Study of AG10 in Amyloid Cardiomyopathy

A Phase 2, Randomized, Placebo-controlled, Dose-ranging Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AG10 in Patients With Symptomatic Transthyretin Amyloid Cardiomyopathy

This prospective, randomized, multicenter, double-blind, parallel group, placebo-controlled, dose-ranging study will evaluate the safety, tolerability, PK (Pharmacokinetic) and PD (Pharmacodynamic) of AG10 compared to placebo administered on a background of stable heart failure therapy. Screening and randomization will be followed by a 28-day blinded, placebo-controlled treatment period.

Study Overview

• Status: Completed
• Conditions: Familial ATTR-CM (ATTRm-CM, or FAC); Wild-type ATTR-CM (ATTRwt-CM)
• Intervention / Treatment: Drug: AG10; Drug: Placebo Oral Tablet

Detailed Description

A Phase 2, Randomized, Placebo-controlled, Dose-ranging Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AG10 in Patients with Symptomatic Transthyretin Amyloid Cardiomyopathy.

The primary objective of this study is to evaluate the safety and tolerability of AG10 administered to adult patients with symptomatic transthyretin amyloid cardiomyopathy (ATTRCM).

This study will be a Phase 2, randomized, placebo-controlled, dose-ranging study in 45 male and/or female patients with symptomatic ATTR-CM aged 18 through 90 years.

If all doses are well tolerated, the duration of each patient's participation in the study will be 28 days of treatment. In addition, there will be a 28-day screening period before treatment and a 30-day follow-up period before the final Follow-up Visit.

This prospective, randomized, multicenter, double-blind, parallel group, placebo-controlled, dose-ranging study will evaluate the safety, tolerability, PK and PD of AG10 compared to placebo administered on a background of stable heart failure therapy. Screening and randomization will be followed by a 28-day blinded, placebo-controlled treatment period. secondary objectives of this study are: to characterize the pharmacokinetics (PK) of AG10 administered orally twice daily in patients with symptomatic ATTRCM, and to describe the pharmacodynamic (PD) properties of AG10 as assessed by established assays of transthyretin (TTR) stabilization, including Fluorescent Probe Exclusion (FPE) assay and Western blot, and to describe the Pharmacokinetic Pharmacodynamic (PKPD) relationship of AG10 in adult patients with symptomatic ATTRCM.

Eligible patients will be randomized in a 1:1:1 ratio to placebo or one of two different doses of AG10 administered twice daily. A minimum of 30% of patients enrolled will be mutant ATTR-CM.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars-Sinai Medical Center
    • Palo Alto, California, United States, 94304
      • Stanford University
    • San Francisco, California, United States, 94143
      • University of California San Francisco
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02127
      • Boston University
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • South Carolina
    • Charleston, South Carolina, United States, 29424
      • Medical University of South Carolina
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
2. Be a male or female ≥18 to ≤90 years of age.
3. Have an established diagnosis of ATTR-CM with either wild-type transthyretin or a variant transthyretin genotype (assessed by genotyping, with patients with concurrent monoclonal gammopathy of undetermined significance requiring a confirmatory test using mass spectrometry) as defined by either positive endomyocardial biopsy or positive technetium pyrophosphate scan.
4. Have a history of heart failure evidenced by at least one prior hospitalization for heart failure or clinical evidence of heart failure (without hospitalization) requiring medical management.
5. Have New York Heart Association (NYHA) Class II-III symptoms.
6. Male patients and female patients of childbearing potential who engage in heterosexual intercourse must agree to use appropriate method(s) of contraception.
7. For patients taking cardiovascular medical therapy, with the exception of diuretic dosing, must be on stable doses (defined as no greater than 50% dose adjustment and no categorical changes of medications) for at least 2 weeks prior to Screening.

Exclusion Criteria:

1. Acute myocardial infarction, acute coronary syndrome or coronary revascularization within 90 days prior to Screening.
2. Experienced stroke within 90 days prior to Screening.
3. Has hemodynamic instability at Screening or Randomization that, in the judgment of the Principal Investigator (PI), would pose too great a risk for participation in the study.
4. Has estimated glomerular filtration rate (GFR) <30 mL/min/1.73 m2 at Screening.
5. Is likely to undergo heart transplantation within the next year.
6. Has confirmed diagnosis of light-chain amyloidosis.
7. Has abnormal liver function tests at Screening, defined as Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >2 × ULN.
8. Has abnormalities in clinical laboratory tests at Screening or Randomization that, in the judgment of the PI, would pose too great a risk for participation in the study.
9. Known hypersensitivity to study drug (AG10 or placebo), its metabolites, or formulation excipient
10. Current treatment with diflunisal, tafamidis, green tea, doxycycline, tauroursodeoxycholic acid (TUDCA)/Ursodiol, Patisiran or Inotersen within 14 days or 5 half-lives of the prior investigational agent (whichever is longer) prior to Screening.
11. Females who are pregnant or breastfeeding. Lactating females must agree to discontinue nursing before the study drug is administered. A negative serum pregnancy test at Screening and a negative urine pregnancy test at Randomization visit are required for female patients of childbearing potential.
12. In the judgment of the investigator, has any clinically significant ongoing medical condition that might jeopardize the patient's safety or interfere with the study, including participation in another investigational drug or investigational device study within the 30 days prior to Screening with potential residual effects that might confound the results of this study.
13. Has any laboratory abnormality or condition that, in the investigator's opinion, could adversely affect the safety of the patient or impair the assessment of study results.
14. Has any condition that, in the opinion of the investigator, would preclude compliance with the study protocol such as a history of substance abuse, alcoholism or a psychiatric condition.
15. Has participated in another investigational study within 14 days or 5 half-lives of the prior investigational agent (whichever is longer) prior to screening. Exceptions can be made in the case of observational and/or registry studies upon consultation with the Medical Monitor.
16. Current treatment with, or chronic use of, a proton pump inhibitor (PPI) or histamine-receptor 2 (H2) antagonist within 14 days or 5 half-lives of the prior agent (whichever is longer) prior to Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: AG10 Low Dose; AG10 400mg tablets twice daily for 28 days	Drug: AG10; TTR stabilizer
ACTIVE_COMPARATOR: AG10 High Dose; AG10 800mg tablets twice daily for 28 days	Drug: AG10; TTR stabilizer
PLACEBO_COMPARATOR: Placebo; Placebo tablets twice daily for 28 days	Drug: Placebo Oral Tablet; Nonactive control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Diastolic Blood Pressure	Change in Diastolic Blood Pressure from Baseline to Day 28 (Postdose)	Baseline to Day 28
Change in Heart Rate	Change in Heart Rate from Baseline to Day 28 (Postdose)	Baseline to Day 28
Change in Respiratory Rate	Change in Respiratory Rate from Baseline to Day 28 (Postdose)	Baseline to Day 28
Change in Temperature	Change in Temperature from Baseline to Day 28	Baseline to Day 28
Change in Systolic Blood Pressure	Change in Systolic Blood Pressure from Baseline to Day 28	Baseline to Day 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Threshold Levels of Overall % Stabilization >= 95% and >= 99% by Fluorescent Probe Exclusion (FPE)	In specialized lab tests on patient samples that measure the stability of the healthy form of TTR, both doses of AG10 were able to reach near complete stabilization.	Day 1 to Day 28
Pharmacokinetic (PK): Steady State Trough Concentration of AG10	Non-fluctuating minimal amount of AG10 in blood at Day 14 and Day 28	Day 14 and Day 28

Collaborators and Investigators

• Sponsor: Eidos Therapeutics, a BridgeBio company
• Investigators: Study Director: MARK MCGOVERN, RN, Eidos Therapeutics, a BridgeBio company

Publications and helpful links

General Publications

• Judge DP, Heitner SB, 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. Transthyretin Stabilization by AG10 in Symptomatic Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2019 Jul 23;74(3):285-295. doi: 10.1016/j.jacc.2019.03.012. Epub 2019 Mar 15.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 27, 2018
• Primary Completion (ACTUAL): October 5, 2018
• Study Completion (ACTUAL): October 5, 2018

Study Registration Dates

• First Submitted: February 7, 2018
• First Submitted That Met QC Criteria: March 1, 2018
• First Posted (ACTUAL): March 8, 2018

Study Record Updates

• Last Update Posted (ACTUAL): November 16, 2022
• Last Update Submitted That Met QC Criteria: October 24, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Cardiomyopathies
• Other Study ID Numbers: AG10-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No