Delving into the Latest Updates on E WE thrombin(Aronora, Inc.) with Synapse

Overview

Basic Info

Drug Type

Enzyme

Synonyms

E WE thrombin, EWE-thrombin, ProCase

+ [4]

Target

protein C

Action

stimulants

Mechanism

protein C stimulants(Vitamin K-dependent protein C stimulants)

Therapeutic Areas

Cardiovascular DiseasesUrogenital Diseases

Active Indication-

Inactive Indication

Kidney Failure, ChronicThrombosis

Originator Organization

Aronora, Inc.

Active Organization-

Inactive Organization

Aronora, Inc.

License Organization-

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Sequence Code 1117836273

This study evaluates the safety and efficacy of AB002 (E-WE thrombin) in patients with end stage renal disease on chronic hemodialysis. Two dose levels will be evaluated in two cohorts. Within each cohort the patients will be randomized to receive either AB002 (E-WE thrombin) or placebo (at a ratio of 2:1 active: placebo).

Start Date03 Jul 2019

Sponsor / Collaborator

Aronora, Inc.

[+1]

NCT03453060

/ CompletedPhase 1

A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of E-WE Thrombin as an Intravenous Bolus in Healthy Adult Subjects

The purpose of this study is to assess the safety, tolerability and pharmacodynamics of a single iv dose of E-WE Thrombin in healthy adult subjects.

Start Date30 May 2018

Sponsor / Collaborator

Aronora, Inc.

100 Clinical Results associated with E WE thrombin(Aronora, Inc.)

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100 Translational Medicine associated with E WE thrombin(Aronora, Inc.)

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100 Patents (Medical) associated with E WE thrombin(Aronora, Inc.)

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4

Literatures (Medical) associated with E WE thrombin(Aronora, Inc.)

17 Apr 2023·Research square

E-WE thrombin, a protein C activator, reduces disease severity and spinal cord inflammation in relapsing-remitting murine experimental autoimmune encephalomyelitis.

Author: Sherman, Larry S ; Verbout, Norah G ; Su, Weiping ; Tucker, Erik I ; Jordan, Kelley ; McCarty, Owen Jt ; Pham, Peter ; Kohs, Tia Cl

ObjectiveRelapses in patients with relapsing-remitting multiple sclerosis (RRMS) are typically treated with high-dose corticosteroids including methylprednisolone. However, high-dose corticosteroids are associated with significant adverse effects, can increase the risk for other morbidities, and often do not impact disease course. Multiple mechanisms are proposed to contribute to acute relapses in RRMS patients, including neuroinflammation, fibrin formation and compromised blood vessel barrier function. The protein C activator, E-WE thrombin is a recombinant therapeutic in clinical development for its antithrombotic and cytoprotective properties, including protection of endothelial cell barrier function. In mice, treatment with E-WE thrombin reduced neuroinflammation and extracellular fibrin formation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We therefore tested the hypothesis that E-WE thrombin could reduce disease severity in a relapsing-remitting model of EAE.MethodsFemale SJL mice were inoculated with proteolipid protein (PLP) peptide and treated with E-WE thrombin (25 μg/kg; iv) or vehicle at onset of detectable disease. In other experiments, E-WE thrombin was compared to methylprednisolone (100 mg/kg; iv) or the combination of both.ResultsCompared to vehicle, administration of E-WE thrombin significantly improved disease severity of the initial attack and relapse and delayed onset of relapse as effectively as methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment, and the combination of both treatments had an additive effect.ConclusionThe data presented herein demonstrate that E-WE thrombin is protective in mice with relapsing-remitting EAE, a widely used model of MS. Our data indicate that E-WE thrombin is as effective as high-dose methylprednisolone in improving disease score and may exert additional benefit when administered in combination. Taken together, these data suggest that E-WE thrombin may be an effective alternative to high-dose methylprednisolone for managing acute MS attacks.

01 Nov 2020·Molecular Cancer TherapeuticsQ2 · MEDICINE

Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody–Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function

Q2 · MEDICINE

Article

Author: Wang, Xin ; Yu, Ker ; Jin, Rui ; Ren, Zhiqiang ; Ma, Lanping ; Liu, Liang ; Shen, Jingkang ; Xing, Yun ; Cong, Ying ; Zhang, Xuesai ; Meng, Tao ; Pei, Jinpeng

AbstractAlthough tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50<0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors, including the RAS-mutant models [minimum effective dose <1 mg/kg]. Treatment with CD73–ADC triggered a robust intratumoral accumulation of proinflammatory macrophages and activated dendritic cells (DC), which were not observed with naked CD73 antibody or standard chemotherapy. Studies with human PBMC-derived systems confirmed CD73-ADC as fully functional in protecting effector T cells and stimulating DCs thus providing dual benefits in killing CD73-high tumors and improving cancer immunity response. These results warrant clinical investigation of CD73-targeted antibody and ADC for treating advanced lung cancer.

27 Feb 2020·BloodQ1 · MEDICINE

The protein C activator AB002 rapidly interrupts thrombus development in baboons

Q1 · MEDICINE

Article

Author: Hinds, Monica T. ; Verbout, Norah G. ; Markway, Brandon D. ; Lorentz, Christina U. ; McCarty, Owen J. T. ; Wood, David C. ; Shatzel, Joseph J. ; Pelc, Leslie A. ; Gruber, András ; Tucker, Erik I. ; Wallisch, Michael ; Di Cera, Enrico

AbstractAlthough thrombin is a key enzyme in the coagulation cascade and is required for both normal hemostasis and pathologic thrombogenesis, it also participates in its own negative feedback via activation of protein C, which downregulates thrombin generation by enzymatically inactivating factors Va and VIIIa. Our group and others have previously shown that thrombin’s procoagulant and anticoagulant activities can be effectively disassociated to varying extents through site-directed mutagenesis. The thrombin mutant W215A/E217A (WE thrombin) has been one of the best characterized constructs with selective activity toward protein C. Although animal studies have demonstrated that WE thrombin acts as an anticoagulant through activated protein C (APC) generation, the observed limited systemic anticoagulation does not fully explain the antithrombotic potency of this or other thrombin mutants. AB002 (E-WE thrombin) is an investigational protein C activator thrombin analog in phase 2 clinical development (clinicaltrials.gov NCT03963895). Here, we demonstrate that this molecule is a potent enzyme that is able to rapidly interrupt arterial-type thrombus propagation at exceedingly low doses (<2 µg/kg, IV), yet without substantial systemic anticoagulation in baboons. We demonstrate that AB002 produces APC on platelet aggregates and competitively inhibits thrombin-activatable fibrinolysis inhibitor (carboxypeptidase B2) activation in vitro, which may contribute to the observed in vivo efficacy. We also describe its safety and activity in a phase 1 first-in-human clinical trial. Together, these results support further clinical evaluation of AB002 as a potentially safe and effective new approach for treating or preventing acute thrombotic and thromboembolic conditions. This trial was registered at www.clinicaltrials.gov as #NCT03453060.

100 Deals associated with E WE thrombin(Aronora, Inc.)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Kidney Failure, Chronic	Phase 2	United States	Aronora, Inc.	03 Jul 2019
Thrombosis	Phase 2	United States	Aronora, Inc.	03 Jul 2019

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03963895 (ASH2023)	Phase 2	Acute Ischemic Stroke	40	AB002 (E-WE thrombin)	ohyjtuacgi(cvefscbrtl) = ryixqnfzjc ulkbeggamp (vvzbxfwbmw ) View more	-	11 Dec 2023
				Saline placebo	ohyjtuacgi(cvefscbrtl) = lcqxqchjoz ulkbeggamp (vvzbxfwbmw ) View more
NCT03963895 (3949, CTgov)	Phase 2	Thrombosis \| Kidney Failure, Chronic	40	AB002 Dose 1 (AB002 (E-WE-thrombin) Dose 1)	noultksigc(ortartuyqz) = dwvglsgakp ibdisxapwf (migcjzujkn, ofhtyhymnh - leggfslpms) View more	-	15 Mar 2022
				AB002 Dose 2 (AB002 (E-WE-thrombin) Dose 2)	noultksigc(ortartuyqz) = ojeyfkobfp ibdisxapwf (migcjzujkn, nmcfwaqrkz - vjyfoljsyb) View more
NCT03453060 (CTgov)	Phase 1	Thrombosis	21	E-WE Thrombin- Dose 1 (E-WE Thrombin Dose 1)	vhqzoeoebf(ifvyobtsef) = dtpsnwppwt aejvzyletj (gbpzgmhbkg, dypitoloyn - tyhtzaywvj) View more	-	29 Oct 2019
				E-WE Thrombin- Dose 2 (E-WE Thrombin Dose 2)	vhqzoeoebf(ifvyobtsef) = prepygfsog aejvzyletj (gbpzgmhbkg, xvrgjikioz - chijjifcjv) View more

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