Multiple sclerosis New Drugs Review
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Cryopreserved vitamin D 3 -tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients

Cryopreserved vitamin D 3 -tolerogenic dendritic cells pulsed with autoantigens as a potential therapy for multiple sclerosis patients | Multiple sclerosis New Drugs Review | Scoop.it
Tolerogenic dendritic cells (tolDC) have been postulated as a potent immunoregulatory therapy for autoimmune diseases such as multiple sclerosis (MS). In a previous study, we demonstrated that the administration of antigen-specific vitamin D3 (vitD3) tolDC in mice showing clinical signs of experimental autoimmune encephalomyelitis (EAE; the animal model of MS) resulted in abrogation of disease progression. With the purpose to translate this beneficial therapy to the clinics, we have investigated the effectivity of vitD3-frozen antigen-specific tolDC pulsed with myelin oligodendrocyte glycoprotein 40-55 peptide (f-tolDC-MOG) since it would reduce the cost, functional variability and number of leukapheresis to perform to the patients. Mice showing EAE clinical signs were treated with repetitive doses of f-tolDC-MOG. Tolerogenic mechanisms induced by the therapy were analysed by flow cytometry and T cell proliferation assays. Treatment with f-tolDC-MOG was effective in ameliorating clinical signs of mice with EAE, inhibiting antigen-specific reactivity and inducing Treg. In addition, the long-term treatment was well tolerated and leading to a prolonged maintenance of tolerogenicity mediated by induction of Breg, reduction of NK cells and activation of immunoregulatory NKT cells. The outcomes of this study show that the use of antigen-specific f-tolDC promotes multiple and potent tolerogenic mechanisms. Moreover, these cells can be kept frozen maintaining their tolerogenic properties, which is a relevant step for their translation to the clinic. Altogether, vitD3 f-tolDC-MOG is a potential strategy to arrest the autoimmune destruction in MS patients.
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Daclizumab (Biogen, Abbott) Review: Multiple sclerosis - Krishan Maggon

Daclizumab (Biogen, Abbott) Review: Multiple sclerosis - Krishan Maggon | Multiple sclerosis New Drugs Review | Scoop.it
Daclizumab is a humanized monoclonal antibody which targets the CD25 alpha subunit of the high affinity receptor and inhibits...
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JCM | PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations

JCM | PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations | Multiple sclerosis New Drugs Review | Scoop.it
PLP1 is located on the X-chromosome and encodes myelin proteolipid protein (PLP), the most abundant protein in central nervous system myelin. Generally, point mutations in PLP1 result in X-linked dysmyelinating disorders, such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2...
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T cells take aim at a ubiquitous autoantigen in multiple sclerosis

T cells take aim at a ubiquitous autoantigen in multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
CD4+ T cells from multiple sclerosis lesions target a ubiquitous self-antigen that is shared by gut commensal bacteria (Planas et al ., this issue).
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An elusive molecule that sparks multiple sclerosis may have been found

An elusive molecule that sparks multiple sclerosis may have been found | Multiple sclerosis New Drugs Review | Scoop.it
Intestinal bacteria produce version of protein that may confuse the immune system...
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Immune-mediated neuropathies

Immune-mediated neuropathies | Multiple sclerosis New Drugs Review | Scoop.it
This Primer discusses the epidemiology, mechanisms, differential diagnosis and management of the immune-mediated neuropathies — a large group of disorders that includes Guillain–Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy, among other...
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Novartis  NDA/MAA filing and acceptance of siponimod by FDA/EMA, the first and only drug shown to meaningfully delay disability progression in typical SPMS patients

Novartis  NDA/MAA filing and acceptance of siponimod by FDA/EMA, the first and only drug shown to meaningfully delay disability progression in typical SPMS patients | Multiple sclerosis New Drugs Review | Scoop.it

Basel, October 08, 2018 Novartis today announced that both the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have accepted the company's New Drug Application (NDA) and Marketing Authorization Application (MAA) respectively, for investigational oral, once-daily siponimod (BAF312) for the treatment of secondary progressive multiple sclerosis (SPMS) in adults. This phase of multiple sclerosis (MS) can substantially impact lives, due to physical and cognitive impairments[2]. To bring this treatment to the MS community as quickly as possible, Novartis used a review voucher to expedite the review of siponimod in the US. Regulatory action for siponimod is anticipated in the US in March of 2019 and in Europe in late 2019.

 

More than 80% of people with relapsing-remitting MS (RRMS) - the most common form of the condition at diagnosis - go on to develop SPMS, with or without relapses[2],[3]. SPMS is a form of MS that leads to progressive, irreversible disability, such as the need for enhanced walking aids and wheelchairs, bladder dysfunction and cognitive decline, largely independent of relapses. Following the initial RRMS course, there is a gradual increase in the number of patients transitioning to SPMS, with around 25% progressing by 10 years post-onset, 50% by 20 years and more than 75% by 30 years[2],[3].

 

The regulatory application is based on data from the EXPAND study, a randomized, double-blind, placebo-controlled Phase III study, comparing the efficacy and safety of siponimod versus placebo in people living with typical SPMS. At study initiation, more than 50% of patients in the EXPAND study relied on a walking aid[1]. Results from the pivotal study showed siponimod significantly reduced the risk of three-month confirmed disability progression versus placebo (primary endpoint; 21% versus placebo, p=0.013). Siponimod also meaningfully delayed the risk of six-month confirmed disability progression (26% vs placebo, p=0.0058) and demonstrated favorable outcomes in other relevant measures of MS disease activity and progression[1]. Further, more advanced analyses of the EXPAND study showed that siponimod reduced the risk of disability progression largely disassociated from relapses (three-month disability progression, range 14-20%; six-month disability progression 29-33%)[1].

 

  • There is a critical need for safe and effective treatments for secondary progressive multiple sclerosis (SPMS) - a highly debilitating form of MS characterized by gradual, irreversible worsening of disability, largely independent of relapses 
     
  • If approved, siponimod (BAF312) would be the first oral disease-modifying therapy with the potential to delay progression and expand possibilities for SPMS patients 
     
  • Filings are supported by Phase III EXPAND data, which showed siponimod had beneficial effects on disability, relapses and magnetic resonance imaging (MRI) disease activities in typical SPMS patients[1]
     
  • Novartis used a priority review voucher to expedite review of siponimod in the US to ensure patients could benefit from the drug as soon as possible, pending approval
Krishan Maggon 's insight:

About Siponimod (BAF312)
Siponimod is an investigational, selective modulator of specific subtypes of the sphingosine-1-phosphate (S1P) receptor[5]. Siponimod binds to the S1P1 sub-receptor on lymphocytes, which prevents them from entering the central nervous system (CNS) of patients with multiple sclerosis. This leads to the anti-inflammatory effects of siponimod.[1] Siponimod also enters the CNS and binds to the S1P5 sub-receptor on specific cells in the CNS (oligodendrocytes and astrocytes)[6]. By binding to these specific receptors, siponimod has the potential to modulate damaging cell activity, and preclinical studies suggest that it may prevent synaptic neurodegeneration and promote remyelination in the CNS[7].

 

Investigational compounds include siponimod (BAF312, a selective modulator of the S1P receptor subtypes 1 and 5), for SPMS, and ofatumumab (OMB157), a fully human monoclonal antibody in development for relapsing MS. Ofatumumab targets CD20, and is currently being investigated in two Phase III pivotal studies.

 

Sales of Gilenya (fingolimod) were $3 billion in 2017

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B cells drive auto-T cells to the brain

B cells drive auto-T cells to the brain | Multiple sclerosis New Drugs Review | Scoop.it
Self-reactive T cells that traffic to the brain tissue of patients with multiple sclerosis are driven by antigen-experienced B cells.
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Biogen Highlights at ECTRIMS 2018 Data on Its Industry-Leading Multiple Sclerosis Portfolio and a Range of Initiatives Aimed at Transforming Patient Care

Biogen Highlights at ECTRIMS 2018 Data on Its Industry-Leading Multiple Sclerosis Portfolio and a Range of Initiatives Aimed at Transforming Patient Care | Multiple sclerosis New Drugs Review | Scoop.it
Biogen Highlights at ECTRIMS 2018 Data on Its Industry-Leading Multiple Sclerosis Portfolio and a Range of Initiatives Aimed at Transforming Patient Care overnewser, The best real-time news sites information. Source: globenewswire.com
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IJMS | Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

IJMS | Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches | Multiple sclerosis New Drugs Review | Scoop.it
Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways.
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Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned

Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned | Multiple sclerosis New Drugs Review | Scoop.it
Progressive multifocal leukoencephalopathy (PML) is a rare, devastating demyelinating
disease of the CNS caused by the JC virus (JCV) that occurs in patients with compromised
immune systems. Detection of PML in systemically immunocompetent patients with multiple sclerosis treated with natalizumab...
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Memory B s Activate Brain-Homing, Autoreactive CD4+ T s in Multiple Sclerosis

Memory B s Activate Brain-Homing, Autoreactive CD4+ T s in Multiple Sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Highlights
Autoproliferation of CD4+ T cells and B cells is involved in multiple sclerosis
The main genetic factor of MS, HLA-DR15, plays a central role in autoproliferation
Memory B cells drive autoproliferation of Th1 brain-homing CD4+ T cells
Autoproliferating T cells recognize antigens expressed in B cells and brain lesions
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Fingolimod vs. Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM

Fingolimod vs. Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM | Multiple sclerosis New Drugs Review | Scoop.it
The New England Journal of Medicine...

 

MS typically appears in young adulthood, but 3% to 5% of cases have an onset in early childhood or adolescence. No disease-modifying therapies have FDA approval for persons younger than 18 years of age. New research findings are summarized in a short video.

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Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis | NEJM | Multiple sclerosis New Drugs Review | Scoop.it
Original Article from The New England Journal of Medicine — Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis...
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Link between gut flora and multiple sclerosis discovered | EurekAlert! Science News

Link between gut flora and multiple sclerosis discovered | EurekAlert! Science News | Multiple sclerosis New Drugs Review | Scoop.it
In multiple sclerosis, a defective response of the body's own immune system leads to brain tissue damage. Gastrointestinal microbiota could play a far greater role in the pathogenesis of the disease than previously assumed, researchers at the University of Zurich have now found.
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Dynamic Balance Is Related to Physiological Impairments in Persons With Multiple Sclerosis

Dynamic Balance Is Related to Physiological Impairments in Persons With Multiple Sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
To compare physiological impairments between persons with multiple sclerosis (MS)
with a history of falls and persons with MS without a history of falls, and to investigate
the association between physiological impairments and dynamic balance.
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GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis

GDP-l-fucose synthase is a CD4+ T cell–specific autoantigen in DRB3*02:02 patients with multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Although it is well established that autoreactive lymphocytes induce demyelination in multiple sclerosis, the exact antigenic targets that initiate disease are undefined. Planas et al . studied CD4+ T cells from the cerebrospinal fluid of patients with multiple sclerosis. One CD4+ T cell clone was reactive to the human enzyme GDP-l-fucose synthase; T cells from other patients were then identified, as well as myelin-reactive cells. Intriguingly, some of the GDP-l-fucose synthase–reactive cells could also be stimulated by a bacterial version of the enzyme. These tantalizing results identify a new autoantigen and suggest that one possible trigger of disease could be cross-reactivity to microbiota-derived peptides.

Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system that develops in genetically susceptible individuals and likely requires environmental triggers. The autoantigens and molecular mimics triggering the autoimmune response in multiple sclerosis remain incompletely understood. By using a brain-infiltrating CD4+ T cell clone that is clonally expanded in multiple sclerosis brain lesions and a systematic approach for the identification of its target antigens, positional scanning peptide libraries in combination with biometrical analysis, we have identified guanosine diphosphate (GDP)–l-fucose synthase as an autoantigen that is recognized by cerebrospinal fluid–infiltrating CD4+ T cells from HLA-DRB3*–positive patients. Significant associations were found between reactivity to GDP-l-fucose synthase peptides and DRB3*02:02 expression, along with reactivity against an immunodominant myelin basic protein peptide. These results, coupled with the cross-recognition of homologous peptides from gut microbiota, suggest a possible role of this antigen as an inducer or driver of pathogenic autoimmune responses in multiple sclerosis.
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Cost of Illness study: New insight into the burden of multiple sclerosis in Europe

Cost of Illness study: New insight into the burden of multiple sclerosis in Europe | Multiple sclerosis New Drugs Review | Scoop.it
The comprehensive MS study Cost of Illness - with a participation of nearly 17,000 people living with MS - marked its first scientific article.
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Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study

Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study | Multiple sclerosis New Drugs Review | Scoop.it
Background
No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS.
Methods
This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144.
Findings
1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups.
Interpretation
Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS.
Funding
Novartis Pharma AG.
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Modulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis

Modulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Demyelination failure in multiple sclerosis (MS) may contribute to the disease progression. This study shows that chondroitin sulfate proteoglycans (CSPGs) can inhibit remyelination in an animal model of MS via CSPG binding with the receptor PTPσ on oligodendrocyte progenitor cells, and disruption...
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Innovations in Clinical Neuroscience Hot Topics in Multiple Sclerosis June 2018

Innovations in Clinical Neuroscience Hot Topics in Multiple Sclerosis June 2018 | Multiple sclerosis New Drugs Review | Scoop.it
June 2018...
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Roche - Roche to present five-year OCREVUS (ocrelizumab) efficacy and safety data in relapsing and primary progressive multiple sclerosis (MS) at ECTRIMS

Roche - Roche to present five-year OCREVUS (ocrelizumab) efficacy and safety data in relapsing and primary progressive multiple sclerosis (MS) at ECTRIMS | Multiple sclerosis New Drugs Review | Scoop.it
Media Release Basel, 02 October 2018 Roche to present five-year OCREVUS (ocrelizumab) efficacy and safety data in relapsing and primary progressive multiple sclerosis (MS) at ECTRIMS Data reinforce importance of early initiation and continuation of OCREVUS treatment New analyses highlight the need for active treatment in underrepresented populations, such as primary progressive MS (PPMS) patients with more advanced disability and relapsing MS (RMS) patients of African descent Roche continues to advance the clinical understanding of MS with new studies incorporating novel clinical endpoints and digital tools Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that new data on OCREVUS® (ocrelizumab) in people with relapsing and primary progressive forms of MS will be presented during the 34th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Berlin, Germany, 10 to 12 October. Fifteen abstracts will be presented throughout the congress, including five-year efficacy and safety OCREVUS data and post-hoc analyses of the Phase III studies that evaluate OCREVUS in underrepresented MS patient populations. A new analysis of the Phase III ORATORIO study shows OCREVUS treatment reduced upper limb disability progression similarly in PPMS patients with or without advanced overall disability (Expanded Disability Status Scale <6.0 and ≥6.0 and nine-hole peg test (9-HPT) times ≤25 seconds and >25 seconds). These analyses informed the ORATORIO-HAND trial, which for the first time ever will use the 9-HPT as the primary outcome to evaluate the long-term efficacy and safety of OCREVUS in people with PPMS including those later in their disease course. A subgroup analysis of the Phase III OPERA I and OPERA II studies in RMS patients of African-descent, who usually have faster MS disease progression than other populations, showed OCREVUS treatment benefit on MRI and composite efficacy outcomes versus interferon beta-1α. A greater proportion of patients of African descent treated with OCREVUS achieved no evidence of disease progression (NEDA) compared with interferon beta-1α (46 percent vs. 10 percent, respectively; p=0.002). “We continue our commitment to people with MS by evaluating OCREVUS in groups that are often overlooked in clinical trials,” said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. “In addition to now having five years of consistent efficacy and safety data results for OCREVUS, other data will be presented at ECTRIMS that advance the clinical understanding of MS. Our goal is to help the MS community better understand and manage their disease.” New tools to rapidly assess the severity of MS symptoms are crucial to improving patient outcomes and optimising care. SymptoMScreen, a novel patient-reported outcome tool to assess symptom severity across twelve domains (walking, hand function/dexterity, spasticity, bodily pain, sensation, bladder control, fatigue, vision, dizziness, cognitive function, depression and anxiety), will be used in two Phase IIIb OCREVUS trials (ENSEMBLE and CASTING). Baseline data from these studies show differences in disease severity on all domains, for example, 31 percent of patients in ENSEMBLE (treatment-naïve relapsing-remitting MS (RRMS) patients) and 41 percent of patients in CASTING (RRMS patients who have had a prior suboptimal response to a disease-modifying therapy) experienced moderate to severe fatigue. Roche will also present final primary endpoint data for the FLOODLIGHT proof-of-concept study evaluating an innovative smartphone-based self-monitoring technology. The data show FLOODLIGHT may be more sensitive than periodic in-clinic disability assessments. There was also high adherence to the technology, with 76 percent adherence to active tests and 71 percent adherence to passive monitoring. Results also showed that satisfaction amongst patients with MS who completed the study was good to excellent (patient-reported 75 average score out of a possible 100 at the last visit). Based on initial results from the FLOODLIGHT proof-of-concept study, Roche has initiated a new, global study called FLOODLIGHT Open with plans to enrol 10,000 people in five years. FLOODLIGHT Open will assess the feasibility of monitoring disease activity and disability progression over the 365 days in a year that someone lives with MS, versus the two or three days they visit with their neurologist. It is an open access study, which means anyone can join and the anonymous data collected through the study is freely available to doctors and scientists to help accelerate research and collaboration. FLOODLIGHT Open is currently enrolling in the United States and Canada and will open in other countries later this year. To learn more and enrol, visit https://floodlightopen.com or download the FLOODLIGHT app on iTunes for iPhone or Google Play for Android. OCREVUS is now approved in 67 countries across North America, South America, the Middle East, Eastern Europe, as well as in Australia, Switzerland and the European Union. Marketing applications are currently under review in more than 20 countries across the world. Additionally, Roche is sponsoring two symposia: “Disease activity: Can starting early with effective treatment offer better outcomes in MS?” on Wednesday, 10 October at 18:15 CEST in Hall A and “Disease progression: Changing how we think about MS” on Thursday, 11 October at 07:30 CEST in Hall B. Follow Roche on Twitter via @Roche and keep up to date with ECTRIMS 2018 news and updates by using the hashtag #ECTRIMS2018. Roche presentations at ECTRIMS 2018 A full list of Roche presentations can be found at: https://www.ectrims-congress.eu/2018/scientific-programme/scientific-programme.html. Select poster presentations at ECTRIMS 2018 include: About OCREVUS® (ocrelizumab) OCREVUS is a humanised monoclonal antibody designed to selectively target CD20-positive B cells, a specific type of immune cell thought to be a key contributor to myelin (nerve cell insulation and support) and axonal (nerve cell) damage. This nerve cell damage can lead to disability in people with multiple sclerosis (MS). Based on preclinical studies, OCREVUS binds to CD20 cell surface proteins expressed on certain B cells, but not on stem cells or plasma cells, and therefore important functions of the immune system may be preserved. OCREVUS is administered by intravenous infusion every six months. The initial dose is given as two 300 mg infusions given two weeks apart. Subsequent doses are given as single 600 mg infusions. About Roche in neuroscience Neuroscience is a major focus of research and development at Roche. The company’s goal is to develop treatment options based on the biology of the nervous system to help improve the lives of people with chronic and potentially devastating diseases. Roche has more than a dozen investigational medicines in clinical development for diseases that include multiple sclerosis, Alzheimer’s disease, spinal muscular atrophy, Parkinson’s disease and autism. About Roche Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve people’s lives. The combined strengths of pharmaceuticals and diagnostics under one roof have made Roche the leader in personalised healthcare – a strategy that aims to fit the right treatment to each patient in the best way possible. Roche is the world’s largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management. Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. Thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Moreover, for the tenth consecutive year, Roche has been recognised as the most sustainable company in the Pharmaceuticals Industry by the Dow Jones Sustainability Indices (DJSI). The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2017 employed about 94,000 people worldwide. In 2017, Roche invested CHF 10.4 billion in R&D and posted sales of CHF 53.3 billion. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com. All trademarks used or mentioned in this release are protected by law.
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Case Study: High-Content Analysis of Drug-Induced Oligodendrocyte Differentiation Promoting Remyelination in Multiple Sclerosis

Case Study: High-Content Analysis of Drug-Induced Oligodendrocyte Differentiation Promoting Remyelination in Multiple Sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
One of the greatest challenges in multiple sclerosis (MS) therapy is the halting or reversal of the failure of remyelination in the brain in order to reverse disabilities in MS patients. This case study highlights the recent work of Dr. Paul Tesar and colleagues at the Case Western Reserve University School of Medicine, which could potentially lead to such novel treatments, as it aims to control the function of stem cells in the body and thereby to help the body repair itself. The case study focusses on the development of a high-content phenotypic assay to identify bioactive small molecules enhancing oligodendrocyte maturation. Summary You will learn: How the Operetta allows for the quantification of complex phenotypic changes, such as changes in the length of processes emanating from oligodendrocyte brain cells How high-content screening (HCS), combined with cutting-edge stem cell technology, plays a key role in enabling drug discovery within this new area of regenerative medicine
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Brain iron on MRI linked to disability in multiple sclerosis

Brain iron on MRI linked to disability in multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
(HealthDay)—Brain iron at quantitative magnetic resonance imaging (MRI) is associated with disability in multiple sclerosis (MS), according to a study recently published in Radiology.
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A new roadmap for repairing the damage of multiple sclerosis – Patient Talk

A new roadmap for repairing the damage of multiple sclerosis – Patient Talk | Multiple sclerosis New Drugs Review | Scoop.it
Research published today in the journal Nature provides new understanding about how drugs can repair damaged brain cells that cause disability in patients with multiple sclerosis. Led by researchers at Case Western Reserve University School of Medicine, the study suggests new drug targets and potent early-stage drug candidates could lead to regenerative medicines for multiple sclerosis and other debilitating neurological diseases. Multiple sclerosis, a chronic and progressive disease affecting millions worldwide, is characterized by damage to the protective sheath that surrounds nerve cells. Without this insulating layer, called myelin, nerve cells in the brain and spinal cord struggle to transmit electrical impulses. As a result, multiple sclerosis patients suffer progressive loss of motor skills, vision and balance. The new study describes how drugs work to replenish myelin destroyed by multiple sclerosis. While the brain is known to have some capacity to regenerate new myelin during the early stages of multiple sclerosis, this innate repair process is overwhelmed as the disease progresses. “Many labs, including at Case Western Reserve, had identified drug candidates that kickstart the formation of new myelin, but exactly how each of these molecules affected brain cell function wasn’t clear,” said Drew Adams, PhD, the Thomas F. Peterson, Jr. Professor of Novel Therapeutics and assistant professor of genetics and genome sciences at Case Western Reserve University School of Medicine. “We were shocked to find that almost all of these previously identified molecules share the ability to inhibit specific enzymes that help to make cholesterol. This insight reorients drug discovery efforts onto these novel, druggable targets.” This study builds on prior work by co-author Paul Tesar, PhD, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and associate professor of genetics and genome sciences at Case Western Reserve University School of Medicine. In work reported in 2015 in Nature, Tesar identified a drug typically used to treat athlete’s foot, called miconazole, as a potent enhancer of new myelin. In the current study, teams led by Adams and Tesar demonstrated that miconazole enhanced myelin formation by inhibiting an enzyme used by brain stem cells to produce cholesterol. Subsequent experiments identified more than 20 new drugs that enhance myelin formation by inhibiting closely-related cholesterol-producing enzymes. Surprisingly, drugs identified previously by labs across the world as enhancing new myelin also inhibited these same enzymes. “The idea that almost all drug candidates that promote myelin repair inhibit the same enzyme targets represents a bold new paradigm for the field and may redirect the course of ongoing drug discovery efforts,” said Tesar. Normally, cellular pathways are crisscrossed, complex diagrams. But cholesterol biosynthesis is linear, said Adams, who is also a Mount Sinai Scholar. “There is only one way in, and one way out. So when you block enzymes in the cholesterol pathway, the metabolites simply accumulate.” In the Adams laboratory, lead authors Zita Hubler and Dharmaraja Allimuthu, PhD, could detect distinct cholesterol intermediaries as they accumulated, allowing them to pinpoint which enzymes were being blocked by which drugs. Notably, several drugs accelerated myelin repair in mouse models of multiple sclerosis. Mouse experiments were performed in collaboration with Robert H. Miller, PhD, the Vivian Gill Distinguished Research Professor and professor of anatomy and cell biology at the George Washington University School of Medicine and Health Sciences. To measure the formation of human myelin in the laboratory, the team used a new three-dimensional nerve cell culture model that closely mimics human brain tissue. Here too, the drug candidates promoted human myelin formation by blocking cholesterol pathway enzymes. A study describing this innovative model, developed in Tesar’s laboratory, was also published today in Nature Methods. “Together these studies provide new drug targets, new drug candidates, and new cholesterol pathway biomarkers to propel the development of medicines that can replenish lost myelin in patients with multiple sclerosis and related diseases,” said Adams. While clinical candidates based on this work are not expected to enter clinical trials until 2019, say the authors, the new understanding of myelin repair provides a promising new path toward novel, regenerative multiple sclerosis treatments. ### Adams, Tesar, and Miller collaborated with researchers from Ludwig-Maximilians University of Munich, Germany; Rice University; Leiden University Medical Center, Netherlands; and the Case Western Reserve University School of Medicine Department of Pediatrics for the study. Hubler, et. al. “Accumulation of 8,9-unsaturated sterols drives oligodendrocyte formation and remyelination.” Nature. This research was supported by grants from the National Institutes of Health, Conrad N. Hilton Foundation, and Mt. Sinai Health Care Foundation. Philanthropic support was generously provided by the Peterson, Fakhouri, Long, Goodman, Geller, Judge, and Weidenthal families. For more information about the Adams and Tesar laboratories, please visit: genetics.case.eduand tesarlab.case.edu. For more information about Case Western Reserve University School of Medicine, please visit: case.edu/medicine.
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The hippocampus in multiple sclerosis

The hippocampus in multiple sclerosis | Multiple sclerosis New Drugs Review | Scoop.it
Some of the clinical manifestations of multiple sclerosis, such as memory impairment
and depression, are, at least partly, related to involvement of the hippocampus. Pathological studies have shown extensive demyelination, neuronal damage, and synaptic abnormalities in the hippocampus of patients...
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Protein structures guide the design of a much-needed tool for neuroscience

Protein structures guide the design of a much-needed tool for neuroscience | Multiple sclerosis New Drugs Review | Scoop.it
The structures of anion-conducting channelrhodopsin proteins have been solved and used to develop a tool for optogenetics. Experts discuss what the structures tell us about ion conduction, and why the tool is needed.
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