hyperlink because no content on hyperlink page. Remove Wikipedia link for Antisense Therapeutics because it diverts to antisense therapy page. Provide two references for copy


_Suggested references

[1] https://multiplesclerosisnewstoday.com/atl1102-multiple-sclerosis/

[2] http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=657331


_Current text

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.[25][needs update]


_Suggested revision

Delete text


_Reason

Remove because not listed on MS Society pipeline page. Also, it has been discontinued from development according to the Wikipedia page on CDP323 (Zaurategrast) due to disappointing phase II results. Ref: https://en.wikipedia.org/wiki/Zaurategrast


_Current text

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.[26][27][needs update]


_Suggested revision

Estrogens: One area of future investigation will be to determine whether estrogens have directly neuroprotective traits, rather than being purely anti-inflammatory. Many more studies are needed to assess any potential role for estrogens in the management of MS.[1]


_Reason

Provided updated ref. Copy altered to reflect content in updated ref


_Suggested references

[1] https://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-Hormones-BasicFacts-FINAL.pdf (p. 3)


_Current text

Inosine: Inosine is a compound that has shown interesting preliminary results in phases I and II clinical trials.[28][29] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion,[30] which is a natural antioxidant;[31] second, it has been shown to induce axonal rewiring in laboratory animals with stroke,[32] and spinal cord injury.[33] However it can cause health problems in a long-term treatment,[34] mainly kidney stones.[35] It seems that its mechanism of action is peroxynitrite inactivation[36] Other reports point to an immune modulation[37]


_Suggested revision

Delete text


_Reason

Remove this section because most of the references are out of date, not listed on the MS Society pipeline and NMSS websites and the 2014 reference “Associated Inosine to interferon: results of a clinical trial in multiple sclerosis” (DOI: 10.1111/ane.12333) concludes : “We cannot conclude inosine is a safe and well-tolerated drug”


_Current text

Ofatumumab, other anti-CD20 monoclonal antibody, also in phase II for MS, and phase III for others autoimmune diseases


_Suggested revision

Ofatumumab is an anti-CD20 antibody that decreases the number of B cells; B cells are a therapeutically relevant target in MS due to their pro-inflammatory role in the disease.[1] ASCLEPIOS I is a phase III trial comparing the efficacy and safety of ofatumumab administered subcutaneously every 4 weeks versus once daily oral teriflunomide for relapsing MS.[2]


_Reason

Provide references and move to phase III section


_Suggested references

[1] https://www.mssociety.org.uk/ms-research/treatments-in-the-pipeline/ofatumumab#LR

[2] https://clinicaltrials.gov/ct2/show/NCT02792218


_Current text

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..[38] Earlier studies in the secondary-progressive stage of MS have failed to shown reversal of neurological symptoms.


_Suggested revision

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 and move to phase III section


_Suggested references

[1] https://www.mssociety.org.uk/ms-research/emerging-areas/stem-cells/AHSCT#AHSCT research to date

[2] https://clinicaltrials.gov/ct2/show/study/NCT00273364#contacts


--Florian Schaub at Merck KGaA (talk) 15:26, 16 October 2017 (UTC)[reply]

Stay away. (See next subsection.)--50.201.195.170 (talk) 02:16, 14 September 2020 (UTC)[reply]

Start to edit the article

As nobody had any objections to my announcement of changes from the 16th October I will now start editing the article. --Florian Schaub at Merck KGaA (talk) 13:58, 30 October 2017 (UTC)[reply]

This account has a very long history of sundry gross policy violations. Most edits made or proposed by this user account should be reverted and any salvaging be done most carefully if at all. --50.201.195.170 (talk) 02:16, 14 September 2020 (UTC)[reply]

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