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A Mechanistically Novel, First Oral Therapy for Multiple Sclerosis: The Development of Fingolimod (FTY720, Gilenya)


Strategies for Protecting Oligodendrocytes and Enhancing Remyelination in Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) characterized by encephalitogenic leukocyte infiltration and multifocal plaques of demyelination. Patients present with debilitating clinical sequelae including motor, sensory, and cognitive deficits. For the past 30 years, immune modulating treatments have entered the marketplace and continue to improve in limiting the frequency and severity of relapses, but no cure has been found and no drug has successfully stopped chronic progressive disease. Recent work focusing on the oligodendrocyte, the myelin-producing cell, has provided needed insight into the process of demyelination, the spontaneous ability of the CNS to regenerate, and the inevitable failure of remyelination. From this a number of promising molecular targets have been identified to protect oligodendrocytes and promote remyelination. Combining immunomodulatory therapy with strategies to protect oligodendrocytes from further degeneration and enhance remyelination presents a very real means to improve clinical outcome for chronic progressive patients in the near future. Here we lay out a combination therapy approach to treating MS and survey the current literature on promising drug candidates potentially capable of mediating oligodendrocyte protection and enhancing remyelination. ... Read more

Relevance of the Type I Interferon Signature in Multiple Sclerosis Towards a Personalized Medicine Approach for Interferon-beta Therapy

Abstract: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system. The disease is characterized by progressive neurological dysfunction due to demyelination of the nerves, which leads to disability. Currently, no curative therapy is available and patients are subjected to a prolonged course of treatment. Interferon-β (IFNβ) was the first agent to show clinical efficacy in the treatment of MS, and is still the best available therapy. Unfortunately, clinical experience indicates that approximately 40% of the patients do not or only poorly respond to IFNβ treatment. Recent advances revealed the presence of an activated type I IFN pathway in a subset of treatment naïve patients with relapsing remitting MS (RRMS), as shown by the presence of an "IFN signature" and type I IFN bioactivity in the blood of these patients. Evidence exists that quantification of the IFN signature in RRMS is informative as a biomarker to predict the clinical response to IFNβ. In this review we summarize the current evidence of type I IFN activation in RRMS and its clinical relevance. ... Read more

Industry Trends: Antegren -- Novel drug for autoimmune diseases

On Feb. 18, 2004, Elan and Biogen Idec announced their plan to submit a Biologics License Application (BLA) for Antegren (natalizumab) to the U.S. FDA for the treatment of multiple sclerosis (MS) by the middle of this year. The surprise announcement was made after a consultation with the FDA of the drug’s one-year data from the two ongoing two-year Phase III trials in MS. The companies are committed to completing two-year trials and would not disclose the one-year data at this time, citing the necessity to protect the integrity of the results of the two-year trials, which will be submitted ... Read more

Book Summary: Curing MS -- How Science Is Solving the Mysteries of Multiple Sclerosis

Abstract: On a grander scale, multiple sclerosis is a battle between a patient's will to fight and the disease's vicious attack on central nerve cells. On a cellular scale, it's between the T helper 1 (Th1) cell, which attacks and destroys the myelin sheath that protects nerve cells, and the Th2 and Th3 cells, which try to bring Th1 cells under control. ... Read more

The Pathogenesis of Progressive Multifocal Leukoencephalopathy

Abstract: Interest in pathogenesis of progressive multifocal leukoencephalopathy (PML) followed the observation of the high risk for the disease in HIV infection and the recent observation of an association with a variety of newer therapeutic modalities, e.g., natalizumab, an α4β1 integrin inhibitor, and efalizumab, an anti-CD11a monoclonal antibody. Any hypothesis of PML pathogenesis must account for a number of facts. Firstly, the causative agent JC virus is ubiquitously present, yet only a vanishingly small number of infected persons develop the disease. Secondly, disorders of cell-mediated immunity increase the risk of the disease, particularly HIV infection. Impaired innate immunity is not a risk for PML, and antibodies against JC virus are not protective. Thirdly, a latent period of several months appears necessary following the administration of natalizumab and efalizumab before PML develops. Fourthly, restoration of the immune system can arrest the PML. It is possible that infection with JC virus occurs with a form of the virus shed in the urine of as many as 40% of all adults and present in sewage worldwide. Once acquired, perhaps through an oropharyngeal route, it may replicate and disseminate. A neurotropic form of JC virus that replicates in glial tissues causes PML when immunosurveillance is impaired. There are many unanswered questions with respect to PML pathogenesis. How is virus acquired? What tissues are infected? What is the origin of the neurotropic form? When does virus enter brain? What is the role of central nervous system immunosurveillance? The lack of an animal model has made answering these questions challenging. ... Read more

Epigenetic Mechanisms in Multiple Sclerosis and the Major Histocompatibility Complex (MHC)

Abstract: Multiple sclerosis (MS) is a complex disorder of the central nervous system characterized by demyelination, axonal loss, and inflammation. The cause of MS is currently unknown although genetic and environmental factors contribute to etiology. The relative importance of each has been disputed; however, now it is clear that much of the disease results from the interaction of the environment and the genetics. Epigenetic modifications within the major histocompatibility complex (MHC) likely mediate interactions at this locus with current known environmental risk factors -- vitamin D, Epstein-Barr virus, and smoking. Maternal parent-of-origin effects, month of birth effects and transgenerational differences in allele frequency are also evident in MS and may be mediated by sex-specific epigenetic mechanisms. Differences in epigenetic marks characterize monozygotic twin pairs and may explain discordance. There is promise of potential therapeutic strategies to be found in the epigenetic mechanisms at work in MS. ... Read more

Axonal Pathology and Demyelination in Viral Models of Multiple Sclerosis

Abstract: Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS). Monozygotic twin studies suggest that while there is a genetic contribution, genetics alone cannot be the sole determining factor in the development of MS. As the rates of MS are increasing, particularly among women, environmental factors such as viral infections are coming to the foreground as potential agents in triggering disease in genetically susceptible individuals. This review highlights pathological aspects related to two pre-clinical viral models for MS; data are consistent between these two models as experimental infection of susceptible mice can induce axonal degeneration associated with demyelination. These data are consistent with observations in MS that axonal damage or Wallerian degeneration is occurring within the CNS contributing to the disability and disease severity. Such early damage, where axonal damage is primary to secondary demyelination, could set the stage for more extensive immune mediated demyelination arising later. ... Read more

Vitamin D Supplementation, Moderate Sun Exposure, and Control of Immune Diseases

Abstract: There is considerable debate about the benefits of vitamin D supplementation for multiple sclerosis, allergic asthma, and type 1 diabetes. This has been driven mainly by observational studies linking vitamin D deficiency and insufficiency with increased prevalence of autoimmune and other diseases driven by immune processes. Randomized controlled trials of vitamin D supplementation to treat these (and other) diseases have been disappointing. This review examines the evidence that circulating vitamin D levels provide a surrogate measure of sun exposure and that it is the other molecules and pathways induced by sun exposure, rather than vitamin D-driven processes, that explain many of the benefits often attributed to vitamin D. ... Read more

Biotechnology/Pharmaceutical Industry News: Biogen, Idec, and Xolair

Biogen and IDEC to Merge, Confronting Slower Growth. Biogen IDEC is Third Largest Biotech Company

On June 23, 2003 Biogen, Inc. of Cambridge, MA and IDEC Pharmaceuticals, San Diego, CA announced plans to merge with a combined capitalization of $12 billion. IDEC shareholders will hold 50.5% and Biogen shareholders 49.5% of the combined companies. The combined company named Biogen IDEC will be headquartered in Cambridge, MA with current IDEC chairman and CEO William H. Rastetter, Ph.D. as Executive Chairman and current Biogen Chairman and CEO James C. Mullen as the CEO. Biogen IDEC will be the third largest biopharmaceutical company after Amgen ... Read more

miRNAs at the Crossroad Between Hematopoietic Malignancies and Autoimmune Pathogenesis

Abstract: The study of microRNA (miRNA) regulation in the pathogenesis of autoimmune diseases and hematopoietic malignancies provides new understanding of the mechanisms of disease and is currently the focus of many researchers in the field. Autoimmune disorders and cancers of immune system comprise a wide range of genetically complex diseases that share certain aspects of dysregulated genetic networks, most notably deactivation of apoptosis. miRNA mechanisms control gene expression at the post-transcriptional level, linking mRNA processing and gene function. Considerable amount of data have been accumulated that indicate that the alteration of miRNA expression closely mirrors the development of immune system diseases and is likely to play a role in their pathogenesis. However, a knowledge gap remains in our understanding of how miRNA dysregulation and the specific effects of miRNAs on target gene expression underlay the disease phenotype. Here we review a number of studies describing miRNA alterations in autoimmune diseases and hematopoietic cancers and discuss potential miRNA-regulated mechanisms that differentially influence the development of autoimmunity as compared to cancer progression. ... Read more

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