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Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial.

BACKGROUND: Symptoms of anaemia due to clinically significant extravascular haemolysis can affect patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab or eculizumab). The aim of this study was to assess the efficacy and safety of danicopan (ALXN2040), an investigational, first-in-class, oral complement factor D inhibitor, as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular haemolysis. METHODS: ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evalu

Delving into Molecular Pathways: Analyzing the Mechanisms of Action of Monoclonal Antibodies Integrated in IMGT/mAb-DB for Myasthenia Gravis.

BackgroundMyasthenia Gravis (MG) is a rare autoimmune disease presenting with auto-antibodies that affect the neuromuscular junction. In addition to symptomatic treatment options, novel therapeutics include monoclonal antibodies (mAbs). IMGT®, the international ImMunoGeneTics information system®, extends the characterization of therapeutic antibodies with a systematic description of their mechanisms of action (MOA) and makes them available through its database for mAbs and fusion proteins, IMGT/mAb-DB.MethodsUsing available literature data combined with amino acid sequence analyses from mAbs m

Updates on C3 Glomerulopathy in Kidney Transplantation: Pathogenesis and Treatment Options.

C3 glomerulopathy is a rare disease, characterized by an abnormal activation of the complement's alternative pathway that leads to the accumulation of the C3 component in the kidney. The disease recurs in more than half of kidney transplant recipients, with a significant impact on graft survival. Recurrence of the primary disease represents the second cause of graft loss after organ rejection. In C3 glomerulopathy, there are several risk factors which can promote a recurrence during transplantation, such as delayed graft function, infection and monoclonal gammopathy. All these events can trigg

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… Long-Term Efficacy and Safety of the Long-Acting Complement C5 Inhibitor Ravulizumab for the Treatment of Atypical Hemolytic Uremic Syndrome in Adults Kidney Int. Rep. 2021 6 1603 1613 10.1016/j.ekir.2021.03.884 34169200 PMC8207473 63. Ariceta G. Dixon B.P. Kim S.H. Kapur G. Mauch T. Ortiz S. …

Disease Activity After Switching From Eculizumab to Ravulizumab in Patients With Paroxysmal Nocturnal Haemoglobinuria: Real World Data From Denmark and Finland.

INTRODUCTION: Ravulizumab replaced eculizumab as the preferred complement inhibitor for Paroxysmal Nocturnal Haemoglobinuria (PNH) in Denmark and Finland after 2020. Data on real-world disease activity after switching are limited. METHODS: We conducted a case series of 20 PNH patients who transitioned from eculizumab to ravulizumab, assessing transfusion needs and breakthrough haemolysis episodes (BTH). RESULTS: In 19 of 20 patients, transfusions and BTH were stable or reduced after switching. Particularly, patients with high transfusion or BTH burden had a marked reduction in these paramete

Therapeutic Antibodies in Hematology: Advances in Malignant and Non-Malignant Disorders.

Therapeutic antibodies have revolutionized hematology, offering targeted and effective treatments for both malignant and non-malignant diseases. In hematologic malignancies, anti-CD20, anti-CD19, anti-CD38, and anti-B-cell maturation antigen (BCMA) antibodies have markedly improved survival outcomes, whereas antibody-drug conjugates and bispecific antibodies continue to expand therapeutic possibilities. Besides cancer, complement inhibitors such as eculizumab, ravulizumab, and the recently approved crovalimab have redefined paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic synd

COVID-19 vaccination prevents a more severe course and treatment with complement inhibitors reduce worsening hemolysis during the Omicron pandemic in patients with PNH: a single-center study.

ObjectiveParoxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease characterized by chronic complement-mediated hemolysis. The concentrated outbreak of coronavirus disease 2019 (COVID-19) in China after 6 December 2022, provided an opportunity to observe the disease course of PNH during an active Omicron infection epidemic.Patients and methodPatients diagnosed with PNH at Peking Union Medical College Hospital (PUMCH) before 6 December 2022, were followed up until 10 April 2023. Clinical data related to coronavirus infection and hemolysis were recorded. Factors influencing the infect

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… The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020;135(12):912–920. doi: 10.1182/blood.2019003399. 7. Risitano AM, Röth A, Soret J, et al. … Complement C5 inhibition in patients with COVID-19 – a promising target? Haematologica. 2020;105(12):2847–2850. 54. Yu J, Yuan X, Chen H, et al. Direct activation of the alternative complement pathway by SARS-CoV-2 spike proteins is blocked by factor D inhibition. …

Aptamers: Potential Diagnostic and Therapeutic Agents for Blood Diseases.

Aptamers are RNA/DNA oligonucleotide molecules that specifically bind to a targeted complementary molecule. As potential recognition elements with promising diagnostic and therapeutic applications, aptamers, such as monoclonal antibodies, could provide many treatment and diagnostic options for blood diseases. Aptamers present several superior features over antibodies, including a simple in vitro selection and production, ease of modification and conjugation, high stability, and low immunogenicity. Emerging as promising alternatives to antibodies, aptamers could overcome the present limitations

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… Researchers used SELEX methodology to develop a specific aptamer for the human complement C5 component. This selection process yielded a 38-mer 2′F RNA anti-C5 aptamer, which inhibits the activity of the human factor C5 of the complement cascade [ 72 ]. … Subsequently, a 38-mer 2′F RNA aptamer was modified by adding 40 kDa PEG to the 5′ end and 3′-3′-linked deoxythymidine to the 3′ end to produce a complement to the C5 inhibitor ARC1905 with a high affinity for complement C5 [ 72 , 107 ]. …

From Traditional to Targeted Immunotherapy in Myasthenia Gravis: Prospects for Research.

Treatment of Myasthenia Gravis (MG) is still based on non-specific immunosuppression. Long-term high dose corticosteroids is still a major cause of side effects, in young as well as in elderly patients in whom comorbidities further increase the burden of chronic immunosuppression. Moreover, awareness of the limits of traditional therapies has led to the concept of "refractory MG." The therapeutic approach to MG is therefore progressively evolving from the classic combination of corticosteroids and immunosuppressive drugs to new biological compounds targeting different immunopathological steps.

Advances in the long-term treatment of neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neuroinflammatory disorder with a prevalence of 1-5/100,000 globally, characterized by attacks of the central nervous system including but not limited to optic neuritis, transverse myelitis and brainstem lesions, including area postrema lesions. These autoimmune attacks can lead to irreversible damage if left untreated, therefore strategies have been developed to prevent relapses. Initial off-label treatments have achieved variable levels of success in relapse prevention, but improved relapse prevention and quality of life rem

Immune mechanisms and immunomodulatory therapies in steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is a complex and refractory kidney disease generally causing chronic kidney dysfunction, characterized by persistent proteinuria despite prolonged corticosteroid therapy. This review comprehensively explores the mechanisms of immunity driving SRNS, mainly focusing on the complex function network within immune cells, pro-inflammatory cytokines, and podocyte injury. Current immunosuppressive therapies show limited efficacy, prompting exploration of precision immunomodulatory strategies. Emerging approaches include IL-17 or low-dose IL-12 modulation, pr

New Targeted Agents in Myasthenia Gravis and Future Therapeutic Strategies.

Myasthenia gravis (MG) is a chronic autoimmune disease for which multiple immunomodulatory therapies are available. Nevertheless, MG has a significant impact on patient quality of life. In recent years, experts' main efforts have focused on optimizing treatment strategies, since disease burden is considerably affected by their safety and tolerability profiles, especially in patients with refractory phenotypes. This article aims to offer neurologists caring for MG patients an overview of the most innovative targeted drugs specifically designed for this disease and summarizes the recent literatu

Drug Treatment of Neuromyelitis Optica Spectrum Disorders: Out with the Old, in with the New?

IntroductionNeuromyelitis optica spectrum disorders (NMOSD) are rare neuroinflammatory demyelinating diseases of the CNS, mainly affecting optic nerves, spinal cord and brainstem regions. The diagnosis depends on clinical symptoms, MRI findings and the detection of autoantibodies against the water channel aquaporin 4 (AQP4-Ab). This autoantibody is particularly important for diagnostic sensitivity and specificity and further sets the course for major therapeutic decisions. Due to a relapsing course with the accumulation of disability, relapse prevention by immunotherapy is crucial in NMOSD. Un

Gemcitabine and carfilzomib induced thrombotic microangiopathy: eculizumab as a life-saving treatment.

Drug-induced aHUS is rare; however, early diagnosis is vital to reduce morbidity and mortality. With confirmation of the diagnosis, eculizumab appears to be a viable treatment option to suppress the pro-inflammatory surge. Furthermore, adverse side effects of medications such as carfilzomib and gemcitabine should be considered in the appropriate settings.

Endothelial cell function and endothelial-related disorders following haematopoietic cell transplantation.

Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life-threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient- and disease-related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular

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… Discordance between free c5 and ch50 complement assays in measuring complement c5 inhibition in patients with aHUS treated with ravulizumab. Blood. 2019;134:1099–1099. 111. Richardson PG, Soiffer RJ, Antin JH, Uno H, Jin Z, Kurtzberg J, et al. …

Autoimmune Neuromuscular Disorders at a Molecular Crossroad: Linking Pathogenesis to Targeted Immunotherapy.

Myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and idiopathic inflammatory myopathies are among the most widely recognized autoimmune neuromuscular disorders. Although they differ in clinical presentation, shared immunopathogenic mechanisms place them at a molecular crossroads. Evidence of overlapping pathways has led to the development of targeted strategies including complement inhibition, FcRn antagonism, B-cell depletion, and the CAR-T cell approach. In this review, we analyze current knowledge regarding pathogenic mechanisms and their link to immunotherapy, extensiv

Novel Treatment Paradigms: Primary IgA Nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Approximately 30% to 45% of patients progress to kidney failure (KF) within 20 to 25 years of diagnosis, and there has long been a lack of effective treatments. The therapeutic landscape in IgAN is rapidly evolving, driven in large part by the acceptance of the surrogate clinical trial end point of proteinuria reduction by regulatory authorities for the accelerated approval of new therapies. Two drugs, targeted release formulation (TRF)-budesonide (nefecon) and sparsentan, have recently been approved under this sch

Pharmacotherapy of Generalized Myasthenia Gravis with Special Emphasis on Newer Biologicals.

Myasthenia gravis (MG) is a chronic, fluctuating, antibody-mediated autoimmune disorder directed against the post-synaptic neuromuscular junctions of skeletal muscles, resulting in a wide spectrum of manifestations ranging from mild to potentially fatal. Given its unique natural course, designing an ideal trial design for MG has been wrought with difficulties and evidence in favour of several of the conventional agents is weak as per current standards. Despite this, acetylcholinesterases and corticosteroids have remained the cornerstones of treatment for several decades with intravenous immuno

IgA Nephropathy: Beyond the Half-Century.

In 1968, Jean Berger first introduced the medical world to IgA nephropathy (IgAN). Fifty-five years later, its pathogenesis is still unclear, but treatments such as renin-angiotensin-aldosterone system inhibitors (RAAS-Is), tonsillectomies, and glucocorticoids are currently used worldwide. There have been great strides in the past 20 years since the discoveries of the specific dysregulation of mucosal immunity, galactose-deficient IgA1 (Gd-IgA1), and Gd-IgA1 immune complexes in patients with IgAN. According to these findings, a multi-hit hypothesis was developed, and this multi-hit hypothesis

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… (1) Eculizumab: Eculizumab (Soliris ® ) is a humanized recombinant monoclonal IgG antibody against human complement C5. Eculizumab inhibits responses at the end of the complement activation pathway. … C5 | Not performed | Not performed | Not performed | Not performed | Too expensive IONIS-FB-LRx | Complement Factor B | Ongoing * | Shown | Not performed | Mild | * Phase 2 study interlim results Atrasentan | Endothelin (ETA receptor) | Performed | Shown | Not performed | Mild–moderate | Sparsentan …

Immunosuppressive and Non-Immunosuppressive Drugs for Heart Xenotransplantation in Humans: Is Europe Ready?

Xenotransplantation is becoming an emerging field of interest for the treatment of end-stage heart disease. In fact, the shortage of human heart donors in European countries requires the increasing investigation of alternative strategies such as heart xenotransplantation. Among different limitations in this peculiar field, the experimental pharmacological management of patients who undergo heart xenotransplantation is primarily narrowed by the indications for which these drugs have been previously authorized by international medicines agencies. In fact, many of these medications have been neve

Экулизумаб для связанной с АТКР тромботической микроангиопатии в китайском реципиенте трансплантации почек с типом 2 диабет: отчет по делу.

ЦЕЛЬ: Данное исследование было направлено на изучение эффективности экулизумаба в лечении недавно разработанной тромботической микроангиопатии (TMA), связанной с острым отторжением с помощью Т-клеток (ATCR) у пациентов с типом 2 диабет после трансплантации почек. МЕТОДЫ: Новая тромботическая микроангиопатия после трансплантации почек является относительно редким, но серьезным осложнением, которое клинически трудно уладить и требует своевременного вмешательства для предотвращения пересадки или ранней потери трансплантатата. В настоящее время в клинической практике отсутствует консенсус в отноше