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Phase III trial shows efficacy in secondary progressive MS

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  • Phase III trial shows efficacy in secondary progressive MS

    Results from a phase III trial are nothing to sneeze at and positive results in any SPMS trial is fantastic. That said, I'd like to see a lot more info before I get too excited. More details will be released at ECTRIMS this September. - D

    Press Release: Novartis announces positive phase III results showing efficacy of BAF312 in patients with secondary progressive MS

    -- The Phase III EXPAND study of BAF312 (siponimod) in secondary progressive multiple sclerosis (SPMS) met its primary endpoint of reducing the risk of three-month confirmed disability progression versus placebo

    -- There are currently very limited treatment options for SPMS, a form of MS associated with gradual worsening of symptoms and accumulation of disability, independent of relapses

    -- EXPAND is the largest study ever conducted in SPMS, and is part of Novartis' ongoing leadership and commitment to people with MS

    Basel, August 25, 2016 - Novartis today announced the Phase III EXPAND study, evaluating the efficacy and safety of oral, once-daily, BAF312 (siponimod) in secondary progressive multiple sclerosis (SPMS), met its primary endpoint of a reduction in the risk of disability progression, compared with placebo. The EXPAND study represents the largest randomized, controlled study in SPMS to date.

    "SPMS is a particularly disabling form of MS, and there is a need for effective treatment options to help delay disability progression in those living with the condition," said Vasant Narasimhan, Global Head of Drug Development and Chief Medical Officer for Novartis. "The positive EXPAND data are encouraging for a disease with such a high unmet need. We look forward to sharing the results at the upcoming ECTRIMS congress, and thank all of the study participants and investigators."

    Topline results of the EXPAND study, including primary and key secondary endpoints, will be presented as a late breaking oral abstract at the 32(nd) Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 17(th) , in London, UK. Novartis will complete full analyses of the data and evaluate next steps in consultation with health authorities.

    About the EXPAND study

    The EXPAND study is a randomized, double-blinded, placebo-controlled Phase III study, comparing the efficacy and safety of BAF312 versus placebo in people with secondary progressive multiple sclerosis (SPMS). The EXPAND study is the largest randomized, controlled study in SPMS to date. The study included 1,651 people with SPMS from 31 countries. Patients were randomized to receive either 2mg BAF312 or placebo in a 2:1 ratio respectively.

    The primary endpoint of the study was an improvement in the time to three-month confirmed disability progression, as measured by the expanded disability status scale (EDSS), versus placebo. Secondary endpoints included delay in the time to six-month confirmed disability progression versus placebo, the time to confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW), T2 lesion volume, annualized relapse rate (ARR), and the safety and tolerability of BAF312 in people with SPMS.

    About BAF312 (siponimod)

    BAF312 (siponimod) is a selective modulator of specific types of the sphingosine-1-phosphate (S1P) receptor. The S1P receptor is commonly found on the surface of specific cells residing in the central nervous system (CNS), that are responsible for causing CNS damage that drives loss of function in secondary progressive MS (SPMS). BAF312 enters the brain and by binding to these specific receptors, may prevent the activation of these harmful cells, helping to reduce loss of physical and cognitive function associated with SPMS.
    Dave Bexfield
    ActiveMSers

  • #2
    Another recent journal article on the drug...

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    Acute relapse after initiation of Siponimod in a patient with secondary progressive MS

    Article in Journal of Neurology 263(3) February 2016
    DOI: 10.1007/s00415-015-7999-6

    1st Rehana Z Hussain

    29.83 University of Texas Southwestern Medical Center

    Abstract

    Sphingosine 1-phosphate (S1P) is a signaling molecule that binds to five G protein-coupled receptors (Proc Natl Acad Sci USA 108:751-756, 2011). Modulation of these receptors has been associated with pleiotropic biological effects in the immune, cardiovascular, and central nervous systems (CNS). The functional S1P receptor antagonist fingolimod was the first member of this class of pharmacotherapeutics to be approved for treatment of relapsing multiple sclerosis (MS). Siponimod is currently in clinical trial in patients with secondary progressive (SP) MS, a clinical trial for which there is an unmet need for disease-modifying agents. 10 weeks into the trial, the patient awoke with blurry vision in his left eye, and was subsequently diagnosed with an acute optic neuritis. Despite discontinuation of siponimod and treatment with pulse corticosteroids, the patient did not regain visual function in the affected eye. This is the first report of disease reactivation shortly after initiating siponimod in a patient with SPMS. This case illustrates that the known changes in lymphocyte numbers and composition in the CNS associated with S1P receptor antagonism during the SPMS disease stage may have adverse outcomes in some patients during treatment initiation, and that close clinical and paraclinical monitoring is advised.
    Dave Bexfield
    ActiveMSers

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    • #3
      And another....

      ------------

      The Sphingosine 1-phosphate (S1P) Receptor Modulator, Siponimod Decreases Oligodendrocyte Cell Death and Axon Demyelination in a Mouse Model of Multiple Sclerosis (I10.011)

      Neurology April 5, 2016 vol. 86 no. 16 Supplement I10.011

      Abstract

      OBJECTIVE: The aim of this study was to assess the therapeutic effects of Siponimod is a sphingosine 1-phosphate (S1P) receptor modulator, Siponimod to inhibit axonal demyelination and degeneration in the cuprizone mouse model of multiple sclerosis (MS). BACKGROUND: Siponimod is selective for S1P1 and S1P5 receptors. S1P1 receptors are essential for lymphocyte egress from lymph nodes. In addition, Siponimod crosses the blood brain barrier, likely modulates S1P receptors on cells within the CNS, such as astrocytes, microglia, or oligodendrocytes. Because the experimental autoimmune encephalomyelitis-EAE mouse models of MS has simultaneous remyelination, demyelination and inflammation, it is extremely difficult to dissect out the potential action of Siponimod on the individual components. Here, we assessed the effect of Siponimod on demyelination and remyelination using the toxic demyelination cuprizone diet+rapamycin model. DESIGN/METHODS: Age and sex matched C57BL/6 mice were gavaged daily with Siponimod (0.11mg/kg/mouse/day) or vehicle either during predominantly demyelinating (4.5week cuprizone+rapamycin) or remyelinating periods ([4.5week cuprizone+rapamycin]+[3weeks normal diet]). Electrophysiology conduction recordings immunohistochemistry and electron microscopy of the corpus callosum were performed. RESULTS: Siponimod-treated demyelinating groups showed a significant 25[percnt] to 40[percnt] decrease in the loss of myelin proteins, mature oligodendrocytes and a decrease in axon damage versus vehicle-treated groups. No significant difference between treated and untreated remyelinating groups by immunohistochemistry but nearly 25[percnt] increased number of myelinated axons were observed by electron microscopy analysis. Electrophysiology analysis is underway to assess the functional consequences of Siponimod on callosal axons. A 40[percnt] decrease in microglia/ macrophages but a 25[percnt] increase in astrocyte numbers was observed in demyelinating and remyelinating Siponimod treated groups. CONCLUSIONS: Our results show that Siponimod significantly protects and potentially improves axon function during chronic demyelination periods. This could be of significant importance as Siponimod could protect axons during relapses and progressive demyelination in MS. A study supported by Novartis Pharmaceutical Industries.

      Disclosure: Dr. Tiwari-Woodruff has received research support from Novartis Pharmaceutical. Dr. Yamate-Morgan has nothing to disclose. Dr. Sekyi has nothing to disclose. Dr. Lauderdale has nothing to disclose. Dr. Hasselmann has nothing to disclose. Dr. Schubart has received research support from Novartis.

      Tuesday, April 19 2016, 1:00 pm-5:30 pm
      Dave Bexfield
      ActiveMSers

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