Oral Treatment For Multiple Sclerosis Research Articles

FDA approves new oral treatment for multiple sclerosis

FDA approves new oral treatment for multiple sclerosis

FDA approves new oral treatment for multiple sclerosis

FDA approves new oral treatment for multiple sclerosis

Fingolimod (FTY720) is not protective in the subacute MPTP mouse model of Parkinson's disease and does not lead to a sustainable increase of brain-derived neurotrophic factor.

Parkinson's disease (PD) is characterized by the loss of midbrain dopaminergic neurons and aggregates of α-synuclein termed Lewy bodies. Fingolimod (FTY720) is an agonist of sphingosine-1 phosphate receptors and an approved oral treatment for multiple sclerosis. Fingolimod elevates brain-derived neurotrophic factor (BDNF), an important neurotrophic factor for dopaminergic neurons. BDNF and fingolimod are beneficial in several animal models of PD. In order to validate the therapeutic potential of fingolimod for the treatment of PD, we tested its effect in the subacute MPTP mouse model of PD. MPTP or vehicle was applied i.p. in doses of 30mg/kg MPTP on five consecutive days. In order to recapitulate the combination of dopamine loss and α-synuclein aggregates found in PD, MPTP was first administered in Thy1-A30P-α-synuclein transgenic mice. Fingolimod was administered i.p. at a dose of 0.1mg/kg every second day. Nigrostriatal degeneration was assayed by stereologically counting the number of dopaminergic neurons in the substantia nigra pars compacta, by analysing the concentration of catecholamines and the density of dopaminergic fibres in the striatum. MPTP administration produced a robust nigrostriatal degeneration, comparable to previous studies. Unexpectedly, we found no difference between mice with and without fingolimod treatment, neither at baseline, nor at 14 or 90days after MPTP. Also, we found no effect of fingolimod in the subacute MPTP mouse model when we used wildtype mice instead of α-synuclein transgenic mice, and no effect with an increased dose of 1mg/kg fingolimod administered every day. In order to explain these findings, we analysed BDNF regulation by fingolimod. We did find an increase of BDNF protein after a single injection of fingolimod 0.1 or 1.0mg/kg, but not after multiple injections, indicating that the BDNF response to fingolimod is unsustainable over time. Taken together we did not observe a neuroprotective effect of fingolimod in the subacute MPTP mouse model of PD. We discuss possible explanations for this discrepancy with previous findings and conclude fingolimod might be beneficial for the nonmotor symptoms of PD. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* and *Open Data* because it provided all relevant information to reproduce the study in the manuscript and because it made the data publicly available. The data can be accessed at https://osf.io/6xgfn/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

DNA methylation changes in CD4+ T cells isolated from multiple sclerosis patients on dimethyl fumarate.

BackgroundDimethyl fumarate is an oral treatment for multiple sclerosis, whose mechanism of action is not fully understood.ObjectiveTo investigate the effects of dimethyl fumarate on DNA methylation in the CD4+ T cells of multiple sclerosis patients.MethodsWe performed Illumina EPIC arrays to investigate the DNA methylation profiles of CD4+ T cells derived from multiple sclerosis patients before and after dimethyl fumarate treatment.ResultsTreatment with dimethyl fumarate resulted in 97% of differentially methylated positions showing hypermethylation. Four genes, SNORD1A, SHTN1, MZB1 and TNF had a differentially methylated region located within the transcriptional start site.ConclusionThis study investigates the effect of dimethyl fumarate on DNA methylation in multiple sclerosis patients.

The multiple sclerosis drug fingolimod (FTY720) stimulates neuronal gene expression, axonal growth and regeneration

Fingolimod (FTY720) is a new generation oral treatment for multiple sclerosis (MS). So far, FTY720 was mainly considered to target trafficking of immune cells but not brain cells such as neurons. Herein, we analyzed FTY720's potential to directly alter neuronal function. In CNS neurons, we identified a FTY720 governed gene expression response. FTY720 upregulated immediate early genes (IEGs) encoding for neuronal activity associated transcription factors such as c-Fos, FosB, Egr1 and Egr2 and induced actin cytoskeleton associated genes (actin isoforms, tropomyosin, calponin). Stimulation of primary neurons with FTY720 enhanced neurite growth and altered growth cone morphology. In accordance, FTY720 enhanced axon regeneration in mice upon facial nerve axotomy. We identified components of a FTY720 engaged signaling cascade including S1P receptors, G12/13G-proteins, RhoA-GTPases and the transcription factors SRF/MRTF.In summary, we uncovered a broader cellular and therapeutic operation mode of FTY720, suggesting beneficial FTY720 effects also on CNS neurons during MS therapy and for treatment of other neurodegenerative diseases requiring neuroprotective and neurorestorative processes.

Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation.

BackgroundFingolimod (FTY720), the first oral treatment for multiple sclerosis (MS), blocks immune cell trafficking and prevents disease relapses by downregulation of sphingosine-1-phosphate receptor. We determined the effect of FTY720 on human T cell activation and effector function.MethodsT cells from MS patients and healthy controls were isolated to measure gene expression profiles in the presence or absence of FTY720 using nanostring and quantitative real-time polymerase chain reaction (qPCR). Cytokine protein expression was measured using luminex assay and flow cytometry analysis. Lentivirus vector carrying short hairpin RNA (shRNA) was used to knock down the expression of specific genes in CD4+ T cells. Chromatin immunoprecipitation was performed to assess T cell factor 1 (TCF-1) binding to promoter regions. Luciferase assays were performed to test the direct regulation of interferon gamma (IFN-γ) and granzyme B (GZMB) by TCF-1. Western blot analysis was used to assess the phosphorylation status of Akt and GSK3β.ResultsWe showed that FTY720 treatment not only affects T cell trafficking but also T cell activation. Patients treated with FTY720 showed a significant reduction in circulating CD4 T cells. Activation of T cells in presence of FTY720 showed a less inflammatory phenotype with reduced production of IFN-γ and GZMB. This decreased effector phenotype of FTY720-treated T cells was dependent on the upregulation of TCF-1. FTY720-induced TCF-1 downregulated the pathogenic cytokines IFN-γ and GZMB by binding to their promoter/enhancer regions and mediating epigenetic modifications. Furthermore, we observed that TCF-1 expression was lower in T cells from multiple sclerosis patients than in those from healthy individuals, and FTY720 treatment increased TCF-1 expression in multiple sclerosis patients.ConclusionsThese results reveal a previously unknown mechanism of the effect of FTY720 on human CD4+ T cell modulation in multiple sclerosis and demonstrate the role of TCF-1 in human T cell activation and effector function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0460-z) contains supplementary material, which is available to authorized users.

INSIDE INDUSTRY

Helsinn Group signs exclusive agreement with Mundipharma for distribution and licensing of netupitant/palonosetron (NEPA) in Brazil. CrystalGenomics partners with Daewoong Pharmaceutical for Acelex commercialization in Korea. Roche acquires Signature Diagnostics to advance translational research for next generation sequencing (NGS) diagnostics. Boehringer Ingelheim renews global technology collaboration agreement with VTU Technology. Maverix wins $150,000 STTR Award by the National Institute on Drug Abuse for detection of RNA modifications. Rosetta Genomics receives first patent allowance in Japan. First-line oral treatment for multiple sclerosis approved in India. LKCMedicine scientist wins Young Investigator Award at 40th Lorne Conference.

Effect of monomethyl-fumarate on experimental stroke

Activation of the cytoprotective Nrf2 pathway has been shown to be beneficial in experimental stroke. Dimethyl-fumarate (DMF) activates the Nrf2 pathway through its active metabolite monomethyl-fumarate (MMF). DMF has been recently registered as an oral treatment of multiple sclerosis. Considering that novel treatment acting through the Nrf2 pathway is already available in clinical practice, here we investigated if MMF given intravenously protects against experimental stroke.

Treatment of MS patients with BG-12 results in a decline in circulating memory T and B lymphocytes (HUM1P.317)

Abstract BG-12 (Tecfidera®) is a recently approved oral treatment for multiple sclerosis that has shown remarkable efficacy. The mechanisms by which BG-12 acts on the human immune system are poorly defined. In the current study, we analyzed the effects of BG-12 treatment on subsets of circulating human T and B lymphocytes using multicolor flow cytometry. Patients treated for four months with BG-12 had decreased total numbers of lymphocytes in their blood that did not reach significance, and no changes in their overall percentages of CD4+ T cells, CD8+ T cells, or CD19+ B cells compared to pretreatment levels. Significant differences were observed when subsets of T and B cells were evaluated. BG-12 treatment resulted in a decrease in percentages of circulating CD4+CD45RO+CD45RAneg memory TH cells and CD8+CD45RO+CD45RAneg memory CTL. Treatment with BG-12 also resulted in significant decreases in circulating CD27+CD19+ memory B cells, and a relative increase in the levels of CD24highCD38highCD19+ regulatory B cells. A CD27+CD24lowCD19+ B cell subset was present in the circulation of some MS patients prior to treatment, but returned to the very low levels found in healthy controls following four months of BG-12 treatment. The data suggest that BG-12 has in vivo down regulatory effects on some lymphocyte subsets, particularly memory T and B cells. Ongoing experiments are focused on measuring functional differences in T and B cell cytokine production in BG-12 treated patients.

Discovery of Clinical Candidate GSK1842799 As a Selective S1P1 Receptor Agonist (Prodrug) for Multiple Sclerosis.

To develop effective oral treatment for multiple sclerosis (MS), we discovered a series of alkyl-substituted biaryl amino alcohols as selective S1P1 modulators. One exemplar is (S)-2-amino-2-(5-(4-(octyloxy)-3-(trifluoromethyl)phenyl)-1,3,4-thiadiazol-2-yl)propan-1-ol (10, GSK1842799). Upon phosphorylation, the compound (10-P) showed subnanomole S1P1 agonist activity with >1000× selectivity over S1P3. The alcohol 10 demonstrated good oral bioavailability and rapid in vivo conversion to 10-P. Dosed orally at 0.1 mg/kg, 10 significantly reduced blood lymphocyte counts 6 h postdose, and at 3 mg/kg, 10 achieved efficacy equivalent to FTY720 in the mouse EAE model of MS. Further pharmacokinetic/pharmacodynamic (PK/PD) study with cynomolgus monkeys indicated that, after oral dosing of 10 at 3.8 mg/kg, the active phosphate reached plasma levels that are comparable to FTY-720 phosphate (FTY-P) revealed in human clinical pharmacokinetics studies. On the basis of the favorable in vitro ADME and in vivo PK/PD properties as well as broad toxicology evaluations, compound 10 (GSK1842799) was selected as a candidate for further clinical development.

Sphingosine-1-Phosphate and Its Receptors: Structure, Signaling, and Influence

The sphingosine-1-phosphate (S1P) receptor signaling system has biological and medical importance and is the first lipid G protein-coupled receptor (GPCR) structure to be solved to 2.8-Å resolution. S1P binds to five high-affinity GPCRs generating multiple downstream signals that play essential roles in vascular development and endothelial integrity, control of cardiac rhythm, and routine oral treatment of multiple sclerosis. Genetics, chemistry, and now structural biology have advanced this integrated biochemical system. The S1P receptors have a novel N-terminal fold that occludes access to the binding pocket from the extracellular environment as well as orthosteric and bitopic ligands with very different physicochemical properties. S1P receptors and metabolizing enzymes have been deleted, inducibly deleted, and knocked in as tagged or altered receptors in mice. An array of genetic models allows analysis of integrated receptor function in vivo. We can now directly understand causal relationships among protein expression, signal, and control points in physiology and pathology.

CPC-121 Report After One Year Using of Fingolimod, the First Oral Treatment For Multiple Sclerosis: Analysis of Patients in a Neurology Unit

BackgroundMultiple sclerosis (MS) is in Europe the most common neurological disease starting between the ages of 20 and 40 years. It affects approximately 2.5 million people worldwide and is the...

How does fingolimod (gilenya(®)) fit in the treatment algorithm for highly active relapsing-remitting multiple sclerosis?

Multiple sclerosis (MS) is a neurological disorder characterized by inflammatory demyelination and neurodegeneration in the central nervous system. Until recently, disease-modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta-interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya®) is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS) for adult patients with high disease activity despite basic treatment (beta-interferon) and for treatment-naïve patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from ten Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients.

Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome

The functional relevance of brain-derived neurotrophic factor (BDNF) is beginning to be well appreciated not only in mice, but also in humans. Because reduced levels typically correlate with impaired neuronal function, increasing BDNF levels with well-tolerated drugs diffusing into the central nervous system may help in ameliorating functional deficits. With this objective in mind, we used the sphingosine-1 phosphate receptor agonist fingolimod, a drug that crosses the blood-brain barrier. In addition, fingolimod has recently been introduced as the first oral treatment for multiple sclerosis. In cultured neurons, fingolimod increases BDNF levels and counteracts NMDA-induced neuronal death in a BDNF-dependent manner. Ongoing synaptic activity and MAPK signaling is required for fingolimod-induced BDNF increase, a pathway that can also be activated in vivo by systemic fingolimod administration. Mice lacking Mecp2, a gene frequently mutated in Rett syndrome, show decreased levels of BDNF, and fingolimod administration was found to partially rescue these levels as well as the size of the striatum, a volumetric sensor of BDNF signaling in rodents. These changes correlate with increased locomotor activity of the Mecp2-deficient animals, suggesting that fingolimod may improve the functional output of the nervous system, in addition to its well-documented effects on lymphocyte egress from lymph nodes.

Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group

SummaryFingolimod is the first oral treatment of multiple sclerosis. It is the first-in-class sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phophate receptors on lymphocytes and via downregulation of the receptor prevents lymphocyte egress from lymphoid tissues into the circulation. This mechanism reduces the infiltration of potentially auto-aggressive lymphocytes into the central nervous system. Two large phase III studies with fingolimod have shown superior efficacy of the drug in two dosages compared to placebo and to weekly intramuscular injections of Interferon beta-1a. Among possible side effects of the drug is a transient bradycardia after the first dose of fingolimod including possible AV blockade and therefore monitoring of pulse rate and blood pressure for 6 h following the first application is needed. During treatment, attention has to be given to specific infections, elevated liver enzymes, and ophthalmologic changes. Recommendations on the use of fingolimod including safety aspects are given in this article.

Evidence⁃based evaluation of treatment strategy for multiple sclerosis

Objective To formulate the best treatment plan for multiple sclerosis (MS) patients by evaluating the therapeutic efficacy and side effect of various evidence ⁃ based programs. Methods Key words were defined as multiple sclerosis, immunomodulatory therapy and therapy, etc. We searched MEDLINE, Cochrane Library, Wanfang data bases for Scientific Journals in China and National Knowledge Infrastructure for Chinese Scientific Journals Database. Additionally, we applied manual searching and screened out conference paper and academic dissertation, etc, from various references. After that we obtained and evaluated by Jadad scales on systematic reviews, randomized controlled trials, controlled clinical trials and observational study cases about glucocorticoids, plasmapheresis, intravenous immunoglobulin, IFN ⁃ β, glatiramer acetate, mitoxantrone, natalizumab, fingolimod. Results After screening, all seventeen selected resources included systematic reviews 6 articles, randomized controlled trials 7 articles, controlled clinical trials 2 articles, observational study cases 2 articles, among which fifteen articles were proved to be high quality (according to Jadad scoring system, five score 4, six score 5, four score 7), two chapters were judged to be low quality scoring 3. Finally, we summerize that: 1) The first choice of treatment for acute relapses is glucocorticoids and we suggest that plasmapheresis or intravenous immunoglobulin may be tried as an alternative therapy in acute MS relapse, especially in case of contraindications to intravenous methylprednisolone. 2) Immunomodulatory or immunosuppressive treatment (IFN ⁃ β, glatiramer acetate, mitoxantrone, natalizumab) can be an option to prevent new relapses and progression of disability. 3) Fingolimod is an oral treatment for multiple sclerosis to improve treatment adherence. Conclusion Using evidence⁃based medicine methods can provide us best clinical evidence on MS treatment. DOI：10.3969/j.issn.1672⁃6731.2012.02.012

Oral treatment for multiple sclerosis

The armamentarium for the treatment of relapsing-remitting multiple sclerosis (RRMS) is increasing rapidly. Several oral treatments have shown benefit and will generate much interest because of the convenience of such administration. However, availability of convenient oral drugs will not necessarily translate into clinical effectiveness and safety. Here, we provide an interim report about the mechanisms of action, and efficacy and safety results that have been reported since January, 2010, for five new oral drugs. Additionally, we draw attention to issues that neurologists and patients will encounter when considering the use of new oral drugs. Positive results have been reported for five new oral drugs for RRMS--fingolimod, cladribine, teriflunomide, laquinimod, and dimethyl fumarate--in phase 3 studies; a few new oral drugs are likely to be approved for RRMS soon. WHERE NEXT?: Emerging oral treatments are ushering in a new era in the treatment of MS, providing not only new treatment options but also new challenges. Since data for some of the new drugs have not been reported in peer-reviewed journals yet and safety profiles are not yet fully developed, opinions about the use of these new oral drugs in practice are preliminary and tentative. Practice will evolve with time as information and experience accumulates. Of importance will be results from comparator trials, information about management of patients with breakthrough disease, results from long-term safety studies, and results of studies to assess the potential for neuroprotective effects of the new drugs.

20th National Meeting of the British Neuroscience Association

20th National Meeting of the British Neuroscience Association

Determination of the immunomodulator laquinimod in human plasma by liquid chromatography/tandem mass spectrometry; development, validation and application of two methods in clinical pharmacokinetic profiling

Laquinimod (ABR-215062) is a synthetic compound currently undergoing clinical development for oral treatment of multiple sclerosis. The present paper describes the development, validation and clinical application of two rapid and sensitive methods for the determination of ABR-215062 in human plasma. Both methods use liquid chromatography/tandem mass spectrometry (LC/MS/MS) with electrospray ionization in positive mode and a stable isotope (13C6)-labeled ABR-215062 as internal standard for calibration. The selected reaction monitoring was based on the transitions m/z 357.1 --> 236.1 for ABR-215062, and either m/z 363.2 --> 236.1 or 365.2 --> 238.1 for 13C6-ABR-215062. Method 1, aimed and validated for low level determinations (0.4-100 nmol/L) of ABR-215062, utilizes solid-phase extraction followed by isocratic elution. Method 2, aimed and validated for wide range determinations (0.75-15000 nmol/L) of ABR-215062, utilizes protein precipitation followed by fast gradient elution. The methods were validated with respect to selectivity, lower limit of quantification (LLOQ), dynamic range, precision, accuracy, extraction recovery and ruggedness. Furthermore, the stability of low level ABR-215062 in plasma was investigated. The methods were also applied in clinical trials. The LLOQs were 0.4 and 0.75 nmol/L for methods 1 and 2, respectively. The intra- and inter-day precision for the methods were 1.6-3.5% and 2.1-5.7%. The extraction recoveries were 90-97% for both methods. ABR-215062 was stable in plasma for at least 3 months when stored at -20 degrees C. In conclusion, our developed methods were found to be selective, sensitive, robust and suitable for applications in clinical pharmacokinetic profiling.

BG 12

Fumapharm AG has developed a second-generation fumarate (fumaric acid) derivative, BG 12 [BG 00012, FAG-201, BG 12/Oral Fumarate], for the oral treatment of psoriasis. Biogen Idec is currently evaluating the product in clinical trials as an oral treatment for multiple sclerosis (phase II) and psoriasis (phase III) trials.BG 12 has an immunomodulatory mechanism of action. It seems that this product has been developed to reduce the adverse effects associated with a first-generation product containing fumaric acid esters (mixed dimethylfumarate and monoethylfumarate salts), Fumaderm. Fumaderm was approved in Germany in August 1994 and is currently the leading oral systemic therapy for moderate-to-severe psoriasis in Germany. One of the problems associated with Fumaderm capsules has been its gastrointestinal adverse effects (including diarrhoea and nausea). In September 2003, Biogen (now Biogen Idec) licensed exclusive worldwide rights (excluding Germany) from Fumapharm to develop and market BG 12. Biogen plans to collaborate with Fumapharm to accelerate phase III development for psoriasis and the registration programme worldwide. Financial terms of the agreement were not disclosed. Development plans for BG 12 include other autoimmune and inflammatory disorders, such as multiple sclerosis. In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Fumapharm completed phase II trials of this second-generation fumarate derivative for psoriasis prior to licensing of the product to Biogen, also with positive results.