Author + information
- Received February 8, 2019
- Revision received February 26, 2019
- Accepted March 9, 2019
- Published online July 15, 2019.
- Daniel P. Judge, MDa,∗,
- Stephen B. Heitner, MDb,∗∗ (, )@HeitnerStephen,
- Rodney H. Falk, MDc,
- Mathew S. Maurer, MDd,
- Sanjiv J. Shah, MDe,
- Ronald M. Witteles, MDf,
- Martha Grogan, MDg,
- Van N. Selby, MDh,
- Daniel Jacoby, MDi,
- Mazen Hanna, MDj,
- Jose Nativi-Nicolau, MDk,
- Jignesh Patel, MDl,
- Satish Rao, PhDm,
- Uma Sinha, PhDm,
- Cameron W. Turtle, DPhilm and
- Jonathan C. Fox, MD, PhDm
- aDepartment of Medicine, Medical University of South Carolina, Charleston, South Carolina
- bKnight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
- cDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- dColumbia University Irving Medical Center, New York, New York
- eNorthwestern University Feinberg School of Medicine, Chicago, Illinois
- fStanford University Medical Center, Stanford, California
- gMayo Clinic, Rochester, Minnesota
- hUniversity of California, San Francisco, San Francisco, California
- iYale University Medical Center, New Haven, Connecticut
- jDepartment of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
- kUniversity of Utah Health, Salt Lake City, Utah
- lCedars-Sinai Medical Center, Los Angeles, California
- mEidos Therapeutics, Inc., San Francisco, California
- ↵∗Address for correspondence:
Dr. Stephen B. Heitner, Oregon Health and Science University, Knight Cardiovascular Institute, 3181 SW Sam Jackson Park Road, UHN62, Portland, Oregon 97239.
Background 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.
Objectives This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure.
Methods 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).
Results 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.
Conclusions 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)
↵∗ Drs. Judge and Heitner contributed equally to this paper as co-first authors.
This study was supported in full by Eidos Therapeutics, Inc. Dr Judge has received research funding for clinical studies from Pfizer, Array, and Eidos; and has received consulting fees from Alnylam, Blade Therapeutics, GlaxoSmithKline, and Pfizer. Dr. Heitner has received research grants from Pfizer, Eidos, and Ionis; has received consulting fees from Pfizer, Alnylam, Ionis, and Eidos; and his spouse is employed by Amgen. Dr. Maurer has received research grants from the National Institutes of Health (RO1 HL139671, R21 AG058348, K24 AG036778, R01 LM006910, R37 DK046335), Pfizer, and Eidos; and has received consulting fees from Akcea, Alnylam, GlaxoSmithKline, Ionis, Pfizer, and Prothena. Dr. Shah has received research grants from the National Institutes of Health (R01 HL107577, R01 HL127028, R01 HL140731), American Heart Association (#16SFRN28780016, #15CVGPSD27260148), Actelion, AstraZeneca, Corvia, and Novartis; and has received consulting fees from Actelion, AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Cardiora, Coridea, CVRx, Eisai, Ionis, Ironwood, Merck, Novartis, Pfizer, Sanofi, Tenax, and United Therapeutics. Dr. Witteles has received research grants from Pfizer, Eidos, and Alnylam; and has received consulting fees from Pfizer and Alnylam. Dr. Grogan has received research funding from Alnylam, Eidos, Pfizer, and Prothena. Dr. Selby has received research funding for clinical studies from Pfizer, Alnylam, and Eidos; has served on Advisory Boards for Alnylam Pharmaceuticals; and has received consulting honoraria from Akcea Therapeutics and Alnylam Pharmaceuticals. Dr. Jacoby has received a research grant from Myokardia; has served on Advisory Boards for Myokardia and Alnylam; has received consulting fees from Abbott, Deerfield Consultants, and Alnylam; and has received research support from the Joshua Gibson Memorial Fund. Dr. Hanna has served on the Advisory Boards of Pfizer, Eidos, Alnylam, and Akcea; and has served as a Speaker for Alnylam. Dr Nativi-Nicolau has received research funding for clinical studies from Pfizer, Akcea, and Eidos; and has served on Advisory Boards for Alnylam Pharmaceuticals, Akcea Therapeutics, and Pfizer. Dr. Patel has received research grants from Pfizer Alnylam and Alexion; has received consulting fees from Pfizer and Alnylam; and has received speaker fees from Alnylam and Akcea. Drs. Rao, Sinha, Turtle, and Fox are employees of and own equity in Eidos Therapeutics.
Listen to this manuscript's audio summary by Editor-in-Chief Dr. Valentin Fuster on JACC.org.
- Received February 8, 2019.
- Revision received February 26, 2019.
- Accepted March 9, 2019.
- 2019 The Authors