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Therapies under investigation for multiple sclerosis



Scientists continue their extensive efforts to create new and better therapies for multiple sclerosis. There are a number of treatments under investigation that may curtail attacks or slow progression of disease. Some of these treatments involve the combination of drugs that are already in use for multiple sclerosis; such as the combination of mitoxantrone and glatiramer acetate (Copaxone). However most treatments already in clinical trials involve drugs that are used in other diseases. These are the cases of alemtuzumab (trade name Campath) or inosine. Other drugs in clinical trials have been designed specifically for MS, like laquinimod or Neurovax. Finally there are also many basic investigations that in the future may be able to find new treatments. Examples of these are the studies trying to understand the influence of Chlamydophila pneumoniae or vitamin D in the origin of the disease.

Contents

Combination of approved drugs

  • A recent study in the United Kingdom revealed promising results when using a combination of mitoxantrone (an immunosuppressive drug normally used in cancer) and glatiramer acetate (Copaxone). In an open study of 27 patients with Relapsing Remitting MS, the combination was found to provide a rapid and sustained suppression of relapses in MS patients experiencing frequent, recurrent and disabling attacks (90% reduction in annualised relapse rate maintained, to date, for a mean of 36 months). A three year controlled study is now being launched at 10 centres across the UK.[1]

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.

  • 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 and an acceptable safety profile.[2] A phase III program is ongoing.[3]
  • 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.[4] The completion of the phase III program is expected for late 2008.
  • BG00012 (a fumarate ester under development by Biogen; anticipated brand name Panaclar). It has completed Phase II investigations[5] and has recently moved to Phase III.[6]
  • 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. This is a life-threatening side-effect but is treatable if detected. Therefore, all patients receiving alemtuzumab should have their platelet count monitored.[7] Phase III has been starting in autumn 2007 and is expected to be completed in 2011.[8],[9]
  • Laquinimod: Laquinimod 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.[10]

Further compounds in phase III include teriflunomide, a derivative of the antirheumatic drug leflunomide; MBP8298, a synthetic myelin basic protein (MBP) consisting of 17 aminoacids; and rituximab, a anti-CD20 monoclonal antibody.

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.

  • Inosine: Inosine is a compound that has shown good results in phases I and II.[13][14] Two different ways of action have been proposed. First, it produces uric acid after ingestion,[15] which is a natural antioxidant,[16][17] second, it has been shown to induce axonal rewiring and is used as a treatment for stroke,[18] and spinal cord injury;[19] and third, it has shown neuroprotective and anti-inflammatory effects independently of the other two.[20]
  • Neurovax is a vaccine being tested for use in MS. In 2005 it was in phase II clinical trials;[21] but in 2007 no results had been published yet.
  • 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.[22]

Off-label treatments

Several medications are commonly prescribed without approval for specific use in MS. Azathioprine, which is the most widely used immunosuppressive treatment in multiple sclerosis,[23] has no regulatory approval in the English-speaking countries but is approved in Germany.

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.[24] 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).[25]
  • Antioxidants, available as supplements, are reported to reduce the blood-brain barrier permeability.[26] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant,[27] and has been observed that raising uric acid levels protects against blood-brain barrier destruction (through peroxynitrite scavenging ).[28] 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[29]
  • Cyclophosphamide: 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.[30] However a review of the different studies that investigate if cyclophosphamide is useful for progressive MS does not support its use in clinical practice.[31] Nevertheless a 2007 open label study finds it equivalent to Mitoxantrone[32]
  • 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[33]
  • Low dose naltrexone: (also known as LDN) Naltrexone, a pure opiate antagonist, licensed in a 50 mg dose by the United States FDA in 1984 for the treatment of alcohol and opioid addictions, is currently being studied at a lower dosage for MS patients. Clinical trials with MS patients are being conducted at the University of California, San Francisco (study ending late 2007), the MindBrain Consortium along with the Department of Psychiatry of Summa Hospital System of Akron, Ohio and the Oak Clinic, and a related trial being conducted at Pennsylvania State University in Hershey, PA using an animal model of MS. In October 2007 data was presented at the European Congress of MS in Prague regarding findings of a pilot study of low dose naltrexone therapy in multiple sclerosis by neurological researchers in Milan, Italy. LDN is currently available to Multiple Sclerosis patients in the United States by 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.[34]
  • 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.[35]
  • 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.[36]
  • Prolactin:In 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of MS.[37] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.[38]
  • Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS.[39] However, as of 2007 there is not sufficient evidence that statins are beneficial in the treatment of human MS patients.
  • Testosterone has been studied for its potential benefits in men with Multiple Sclerosis, but the results are preliminary.[40]
  • 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.[41]

References

  1. ^ United Kingdom early Mitoxantrone Copaxone trial
  2. ^ 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.
  3. ^ Information on the phase III trial for fingolimod [1]
  4. ^ clinicaltrial.gov CLARITY Study. Retrieved on 25 November 2007.
  5. ^ 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.
  6. ^ Efficacy and Safety of BG00012 in Relapsing-Remitting Multiple Sclerosis. ClinicalTrials.gov (2007-09-1). Retrieved on 2007-11-12.
  7. ^ Information from GenZyme on its clinical trial for Alemtuzumab [2]
  8. ^ clinicaltrial.gov Phase III Alemtuzumab Study 1. Retrieved on 25 November 2007.
  9. ^ clinicaltrial.gov Phase III Alemtuzumab Study 2. Retrieved on 25 November 2007.
  10. ^ 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.
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  23. ^ Casetta I, Iuliano G, Filippini G (2007). "Azathioprine for multiple sclerosis". Cochrane database of systematic reviews (Online) (4): CD003982. doi:10.1002/14651858.CD003982.pub2. PMID 17943809.
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  28. ^ 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[5]
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  36. ^ Gonsette RE, Dubois B (2004). "Pixantrone (BBR2778): a new immunosuppressant in multiple sclerosis with a low cardiotoxicity". J. Neurol. Sci. 223 (1): 81-6. doi:10.1016/j.jns.2004.04.024. PMID 15261566.
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v • d • e
Multiple sclerosis
Signs and symptomsAtaxia · Depression · Diplopia · Dysarthria · Dysphagia · Fatigue · Incontinence · Neurological fatigue · Nystagmus · Optic neuritis · Pain
Diagnosis and evolution followingMcDonald criteria · EDSS
InvestigationPathophysiology · Experimental autoimmune encephalomyelitis
TreatmentInterferon · Glatiramer acetate · Mitoxantrone · Natalizumab · Therapies under investigation
Borderline formsAcute disseminated encephalomyelitis · Balo concentric sclerosis · Devic's disease · Guillain-Barré syndrome · Marburg multiple sclerosis · Schilder's disease
OtherList of people with multiple sclerosis · List of multiple sclerosis organizations
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Therapies_under_investigation_for_multiple_sclerosis". A list of authors is available in Wikipedia.
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