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1.
Lancet Haematol ; 9(9): e648-e659, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36055332

RESUMO

BACKGROUND: In the PEGASUS trial, the complement C3 inhibitor, pegcetacoplan, showed superiority to eculizumab in improving haematological outcomes in adult patients with paroxysmal nocturnal haemoglobinuria and suboptimal response to eculizumab at 16 weeks. The aim of the open-label period was to evaluate the long-term efficacy and safety of pegcetacoplan through to 48 weeks. METHODS: PEGASUS was a phase 3, randomised, open-label, active-comparator controlled trial conducted in 44 centres in Australia, Belgium, Canada, France, Germany, Japan, Russia, South Korea, Spain, the UK, and the USA. Eligible participants were aged 18 years or older, had paroxysmal nocturnal haemoglobinuria, and had a haemoglobin concentration of less than 10·50 g/dL after 3 months or longer of stable eculizumab treatment. After a 4-week run-in with eculizumab plus pegcetacoplan, patients were randomly assigned (1:1) by interactive response technology to pegcetacoplan (1080 mg subcutaneously twice weekly) or eculizumab (according to their regimen at enrolment) for 16 weeks and could continue to the open-label period (32 weeks of pegcetacoplan monotherapy [pegcetacoplan-to-pegcetacoplan] or 28 weeks of pegcetacoplan monotherapy [eculizumab-to-pegcetacoplan]). Randomisation was stratified by platelet count and number of previous blood transfusions. The primary endpoint was change from baseline in haemoglobin at week 16, which has previously been reported. The outcomes of the open-label period (week 16 to week 48) are reported here. At 48 weeks, efficacy (including mean haemoglobin concentration and quality of life measured on the Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scale) was assessed in the intention-to-treat population and safety was assessed per protocol. This trial was registered with ClinicalTrials.gov, NCT03500549, and has been completed. FINDINGS: Between June 14, 2018, and Nov 14, 2019, 80 patients were randomly assigned to receive treatment with pegcetacoplan (41 patients) or eculizumab (39 patients). Most participants were women (49 [61%]) and 31 (39%) were men; 12 (15%) were Asian, two (3%) were Black, 49 (61%) were White, and 17 (21%) were another race or did not report their race. The open-label period had 77 participants (38 pegcetacoplan-to-pegcetacoplan, 39 eculizumab-to-pegcetacoplan). Patients in the pegcetacoplan-to-pegcetacoplan group maintained high mean haemoglobin concentrations between 16 weeks (11·54 g/dL [SD 1·96]) and 48 weeks (11·30 g/dL [1·77]; p=0·14). Patients in the eculizumab-to-pegcetacoplan group had significantly greater mean haemoglobin concentrations at 48 weeks (11·57 g/dL [2·21]) versus 16 weeks (8·58 g/dL [0·96]; p<0·0001). Clinically meaningful improvements in FACIT-Fatigue scores were observed at 48 weeks, with a mean change from baseline for all patients receiving pegcetacoplan monotherapy of 9·89 points (SD 9·63), for patients in the pegcetacoplan-to-pegcetacoplan group mean 10·14 points (9·06), and for patients in the eculizumab-to-pegcetacoplan group mean 9·62 points (10·34). During the entire study period, 13 (16%) of 80 patients discontinued treatment (three [7%] of 41 through to week 16 due to breakthrough haemolysis, and ten [13%] of 77 due to severe treatment-emergent adverse events) and 18 patients (eight pegcetacoplan-to-pegcetacoplan, ten eculizumab-to-pegcetacoplan) had at least one serious treatment-emergent adverse event during the open-label period, four were considered to be related to pegcetacoplan treatment. The most common treatment-emergent adverse events (in ≥10% patients) among both pegcetacoplan-treated groups during the open-label period were injection site reactions (in 20 [26%] of 77 patients), haemolysis (15 [19%]), nasopharyngitis (12 [16%]), and diarrhoea (ten [13%]). No treatment-related deaths occurred throughout the duration of the study. INTERPRETATION: The durability of improved haematological outcomes and favourable safety profile over 48 weeks of treatment suggests that pegcetacoplan has the potential to improve treatment benefit and alter treatment goals in patients with paroxysmal nocturnal haemoglobinuria. FUNDING: Apellis Pharmaceuticals.


Assuntos
Hemoglobinúria Paroxística , Adulto , Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Fadiga , Feminino , Seguimentos , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos , Fatores Imunológicos , Masculino , Peptídeos Cíclicos , Qualidade de Vida , Resultado do Tratamento
2.
BMJ Case Rep ; 15(8)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36107725

RESUMO

A male in his teens with a history of liver transplant for biliary atresia (aged 2 years) and autoimmune haemolytic anaemia (AIHA, aged 6 years) presented with jaundice, dark urine, fatigue and chest discomfort that began 48 hours after the first dose of SARS-CoV-2 Pfizer-BioNTech vaccine (BNT162b2 mRNA). Investigations revealed a warm AIHA picture. Over 4 weeks the patient developed life-threatening anaemia culminating in haemoglobin of 35 g/L (after transfusion), lactate dehydrogenase of 1293 units/L and bilirubin of 228 µmol/L, refractory to standard treatment with corticosteroids and rituximab. An emergency splenectomy was performed that slowed haemolysis but did not completely ameliorate it. Eculizumab, a terminal complement pathway inhibitor, was initiated to arrest intravascular haemolysis and showed a favourable response. AIHA is rare but described after the SARS-CoV-2 Pfizer-BioNTech vaccine. This case highlights the rare complication of AIHA, the use of emergency splenectomy for disease control, and the use of eculizumab.


Assuntos
Anemia Hemolítica Autoimune , Vacina BNT162 , COVID-19 , Adolescente , Anemia Hemolítica Autoimune/complicações , Anticorpos Monoclonais Humanizados , Vacina BNT162/administração & dosagem , Vacina BNT162/efeitos adversos , Bilirrubina , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Inativadores do Complemento/uso terapêutico , Hemoglobinas , Hemólise , Humanos , Fatores Imunológicos/uso terapêutico , Lactato Desidrogenases , Masculino , RNA Mensageiro/uso terapêutico , Rituximab/uso terapêutico , SARS-CoV-2 , Esplenectomia/efeitos adversos
3.
Nat Commun ; 13(1): 5519, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127336

RESUMO

With the addition of the compstatin-based complement C3 inhibitor pegcetacoplan, another class of complement targeted therapeutics have recently been approved. Moreover, compstatin derivatives with enhanced pharmacodynamic and pharmacokinetic profiles are in clinical development (e.g., Cp40/AMY-101). Despite this progress, the target binding and inhibitory modes of the compstatin family remain incompletely described. Here, we present the crystal structure of Cp40 complexed with its target C3b at 2.0-Å resolution. Structure-activity-relationship studies rationalize the picomolar affinity and long target residence achieved by lead optimization, and reveal a role for structural water in inhibitor binding. We provide explanations for the narrow species specificity of this drug class and demonstrate distinct target selection modes between clinical compstatin derivatives. Functional studies provide further insight into physiological complement activation and corroborate the mechanism of its compstatin-mediated inhibition. Our study may thereby guide the application of existing and development of next-generation compstatin analogs.


Assuntos
Complemento C3 , Inativadores do Complemento , Inativadores do Complemento/farmacologia , Peptídeos Cíclicos , Água/química
4.
Respir Res ; 23(1): 202, 2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-35945604

RESUMO

BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear. METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO2/FiO2 below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15. RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO2/FiO2 from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) - 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified. CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO2/FiO2) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.


Assuntos
Anti-Infecciosos , COVID-19 , COVID-19/tratamento farmacológico , Complemento C5 , Inativadores do Complemento/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos Cíclicos , SARS-CoV-2 , Resultado do Tratamento
5.
J Pharm Biomed Anal ; 220: 115004, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-35988306

RESUMO

A recombinant humanized monoclonal antibody (mAb) Eculizumab, C5-complement cascade inhibitor, is an important treatment of complement-based diseases recommended by international guidelines. Elizaria® Drug Product (DP), developed by IBC Generium, Russia, is the world's first registered biosimilar of eculizumab (Soliris®, Alexion Pharmaceuticals). Using sensitive state-of-the-art analytical techniques extensive similarity assessment has been conducted to demonstrate the structural and functional similarity of original Soliris® (Eculizumab Reference Product, RP) and the biosimilar Elizaria®, focusing on the physicochemical and biological quality attributes, including those known to affect the mechanisms of action. A multitude of analyses revealed that amino acid sequence is identical, the higher order structures, post-translational modifications, purity, and product variants are highly similar between Elizaria® DP and Eculizumab RP, except for minor differences in the relative abundance of the charge variants and glycan moieties considered not clinically significant. The results demonstrate that Elizaria® is highly analytically similar to Eculizumab RP in terms of physicochemical properties and biological activities.


Assuntos
Medicamentos Biossimilares , Hemoglobinúria Paroxística , Anticorpos Monoclonais Humanizados/uso terapêutico , Medicamentos Biossimilares/química , Inativadores do Complemento , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Preparações Farmacêuticas
6.
Mol Immunol ; 150: 90-98, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36027818

RESUMO

Paul Ehrlich was a pioneering Immunobiologist and physician who coined the term 'complement' in the year 1899. He was a leading visionary scientist who worked in the late 19th and early 20th centuries in Berlin and Frankfurt. He received numerous awards and honors for his substantial contributions to immunobiology and medicine, including the identification of complement, and he received the Nobel Prize in Physiology or Medicine in 1908 in recognition of his work on immunity. During his clinical work, Paul Ehrlich treated a patient with paroxysmal hemoglobinuria and reported his diagnostic approaches, including those related to erythrocyte lysis and microscopic cell analysis, to the Verein für Innere Medicine/Society of Internal Medicine, Berlin. Paroxysmal nocturnal hemoglobinuria was shown to be a complement-mediated disease; treatment of this disease with the complement inhibitor Eculzimab/Soliris was approved by the European Medicines Agency in 2003 and by the United States Food and Drug Administration in 2007.


Assuntos
Prêmio Nobel , Médicos , Inativadores do Complemento , História do Século XX , Humanos , Masculino , Estados Unidos
7.
Immunotherapy ; 14(13): 995-1006, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35860926

RESUMO

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a publication about the FILLY study, which was published in Ophthalmology in 2020. The FILLY study looked at an investigational medicine called pegcetacoplan as a possible treatment for geographic atrophy. Geographic atrophy, also known as GA, is the late stage of an eye disease called dry age-related macular degeneration, also known as dry AMD. In people with GA, lesions form on a part of the back of the eye called the retina. GA lesions are patches of thin retina. Growth of GA lesions ultimately causes blindness, which cannot be reversed. There is currently no approved treatment for GA. Pegcetacoplan, also called APL-2, could be a possible treatment for GA. Pegcetacoplan is an investigational medicine, which means it has not yet been approved. It is currently being studied in clinical studies to see how well it works. WHAT HAPPENED IN THE FILLY STUDY?: The FILLY study included participants with GA and tested how well pegcetacoplan worked compared to a sham injection (an injection that looks like the study treatment but does not have any medicine in it). The study also looked at how safe it was in adults with GA. WHAT WERE THE RESULTS?: The main questions the researchers wanted to answer were: Did pegcetacoplan slow the growth of the study participants' GA lesions? ○Yes. Overall, the researchers found that pegcetacoplan did slow the growth of the study participants' GA lesions. Did pegcetacoplan change the participants' vision? ○No. Overall, the researchers found that pegcetacoplan did not change the participants' vision. What medical problems happened after the participants received pegcetacoplan? ○The researchers kept track of any serious medical problems that happened during the study, also called serious adverse events. They also kept track of other medical problems that happened, or got worse, only at some point after the participants received the study treatment. These are called treatment emergent adverse events, also known as TEAEs. The serious adverse events and TEAEs that the participants had are described later in this summary. WHAT DO THE RESULTS OF THE STUDY MEAN?: Overall, results from this study showed that participants who received pegcetacoplan had slower growth of GA lesions than participants who received the sham injection. After the participants had stopped receiving pegcetacaoplan, the effect of the treatment seemed to be reduced. Pegcetacoplan did not change how well the participants could see during their vision tests in this trial. ClinicalTrials.gov NCT number: NCT02503332.


Assuntos
Atrofia Geográfica , Degeneração Macular , Animais , Complemento C3/uso terapêutico , Inativadores do Complemento/uso terapêutico , Feminino , Atrofia Geográfica/complicações , Atrofia Geográfica/tratamento farmacológico , Cavalos , Humanos , Idioma , Degeneração Macular/complicações , Degeneração Macular/tratamento farmacológico , Peptídeos Cíclicos , Acuidade Visual
8.
Ann Hematol ; 101(9): 1971-1986, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35869170

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder characterized by complement-mediated hemolysis. C5 inhibitors (eculizumab/ravulizumab) control intravascular hemolysis but do not prevent residual extravascular hemolysis. The newly approved complement inhibitor, pegcetacoplan, inhibits C3, upstream of C5, and has the potential to improve control of complement-mediated hemolysis. The PADDOCK and PALOMINO clinical trials assessed the safety and efficacy of pegcetacoplan in complement inhibitor-naïve adults (≥ 18 years) diagnosed with PNH. Patients in PADDOCK (phase 1b open-label, pilot trial) received daily subcutaneous pegcetacoplan (cohort 1: 180 mg up to day 28 [n = 3]; cohort 2: 270-360 mg up to day 365 [n = 20]). PALOMINO (phase 2a, open-label trial) used the same dosing protocol as PADDOCK cohort 2 (n = 4). Primary endpoints in both trials were mean change from baseline in hemoglobin, lactate dehydrogenase, haptoglobin, and the number and severity of treatment-emergent adverse events. Mean baseline hemoglobin levels were below the lower limit of normal in both trials (PADDOCK: 8.38 g/dL; PALOMINO: 7.73 g/dL; normal range: 11.90-18.00 g/dL), increased to within normal range by day 85, and were sustained through day 365 (PADDOCK: 12.14 g/dL; PALOMINO: 13.00 g/dL). In PADDOCK, 3 serious adverse events (SAE) led to study drug discontinuation, 1 of which was deemed likely related to pegcetacoplan and 1 SAE, not deemed related to study drug, led to death. No SAE led to discontinuation/death in PALOMINO. Pegcetacoplan was generally well tolerated and improved hematological parameters by controlling hemolysis, while also improving other clinical PNH indicators in both trials. These trials were registered at www.clinicaltrials.gov (NCT02588833 and NCT03593200).


Assuntos
Inativadores do Complemento , Hemoglobinúria Paroxística , Peptídeos Cíclicos , Adulto , Biomarcadores , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Inativadores do Complemento/efeitos adversos , Hemoglobinas , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos , Peptídeos Cíclicos/efeitos adversos
9.
Int J Mol Sci ; 23(13)2022 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-35806224

RESUMO

Complement-mediated diseases or complementopathies, such as Paroxysmal nocturnal hemoglobinuria (PNH), cold agglutinin disease (CAD), and transplant-associated thrombotic microangiopathy (TA-TMA), demand advanced complement diagnostics and therapeutics be adopted in a vast field of medical specialties, such as hematology, transplantation, rheumatology, and nephrology. The miracle of complement inhibitors as "orphan drugs" has dramatically improved morbidity and mortality in patients with otherwise life-threatening complementopathies. Efficacy has been significantly improved by upstream inhibition in patients with PNH. Different molecules may exert diverse characteristics in vitro and in vivo. Further studies remain to show safety and efficacy of upstream inhibition in other complementopathies. In addition, cost and availability issues are major drawbacks of current treatments. Therefore, further developments are warranted to address the unmet clinical needs in the field of complementopathies. This state-of-the-art narrative review aims to delineate novel insights into factor D inhibition as a promising target for complementopathies.


Assuntos
Fator D do Complemento , Hemoglobinúria Paroxística , Anticorpos Monoclonais Humanizados/farmacologia , Inativadores do Complemento/farmacologia , Inativadores do Complemento/uso terapêutico , Proteínas do Sistema Complemento , Hemólise , Humanos
11.
Adv Clin Exp Med ; 31(6): 707-710, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35699586

RESUMO

BACKGROUND: Eculizumab is an antibody targeting the C5 complement protein. Clinical trials suggest that eculizumab significantly reduces transfusion requirements and prevents disease complications in patients with paroxysmal nocturnal hemoglobinuria (PNH). OBJECTIVES: To analyze the outcome of pregnancies among Polish women with PNH treated with eculizumab as a part of the Polish National Health Fund program. MATERIAL AND METHODS: We report the outcomes of 3 pregnancies among women treated with eculizumab between 2017 and 2020. For 1 of these woman, it was the 1st pregnancy, while the remaining 2 patients had previously had 1 previous successful pregnancy each. RESULTS: All 3 mothers survived pregnancy, and all children were born alive. One of the patients had a vaginal delivery. Another required cesarean delivery at the 34th week due to a decreasing platelet count. In 1 case, premature rupture of the fetal membranes occurred at week 36, followed by artificial labor induction. All children were born without any inborn defects. The 2 prematurely born babies required a prolonged hospital stay. CONCLUSION: Treatment with eculizumab seems to reduce the risk to a mother and a child associated with PNH. However, more data are necessary to confirm this notion.


Assuntos
Hemoglobinúria Paroxística , Anticorpos Monoclonais Humanizados/uso terapêutico , Criança , Inativadores do Complemento/uso terapêutico , Feminino , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Polônia , Gravidez , Gestantes
12.
Int J Hematol ; 116(1): 55-59, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35668275

RESUMO

Autoimmune and complement-related hematological side effects have been observed with messenger ribonucleic acid (mRNA) vaccines. Here, we report the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). We reviewed the medical records of seventeen patients with PNH visiting the University of Tsukuba Hospital who had received two doses of the SARS-CoV-2 mRNA vaccine between May 2021 and November 2021. Twelve patients were being treated with complement inhibitors. The median age of all patients was 62 years (range 29-89 years).; six were males and eleven were females. Fourteen patients received the BNT162b2 vaccine (Pfizer/BioNTech) and three received the mRNA-1273 vaccine (Moderna). The median percentages of PNH clones in erythrocytes and granulocytes were 37.61% (range 8.11-85.71%) and 59.73% (range 3.76-97.82%), respectively. Of the twelve patients receiving complement inhibitors, only one had a hemolytic reaction after vaccination, but it did not meet the definition of breakthrough hemolysis. By contrast, hemolytic attacks were observed in two of the five untreated patients with PNH, and one of them required a blood transfusion. Appropriate administration of complement inhibitors to patients with PNH may prevent hemolysis induced by SARS-CoV-2 mRNA vaccination.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Hemoglobinúria Paroxística , Hemólise , Vacina de mRNA-1273 contra 2019-nCoV/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacina BNT162/efeitos adversos , COVID-19/complicações , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Inativadores do Complemento/uso terapêutico , Feminino , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Vacinação/efeitos adversos
13.
Am J Case Rep ; 23: e936116, 2022 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-35671252

RESUMO

BACKGROUND Secondary thrombotic microangiopathies (TMAs) are induced by several underlying conditions and most are resolved by treating the underlying disease. Eculizumab, a human monoclonal antibody, blocks the final stages of the complement system. Several studies have shown that complement C5 monoclonal antibodies are effective in treating secondary TMA. Systemic sclerosis (SSc) is one of the most common causes of secondary TMA, and early diagnosis is important because TMA secondary to SSc has a poor prognosis. We report a case of TMA secondary to SSc that did not respond to eculizumab, despite the presence of severe complement activation. CASE REPORT A 61-year-old previously healthy man was admitted for acute renal failure and thrombocytopenia. TMA was suspected because hemolytic anemia, thrombocytopenia, and organ damage were detected. Based on the physical findings, we suspected SSc as the underlying cause. All tests for specific antibodies, including Scl-70, were negative, and C5b-9 levels were markedly elevated (11 041 ng/mL). We initiated plasma exchange on day 3, followed by eculizumab therapy, but with limited improvement. SSc with secondary TMA was identified upon further testing. After completion of the plasma exchange, the platelet count was maintained above 30 000/µL. Creatinine levels gradually decreased, and the patient was weaned off dialysis. Steroid treatment for SSc was continued, and the patient was eventually discharged. CONCLUSIONS A case of SSc-TMA was ineffectively treated with eculizumab, despite abnormal activation of the complement system. Continuous monitoring and investigation are required, and discontinuation of eculizumab should be determined according to the final diagnosis.


Assuntos
Escleroderma Sistêmico , Microangiopatias Trombóticas , Anticorpos Monoclonais Humanizados , Ativação do Complemento , Inativadores do Complemento/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/tratamento farmacológico , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia
14.
Semin Hematol ; 59(1): 38-46, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-35491057

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, thrombosis and bone marrow failure. Prior to the availability of specific therapy, PNH led to the death of around half of affected individuals, mainly through thrombotic complications, with a particular grim prognosis for patients presenting with classic PNH. The anti-C5 monoclonal antibody eculizumab has revolutionized treatment, controlling intravascular hemolysis and thrombosis occurrence, with improved long-term survival. However, eculizumab is infused on a lifelong 2 week basis and most of the patients are anemic, with some remaining transfusion-dependent. New anti-C5 agents reproduce the safety and efficacy of eculizumab, with improved patient convenience, while proximal complement inhibitors have been developed to address C3-mediated extravascular hemolysis, aiming to eventually improve hematological response. This review will describe the spectacular medical progress in PNH of the last 20 years, as well as the risks and benefits of a novel approach.


Assuntos
Hemoglobinúria Paroxística , Trombose , Inativadores do Complemento , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos
15.
Expert Rev Hematol ; 15(5): 385-392, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35502699

RESUMO

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal stem cell disease harvesting a somatic mutation in the phosphatidylinositol glycan class A (PIG-A) gene. This mutation results in a deficiency in cell membrane complement regulators leading to activation of the terminal complement pathway, clinically presenting as hemolytic anemia and thrombosis, and frequently associated with bone marrow failure. This condition was historically managed with supportive care and bone marrow transplant. AREAS COVERED: This paper will review primary data on the pharmacology, efficacy, and safety of ravulizumab in the pediatric/adolescent population gathered from literature search from PubMed, abstracts from annual meetings, and medication package inserts. Eligible clinical trials identified on the clinicaltrials.gov website are also briefly discussed. EXPERT OPINION: The discovery of eculizumab, a monoclonal antibody against complement protein 5, has revolutionized the PNH landscape, with decreased hemolysis and risk of thrombosis, improved quality-of-life, and has become the standard of care. Ravulizumab, a longer-acting C5-inhibitor with 4 times the half-life of eculizumab, was recently approved for pediatric patients with PNH. Ravulizumab is effective, safe, and has the potential to improve quality of life further. In addition, ongoing clinical trials using second-generation complement inhibitors may provide promising new interventions in PNH.


Assuntos
Hemoglobinúria Paroxística , Trombose , Adolescente , Anticorpos Monoclonais Humanizados , Criança , Inativadores do Complemento/uso terapêutico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos , Qualidade de Vida , Trombose/tratamento farmacológico
16.
Expert Opin Investig Drugs ; 31(7): 715-727, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35531637

RESUMO

INTRODUCTION: Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease of unknown cause. Autoantibodies, self-reactive T cells and other immune abnormalities, with impairment of platelet production, lead to a reduced platelet count. Until recently, therapy was largely empirical using immune suppressants (none of which have undergone randomized clinical trials). These therapies have variable efficacy and are associated with predictable unwanted effects which impact patient quality-of-life. With greater understanding of the underlying pathophysiology, better, more targeted therapies have been developed; however, there is still an urgent need for additional classes of treatment. AREAS COVERED: This article covers new TPO receptor agonists, Syk inhibitors, Fcγ receptor antagonists, BTK and complement inhibitors, and other therapies. Insights into the most promising therapies are offered. Novel ITP treatments currently in clinical trials and those recently approved come under the spotlight. EXPERT OPINION: Thrombopoietin receptor agonists remain the most effective treatment for ITP and have changed the ITP therapeutic landscape remarkably. Other new molecules such as Fcγ receptor blockers, Bruton tyrosine kinase, complement inhibitors, and others are unlikely to enjoy the same success rate as the TPO-RAs, but nonetheless they will find a place in the management of patients with ITP.


Assuntos
Púrpura Trombocitopênica Idiopática , Inativadores do Complemento , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptores de IgG/uso terapêutico , Receptores de Trombopoetina/agonistas , Receptores de Trombopoetina/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Trombopoetina/agonistas , Trombopoetina/uso terapêutico
17.
Eur J Haematol ; 109(3): 205-214, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35502600

RESUMO

OBJECTIVES: The complement component 5 (C5) inhibitor ravulizumab demonstrated non-inferiority to eculizumab following 26 weeks of treatment in complement inhibitor-naïve and complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH; studies 301 and 302, respectively). This study aims to describe the results of both studies from 27 weeks to 2 years. METHODS: Patients (N = 441) continued to receive ravulizumab throughout the extension period. Efficacy endpoints included lactate dehydrogenase (LDH) normalization, transfusion avoidance and fatigue score (FACIT-F). Safety analyses were also performed. RESULTS: From 27 weeks to 2 years, improvements in LDH levels were maintained in both study populations. Transfusion avoidance was maintained in 81.9% (study 301) and 85.6% (study 302) of patients, and FACIT-F scores remained stable. Ravulizumab was well tolerated, and the incidence of adverse events (AEs) were similar between patients of both studies. Incidence of serious AEs deemed related to ravulizumab treatment was low (<3%). CONCLUSIONS: This study reports, to date, the longest period of follow-up in over 400 patients with PNH treated with ravulizumab (662 patient-years). Long-term, ravulizumab demonstrated durable efficacy and was well tolerated, highlighting the importance of C5 inhibitors as the mainstay of PNH treatment.


Assuntos
Hemoglobinúria Paroxística , Anticorpos Monoclonais Humanizados , Complemento C5 , Inativadores do Complemento/efeitos adversos , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemólise , Humanos
18.
J Clin Neuromuscul Dis ; 23(4): 210-218, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35608645

RESUMO

OBJECTIVES: To evaluate the impact of treatment with eculizumab, a terminal complement inhibitor, on academic and employment status in patients with refractory generalized myasthenia gravis (MG). METHODS: Case review of 7 US patients. RESULTS: Six patients were aged ≤65 years; one was a full-time student and the remainder were in employment before MG diagnosis. After diagnosis, all patients gave up work (n = 3) or reduced their study/working hours (n = 4). In the 12 months after eculizumab initiation, patients who had stopped work resumed working in some capacity, whereas those who had changed their work/study hours returned to their original work/study pattern. Patients also experienced a reduction in the number of MG exacerbations, and a clinically significant improvement in MG-Activities of Daily Living scores, and were able to reduce other MG medications. CONCLUSIONS: These results suggest that treatment with eculizumab may help maintain education/employment activity in patients with refractory generalized MG.


Assuntos
Atividades Cotidianas , Miastenia Gravis , Anticorpos Monoclonais Humanizados , Inativadores do Complemento/uso terapêutico , Emprego , Humanos , Miastenia Gravis/tratamento farmacológico
19.
Drugs ; 82(8): 865-887, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35639288

RESUMO

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 immunoglobulins (IVIG) and therapeutic plasma exchange (PLEX) offering rapid treatment response, especially in crises. However, the treatment of MG entails long-term immunosuppression and conventional agents are viable options but take longer to act and have a number of class-specific adverse effects. Advances in immunology, translational medicine and drug development have seen the emergence of several newer biological agents which offer selective, target-specific immunotherapy with fewer side effects and rapid onset of action. Eculizumab is one of the newer agents that belong to the class of complement inhibitors and has been approved for the treatment of refractory general MG. Zilucoplan and ravulizumab are other agents in this group in clinical trials. Neisseria meningitis is a concern with all complement inhibitors, mandating vaccination. Neonatal Fc receptor (FcRn) inhibitors prevent immunoglobulin recycling and cause rapid reduction in antibody levels. Efgartigimod is an FcRn inhibitor recently approved for MG treatment, and rozanolixizumab, nipocalimab and batoclimab are other agents in clinical trial development. Although lacking high quality evidence from randomized clinical trials, clinical experience with the use of anti-CD20 rituximab has led to its use in refractory MG. Among novel targets, interleukin 6 (IL6) inhibitors such as satralizumab are promising and currently undergoing evaluation. Cutting-edge therapies include genetically modifying T cells to recognise chimeric antigen receptors (CAR) and chimeric autoantibody receptors (CAAR). These may offer sustained and long-term remissions, but are still in very early stages of evaluation. Hematopoietic stem cell transplantation (HSCT) allows immune resetting and offers sustained remission, but the induction regimens often involve serious systemic toxicity. While MG treatment is moving beyond conventional agents towards target-specific biologicals, lack of knowledge as to the initiation, maintenance, switching, tapering and long-term safety profile necessitates further research. These concerns and the high financial burden of novel agents may hamper widespread clinical use in the near future.


Assuntos
Miastenia Gravis , Anticorpos Monoclonais/uso terapêutico , Complemento C5 , Inativadores do Complemento/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Recém-Nascido , Miastenia Gravis/tratamento farmacológico , Peptídeos Cíclicos , Rituximab/uso terapêutico
20.
Neurol Sci ; 43(7): 4081-4083, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35364770

RESUMO

Eculizumab, a humanized monoclonal antibody, is a complement inhibitor indicated for refractory generalized myasthenia gravis (MG). However, there are limited data on the safety of eculizumab for MG during coronavirus disease 2019 (COVID-19) infection. We report a case in which eculizumab was continued for MG after contracting COVID-19, followed by a favorable outcome.


Assuntos
COVID-19 , Miastenia Gravis , Anticorpos Monoclonais Humanizados/uso terapêutico , Inativadores do Complemento/uso terapêutico , Humanos , Miastenia Gravis/complicações , Miastenia Gravis/tratamento farmacológico
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