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Alberto Gajofatto, Marco Turatti, Maria Donata Benedetti
Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system with heterogeneous features. Primary progressive (PP) MS is a rare disease subtype characterized by continuous disability worsening from onset. No disease-modifying therapy is currently approved for PP MS due to the negative or inconsistent results of clinical trials conducted on a wide range of interventions, which are reviewed in the present paper. Areas covered: The features and results of randomized trials of disease-modifying treatments for PP MS are discussed, including immunosuppressants, immunomodulators, monoclonal antibodies, and putative neuroprotective agents...
November 4, 2016: Expert Review of Neurotherapeutics
Marisa P McGinley, Brandon P Moss, Jeffrey A Cohen
Monoclonal antibodies are a potent therapeutic approach for relapsing-remitting multiple sclerosis. This group of medications comprises diverse mechanisms of action resulting in both shared and unique adverse effects. Areas covered: The major trials and safety profiles of natalizumab, alemtuzumab, daclizumab, rituximab, and ocrelizumab are discussed. While each drug has a unique safety profile, one of the potential safety concerns for all of these drugs is infection, including for some progressive multifocal leukoencephalopathy...
October 19, 2016: Expert Opinion on Drug Safety
Irene Del Pilar Moreno Torres, Antonio García-Merino
INTRODUCTION: The therapeutic utility of the anti-CD20 monoclonal antibodies (mAbs) is currently being evaluated in multiple sclerosis (MS) in line with the better understanding of the role of B lymphocytes in MS pathogenesis. AREA COVERED: We conducted a literature search using Medline/Pub Med database of basic research and available controlled trials about anti-CD20 mAbs in MS. Additionally, ongoing studies were identified in the database. B cells exert multiple inflammatory and regulatory functions playing an important role in MS pathogenesis as is demonstrated by the production of autoantibodies, infiltration of B cells in MS lesions and the formation of ectopic B cell follicle-like structures in meninges, among others...
October 10, 2016: Expert Review of Neurotherapeutics
Til Menge, Divyanshu Dubey, Clemens Warnke, Hans-Peter Hartung, Olaf Stüve
INTRODUCTION: Despite recent advances in pharmacological management, multiple sclerosis (MS), an autoimmune disease of the central nervous system, remains a leading cause of disability. In relapsing-remitting (RR)MS, neurologists most commonly utilize immunomodulatory or immunosuppressive agents to benefit their patients. With the introduction of humanized monoclonal antibodies (mAbs) ablation of distinct immune populations has become possible. Depletion of B cells by anti-CD20 mAbs has repeatedly proven to be a very rapid and effective means to diminish disease activity in RRMS...
October 2016: Expert Review of Neurotherapeutics
Yves Marie Pers, Christian Jorgensen
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune condition viewed as a severe destructive disease. The treatment strategies include anti-CD20 monoclonal antibody (mAb)-targeting B cells. Ofatumumab specifically targets a membrane-proximal epitope on the CD20 molecule distinct from other anti-CD20 antibodies including rituximab and ocrelizumab, and bind the epitope located on the large loop of CD20. This explains a more durable B-cell depletion and a different pharmacodynamic. We review the pharmacodynamic of B-cell depletion and analyze the results in RA and other B-cell-mediated autoimmune diseases...
September 2016: Immunotherapy
M Diebold, L Kappos, T Derfuss
BACKGROUND: The treatment of autoimmune disorders of the nervous system is based on interventions for the underlying immune phenomena. OBJECTIVE: To summarize concepts of cell depletion and myeloablation studied in the context of neuroimmunological disorders. METHOD: Evaluation of the available literature on multiple sclerosis as the most widely studied neuroimmunological entity. RESULTS: Three concepts have been introduced: classical immunosuppressants, such as azathioprine, mitoxantrone and cyclophosphamide exert general lymphopenic effects and thereby moderately decrease disease activity...
August 2016: Der Nervenarzt
Venkat Reddy, Lekh N Dahal, Mark S Cragg, Maria Leandro
In Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE), B-cell depletion therapy using rituximab results in variable clinical responses between individuals, which likely relates to variable B-cell depletion in the presence of immune defects. Outcomes in clinical trials with other type I anti-CD20 mAbs, ocrelizumab and ofatumumab, are comparable to rituximab. A mechanistically different type II mAb, obinutuzumab (OBZ), with greater capacity for B-cell depletion, has recently entered clinical trials in SLE...
August 2016: Drug Discovery Today
O Fernandez, A Rodriguez-Antiguedad, J Olascoaga, C Oreja-Guevara, J M Prieto, M M Mendibe-Bilbao, J A Garcia-Merino, Ll Ramio-Torrenta, R Ginestal, J E Meca-Lallana, L Romero-Pinel, D Munoz, A Saiz, M C Calles-Hernandez, G Izquierdo, L M Villar, P Oliva-Nacarino, C Arnal-Garcia, M Comabella, Ll Brieva, R Arroyo, X Montalban
Renowned national specialists in multiple sclerosis (MS) met, for the eighth year in a row, to give details of the latest novelties presented at the last ECTRIMS Congress 2015, which are included in this review. One of the highlights at this Congress was the new classification of the phenotypes of MS. Both the diagnostic criteria of the neuromyelitis optica spectrum and the problems involved in the differential diagnosis derived from the lack of definition of the radiological spectrum were reviewed. The microbiota comes to the fore as a possible factor determining the disease, together with extrinsic factors such as tobacco, salt ingestion or vitamin D deficiency...
June 16, 2016: Revista de Neurologia
Barry A Singer
Improved disease control is critical for enhancing the lives of those living with multiple sclerosis. With specific immunologic targets, monoclonal antibody (mAb) treatments are highly effective options for relapsing forms of multiple sclerosis. The mechanism, efficacy, and current safety profiles are detailed for the two mAb therapies, natalizumab and alemtuzumab, with regulatory approval in multiple countries. Daclizumab, which targets the interleukin-2 receptor, and ocrelizumab, which depletes B cells, have convincing phase 3 clinical trial data and may very well provide new options in the near future...
April 2016: Seminars in Neurology
Divyanshu Dubey, Peter Sguigna, Olaf Stüve
Patients with progressive forms of multiple sclerosis have various symptoms which affect their quality of life significantly including depression, cognitive decline, sleep changes, bladder dysfunction, sexual dysfunction, and spasticity. Despite recent promising results on the effects of ocrelizumab on neurological disability in patients with PPMS, currently none of the immunomodulatory therapies are approved for progressive forms of multiple sclerosis. Therefore, clinicians currently mostly focus on management of well-recognized comorbidities of this disease phenotype in order to improve patients' quality of life...
June 2016: Current Treatment Options in Neurology
Lawrence Steinman, Scott S Zamvil
PURPOSE OF REVIEW: The review discusses future directions in research on multiple sclerosis and neuromyelitis optica, as long-held beliefs about these diseases are undermined with data from recent clinical trials. RECENT FINDINGS: Results of clinical trials for registration (phase 3) were reported in the last year. Anti-inflammatory approaches, such as daclizumab high-yield process targeting IL-2 receptor, and ocrelizumab targeting CD20 B cells, confirmed a beneficial role of immune suppression in relapsing-remitting disease...
June 2016: Current Opinion in Neurology
Ron Milo
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk-benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing-remitting (RR) and primary-progressive (PP) MS in phase III clinical trials...
July 2016: Autoimmunity Reviews
Per Soelberg Sorensen, Morten Blinkenberg
B cells play a central role in the pathogenesis in multiple sclerosis (MS), being involved in the activation of proinflammatory T cells, secretion of proinflammatory cytokines, and production of autoantibodies directed against myelin. Hence, the usage of B-cell-depleting monoclonal antibodies as therapy for autoimmune diseases including MS lay near at hand. Rituximab was the first therapeutic B-cell-depleting chimeric monoclonal antibody to be used successfully in MS. Ocrelizumab, a second-generation humanized anti-CD20 antibody, was explored in a large phase II, randomized, placebo-controlled multicentre trial in patients with relapsing-remitting disease...
January 2016: Therapeutic Advances in Neurological Disorders
Christiane Gasperi, Olaf Stüve, Bernhard Hemmer
Multiple sclerosis (MS) is a chronic inflammatory neurological disease of the CNS that goes along with demyelination and neurodegeneration. It is probably caused by an autoimmune response against the CNS, which emerges from the interplay of genetic and environmental factors. Although major progress has been made in the treatment of MS, it is still the leading cause for acquired nontraumatic neurological disability in young adults. Several therapeutic agents have been approved for the treatment of relapsing-remitting MS (RRMS), aiming at the reduction of relapses and a delay in disability progression...
2016: Neurodegenerative Disease Management
Lea Radick, Stanton R Mehr
Several new medications are being investigated in late-phase studies for the treatment of patients with relapsing or progressive multiple sclerosis (MS). These agents represent a variety of mechanisms of action and provide not only lower relapse rates but also improvement in disabilities. The majority of investigational trials involve selective sphingosine-1-phosphate receptor 1 immunomodulators, such as laquinimod, ozanimod, ponesimod, and siponimod, in an effort to build on the success of fingolimod. Ocrelizumab is a CD20-positive B-cell-targeting monoclonal antibody with a promising new mechanism of action...
November 2015: American Health & Drug Benefits
Janice M Reichert
The number of novel antibody therapeutics that received first marketing approvals in 2015 met expectations, with 6 (alirocumab (Praluent®), evolocumab (Repatha®), daratumumab (Darzalex®), dinutuximab (Unituxin®), idarucizumab (Praxbind®), mepolizumab (Nucala®)) granted first approvals as of mid-November*. Seven novel antibody therapeutics (begelomab, brodalumab, elotuzumab, ixekizumab, necitumumab, obiltoxaximab, reslizumab) are in regulatory review, and thus a similar number, if not more, are projected to gain first approvals in 2016...
2016: MAbs
Jan Lycke
Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation...
November 2015: Therapeutic Advances in Neurological Disorders
Alasdair Coles
The newer immunotherapies for multiple sclerosis (fingolimod, natalizumab, dimethyl fumarate, teriflunomide, alemtuzumab) offer advantages of efficacy or tolerability over the injectable therapies of the 1990s. But they also have greater risks. As further treatments emerge (daclizumab and ocrelizumab are likely to be licensed in the next two years), the physician needs to be able to place them within a complex landscape of drugs and a specific treatment strategy, which may be an "escalation" or "induction" approach...
September 2015: Annals of Indian Academy of Neurology
Ian Fyfe
No abstract text is available yet for this article.
December 2015: Nature Reviews. Neurology
Siddharama Pawate, Francesca Bagnato
BACKGROUND: Multiple sclerosis (MS) is the most common cause of nontraumatic neurological disability in young adults. There is great need for developing effective treatments to arrest the disease. As of today, there is no cure for MS but several agents mitigating its effects are available. The era of disease-modifying therapy began with the use of interferon beta and glatiramer acetate in the 1990s. Given the injectable nature and the limited efficacy of these agents, efforts are ongoing to develop new treatments...
April 2015: Neurologist
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