Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy

Daniel P. Judge, Stephen Heitner, Rodney H. Falk, Mathew S. Maurer, Sanjiv J. Shah, Ronald M. Witteles, Martha Grogan, V. N. Selby, Daniel Jacoby, M. Hanna, Jose Nativi-Nicolau, Jignesh Patel, Satish Rao, Uma Sinha, Cameron W. Turtle, Jonathan C. Fox

    Research output: Contribution to journalArticle

    11 Citations (Scopus)

    Abstract

    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)

    Original languageEnglish (US)
    Pages (from-to)285-295
    Number of pages11
    JournalJournal of the American College of Cardiology
    Volume74
    Issue number3
    DOIs
    StatePublished - Jul 23 2019

    Fingerprint

    Prealbumin
    Cardiomyopathies
    Amyloid
    Placebos
    Serum
    Fluorescent Dyes
    Mutation
    Safety
    Reference Values
    Therapeutics
    Heart Failure
    Pharmacokinetics
    Western Blotting

    Keywords

    • AG10
    • amyloidosis
    • ATTR-CM
    • cardiomyopathy
    • heart failure
    • transthyretin

    ASJC Scopus subject areas

    • Cardiology and Cardiovascular Medicine

    Cite this

    Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. / Judge, Daniel P.; Heitner, Stephen; Falk, Rodney H.; Maurer, Mathew S.; Shah, Sanjiv J.; Witteles, Ronald M.; Grogan, Martha; Selby, V. N.; Jacoby, Daniel; Hanna, M.; Nativi-Nicolau, Jose; Patel, Jignesh; Rao, Satish; Sinha, Uma; Turtle, Cameron W.; Fox, Jonathan C.

    In: Journal of the American College of Cardiology, Vol. 74, No. 3, 23.07.2019, p. 285-295.

    Research output: Contribution to journalArticle

    Judge, DP, Heitner, S, Falk, RH, Maurer, MS, Shah, SJ, Witteles, RM, Grogan, M, Selby, VN, Jacoby, D, Hanna, M, Nativi-Nicolau, J, Patel, J, Rao, S, Sinha, U, Turtle, CW & Fox, JC 2019, 'Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy', Journal of the American College of Cardiology, vol. 74, no. 3, pp. 285-295. https://doi.org/10.1016/j.jacc.2019.03.012
    Judge, Daniel P. ; Heitner, Stephen ; Falk, Rodney H. ; Maurer, Mathew S. ; Shah, Sanjiv J. ; Witteles, Ronald M. ; Grogan, Martha ; Selby, V. N. ; Jacoby, Daniel ; Hanna, M. ; Nativi-Nicolau, Jose ; Patel, Jignesh ; Rao, Satish ; Sinha, Uma ; Turtle, Cameron W. ; Fox, Jonathan C. / Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. In: Journal of the American College of Cardiology. 2019 ; Vol. 74, No. 3. pp. 285-295.
    @article{430e52676ffe494b850e65e1e08fdd9e,
    title = "Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy",
    abstract = "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)",
    keywords = "AG10, amyloidosis, ATTR-CM, cardiomyopathy, heart failure, transthyretin",
    author = "Judge, {Daniel P.} and Stephen Heitner and Falk, {Rodney H.} and Maurer, {Mathew S.} and Shah, {Sanjiv J.} and Witteles, {Ronald M.} and Martha Grogan and Selby, {V. N.} and Daniel Jacoby and M. Hanna and Jose Nativi-Nicolau and Jignesh Patel and Satish Rao and Uma Sinha and Turtle, {Cameron W.} and Fox, {Jonathan C.}",
    year = "2019",
    month = "7",
    day = "23",
    doi = "10.1016/j.jacc.2019.03.012",
    language = "English (US)",
    volume = "74",
    pages = "285--295",
    journal = "Journal of the American College of Cardiology",
    issn = "0735-1097",
    publisher = "Elsevier USA",
    number = "3",

    }

    TY - JOUR

    T1 - Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy

    AU - Judge, Daniel P.

    AU - Heitner, Stephen

    AU - Falk, Rodney H.

    AU - Maurer, Mathew S.

    AU - Shah, Sanjiv J.

    AU - Witteles, Ronald M.

    AU - Grogan, Martha

    AU - Selby, V. N.

    AU - Jacoby, Daniel

    AU - Hanna, M.

    AU - Nativi-Nicolau, Jose

    AU - Patel, Jignesh

    AU - Rao, Satish

    AU - Sinha, Uma

    AU - Turtle, Cameron W.

    AU - Fox, Jonathan C.

    PY - 2019/7/23

    Y1 - 2019/7/23

    N2 - 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)

    AB - 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)

    KW - AG10

    KW - amyloidosis

    KW - ATTR-CM

    KW - cardiomyopathy

    KW - heart failure

    KW - transthyretin

    UR - http://www.scopus.com/inward/record.url?scp=85067358001&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=85067358001&partnerID=8YFLogxK

    U2 - 10.1016/j.jacc.2019.03.012

    DO - 10.1016/j.jacc.2019.03.012

    M3 - Article

    C2 - 30885685

    AN - SCOPUS:85067358001

    VL - 74

    SP - 285

    EP - 295

    JO - Journal of the American College of Cardiology

    JF - Journal of the American College of Cardiology

    SN - 0735-1097

    IS - 3

    ER -