Language:

Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy

Journal of the American College of Cardiology, 2019-07, Vol.74 (3), p.285-295 [Peer Reviewed Journal]

2019 The Authors ;Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. ;2019. The Authors ;ISSN: 0735-1097 ;EISSN: 1558-3597 ;DOI: 10.1016/j.jacc.2019.03.012 ;PMID: 30885685

Full text available

Citations Cited by

Actions
1. Add to My Research
2. Remove from My Research
3. E-mail
4. Print
5. Permalink
6. Citation
7. EasyBib
8. EndNote
9. RefWorks
10. Delicious
11. Export RIS
12. Export BibTeX

Title:
Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy
Author: Judge, Daniel P. ; Heitner, Stephen B. ; Falk, Rodney H. ; Maurer, Mathew S. ; Shah, Sanjiv J. ; Witteles, Ronald M. ; Grogan, Martha ; Selby, Van N. ; Jacoby, Daniel ; Hanna, Mazen ; Nativi-Nicolau, Jose ; Patel, Jignesh ; Rao, Satish ; Sinha, Uma ; Turtle, Cameron W. ; Fox, Jonathan C.
Subjects: AG10 ; Aged ; Aged, 80 and over ; Aging ; Amyloid Neuropathies, Familial - diagnosis ; Amyloid Neuropathies, Familial - drug therapy ; Amyloidosis ; ATTR-CM ; Benzoates - pharmacology ; Benzoates - therapeutic use ; Binding sites ; Cardiology ; Cardiomyopathy ; Chronic illnesses ; Clinical trials ; Destabilization ; Double-Blind Method ; Female ; Fluorescent indicators ; Heart ; Heart diseases ; Heart failure ; Heart Failure - diagnosis ; Heart Failure - drug therapy ; Humans ; Hydrogen bonds ; Male ; Middle Aged ; Mortality ; Mutation ; Patients ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Plasma levels ; Pyrazoles - pharmacology ; Pyrazoles - therapeutic use ; Randomization ; Safety ; Stability analysis ; Transthyretin
Is Part Of: Journal of the American College of Cardiology, 2019-07, Vol.74 (3), p.285-295
Description: Transthyretin (TTR) amyloidosis is an underdiagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation. This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure. ATTR-CM, New York Heart Association functional class II to III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400 mg, AG10 800 mg, or placebo twice daily for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR, and 2 established ex vivo assays (fluorescent probe exclusion and Western blot). AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by fluorescent probe exclusion of 92 ± 10% (mean ± SD) at trough and 96 ± 9% at peak (both p < 10−12 vs. placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 and 800 mg, respectively (both p < 0.0001 vs. placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects. AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A phase 3 trial is ongoing. (Study of AG10 in Amyloid Cardiomyopathy; NCT03458130) [Display omitted]
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0735-1097
EISSN: 1558-3597
DOI: 10.1016/j.jacc.2019.03.012
PMID: 30885685
Source: GFMER Free Medical Journals
MEDLINE
Alma/SFX Local Collection

Back to results list


INSPIRE LIBRARY - TON DUC THANG UNIVERSITY	(84-028) 37 755 057	Feedback
19 Nguyen Huu Tho St. Dist.7, HCM	thuvien@tdtu.edu.vn	Feedback

Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy

2019 The Authors ;Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved. ;2019. The Authors ;ISSN: 0735-1097 ;EISSN: 1558-3597 ;DOI: 10.1016/j.jacc.2019.03.012 ;PMID: 30885685

Searching Remote Databases, Please Wait