Author + information
- Received February 8, 2019
- Revision received February 26, 2019
- Accepted March 9, 2019
- Published online March 15, 2019.
- Daniel P. Judge, MDa,
- Rodney H. Falk, MDb,
- Mathew S. Maurer, MDc,
- Sanjiv J. Shah, MDd,
- Ronald M. Witteles, MDe,
- Martha Grogan, MDf,
- Van N. Selby, MDg,
- Daniel Jacoby, MDh,
- Mazen Hanna, MDi,
- Jose Nativi-Nicolau, MDj,
- Jignesh Patel, MDk,
- Satish Rao, PhDl,
- Uma Sinha, PhDl,
- Cameron W. Turtle, DPhill,
- Jonathan C. Fox, MD, PhDl and
- Stephen B. Heitner, MDm,∗∗ (, )@HeitnerStephen@OHSUCardio
- aDepartment of Medicine, Medical University of South Carolina, Charleston, South Carolina
- bDivision of Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- cColumbia University Irving Medical Center, New York, NY
- dNorthwestern University Feinberg School of Medicine, Chicago, IL
- eStanford University Medical Center, Stanford, CA
- fMayo Clinic, Rochester, MN
- gUniversity of California, San Francisco, San Francisco, CA
- hYale University Medical Center, New Haven, CT
- iDepartment of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH
- jUniversity of Utah Health, Salt Lake City, UT
- kCedars-Sinai Medical Center, Los Angeles, CA
- lEidos Therapeutics, Inc., San Francisco, CA
- mKnight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
- ↵∗Address for correspondence: Stephen B. Heitner, MD Oregon Health and Science University Knight Cardiovascular Institute 3181 SW Sam Jackson Park Rd, UHN62 Portland, Oregon 97239 Telephone: 5034948750 Fax: 5034948550.
Background Transthyretin (TTR) amyloidosis (ATTR) is an under-diagnosed 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 ATTR 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, NYHA Class II-III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400mg, 800mg or placebo bid 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 two established ex vivo assays (Fluorescent Probe Exclusion [FPE] 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 FPE 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 mg 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 planned.
↵∗ Drs. Judge and Heitner contributed equally to this manuscript and are designated co-first authors accordingly.
Tweet: AG10 demonstrates proof-of-concept in ATTR-CM with good tolerability and near-complete stabilization of TTR in Phase 2 study; Phase 3 trial (ATTRibute-CM) now under way.
Funding: This study was supported in full by Eidos Therapeutics, San Francisco, California
Dr Judge reports research funding for clinical studies from Pfizer, Array, and Eidos, and has received consulting fees from Alnylam, GSK, and Pfizer.
Dr. Heitner reports research grants from Pfizer, Eidos, and Ionis and has received consulting fees from Pfizer and Alnylam, Ionis and Eidos.
Dr. Falk TBA
Dr. Maurer reports research grants from the National Institutes of Health (RO1 HL139671, R21 AG058348, K24 AG036778, R01 LM006910, R37 DK046335), Pfizer, Eidos and has received consulting fees from Akcea, Alnylam, GSK, Ionis, Pfizer and Prothena.
Dr. Shah reports 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 reports research grants from Pfizer, Eidos, and Alnylam and has received consulting fees from Pfizer and Alnylam.
Dr Grogan reports esearch funding from Alnylam, Eidos, Pfizer, and Prothena.
Dr Selby reports research funding for clinical studies from Pfizer, Alnylam and Eidos, advisory boards from Alnylam Pharmaceuticals, and consulting honoraria from Akcea Therapeutics.
Dr. Jacoby reports a research grant from Myokardia, advisory boards for Myokardia and Alnylam, consulting fees from Abbott, Deerfield Consultants, and Alnylam, and research support from the Joshua Gibson Memorial Fund.
Dr. Hanna TBA
Dr Nativi-Nicolau reports research funding for clinical studies from Pfizer, Akcea and Eidos. Advisory boards for Alnylam Pharmaceuticals, Akcea Therapeutics, and Pfizer.
Dr Patel reports research grants from Pfizer Alnylam and Alexion, consulting fees from Pfizer and Alnylam and speaker fees from Alnylam and Akcea.
Drs. Fox, Rao, Turtle, and Sinha are employees of Eidos Therapeutics, Inc.
- Received February 8, 2019.
- Revision received February 26, 2019.
- Accepted March 9, 2019.
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