AEB071 is a potent selective pan PKC inhibitor

Multiple sclerosis is a chronic and debilitating immune-mediated disease of the central nervous system . Recent epidemiological data supports the established view that the incidence of AEB071 MS peaks at about 30 years of age and that it is a disease with a positive female-to-male ratio.1 Widespread axonal pathology has already been reported in early stages of MS, including clinically isolated syndrome . Thus, treatment initiation at an early stage in the disease seems crucial; this is supported by positive clinical trial data for first-line disease-modifying drugs in delaying conversion of CIS to MS in patients. Paraclinical surrogate parameters are currently under investigation to predict disease progression and conversion from CIS to MS, including magnetic resonance imaging criteria at initial presentation and the presence of oligoclonal bands or levels of CXCL-13 in cerebrospinal fluid . However, these ABT-869 surrogates are not yet able to predict the future grade of disability on an individual basis with certainty.6 In the European Union , the three different interferon-beta formulations available, as well as glatiramer acetate , are considered as first-line treatments based on class I evidence for similar efficacy and a positive safety profile.

Recent head-to-head studies did not detect differences in the primary endpoints between IFN?and GA. When selecting a treatment from among these injectable drugs, individual decisions will be based mainly on the preferred route of application and the individual tolerability of the compound used. Until recently, natalizumab was the established second choice for patients failing first-line DMDs. In addition, it has been approved as a primary treatment for patients with highly active relapsing-remitting MS . Natalizumab is a humanized Afatinib monoclonal IgG4 antibody, designed to target the alpha-4 integrin, and is most relevant for leukocyte migration across endothelial barriers. Class I evidence is available for superiority regarding clinical outcome measures of natalizumab compared with placebo and for the combination of natalizumab and IM IFN?-1a compared with IM IFN-1a alone. However, no class I evidence is available directly comparing efficacy of natalizumab with first-line DMDs. When looking at the efficacy of natalizumab and first-line DMDs across different clinical trials on clinical outcome measures such as the annualized relapse rate , the data available suggest superiority of natalizumab; this is supported by clinical experience .
Therefore, restricted approval as a second-line treatment is not explained by inferiority compared with first-line DMDs or by study design of trials relevant for approval; it is explained mainly by the occurrence of cases of progressive multifocal leukoencephalopathy in around 1/1000 patients treated with natalizumab. The risk of this potentially lethal or highly disabling adverse event increases to up to AG-1478 8.1/1000 patients among a subset of patients with prior immunosuppressant treatment who have been treated with natalizumab for more than 2 years, and who show evidence of JC virus exposure as assessed by JC virus serology. Furthermore, mitoxantrone was licensed in 2002 for treatment of patients with secondary progressive MS or where progressive relapsing MS is failing or not tolerating previous immunomodulatory therapy.However, the risk of cardiomyopathy and secondary leukemia, overall observed in 1/250 to 1/800 patients treated, limits the use of this drug and makes it a third-line treatment for patients with relapsing forms of MS.
On September 22, 2010, the US Food and Drug Administration approved fingolimod 0.5 mg, a sphingosine 1-phosphate receptor modulator, as the first oral medication for treatment of RRMS.17 In March 2011, the European Medicines Agency approved fingolimod in Europe. However, the European authorities restricted the approval to patients with high disease activity despite treatment with IFN?? and to patients with rapidly evolving RRMS. The EMA defined nonresponders to IFN??as those having failed to respond to "normally at least one year of treatment of IFN." According to EMA recommendations, these patients should have experienced a minimum of one relapse in the previous year while on IFN?, and at least nine T2-hyperintense lesions in cranial MRI or at least one gadolinium-enhancing Akt inhibition lesion, or should have had an "unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year." The second group of patients with rapidly evolving severe RRMS was defined "by 2 or more disabling relapses in 1 year, and with one or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared with a previous recent MRI." Thus, a restricted approval in the EU is given for two compounds, natalizumab and fingolimod, available for the same indication: first-line therapy for highly active MS or second-line therapy in patients not tolerating or not responding to first-line DMDs. In this review, the authors give an overview of clinical trial efficacy and safety data available that is relevant for the approval of fingolimod by the US and the European authorities; the authors then evaluate the current and future potential of fingolimod within the treatment algorithms for MS.

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S2791 Sotrastaurin Sotrastaurin is a potent and selective pan-PKC inhibitor, mostly for PKCθ with Ki of 0.22 nM in a cell-free assay; inactive to PKCζ. Phase 2. (11) (4)

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