Hepatocyte Growth Factor Mimetic ANG-3777 for Cardiac Surgery–Associated Acute Kidney Injury

Abstract

Introduction: Nearly one-third of patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) experience cardiac surgery-associated (CSA) acute kidney injury (AKI); 5% require renal replacement therapy. ANG-3777 is a hepatocyte growth factor mimetic. In vitro, ANG-3777 reduces apoptosis and increases cell proliferation, migration, morphogenesis, and angiogenesis in injured kidneys. In animal models, ANG-3777 mitigates the effects of renal damage secondary to ischemia reperfusion injury and nephrotoxic chemicals. Phase 2 data in AKI of renal transplantation have shown improved renal function and comparable safety relative to placebo. The Guard Against Renal Damage (GUARD) study is a phase 2 proof of concept trial of ANG-3777 in CSA-AKI. Methods: GUARD is a 240-patient, multicenter, double-blind, randomized placebo-controlled trial to assess the efficacy and safety of ANG-3777 in patients at elevated pre-surgery risk for AKI undergoing coronary artery bypass graft (CABG) or heart valve repair/replacement requiring CPB. Subjects are randomized 1:1 to receive ANG-3777 (2 mg/kg) or placebo. Study drug is dosed via 4 daily intravenous 30minute infusions. The first dose is administered less than 4 hours after completing CPB, second at 24 AE 2 hours post-CPB, with two subsequent doses at 24 AE 2 hours after the previous dose. Results: The primary efficacy endpoint is percent change from baseline serum creatinine to mean area under the curve from days 2 through 6. Secondary endpoints include change in estimated glomerular filtration rate from baseline to day 30, the proportion of patients diagnosed with AKI by stage through day 5, and the length of CSA-AKI hospitalization. Safety will include adverse events and laboratory measures. Conclusion: This phase 2 study of ANG-3777 provides data to develop a phase 3 registrational study in this medically complex condition.

cMet agonistic antibody prevents acute kidney injury to chronic kidney disease transition by suppressing Smurf1 and activating Smad7

“…Antifibrotic effects of HGF and cMet have been explored in various in vitro and in vivo models of liver, lung, and kidney Downloaded from http://portlandpress.com/clinsci/article-pdf/doi/10.1042/CS20210013/913136/cs-2021-0013.pdf by guest on 07 June 2021 fibrosis [35][36][37][38][39]. Therefore, HGF has attracted attention as a novel therapeutic modality for kidney diseases [40]. However, its short half-life (< 10 min) has reduced its efficacy as a therapeutic agent in AKI and kidney fibrosis.…”

Correction: Liu et al. Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways. Biomolecules 2023, 13, 1179

“…With this change, two more references were added: [59] and [60] (see [2,3]), and the original [59] and [60] have been modified to [61] and [62].…”

A Process for the Design and Development of Novel Bone Morphogenetic Protein-7 (BMP-7) Mimetics With an Example: THR-184

“…Furthermore, research by this company is assessing whether ANG-3777 can reduce the severity of delayed graft function in recipients of a deceased donor kidney. A phase two study to assess the safety and efficacy of ANG-3777 in patients who develop AKI after cardiac surgery is ongoing (Ayad et al, 2020).…”