Title

Evaluation of AG10 as a Potential Therapy for Transthyretin Cardiac Amyloidosis

Poster Number

20

Lead Author Affiliation

Pharmaceutics and Medicinal Chemistry

Introduction

Cardiac amyloidoses, which are most commonly caused by aggregation of immunoglobulin light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. As no FDA-approved drugs are currently available for treatment of these diseases, the development of therapeutics that prevents TTR-mediated cardiotoxicity are highly desired. Recently we reported the discovery of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents the dissociation of TTR in serum samples obtained from patients with amyloid cardiomyopathy and inhibits the toxicity of TTR aggregates towards human cardiomyocytes.

Purpose

The efficacy of AG10 towards TTR stabilization in whole serum exceeded those for other TTR stabilizers currently in clinical trials. However, to be potential drug candidate it would be desirable to evaluate preliminary pre-clinical toxicity and pharmacokinetics (PK) of AG10 in rats.

Method

Single intravenous (IV) and per oral (PO) doses of AG10 (administered as a sodium salt in water) at 3mg/kg and 30mg/kg, respectively, was explored in CD rats (n=3). In addition, an IV dose escalation study ranging from 5mg/kg to 50mg/kg was also studied in CD rats (n=3). Analysis of plasma samples was performed using validated high performance liquid chromatography method and the PK parameters were estimated using Winnonlin. We also performed a sub-acute toxicity study to assess effects of a daily PO administration of 50 mg/kg AG10 in CD rats over a period of 28 days. End points included clinical observations, body weight changes, hematology and histopathology.

Results

Our data indicates that AG10 is orally bioavailable in rats. The peak AG10 plasma concentrations were generally observed between 0.5 and 2hrs hours post PO dose; the concentrations remained measurable for 48 hours post dose. The pharmacokinetic profiles appeared biphasic. Plasma AG10 exposure increases were approximately dose proportional for the 5 to 50 mg/kg IV dose range The 28 day sub-acute toxicity study revealed that AG10 was well tolerated in rats as demonstrated by both clinical and tissue examinations. There appears to be no significant differences in body weight changes, hematology and histopathology between the treatment and control groups.

Significance

AG10 pharmacokinetic parameters were determined upon single IV and PO dose in CD rats. AG10 exposure in rats was dose-proportional with a long t1/2. In summary, the oral bioavailability, lack of toxicity, and additional favorable pharmacokinetic properties in rats make AG10 a very promising candidate for treatment of TTR cardiac amyloidosis.

Location

DeRosa University Center, Stockton campus, University of the Pacific

Format

Poster Presentation

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Apr 25th, 10:00 AM Apr 25th, 12:00 PM

Evaluation of AG10 as a Potential Therapy for Transthyretin Cardiac Amyloidosis

DeRosa University Center, Stockton campus, University of the Pacific

Cardiac amyloidoses, which are most commonly caused by aggregation of immunoglobulin light chains or transthyretin (TTR) in the cardiac interstitium and conducting system, represent an important and often underdiagnosed cause of heart failure. As no FDA-approved drugs are currently available for treatment of these diseases, the development of therapeutics that prevents TTR-mediated cardiotoxicity are highly desired. Recently we reported the discovery of AG10, a potent and selective kinetic stabilizer of TTR. AG10 prevents the dissociation of TTR in serum samples obtained from patients with amyloid cardiomyopathy and inhibits the toxicity of TTR aggregates towards human cardiomyocytes.