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Drugs Sep 2023Rozanolixizumab (rozanolixizumab-noli; RYSTIGGO) is a high affinity humanized immunoglobulin G4 monoclonal antibody directed against human neonatal Fc receptor (FcRn).... (Review)
Review
Rozanolixizumab (rozanolixizumab-noli; RYSTIGGO) is a high affinity humanized immunoglobulin G4 monoclonal antibody directed against human neonatal Fc receptor (FcRn). Administered subcutaneously, it is being developed by UCB Pharma for the treatment of autoimmune diseases and received its first approval on 27 June 2023 in the USA for the treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) or anti-muscle-specific kinase (MuSK) antibody positive. Rozanolixizumab is the first agent to be approved in the USA for both anti-AChR and anti-MuSK antibody-positive gMG. A regulatory assessment of rozanolixizumab for the treatment of gMG is currently underway in the EU and Japan. Clinical development is ongoing for the treatment of leucine-rich glioma-inactivated 1 autoimmune encephalitis, myelin oligodendrocyte glycoprotein (MOG) antibody disease and severe fibromyalgia syndrome. This article summarizes the milestones in the development of rozanolixizumab leading to this first approval for the treatment of gMG in adults who are anti-AChR or anti-MuSK antibody positive.
Topics: Adult; Infant, Newborn; Humans; Antibodies, Monoclonal, Humanized; Encephalitis; Glioma; Myasthenia Gravis
PubMed: 37656420
DOI: 10.1007/s40265-023-01933-1 -
Journal of Neurology Jul 2023Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair... (Review)
Review
Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair acetylcholine receptor function. Weakness of respiratory muscles represents the most severe MG manifestation, and 10-15% of all patients experience an MG crisis with the need of mechanical ventilatory support at least once in their life. MG patients with respiratory muscle weakness need active immunosuppressive drug treatment long term, and they need regular specialist follow-up. Comorbidities affecting respiratory function need attention and optimal treatment. Respiratory tract infections can lead to MG exacerbations and precipitate an MG crisis. Intravenous immunoglobulin and plasma exchange are the core treatments for severe MG exacerbations. High-dose corticosteroids, complement inhibitors, and FcRn blockers represent fast-acting treatments that are effective in most MG patients. Neonatal myasthenia is a transient condition with muscle weakness in the newborn caused by mother's muscle antibodies. In rare cases, treatment of respiratory muscle weakness in the baby is required.
Topics: Infant, Newborn; Humans; Myasthenia Gravis; Neuromuscular Junction; Neuromuscular Diseases; Muscle Weakness; Respiratory Tract Diseases
PubMed: 37101094
DOI: 10.1007/s00415-023-11733-y -
Journal of Neurology Aug 2023Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients...
Long-term efficacy and safety of ravulizumab in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis: results from the phase 3 CHAMPION MG open-label extension.
INTRODUCTION
Ravulizumab demonstrated efficacy and an acceptable safety profile versus placebo in the randomized controlled period (RCP) of the phase 3 CHAMPION MG trial in patients with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. We report an interim analysis of the ongoing open-label extension (OLE) designed to evaluate long-term treatment effects.
METHODS
Following completion of the 26-week RCP, patients could enter the OLE; patients who received ravulizumab in the RCP continued the drug; patients who previously received placebo switched to ravulizumab. Patients receive body-weight-based maintenance dosing of ravulizumab every 8 weeks. Efficacy endpoints up to 60 weeks included Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores, with least-squares (LS) mean change and 95% confidence intervals (95% CI) reported.
RESULTS
Long-term efficacy and safety in the OLE were analyzed in 161 and 169 patients, respectively. Improvements in all scores were maintained through 60 weeks in patients who received ravulizumab during the RCP; LS mean change from RCP baseline in MG-ADL score was - 4.0 (95% CI: - 4.8, - 3.1; p < 0.0001). Rapid (within 2 weeks) and sustained improvements occurred in patients previously receiving placebo; LS mean change in MG-ADL score from OLE baseline to Week 60 was - 1.7 (95% CI: - 2.7, - 0.8; p = 0.0007). Similar trends were seen in QMG scores. Ravulizumab treatment was associated with a decreased rate of clinical deterioration events compared with placebo. Ravulizumab was well tolerated; no meningococcal infections were reported.
CONCLUSION
Findings support the sustained efficacy and long-term safety of ravulizumab, administered every 8 weeks, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.
CLINICALTRIALS
gov identifier: NCT03920293; EudraCT: 2018-003243-39.
Topics: Adult; Humans; Activities of Daily Living; Autoantibodies; Myasthenia Gravis; Receptors, Cholinergic; Treatment Outcome
PubMed: 37103755
DOI: 10.1007/s00415-023-11699-x -
Diagnostics (Basel, Switzerland) Aug 2023Encephalitis is a condition with a variety of etiologies, clinical presentations, and degrees of severity. The causes of these disorders include both neuroinfections and... (Review)
Review
Autoimmune Encephalitis with Antibodies: Anti-NMDAR, Anti-AMPAR, Anti-GQ1b, Anti-DPPX, Anti-CASPR2, Anti-LGI1, Anti-RI, Anti-Yo, Anti-Hu, Anti-CV2 and Anti-GABAAR, in the Course of Psychoses, Neoplastic Diseases, and Paraneoplastic Syndromes.
Encephalitis is a condition with a variety of etiologies, clinical presentations, and degrees of severity. The causes of these disorders include both neuroinfections and autoimmune diseases in which host antibodies are pathologically directed against self-antigens. In autoimmune encephalitis, autoantibodies are expressed in the central nervous system. The incidence of this disease is approximately 4% of all reported cases of encephalitis. Autoimmune encephalitis can be induced by antibodies against neuronal surface antigens such as N-methyl-D-aspartate-activated glutamate receptors (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPAR) or gangliosides GQ1b, DPPX, CASPR2, LGI1, as well as by antibodies against neuronal intracellular antigens. The paper presents a number of both mental and neurological symptoms of autoimmune encephalitis. Moreover, the coexistence of psychoses, neoplastic diseases, and the methods of diagnosing autoimmune encephalitis are discussed. Attention was also drawn to the fact that early diagnosis, as well as early initiation of targeted treatment, increases the chance of a successful course of the therapeutic process. Strategy and Methodology: The articles on which the following paper was based were searched using search engines such as PubMed and Medline. Considering that anti-NMDAR antibodies were first described in 2007, the articles were from 2007 to 2023. The selection of papers was made by entering the phrases "autoimmune encephalitis and psychosis/paraneplastic syndromes or cancer". The total number of articles that could be searched was 747, of which 100 items were selected, the most recent reports illustrating the presented topic. Thirty-four of them were rejected in connection with case reports or papers that could not be accessed.
PubMed: 37568953
DOI: 10.3390/diagnostics13152589 -
Frontiers in Immunology 2023Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck,... (Review)
Review
Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.
Topics: Humans; Autoantibodies; Immunoglobulin G; Immunotherapy; Myasthenia Gravis; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 37564637
DOI: 10.3389/fimmu.2023.1212757 -
Drugs Jan 2024Zilucoplan (Zilbrysq) is a subcutaneously administered macrocyclic peptide inhibitor of complement component 5 (C5 inhibitor) being developed by UCB for the treatment of... (Review)
Review
Zilucoplan (Zilbrysq) is a subcutaneously administered macrocyclic peptide inhibitor of complement component 5 (C5 inhibitor) being developed by UCB for the treatment of generalised myasthenia gravis (gMG). Zilucoplan received its first approval, in Japan, in September 2023 for the treatment of gMG in adult patients who inadequately respond to steroids or other immunosuppressants and are positive for anti-acetylcholine receptor (AChR) antibodies. Subsequently, zilucoplan was approved in the USA in October 2023 for the treatment of gMG in adult patients who are anti-AChR antibody positive and in the EU in December 2023 as an add-on to standard therapy for the treatment of gMG in adult patients who are anti-AChR antibody positive. Zilucoplan is also currently under regulatory review in Australia and Canada for use in the treatment of gMG. This article summarises the milestones in the development of zilucoplan leading to this first approval for gMG.
Topics: Adult; Humans; Myasthenia Gravis; Receptors, Cholinergic; Complement C5; Autoantibodies; Peptides, Cyclic
PubMed: 38093160
DOI: 10.1007/s40265-023-01977-3