ANGION IS A LATE-STAGE CLINICAL COMPANY DEVELOPING SMALL MOLECULES TARGETING ACUTE ORGAN INJURY AND CHRONIC FIBROSIS
Mechanism of Action
ANG-3777 is potentially a first-in-class hepatocyte growth factor (HGF) mimetic. We engineered ANG-3777 to mimic the biological activity of HGF in activating critical pathways in the body’s natural organ repair process following an acute organ injury.
ANG-3777 is an investigational product and is not approved by any regulatory authority.
Potential Advantages of ANG-3777
Enhances key natural repair pathway — ANG-3777 is an HGF mimetic selectively activating the HGF/c-Met pathway, an early and essential pathway in acute organ injury repair. By initiating the HGF/c-Met cascade, ANG-3777 triggers downstream activation of multiple processes we believe both attenuate further organ injury and promote organ repair.
Expands treatment window — Our studies have shown treatment with ANG-3777 can be successfully administered up to 48 hours after injury, increasing the viable window for intervention and significantly expanding the addressable patient population.
Favorable adverse event profile — In our Phase 2 clinical trial, the overall incidence of adverse events and serious adverse events was similar between the treatment and placebo arms, no serious adverse event was attributed to ANG-3777 by investigators and no patient on treatment withdrew because of a serious adverse event.
Ease of administration — ANG-3777 has demonstrated a half-life of approximately three hours compared to a half-life of less than five minutes for native or recombinant HGF. Due to its longer half-life, ANG-3777 can be administered once daily intravenously (IV).
Reduces pharmacoeconomic burden — Acute organ injury results in substantial costs to the healthcare system. A therapy that effectively attenuates organ injury could significantly reduce this economic burden by decreasing short-term costs, including increased hospital days and re-admissions, as well as long-term costs, including costs associated with outpatient dialysis and other outpatient services.
Phase 2 Clinical Trial in Delayed Graft Function
Our Phase 2 multi-center, randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of ANG-3777 for improving kidney function in patients undergoing transplantation who showed signs of kidney injury and were considered to be at high risk of DGF. Transplant recipients with low or no urine output during any eight consecutive hours over the first 24 hours following transplant were randomized to receive a total of three doses of ANG-3777 once daily for three days (2.0 mg/kg IV infusion) or placebo once daily for three days.
A total of 28 patients (19 in the ANG-3777 treatment arm and 9 in the placebo arm) were enrolled and randomized, which constitutes the intent-to-treat analytic group. Patient baseline characteristics were generally balanced between the ANG-3777 and placebo arms. ANG-3777 demonstrated clinically meaningful improvements as compared to placebo on the primary endpoint as well as a key secondary endpoint, mean serum creatinine.
Phase 2 DGF trial primary endpoint
The pre-specified primary endpoint for the Phase 2 was time to production of 1,200 cc of urine over 24 hours. ANG-3777 demonstrated clinically meaningful improvements as compared to placebo on the primary endpoint as well as a key secondary endpoint, mean serum creatinine. As reflected in the following figure, at Day 28, 83% of patients in the ANG-3777 arm had achieved greater than 1,200cc urine output over 24 hours, versus 50% in the placebo arm, though such results were not statistically significant (p=0.09). In addition, the median number of days to achieve the primary endpoint was five for the ANG-3777 treatment arm and fourteen for the placebo arm. Though urine production was similar between groups on Day 1 after transplantation, ANG-3777 patients showed greater increases in urine production during the subsequent two weeks. Two subjects, one from each arm, were excluded from the pre-specified primary endpoint analysis as they reached greater than 1,200 cc urine output over 24 hours prior to the start of first infusion of study product.
Patients treated with ANG-3777 demonstrated a durable benefit to eGFR at 6- and 12-months post-transplantation, with statistical significance (p=0.039) at the 12-month mark.
For purposes of designing our ongoing Phase 3 study, certain post hoc analyses, like this analysis of eGFR, were conducted. These analyses were done in response to the March 2017 FDA Draft Guidance for Industry on Delayed Graft Function in Kidney Transplantation for the purpose of planning our Phase 3 clinical trial. Based upon these analyses, and subsequent interactions with the FDA, our ongoing Phase 3 Study in DGF employs a primary endpoint of eGFR at 12 months.
Our analyses have shown six and twelve-month eGFR are the best predictors of long-term graft survival in kidney transplantation recipients. In addition, improved eGFR is correlated with significantly increased life expectancies based on the National Kidney Foundation’s predictive CKD staging system.
Transplant-Associated Acute Kidney Injury (Delayed Graft Function): ANG-3777 is currently in a randomized, double-blind placebo-controlled Phase 3 trial for acute kidney injury associated with delayed graft function. Topline data are expected by the second half of 2021.
Acute Kidney Injury Associated with Cardiac Surgery Involving Cardiopulmonary Bypass (CSA-AKI): A randomized, double-blind, placebo-controlled Phase 2 trialexamining the efficacy of ANG-3777 in reducing acute kidney injury in 240 patients after a cardiac procedure is currently enrolling. Topline data are expected by the first quarter of 2021.
Acute Lung Injury Associated with COVID-19 Pneumonia: ANG-3777 is currently conducting, in Brazil, a multicenter, prospective, randomized, double-blind, placebo-controlled Phase 2 proof-of-concept study to assess safety and efficacy of ANG-3777 in patients hospitalized with confirmed COVID-19 pneumonia. Top line data are expected in the second half of 2020.