An Open-Label, Single-arm Study to Evaluate the Pharmacokinetics (PK), Pharmacodynamics (PD), Safety, and Efficacy of Gefurulimab in Pediatric Patients (6 to < 18 Years of Age) With Generalized Myasthenia Gravis (gMG) Who Express Acetylcholine Receptor Antibodies (AChR+)

The primary objective of this study is to assess the pharmacokinetics and pharmacodynamics of gefurulimab in pediatric participants with AChR+ gMG for the duration of the study.

Start Date04 Mar 2025

Sponsor / Collaborator

Alexion Pharmaceuticals, Inc.

NCT06208488 / CompletedPhase 1

A Phase 1, Open-label, Randomized, Parallel-group Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, Immunogenicity, and Device Performance of ALXN1720 (Gefurulimab) Administered Subcutaneously Using Prefilled Syringe Versus Autoinjector in Adult Healthy Participants

This study will evaluate the pharmacokinetics (PK), pharmacodynamics (PD), safety, immunogenicity, and device performance of gefurulimab.

Start Date22 Nov 2023

Sponsor / Collaborator

Alexion Pharmaceuticals, Inc.

[+1]

CTR20232711 / Active, not recruitingPhase 3

一项在全身型重症肌无力成人患者中评价ALXN1720的安全性和有效性的III期、随机、双盲、安慰剂对照、平行、多中心研究

[Translation] A Phase III, randomized, double-blind, placebo-controlled, parallel, multicenter study to evaluate the safety and efficacy of ALXN1720 in adult patients with generalized myasthenia gravis

主要目的：根据MG-ADL总评分的变化，评估ALXN1720与安慰剂相比治疗gMG的有效性关键次要目的：根据QMG总评分的变化，评估ALXN1720与安慰剂相比治疗gMG的有效性次要目的：根据QMG总评分的改善水平，评估ALXN1720与安慰剂相比治疗gMG的有效性、根据MG-ADL总评分的改善水平，评估ALXN1720与安慰剂相比治疗gMG的有效性、根据MGC总评分的变化，评估ALXN1720与安慰剂相比治疗gMG的有效性

[Translation]

Primary objective: To evaluate the effectiveness of ALXN1720 compared with placebo in the treatment of gMG based on the change in the MG-ADL total score Key secondary objective: To evaluate the effectiveness of ALXN1720 compared with placebo in the treatment of gMG based on the change in the QMG total score Secondary objectives: To evaluate the effectiveness of ALXN1720 compared with placebo in the treatment of gMG based on the level of improvement in the QMG total score, To evaluate the effectiveness of ALXN1720 compared with placebo in the treatment of gMG based on the level of improvement in the MG-ADL total score, To evaluate the effectiveness of ALXN1720 compared with placebo in the treatment of gMG based on the change in the MGC total score

Start Date18 Oct 2023

Sponsor / Collaborator

AstraZeneca Global R&D (China) Co., Ltd.

100 Clinical Results associated with C5 x albumin

100 Translational Medicine associated with C5 x albumin

0 Patents (Medical) associated with C5 x albumin

Literatures (Medical) associated with C5 x albumin

01 Jan 2024·Molecular Immunology

Characterization of the bispecific VHH antibody gefurulimab (ALXN1720) targeting complement component 5, and designed for low volume subcutaneous administration

Article

Author: Pedersen, Dennis Vestergaard ; Patel, Rekha ; Zhang, Yuchun ; Cone, Josh ; Andersen, Gregers Rom ; Gera, Nimish ; Sheridan, Douglas ; Neill, Alyssa ; Jindal, Siddharth ; Millman, Ellen E ; Carlin, Dan ; Tamburini, Paul ; Chandler, Julian ; Puffer, Bridget ; Yuan, Chao-Xing

The bispecific antibody gefurulimab (also known as ALXN1720) was developed to provide patients with a subcutaneous treatment option for chronic disorders involving activation of the terminal complement pathway. Gefurulimab blocks the enzymatic cleavage of complement component 5 (C5) into the biologically active C5a and C5b fragments, which triggers activation of the terminal complement cascade. Heavy-chain variable region antigen-binding fragment (VHH) antibodies targeting C5 and human serum albumin (HSA) were isolated from llama immune-based libraries and humanized. Gefurulimab comprises an N-terminal albumin-binding VHH connected to a C-terminal C5-binding VHH via a flexible linker. The purified bispecific VHH antibody has the expected exact size by mass spectrometry and can be formulated at greater than 100 mg/mL. Gefurulimab binds tightly to human C5 and HSA with dissociation rate constants at pH 7.4 of 54 pM and 0.9 nM, respectively, and cross-reacts with C5 and serum albumin from cynomolgus monkeys. Gefurulimab can associate with C5 and albumin simultaneously, and potently inhibits the terminal complement activity from human serum initiated by any of the three complement pathways in Wieslab assays. Electron microscopy and X-ray crystallography revealed that the isolated C5-binding VHH recognizes the macroglobulin (MG) 4 and MG5 domains of the antigen and thereby is suggested to sterically prevent C5 binding to its activating convertase. Gefurulimab also inhibits complement activity supported by the rare C5 allelic variant featuring an R885H substitution in the MG7 domain. Taken together, these data suggest that gefurulimab may be a promising candidate for the potential treatment of complement-mediated disorders.

23 Jul 2023·Biomedicines

Biomarkers of the Complement System Activation (C3a, C5a, sC5b-9) in Serum of Patients before and after Liver Transplantation.

Article

Author: Hukowska-Szematowicz, Beata ; Rykowski, Paweł ; Zieniewicz, Krzysztof ; Dołęgowska, Barbara ; Pietrzak, Radosław ; Siennicka, Aldona ; Nazarewski, Łukasz ; Cecerska-Heryć, Elżbieta ; Ostrycharz, Ewa ; Budkowska, Marta ; Poręcka, Marta ; Serwin, Natalia Maria

The liver has a huge impact on the functioning of our body and the preservation of homeostasis. It is exposed to many serious diseases, which may lead to the chronic failure of this organ, which is becoming a global health problem today. Currently, the final form of treatment in patients with end-stage (acute and chronic) organ failure is transplantation. The proper function of transplanted organs depends on many cellular processes and immune and individual factors. An enormous role in the process of acceptance or rejection of a transplanted organ is attributed to, among others, the activation of the complement system. The aim of this study was the evaluation of the concentration of selected biomarkers' complement system activation (C3a, C5a, and sC5b-9 (terminal complement complex)) in the serum of patients before and after liver transplantation (24 h, two weeks). The study was conducted on a group of 100 patients undergoing liver transplantation. There were no complications during surgery and no transplant rejection in any of the patients. All patients were discharged home 2-3 weeks after the surgery. The levels of all analyzed components of the complement system were measured using the ELISA method. Additionally, the correlations of the basic laboratory parameters-C-reactive protein (CRP), hemoglobin (Hb), total bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), and albumin-with the parameters of the complement system (C3a, C5a, and sC5b-9) were determined. In our study, changes in the concentrations of all examined complement system components before and after liver transplantation were observed, with the lowest values before liver transplantation and the highest concentration two weeks after. The direct increase in components of the complement system (C3a, C5a, and sC5b-9) 24 h after transplantation likely affects liver damage after ischemia-reperfusion injury (IRI), while their increase two weeks after transplantation may contribute to transplant tolerance. Increasingly, attention is being paid to the role of C3a and CRP as biomarkers of damage and failure of various organs. From the point of view of liver transplantation, the most interesting correlation in our own research was found exactly between CRP and C3a, 24 h after the transplantation. This study shows that changes in complement activation biomarkers and the correlation with CRP in blood could be a prognostic signature of liver allograft survival or rejection.

01 Jan 2023·Journal of the Neurological Sciences

Serum C3 complement levels predict prognosis and monitor disease activity in Guillain-Barré syndrome

Review

Author: Kim, Sang-Jeong ; Jeong, Han-Yeong ; Ban, Jae-Jun ; Kim, Sung-Min ; Shin, Je-Young ; Hong, Yoon-Ho ; Kwon, Young Nam ; Sung, Jung-Joon ; Seo, Jae-Woo ; Ha, Ye-Eun ; Ju, Woohee ; Min, Young Gi

OBJECTIVEBiomarkers are needed to predict prognosis and disease activity in patients with Guillain-Barré syndrome (GBS). The complement system is a key player in the pathogenesis of GBS. This study aimed to assess the potential utility of serum complement proteins as novel biomarkers in GBS.METHODSWe reviewed the medical records of 76 GBS patients with C3 and C4 measurements during hospitalization between 2010 and 2021. Clinical outcomes were correlated with baseline serum C3, C4, and seven additional predictors: four existing biomarkers (GM1, albumin, immunoglobulin G, neutrophil-lymphocyte ratio) and three clinical factors from the modified Erasmus GBS outcome score model. Five complement activation products (C3a, C4a, C5a, soluble C5b-9, factor Bb) were measured in 35 patients and were compared with C3 and C4 levels. Longitudinal changes in C3 and C4 levels were compared with the disease course in 12 patients.RESULTSHigher C3, but not C4, was associated with poorer outcomes: lower Medical Research Council sum scores (MRCSS), higher GBS disability score (GBSDS), longer hospitalization, and more frequent treatment-related fluctuations. Age, MRCSS at admission, and baseline serum C3 were significant independent indicators of 1- and 3-month GBSDS. We found that C3 was positively correlated with C3a (r = 0.32) and C5a (r = 0.37), which indicates an activated complement cascade with high C3. Longitudinal change of C3 coincided with clinical severity of the disease course.INTERPRETATIONThis study highlights the use of serum C3 as a novel mechanistic biomarker in GBS. Larger prospective studies are needed to validate our findings.

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