Therapies under investigation for multiple sclerosis

Scientists continue their efforts to create new and better therapies for multiple sclerosis. There are a number of treatments under investigation that may improve function, curtail attacks, or limit the progression of the underlying disease. Many treatments already in clinical trials involve drugs that are used in other diseases or medications that have not been designed specifically for MS. There are also trials involving the combination of drugs that are already in use for multiple sclerosis. Finally, there are also many basic investigations that try to understand better the disease and in the future may help to find new treatments.

The interventions below are sorted in alphabetical order.

Disease-modifying drugs in phase II and III clinical trials

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

Phase III

Phase III programs consist of studies on large patient groups (300 to 3,000 or more) and are aimed at being the definitive assessment of how effective and safe a test drug will be. It is the last stage of drug development and is followed by a submission to the appropriate regulatory agencies (e.g., EMEA for the European Union, FDA for the USA, TGA for Australia, etc.) to obtain approval for marketing. Treatment in MS phase III studies is usually 2 years per patient.

*Alemtuzumab (brand name: "Campath"; 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 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. [Information from GenZyme on its clinical trial for Alemtuzumab [http://www.genzyme.com/corp/media/GENZ%20PR-050207.asp] ] Phase III has been starting in autumn 2007 and is expected to be completed in 2011. [ [http://www.clinicaltrial.gov/ct2/show/NCT00530348?term=alemtuzumab&rank=38 clinicaltrial.gov Phase III Alemtuzumab Study 1.] Retrieved on 25 November 2007.] , [ [http://www.clinicaltrial.gov/ct2/show/NCT00548405?term=alemtuzumab&rank=31 clinicaltrial.gov Phase III Alemtuzumab Study 2.] Retrieved on 25 November 2007.]

*BG00012 (an oral fumarate ester under development by Biogen; anticipated brand name "Panaclar"). It has completed Phase II investigations [ [http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=31741&XNSPRACHE_ID=2&XNKONGRESS_ID=39&XNMASKEN_ID=900 Kappos L, Miller DH, MacManus DG et al. "BG00012, a novel fumarate is effective in patients with relapsing-remitting multiple sclerosis". Mult Scler 2006;12:S85.] ] and has recently moved to Phase III. [ [http://www.clinicaltrials.gov/ct2/show/NCT00420212?term=biogen&recr=Open&rank=12 Efficacy and Safety of BG00012 in Relapsing-Remitting Multiple Sclerosis.] ClinicalTrials.gov (2007-09-1). Retrieved on 2007-11-12.]

*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. [ [http://www.clinicaltrial.gov/ct2/show/NCT00213135?term=clarity&rank=3 clinicaltrial.gov CLARITY Study.] Retrieved on 25 November 2007.] The completion of the phase III program is expected for late 2008.

*Dirucotide (MBP8298), a synthetic myelin basic protein (MBP) consisting of 17 aminoacids, is currently in FDA fast-track for approval for SPMS.

*Fingolimod (under development by Novartis) 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. [cite journal |author=Kappos L, Antel J, Comi G, "et al" |title=Oral fingolimod (FTY720) for relapsing multiple sclerosis |journal=N. Engl. J. Med. |volume=355 |issue=11 |pages=1124–40 |year=2006 |pmid=16971719 |doi=10.1056/NEJMoa052643] A phase III program is ongoing. [Information on the phase III trial for fingolimod [http://www.clinicaltrials.gov/ct/show/NCT00289978] ]

*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.cite journal |author=Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T |title=Treatment with laquinimod reduces development of active MRI lesions in relapsing MS |journal=Neurology |volume=64 |issue=6 |pages=987–91 |year=2005 |pmid=15781813 |doi=10.1212/01.WNL.0000154520.48391.69]

*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% [MS therapy shows promise in test, By Thomas H. Maugh II, Los Angeles Times Staff Writer [http://www.latimes.com/news/science/la-sci-ms14feb14,0,2437448.story] ] . 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. [Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH; HERMES Trial Group. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. [http://www.ncbi.nlm.nih.gov/pubmed/18272891] ] . Due to the side-effect profile, Rituximab's further trials are limited to primary progressive MS only, where no treatment is currently available. Unfortunately, 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.cite web |url=http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=11147 |title=Genentech: Newsroom: Press Releases: News Release April 14, 2008 |accessdate=2008-04-14 |date=2008-04-14 |publisher=Genentech]

*Teriflunomide, the active metabolite of the antirheumatic drug leflunomide, is currently under investigation for treatment of MS.

Phase II

Phase II studies are performed on mid-sized groups of patients (20 to 300) and are designed to assess whether a drug may work in the targeted disease area, as well as to continue earlier safety assessments obtained in healthy volunteers. Treatment in MS phase II studies is with 4–12 months usually shorter than in phase III studies.

*ATL1102 (under development by Teva and Antisense Therapeutics) is a second-generation antisense inhibitor of CD49d, a subunit of VLA-4 (Very Late Antigen-4). Results of a Phase IIa have been reported.
*CDP323 (under development by UCB S.A. and Biogen) is a compound for oral intake acting against α4-integrin, i.e., it has the same mechanism of action as natalizumab. Phase II investigations started in 2007. [ [http://www.clinicaltrial.gov/ct2/show/NCT00484536?term=cdp323&rank=1 clinicaltrial.gov CDP323 Phase II Study.] Retrieved on 25 November 2007.] ]
*Daclizumab (brand name "Zenapax"; under development by Biogen and PDL) is an anti-IL2 monoclonal antibody and an immunosuppressant used to prevent rejection after organ transplantation. Results from two Phase II were reported in 2007. [Montalban X, Wynn D, Kaufman M et al. "Preliminary CHOICE results". [http://registration.akm.ch/einsicht.php?XNABSTRACT_ID=52168&XNSPRACHE_ID=2&XNKONGRESS_ID=63&XNMASKEN_ID=900 ECTRIMS 2007] ] cite journal |author=Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG |title=Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results |journal=Neurology |volume=69 |issue=8 |pages=785–9 |year=2007 |pmid=17709711 |doi=10.1212/01.wnl.0000267662.41734.1f] It is expected that phase III studies will start soon.
*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 [cite journal |author=Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR |title=Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER){alpha} and ER{beta} ligand treatment |journal= |volume= |issue= |pages= |year=2007 |pmid=17785421 |doi=10.1073/pnas.0703783104] [cite web |url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T03-4BN5329-4&_user=10&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=13389a85a451935d43e24c22c082e53a |title=ScienceDirect - Journal of Neuroimmunology : Estriol treatment ameliorates disease in males with experimental autoimmune encephalomyelitis: implications for multiple sclerosis |accessdate=2008-04-07 |format= |work=]
*Inosine: Inosine is a compound that has shown interesting preliminary results in phases I and II clinical trials. [cite web| url=http://www.clinicaltrials.gov/ct/show/NCT00067327| title=Treatment of Multiple Sclerosis Using Over the Counter Inosine| date=March 16, 2006| accessdate=2006-05-10| publisher=ClinicalTrials.gov] [Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17121380&query_hl=17&itool=pubmed_docsum] ] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion, [cite journal |author=Koch M, De Keyser J |title=Uric acid in multiple sclerosis |journal=Neurol. Res. |volume=28 |issue=3 |pages=316–9 |year=2006 |pmid=16687059 |doi=10.1179/016164106X98215] which is a natural antioxidant [cite journal |author=Rentzos M, Nikolaou C, Anagnostouli M, "et al" |title=Serum uric acid and multiple sclerosis |journal=Clinical neurology and neurosurgery |volume=108 |issue=6 |pages=527–31 |year=2006 |pmid=16202511 |doi=10.1016/j.clineuro.2005.08.004] ; second, it has been shown to induce axonal rewiring in laboratory animals with stroke, [cite journal| url=http://www.pnas.org/cgi/content/full/99/13/9031| journal=PNAS | month= June 25| year=2002 | volume= 99 | issue=13 | pages=9031–9036| title=Inosine induces axonal rewiring and improves behavioral outcome after stroke| first=Peng| last=Chen| coauthors=David E. Goldberg, Bryan Kolb, Marc Lanser, and Larry I. Benowitz| accessdate=2006-05-10| doi=10.1073/pnas.132076299] and spinal cord injury [cite journal |author=Liu F, You SW, Yao LP, "et al" |title=Secondary degeneration reduced by inosine after spinal cord injury in rats |journal=Spinal Cord |volume=44 |issue=7 |pages=421–6 |year=2006 |pmid=16317421 |doi=10.1038/sj.sc.3101878] . However it can cause health problems in a long-term treatment [cite journal |author=McNaughton L, Dalton B, Tarr J |title=Inosine supplementation has no effect on aerobic or anaerobic cycling performance |journal=International journal of sport nutrition |volume=9 |issue=4 |pages=333–44 |year=1999 |pmid=10660865 |doi=] .
*Neurovax is a vaccine against autoreactive T-Cells, being tested for use in MS. In 2005 it was in phase II clinical trials; [cite journal |author=Darlington CL |title=Technology evaluation: NeuroVax, Immune Response Corp |journal=Curr. Opin. Mol. Ther. |volume=7 |issue=6 |pages=598–603 |year=2005 |pmid=16370383 |doi=] but in 2007 no results had been published yet.
*Tovaxin. Also a vaccine against T-Cells, which in this case consist of attenuated autoreactive T cells. It is developed by Opexa Therapeutics, (previously known as PharmaFrontiers), and finished a phase IIb September 2008 [Opexa shares lose most of value on study data [http://www.forbes.com/feeds/ap/2008/09/19/ap5448876.html] ] , failing its primary target though in March 2008 was still performing good [Opexa Therapeutics Announces Completion Of Mid Study Descriptive Analysis On Phase IIb Trial Of Tovaxin [http://www.medicalnewstoday.com/articles/100415.php] ] .

Other investigations on possible treatments

*Antimicrobial agents against "Chlamydophila pneumoniae": MS patients are more likely to have detectable levels of "Chlamydophila pneumoniae" DNA in their cerebrospinal fluid, compared to other patients with neurological diseases; however these findings are insufficient to establish an etiologic relation. [cite journal |author=Bagos PG, Nikolopoulos G, Ioannidis A |title=Chlamydia pneumoniae infection and the risk of multiple sclerosis: a meta-analysis |journal=Mult. Scler. |volume=12 |issue=4 |pages=397–411 |year=2006 |pmid=16900753 |doi=] 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). [cite journal |author=Sriram S, Yao SY, Stratton C, Moses H, Narayana PA, Wolinsky JS |title=Pilot study to examine the effect of antibiotic therapy on MRI outcomes in RRMS |journal=J. Neurol. Sci. |volume=234 |issue=1-2 |pages=87–91 |year=2005 |pmid=15935383 |doi=10.1016/j.jns.2005.03.042]

*Antioxidants, available as supplements, are reported to reduce the blood-brain barrier permeability. [Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11746387&query_hl=43&itool=pubmed_docsum] ] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant, [cite web| url=http://www.geocities.com/hotsprings/3468/uric_acid-peroxynitrite2-98.html| title=Uric Acid In Multiple Sclerosis| year=01/02/2006| accessdate=2006-05-10] and has been observed that raising uric acid levels protects against blood-brain barrier destruction (through peroxynitrite scavenging ). [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 [http://www.jimmunol.org/cgi/content/full/165/11/6511] ] 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 [cite journal |author=Schreibelt G, van Horssen J, van Rossum S, Dijkstra CD, Drukarch B, de Vries HE |title=Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology |journal= |volume= |issue= |pages= |year=2007 |pmid=17761296 |doi=10.1016/j.brainresrev.2007.07.005]

*Bilirubin has been found to have immunomodulatory properties, apart of the already known antioxidant properties, and is a possible future treatment [cite journal |author=Liu Y, Li P, Lu J, Xiong W, Oger J, Tetzlaff W, Cynader M. |title=Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis |journal= |volume= |issue= |pages= |year=2007 |pmid=18641326 |doi=] .

*Cyclophosphamide (trade name Revimmune): About RR-MS variant, in a 2006 study cyclophosphamide was given to patients with moderate to severe refractory (They had already tried approved medication) multiple sclerosis for four days. These patients were followed for two years. They showed a disease stabilization and improved functionality.cite journal |author=Gladstone DE, Zamkoff KW, Krupp L, "et al" |title=High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis |journal=Arch. Neurol. |volume=63 |issue=10 |pages=1388–93 |year=2006 |pmid=16908728 |doi=10.1001/archneur.63.10.noc60076] . Later, a 2007 open label study found it equivalent to Mitoxantronecite journal |author=Zipoli V, Portaccio E, Hakiki B, Siracusa G, Sorbi S, Pia Amato M |title=Intravenous mitoxantrone and cyclophosphamide as second-line therapy in multiple sclerosis: An open-label comparative study of efficacy and safety |journal= |volume= |issue= |pages= |year=2007 |pmid=17870094 |doi=10.1016/j.jns.2007.08.023] and in 2008 evidence appeared that it can reverse dissability [cite journal |author=Krishnan C, Kaplin AI, Brodsky RA, "et al" |title=Reduction of Disease Activity and Disability With High-Dose Cyclophosphamide in Patients With Aggressive Multiple Sclerosis |journal=Arch. Neurol. |volume= |issue= |pages= |year=2008 |month=June |pmid=18541787 |doi=10.1001/archneurol.65.8.noc80042 |url=] . About progressive variants, a review of the different studies that investigate its effects did not support its use in these casescite journal |author=La Mantia L, Milanese C, Mascoli N, D'Amico R, Weinstock-Guttman B |title=Cyclophosphamide for multiple sclerosis |journal=Cochrane database of systematic reviews (Online) |volume= |issue=1 |pages=CD002819 |year=2007 |pmid=17253481 |doi=10.1002/14651858.CD002819.pub2]

*Helminthic therapy: A study published in 2007 showed a negative association between multiple sclerosis and infection with intestinal parasites, such as hookworm indicating that parasites may protect against multiple sclerosis. [cite journal |author=Correale J, Farez M |title=Association between parasite infection and immune responses in multiple sclerosis |journal=Ann. Neurol. |volume=61 |issue=2 |pages=97–108 |year=2007 |pmid=17230481 |doi=10.1002/ana.21067]

*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 [ [http://clinicaltrials.gov/ct2/show/NCT00501696?term=Low+dose+naltrexone+Multiple+Sclerosis&rank=1 2007 clinical trial using LDN] ] 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. However, no compelling efficacy results for LDN in MS therapy have been published. LDN is currently available to MS patients in the USA by off-label prescription.

*Minocycline: the antibiotic minocycline has shown an effect on clinical and magnetic resonance imaging (MRI) outcomes and serum immune molecules in MS patients over 24 months of open-label minocycline treatment. Despite a moderately high pretreatment relapse rate in patients in the study prior to treatment, no relapses occurred between months 6 and 24. The only patient with gadolinium-enhancing lesions on MRI at 12 and 24 months was on half-dose minocycline. Clinical and MRI outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in MS.cite journal |author=Zabad RK, Metz LM, Todoruk TR, "et al" |title=The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study |journal=Mult. Scler. |volume=13 |issue=4 |pages=517–26 |year=2007 |pmid=17463074 |doi=10.1177/1352458506070319"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 it's low cost, means that large pharmaceutical companies will fight to prevent its introduction as an MS treatment. ] [http://www.mult-sclerosis.org/news/May2003/EmergingTherapiesforMS.html] [http://www.annals.org/cgi/content/full/122/2/81]

*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.cite journal |author=Gonsette RE, Dubois B |title=Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity |journal=J. Neurol. Sci. |volume=223 |issue=1 |pages=81–6 |year=2004 |pmid=15261566 |doi=10.1016/j.jns.2004.04.024]

*Prolactin:In 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of MS. [cite journal |author=Gregg C, Shikar V, Larsen P, "et al" |title=White matter plasticity and enhanced remyelination in the maternal CNS |journal=J. Neurosci. |volume=27 |issue=8 |pages=1812–23 |year=2007 |pmid=17314279 |doi=10.1523/JNEUROSCI.4441-06.2007] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.cite journal |author=Vukusic S, Confavreux C |title= [Multiple sclerosis and pregnancy] |language=French |journal=Rev. Neurol. (Paris) |volume=162 |issue=3 |pages=299–309 |year=2006 |pmid=16585885 |doi=]

*Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS. [cite journal |author=Weber MS, Prod'homme T, Steinman L, Zamvil SS |title=Drug Insight: using statins to treat neuroinflammatory disease |journal=Nature clinical practice. Neurology |volume=1 |issue=2 |pages=106–12 |year=2005 |pmid=16932506 |doi=10.1038/ncpneuro0047] 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.

*Testosterone has been studied for its potential benefits in men with Multiple Sclerosis, but the results are preliminary.cite journal |author=Sicotte NL, Giesser BS, Tandon V, "et al" |title=Testosterone treatment in multiple sclerosis: a pilot study |journal=Arch. Neurol. |volume=64 |issue=5 |pages=683–8 |year=2007 |pmid=17502467 |doi=10.1001/archneur.64.5.683]

*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. [cite journal |author=Munger KL, Zhang SM, O'Reilly E, "et al" |title=Vitamin D intake and incidence of multiple sclerosis |journal=Neurology |volume=62 |issue=1 |pages=60–5 |year=2004 |pmid=14718698 |doi=]

Combination of approved drugs

* Mitoxantrone & Copaxone: A recent study in the United Kingdom revealed interesting results when using a combination of mitoxantrone and copaxone. In an open-label study of 27 patients with RRMS, the results suggested a rapid and sustained suppression of relapses. A three year controlled study of 60 patients is now being launched at 10 centres across the UK. [ [http://www.mxga-mstrial.co.uk United Kingdom early Mitoxantrone Copaxone trial] ] . In another clinical trial, Glatimer 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 [Glatiramer acetate after induction therapy with mitoxantrone in relapsing multiple sclerosis [PMID 18424479] ] .
* Avonex & Inosine: Avonex (interferon beta-1a) was combined with Inosine. Available data suggests that this combination is safe and well tolerated, though with some adverse effects [Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman [http://www.medscape.com/viewarticle/510002] ] . There is doubt whether Inosine could be used in long-term treatment [cite journal |author=McNaughton L, Dalton B, Tarr J |title=Inosine supplementation has no effect on aerobic or anaerobic cycling performance |journal=International journal of sport nutrition |volume=9 |issue=4 |pages=333–44 |year=1999 |pmid=10660865 |doi=] .
* Avonex & Atorvastatin: Avonex has also been combined with Atorvastatin in a clinical trial showing that is safe in its conditions [Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis, [PMID 18398457] ] , even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term [Patient Management in Multiple Sclerosis: A Canadian Expert Viewpoint, Mark S. Freedman [http://www.medscape.com/viewarticle/510002] ] . Other clinical trials have found problems combining IFN beta with Atorvastatin [Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/18525027?ordinalpos=25&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum] ]
*Cyclophosphamide & Beta-interferon has been tried on IFNbeta-unresponsive patients with success, but it is still under study [Perini P, Calabrese M, Rinaldi L, Gallo P. Cyclophosphamide-based combination therapies for autoimmunity PMID 18690502] .
*Mitoxantrone & beta-interferon: This combination has worked in some cases but not in others [Zaffaroni M, Rizzo A, Baldini SM, Ghezzi A, Comi G. Induction and add-on therapy with mitoxantrone and interferon beta in multiple sclerosis PMID 18690501]

Investigation for progressive variants

Progressive variants have proved more difficult to treat than RRMS. This is the status of the research into progressive variants.

Primary progressive

This variant does not have any approved treatment currently. Some possible treatments have been published, such as methylprednisolone pulses [cite journal |author=Araújo EA, Freitas MR. |title=Benefit with methylprednisolone in continuous pulsetherapy in progressive primary form of multiple sclerosis: study of 11 cases in 11 years |journal= |volume= |issue= |pages= |year= |pmid=18641870 |doi=] or riluzole [Killestein J, Kalkers NF, Polman CH. Glutamate inhibition in MS: the neuroprotective properties of riluzole PMID 15949499] , but there is nothing conclusive still.

econdary progressive

Only Mitoxantrone has been approved, but most of the previous pipeline drugs have been or will be tried on it at some point. Since September 2008 Dirucotide is on fast-track for approval for SPMS.

References