Therapies under investigation for multiple sclerosis

From Wikipedia, the free encyclopedia

Scientists continue their extensive 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.

Contents 1 Disease-modifying drugs in phase II and III clinical trials 1.1 Phase III 1.2 Phase II 2 Other investigations on possible treatments 3 Combination of approved drugs 4 References

[edit] 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.

[edit] 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.^[1] Phase III has been starting in autumn 2007 and is expected to be completed in 2011.^[2],^[3]

• BG00012 (a fumarate ester under development by Biogen; anticipated brand name Panaclar). It has completed Phase II investigations^[4] and has recently moved to Phase III.^[5]

• 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 is expected for late 2008.

• 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.^[7] A phase III program is ongoing.^[8]

• 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.^[9]

• 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%^[10]. 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 wonder about the traditional model of the MS attacks.^[11]. 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.^[12]

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

[edit] 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.

• 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.^[13]

• 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.^[14][15] 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^[16][17]

• Inosine: Inosine is a compound that has shown interesting preliminary results in phases I and II clinical trials.^[18][19] Two different mechanisms of action have been proposed. First, it produces uric acid after ingestion,^[20] which is a natural antioxidant^[21]; second, it has been shown to induce axonal rewiring in laboratory animals with stroke,^[22] and spinal cord injury^[23]. However there is doubt whether it could find a place in long-term treatment^[24].

• Neurovax is a vaccine against autoreactive T-Cells, being tested for use in MS. In 2005 it was in phase II clinical trials;^[25] 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 March 2008^[26].

[edit] 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.^[27] 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).^[28]

• Antioxidants, available as supplements, are reported to reduce the blood-brain barrier permeability.^[29] Related to this, MS patients have been reported to have low levels of uric acid, which is a natural antioxidant,^[30] and has been observed that raising uric acid levels protects against blood-brain barrier destruction (through peroxynitrite scavenging ).^[31] 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^[32]

• 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.^[33] However a review of the different studies that investigate if cyclophosphamide is useful for progressive MS does not support its use in clinical practice.^[34] Nevertheless a 2007 open label study finds it equivalent to Mitoxantrone^[35]

• 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.^[36]

• 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^[37] 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.^[38][12][13]

• 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.^[39]

• Prolactin:In 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of MS.^[40] This effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women.^[41]

• Statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of MS.^[42] 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.^[43]

• 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.^[44]

[edit] Combination of approved drugs

• A recent study in the United Kingdom revealed interesting results when using a combination of mitoxantrone (an immunosuppressive drug normally used in cancer) and glatiramer acetate (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.^[45]
• Avonex (interferon beta-1a) was combined with Inosine. Available data suggests that this combination is safe and well tolerated, though with some adverse effects^[46]. There is doubt whether Inosine could be used in long-term treatment^[47].
• Avonex has also been combined with Atorvastatin in a clinical trial showing that is safe in its conditions^[48], even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term^[49]. Other clinical trials have found problems combining IFN beta with Atorvastatin^[50]
• Glatimer Acetate has been combined with Mitoxantrone in such a way that every course of Mitoxantrone is followed by Ga treatment. It has yielded promising results^[51].

[edit] References

v • d • e Multiple sclerosis Signs and symptoms Ataxia · Depression · Diplopia · Dysarthria · Dysphagia · Fatigue · Incontinence · Neurological fatigue · Nystagmus · Optic neuritis · Pain · Uhthoff's phenomenon Diagnosis and evolution following McDonald criteria · EDSS Investigation Pathophysiology · Experimental autoimmune encephalomyelitis Treatment Interferon · Glatiramer acetate · Mitoxantrone · Natalizumab · Therapies under investigation Borderline forms Acute disseminated encephalomyelitis · Balo concentric sclerosis · Devic's disease · Guillain-Barré syndrome · Marburg multiple sclerosis · Schilder's disease Other List of people with multiple sclerosis · List of multiple sclerosis organizations