A Phase IIa Randomized, Double-blind, Parallel Group, Placebo-controlled, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of Multiple Intravenous Injection of SY-005 in Sepsis Subjects

This Phase IIa Randomized, Double-blind, Parallel Group, Placebo-controlled, multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy of Multiple Intravenous Injection of SY-005（recombinant human annexin A5） in Sepsis Subjects. 96 patients will be entered into the study and randomised in a 1:1:1:1 ratio to receive SY-005 2.5mg or SY-005 5mg or SY-005 10mg or placebo.

Start Date02 Jan 2022

Sponsor / Collaborator

Suzhou Yabao Pharmaceutical R&D Co. Ltd.

CTR20211345

/ CompletedPhase 2

一项随机、双盲、平行、安慰剂对照、多中心Ⅱa期研究评价在脓毒症患者中不同剂量下多次静脉注射SY-005注射液的安全性、耐受性以及药代动力学/药效学特征

[Translation] A randomized, double-blind, parallel, placebo-controlled, multicenter Phase IIa study to evaluate the safety, tolerability, and pharmacokinetic/pharmacodynamic characteristics of multiple intravenous injections of SY-005 injection at different doses in patients with sepsis

主要目的：评估在中国脓毒症患者中不同剂量下多次静脉注射SY-005注射液的安全性和耐受性。次要目的：评估在中国脓毒症患者中不同剂量下多次静脉注射SY-005注射液的药代动力学（PK）/药效学（PD）特征和免疫原性，并初步探索其有效性。

[Translation]

Primary objective: To evaluate the safety and tolerability of multiple intravenous injections of SY-005 injection at different doses in Chinese patients with sepsis. Secondary objective: To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics and immunogenicity of multiple intravenous injections of SY-005 injection at different doses in Chinese patients with sepsis, and to preliminarily explore its effectiveness.

Start Date02 Jan 2022

Sponsor / Collaborator

Suzhou Yabao Pharmaceutical R&D Co. Ltd.

NCT04748757

/ CompletedPhase 2IIT

Annexin A5 in Patients With Severe COVID-19 Disease: A Single Centre, Randomized, Double-blind, Placebo-controlled Pilot Trial

Randomized, double-blind, placebo-controlled trial comparing 2 doses of SY-005 (recombinant human Annexin A5) to placebo in patients with severe coronavirus 2019 disease in a single hospital centre with 2 intensive care units

Start Date20 Apr 2021

Sponsor / Collaborator

Lawson Health Research Institute

[+2]

100 Clinical Results associated with Recombinant human annexin 5 protein(Yabao Pharmaceutical Group Co., Ltd.)

100 Translational Medicine associated with Recombinant human annexin 5 protein(Yabao Pharmaceutical Group Co., Ltd.)

100 Patents (Medical) associated with Recombinant human annexin 5 protein(Yabao Pharmaceutical Group Co., Ltd.)

Literatures (Medical) associated with Recombinant human annexin 5 protein(Yabao Pharmaceutical Group Co., Ltd.)

01 Dec 2024·Regenerative Therapy

Recombinant human annexin A5 accelerates diabetic wounds healing by regulating skin inflammation

Article

Author: Li, Wei ; Dong, Yushan ; Zhang, Wenjie ; Jia, Zhuoxuan ; Kang, Bijun

BackgroundOne of the key obstacles to the healing of diabetic wound is the persistence of active inflammation. We previously demonstrated the potential of cell-free fat extract (CEFFE) to promote the healing of diabetic wounds, and annexin A5 (A5) is a crucial anti-inflammatory protein within CEFFE. This study aimed to evaluate the therapeutic potential of A5 in diabetic wounds.MethodsA5 was loaded into GelMA hydrogels and applied to skin wounds of diabetic mice in vivo. The diabetic wounds with the treatment of GelMA-A5 were observed for 14 days and evaluated by histological analysis. Accessment of inflammation regulation were conducted through anti-CD68 staining, anti-CD86 and anti-CD206 staining, and qRT-PCR of wound tissue. In presence of A5, macrophages stimulated by lipopolysaccharide (LPS) in vitro, and detected through qRT-PCR, flow cytometry, and immunocytofluorescence staining. Besides, epithelial cells were co-cultured with A5 for epithelialization regulation by CCK-8 assay and cell migration assay.ResultsA5 could promote diabetic wound healing and regulate inflammations by promoting the transition of macrophages from M1 to M2 phenotype. In vitro experiments demonstrated that A5 exerted a significant effect on reducing pro-inflammatory factors and inhibiting the polarization of macrophages from M0 toward M1 phenotype. A5 significantly promoted the migration of epithelial cells.ConclusionAnnexin A5 has a significant impact on the regulation of macrophage inflammation and promotion of epithelialization.

01 Jul 2015·ShockQ2 · MEDICINE

Recombinant Human Annexin A5 Can Repair the Disrupted Cardiomyocyte Adherens Junctions in Endotoxemia

Q2 · MEDICINE

Article

Author: Gu, Changping ; Liu, Mengjie ; Zhao, Tao ; Wang, Yuelan ; Zhai, Lijie

Recombinant human annexin A5 (Anx5) is known to protect cardiac function during endotoxemia, although the underlying mechanisms have yet to be elucidated. In this study, we demonstrated that Anx5 could repair the disrupted cardiomyocyte adherens junctions and improve the myocardial contractile function in lipopolysaccharide (LPS)-induced endotoxemia. Mechanistic studies revealed that Anx5 could antagonize the disassociation between p120-catenin (p120) and N-cadherin as well as the dephosphorylation of p120 in LPS-treated cardiomyocytes. Small interference RNA and specific inhibitors experiment demonstrated that Anx5 regulated p120 functions by inhibition of p21-activated kinase 5 in a protein kinase Cα-dependent way. Moreover, Anx5 could inhibit nuclear factor κB activation and downregulate the level of inflammatory cytokines, such as tumor necrosis factor α and interleukin 1β, which contributed to improving tissue pathological damage in LPS-induced mouse endotoxemia model. Taken together, Anx5 could protect cardiomyocytes adherens junctions and improve myocardial contractile function via regulation of p120 and anti-inflammation in LPS-induced endotoxemia. This study provided novel insights in the prevention and treatment of septic shock.

01 Jan 2014·Critical Care Medicine

Recombinant Human Annexin A5

Communications

Author: Hu, Guochang

Sepsis is characterized by activation of the innate immune response with production of massive inflammatory cytokines, which contributes to multiple organ failure and death. Pattern recognition receptors (PRRs) sense pathogen-associated molecular patterns and endogenous stress signals termed danger-associated molecular patterns to initiate a signaling cascade leading to immune responses. Toll-like receptors (TLRs) are the best characterized PRRs and importantly contribute to the innate immune response to bacterial and viral infections. Bacterial lipopolysaccharide (LPS), the major structural component of the outer wall of all Gram-negative bacteria, is recognized by TLR4/myeloid differentiation factor 2 (MD-2)/CD14 complex to initiate myeloid differentiation factor (MyD88)-dependent and MyD88-independent signaling pathways to activate inflammatory gene expression (1, 2). Recruitment of the adaptor protein MyD88 initiates the early activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) which in turn induce release of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6. In parallel, the MyD88-independent pathway leads to delayed NF-κB activation but rapid activation of interferon regulatory factor 3. MyD88 promotes association with IL-1 receptor-associated kinase (IRAK)-4 and IRAK-1. TNF-associated factor (TRAF)-6 is recruited to IRAK-1. The complex IRAK-4/IRAK-1/TRAF-6 dissociates from the receptor and then interacts with transforming growth factor-β-activated kinase (TAK1) complex. TAK1 activates IκB kinase, leading to phosphorylation and degradation of IκB, and consequent release of NF-κB (2, 3). Once translocated into the nucleus, NF-κB induces the expression of inflammatory chemokines and cytokines. MAPK-mediated activation of transcription factors activator protein-1 and cAMP response element-binding protein also coordinates the induction of many genes encoding adhesion molecules and inflammatory mediators (1–3). Management of severe sepsis and septic shock includes source control, early antimicrobial therapy, supportive, and adjunctive therapies as there is no specific treatment strategy for the inflammation of sepsis (4). The pathophysiology of sepsis entails a complex host immune response to infection, involving initial cytokine-mediated hyperinflammation followed by immunosuppression (5). Activation of TLR4 signaling not only induces inflammatory cytokine production which plays a pathogenic role in the early stage of sepsis but also is required to combat bacterial and viral infection. Consequently, appropriate modulation of excessive inflammatory response through inhibition of TLR4 signaling pathways may have considerable potential as therapeutics for inflammatory disorders (6). In the past two decades, independent efforts have been made to improve the outcome of patients with sepsis by means of blocking inflammation and immune activation. Unfortunately, all clinical trials of agents that are designed to interfere with proinflammatory mediators conducted to date have failed to show efficacy (7). It is worthy of note that among all anti-inflammatory agents, MD-2/TLR4 inhibitor Eritoran recently also failed to show reduced mortality in patients with severe sepsis and septic shock in the ACCESS trial (phase III) (8). However, a more recent study provided compelling evidence that Eritoran improved influenza-induced lethality, lung injury, clinical symptoms, and cytokine levels in mice (9). Annexins A5 (or annexin V) is a member of a highly conserved and ubiquitous phospholipid-binding protein superfamily, the annexins. It binds reversibly to phosphatidylserine-expressing membranes with high affinity in the presence of Ca2+. Annexin A5 has been widely accepted as an early marker of apoptosis because it recognizes phosphatidylserine exposed on the apoptotic cell surface resulting from loss of membrane asymmetry. Although annexin A5-deficient mice are viable and reveal no significant alterations in the biochemical variables characteristic for metabolic or functional defects (10), evidence has accumulated that annexin A5 acts as a critical regulator of antithrombotic function, Ca2+ homeostasis, endocytosis, and phagocytosis (11, 12). Annexin A5 has recently been shown to prevent wound expansion and promoted membrane resealing via its binding to torn membrane edges (12). Furthermore, annexin A5 was able to bind to bacteria and LPS and attenuated LPS-induced TNF-α production (13). These findings suggest that annexin A5 may play an important role in the pathogenesis and progression of sepsis. In this issue of Critical Care Medicine, Arnold et al (14) investigated the potential therapeutic effect of recombinant human annexin A5 on sepsis in a murine endotoxin model. Their results showed that recombinant human annexin A5 significantly attenuated myocardial inflammation and improved cardiac function and animal survival via its suppression of TLR4 signaling. Annexin A5 precludes the engagement of LPS with the TLR4/MD-2 receptor complex in myocardial cells, leading to inhibition of both MAPK and PI3K/Akt signaling pathways, which finally block NF-κB activation and subsequent release of proinflammatory cytokines TNF-α and IL-1β. Therefore, it is likely that recombinant human annexin A5 may offer potential life-saving treatment for sepsis. Several interesting and important questions remain unanswered. In this study, Arnold et al (14) used a mouse model of LPS-induced endotoxemia to address the effects of recombinant human annexin A5 on Gram-negative sepsis. It is unclear whether recombinant human annexin A5 also has therapeutic effects on cardiac function and animal survival in a clinically relevant model of cecal ligation and puncture–induced polymicrobial sepsis (15). Furthermore, endotoxemia caused by LPS can induce multiple organ injury and dysfunction, which relates closely to animal death. It will be important to determine the potential protective effects of recombinant human annexin A5 on other vital organs (lung, liver, and kidney) during sepsis. In addition, the molecular mechanisms by which annexin A5 regulates TLR4 signaling pathway remain further investigation. Although the current finding indicates the association between annexin A5 and TLR4, it is not known how this association blocks TLR4 signaling. Whether annexin A5 directly regulates downstream signaling molecules is not clear. Despite these limitations, Arnold et al (14) have taken an important step in bringing an exciting arena of investigation to the treatment of patients with sepsis. This work and further investigation sure to follow will undoubtedly help us gain new insights into the role and mechanism of recombinant human A5 in the treatment of sepsis and the potential for a novel therapeutic drug. Systematical and delicate animal experiments will be required to define whether these promising observations can be translated into human trials.

100 Deals associated with Recombinant human annexin 5 protein(Yabao Pharmaceutical Group Co., Ltd.)

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Indication	Highest Phase	Country/Location	Organization	Date
Sepsis	Phase 2	China	Suzhou Yabao Pharmaceutical R&D Co. Ltd.	02 Jan 2022

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