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High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing-Remitting Multiple Sclerosis.CNS Drugs Dec 2022There are > 18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration for the... (Review)
Review
There are > 18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). Given the multitude of available treatment options, and recent international consensus guidelines offering differing recommendations, there is broad heterogeneity in how the DMTs are used in clinical practice. Choosing a DMT for newly diagnosed patients with MS is currently a topic of significant debate in MS care. Historically, an escalation approach to DMT was used for newly diagnosed patients with RRMS. However, the evidence for clinical benefits of early treatment with high-efficacy therapies (HETs) in this population is emerging. In this review, we provide an overview of the DMT options and MS treatment strategies, and discuss the clinical benefits of HETs (including ofatumumab, ocrelizumab, natalizumab, alemtuzumab, and cladribine) in the early stages of MS, along with safety concerns associated with these DMTs. By minimizing the accumulation of neurological damage early in the disease course, early treatment with HETs may enhance long-term clinical outcomes over the lifetime of the patient.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis; Immunologic Factors; Natalizumab; Alemtuzumab
PubMed: 36350491
DOI: 10.1007/s40263-022-00965-7 -
Multiple Sclerosis (Houndmills,... Sep 2022In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide.
OBJECTIVES
To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS.
METHODS
Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events.
RESULTS
Data were analysed from 615 RDTN participants (ofatumumab: = 314; teriflunomide: = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population.
CONCLUSION
The favourable benefit-risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients.ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231).
Topics: Antibodies, Monoclonal, Humanized; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Recurrence; Toluidines
PubMed: 35266417
DOI: 10.1177/13524585221078825 -
Frontiers in Immunology 2022Nephrotic proteinuria is the hallmark of several glomerulonephritis determined by different pathogenetic mechanisms, including autoimmune, degenerative and inflammatory.... (Review)
Review
Nephrotic proteinuria is the hallmark of several glomerulonephritis determined by different pathogenetic mechanisms, including autoimmune, degenerative and inflammatory. Some conditions such as Minimal Change Nephropathy (MCN) and Focal Segmental Glomerulosclerosis (FSGS) are of uncertain pathogenesis. Chimeric anti-CD20 monoclonal antibodies have been used with success in a part of proteinuric conditions while some are resistant. New human and humanized monoclonal anti-CD 20 antibodies offer some advantages based on stronger effects on CD20 cell subtypes and have been already administered in hematology and oncology areas as substitutes of chimeric molecules. Here, we revised the literature on the use of human and humanized anti-CD 20 monoclonal antibodies in different proteinuric conditions, resulting effective in those conditions resistant to rituximab. Literature on the use of human anti-CD 20 monoclonal antibodies in different proteinuric diseases is mainly limited to ofatumumab, with several protocols and doses. Studies already performed with ofatumumab given in standard doses of 1,500 mg 1.73m suggest no superiority compared to rituximab in children and young adults with steroid dependent nephrotic syndrome. Ofatumumab given in very high doses (300 mg/1.73m followed by five infusion 2,000 mg/1.73 m) seems more effective in patients who are not responsive to common therapies. The question of dose remains unresolved and the literature is not concordant on positive effects of high dose ofatumumab in patients with FSGS prior and after renal transplantation. Obinutuzumab may offer some advantages. In the unique study performed in patients with multidrug dependent nephrotic syndrome reporting positive effects, obinutuzumab was associated with the anti-CD38 monoclonal antibody daratumumab proposing the unexplored frontier of combined therapies. Obinutuzumab represent an evolution also in the treatment of autoimmune glomerulonephritis, such as membranous nephrotahy and lupus nephritis. Results of randomized trials, now in progress, are awaited to add new possibilities in those cases that are resistant to other drugs. The aim of the present review is to open a discussion among nephrologists, with the hope to achieve shared approaches in terms of type of antibodies and doses in the different proteinuric renal conditions.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Child; Glomerulosclerosis, Focal Segmental; Humans; Nephrotic Syndrome; Rituximab
PubMed: 35222385
DOI: 10.3389/fimmu.2022.805697 -
Journal of Neuroinflammation Sep 2021Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse... (Review)
Review
Neuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange.Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19 B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.
Topics: Animals; Antibodies, Monoclonal, Humanized; Aquaporin 4; Astrocytes; Autoantibodies; Azathioprine; Clinical Trials, Phase III as Topic; Humans; Immunosuppressive Agents; Neuromyelitis Optica
PubMed: 34530847
DOI: 10.1186/s12974-021-02249-1 -
Journal of Neurology Mar 2022Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease affecting the central nervous system (CNS), often characterized by the accumulation of irreversible clinical disability over time. During last years, there has been a dramatic evolution in several key concepts of immune pathophysiology of MS and in the treatment of this disease. The demonstration of the strong efficacy and good safety profile of selective B-cell-depleting therapies (such as anti-CD20 monoclonal antibodies) has significantly expanded the therapeutic scenario for both relapsing and progressive MS patients with the identification of a new therapeutic target. The key role of B cells in triggering MS disease has been also pointed out, determining a shift from the traditional view of MS activity as largely being 'T-cell mediated' to the notion that MS-related pathological processes involve bi-directional interactions between several immune cell types, including B cells, both in the periphery and in the CNS. This review provides an updated overview of the involvement of B cells in the immune pathophysiology and pathology of MS. We summarize the rationale regarding the use of anti-CD20 therapies and the results of the main randomized controlled trials and observational studies investigating the efficacy and safety profile of rituximab, ocrelizumab, ofatumumab and ublituximab. Suggestions regarding vaccinations and management of MS patients during COVID-19 pandemic with anti-CD20 therapies are also discussed. Finally, therapies under investigation and future perspectives of anti-CD20 therapies are taken into consideration.
Topics: COVID-19; Humans; Multiple Sclerosis; Neurodegenerative Diseases; Pandemics; SARS-CoV-2
PubMed: 34382120
DOI: 10.1007/s00415-021-10744-x -
Drugs Jan 2022Ofatumumab (Kesimpta) is a fully human anti-CD20 monoclonal antibody that can be self-administered by patients and is approved in several countries worldwide for the... (Review)
Review
Ofatumumab (Kesimpta) is a fully human anti-CD20 monoclonal antibody that can be self-administered by patients and is approved in several countries worldwide for the treatment of relapsing forms of multiple sclerosis (MS). In two identical phase III trials in adults with relapsing forms of MS, subcutaneous ofatumumab was more effective than oral teriflunomide in reducing the annualized relapse rate, as well as reducing MRI-detected lesion activity and limiting worsening of disability. Ofatumumab had a generally manageable tolerability profile; the most common adverse events (AEs) included nasopharyngitis, headache, upper respiratory tract infections and urinary tract infections. AEs of special interest (AESIs) included infections and injection-related reactions, which were generally manageable. There was no apparent association between changes in immunoglobulin G or M levels and the risk of serious infections after 3.5 years of ofatumumab treatment. Thus, ofatumumab is a convenient treatment option that is effective and has a generally manageable tolerability profile in adults with relapsing forms of MS.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Clinical Trials as Topic; Humans; Multiple Sclerosis, Relapsing-Remitting
PubMed: 34897575
DOI: 10.1007/s40265-021-01650-7 -
Advances in Therapy Oct 2017Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various... (Review)
Review
UNLABELLED
Rituximab is a human/murine, chimeric anti-CD20 monoclonal antibody with established efficacy, and a favorable and well-defined safety profile in patients with various CD20-expressing lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin lymphoma. Since its first approval 20 years ago, intravenously administered rituximab has revolutionized the treatment of B-cell malignancies and has become a standard component of care for follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, and mantle cell lymphoma. For all of these diseases, clinical trials have demonstrated that rituximab not only prolongs the time to disease progression but also extends overall survival. Efficacy benefits have also been shown in patients with marginal zone lymphoma and in more aggressive diseases such as Burkitt lymphoma. Although the proven clinical efficacy and success of rituximab has led to the development of other anti-CD20 monoclonal antibodies in recent years (e.g., obinutuzumab, ofatumumab, veltuzumab, and ocrelizumab), rituximab is likely to maintain a position within the therapeutic armamentarium because it is well established with a long history of successful clinical use. Furthermore, a subcutaneous formulation of the drug has been approved both in the EU and in the USA for the treatment of B-cell malignancies. Using the wealth of data published on rituximab during the last two decades, we review the preclinical development of rituximab and the clinical experience gained in the treatment of hematologic B-cell malignancies, with a focus on the well-established intravenous route of administration. This article is a companion paper to A. Davies, et al., which is also published in this issue.
FUNDING
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Topics: Animals; Antineoplastic Agents, Immunological; B-Lymphocytes; Hematologic Neoplasms; History, 20th Century; History, 21st Century; Humans; Lymphoma, B-Cell; Rituximab
PubMed: 28983798
DOI: 10.1007/s12325-017-0612-x -
Frontiers in Immunology 2023The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the... (Review)
Review
The immune system plays a significant role in multiple sclerosis. While MS was historically thought to be T cell-mediated, multiple pieces of evidence now support the view that B cells are essential players in multiple sclerosis pathogenic processes. High-efficacy disease-modifying therapies that target the immune system have emerged over the past two decades. Anti-CD20 monoclonal antibodies selectively deplete CD20+ B and CD20+ T cells and efficiently suppress inflammatory disease activity. These monotherapies prevent relapses, reduce new or active magnetic resonance imaging brain lesions, and lessen disability progression in patients with relapsing multiple sclerosis. Rituximab, ocrelizumab, and ofatumumab are currently used in clinical practice, while phase III clinical trials for ublituximab have been recently completed. In this review, we compare the four anti-CD20 antibodies in terms of their mechanisms of action, routes of administration, immunological targets, and pharmacokinetic properties. A deeper understanding of the individual properties of these molecules in relation to their efficacy and safety profiles is critical for their use in clinical practice.
Topics: Humans; Antigens, CD20; B-Lymphocytes; Multiple Sclerosis; Recurrence; Rituximab; Immunologic Factors; Antibodies, Monoclonal; T-Lymphocytes
PubMed: 37033984
DOI: 10.3389/fimmu.2023.1004795 -
Current Treatment Options in Neurology 2021This review presents a comprehensive analysis of the current high-efficacy disease-modifying therapies (DMTs) available for treatment of multiple sclerosis (MS). We... (Review)
Review
PURPOSE OF REVIEW
This review presents a comprehensive analysis of the current high-efficacy disease-modifying therapies (DMTs) available for treatment of multiple sclerosis (MS). We discuss the existing approved and emerging therapeutics in patients with relapsing and progressive forms of MS using data from clinical trials and observational studies. Treatment considerations in pediatric and pregnant populations are also reviewed. Finally, we discuss the treatment paradigms of the escalation and early aggressive approaches to treatment of MS, with review of ongoing clinical trials to compare these approaches.
RECENT FINDINGS
Natalizumab has shown promising data on efficacy in not only randomized trials but also observational studies when compared with placebo, the injectable DMTs, and fingolimod. The anti-CD20 B cell depleting therapies (rituximab, ocrelizumab, and ofatumumab) have also demonstrated superiority in randomized clinical trials compared to their comparator group (placebo, interferon, and teriflunomide, respectively) and rituximab has shown in observational studies to be more effective than older injectable therapies and some of the oral therapies. Alemtuzumab has shown good efficacy in randomized controlled trials and observational studies yet has several potentially severe side effects limiting its use. Mitoxantrone has similarly demonstrated significant reduction in new disease activity compared to placebo but is rarely used due to its severe side effects. Cladribine is an oral DMT often grouped in discussion with other higher efficacy DMTs but may be slightly less effective than the other therapies described in this review. Many emerging targets for therapeutic intervention are currently under investigation that may prove to be beneficial in early aggressive MS, including autologous hematopoietic stem cell transplantation.
SUMMARY
Traditionally, MS has been treated with an escalation approach, starting patients on a modestly effective DMT and subsequently escalating to a higher efficacy DMT when there is evidence of clinical and/or radiologic breakthrough activity. With the development of higher efficacy therapies and emerging data showing the potential positive long-term impact of these therapies when started earlier in the disease course, many clinicians have shifted to an early aggressive treatment approach in which patients are initially started on a higher efficacy DMT. Two clinical trials, the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial and the Determining the Effectiveness of earLy Intensive Versus Escalation approaches for the treatment of Relapsing-remitting MS (DELIVER-MS) trial, aim to directly compare these treatment strategies and their impact on clinical and radiologic outcomes.
PubMed: 34025110
DOI: 10.1007/s11940-021-00677-1 -
Journal of Comparative Effectiveness... Apr 2021The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought... (Meta-Analysis)
Meta-Analysis
The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.
Topics: Cladribine; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Network Meta-Analysis; Recurrence
PubMed: 33620251
DOI: 10.2217/cer-2020-0267