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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03458130

Enrollment

Registered

2018-03-08

Start date

2018-04-27

Completion date

2018-10-05

Last updated

2022-11-16

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Familial ATTR-CM (ATTRm-CM, or FAC), Wild-type ATTR-CM (ATTRwt-CM)

Brief summary

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.

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.

Interventions

DRUGAG10

TTR stabilizer

DRUGPlacebo Oral Tablet

Nonactive control

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Intervention model description

A randomized, doubleblind, placebo-controlled, dose-ranging design is considered to be the most appropriate study design for meeting this objective. On the basis of information gained from previous clinical experience with AG10, the doses used in this study will be selected to determine the dose with the better safety and tolerability profile.

Eligibility

Sex/Gender

ALL

Age

18 Years to 90 Years

Healthy volunteers

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.

Design outcomes

Primary

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

Secondary

Measure	Time frame	Description
Pharmacokinetic (PK): Steady State Trough Concentration of AG10	Day 14 and Day 28	Non-fluctuating minimal amount of AG10 in blood at Day 14 and Day 28
Number of Participants With Threshold Levels of Overall % Stabilization >= 95% and >= 99% by Fluorescent Probe Exclusion (FPE)	Day 1 to Day 28	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
AG10 400mg AG10 400mg twice daily for 28 days; tablets AG10: TTR stabilizer	16
AG10 800mg AG10 800mg twice daily for 28 days; tablets AG10: TTR stabilizer	16
Placebo Placebo twice daily for 28 days; tablets	17
Total	49

Baseline characteristics

Characteristic	AG10 400mg	AG10 800mg	Placebo	Total
Age, Continuous	73.8 Years STANDARD_DEVIATION 5.65	75.4 Years STANDARD_DEVIATION 6.81	73.2 Years STANDARD_DEVIATION 7.35	74.1 Years STANDARD_DEVIATION 6.58
Body Mass Index (BMI)	25.42 kg/meters squared STANDARD_DEVIATION 3.284	26.29 kg/meters squared STANDARD_DEVIATION 3.705	27.05 kg/meters squared STANDARD_DEVIATION 3.604	26.27 kg/meters squared STANDARD_DEVIATION 3.528
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	1 Participants	2 Participants	4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	14 Participants	14 Participants	15 Participants	43 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants	1 Participants	0 Participants	2 Participants
Height	172.68 Centimeters STANDARD_DEVIATION 7.055	175.59 Centimeters STANDARD_DEVIATION 9.738	174.52 Centimeters STANDARD_DEVIATION 8.22	174.27 Centimeters STANDARD_DEVIATION 8.317
Race/Ethnicity, Customized Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race (NIH/OMB) Asian	1 Participants	0 Participants	0 Participants	1 Participants
Race/Ethnicity, Customized Race (NIH/OMB) Black or African American	4 Participants	3 Participants	3 Participants	10 Participants
Race/Ethnicity, Customized Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race (NIH/OMB) Native Hawaiian or Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race (NIH/OMB) Other	1 Participants	1 Participants	1 Participants	3 Participants
Race/Ethnicity, Customized Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race (NIH/OMB) White	10 Participants	12 Participants	13 Participants	35 Participants
Region of Enrollment United States	16 participants	16 participants	17 participants	49 participants
Sex: Female, Male Female	2 Participants	2 Participants	0 Participants	4 Participants
Sex: Female, Male Male	14 Participants	14 Participants	17 Participants	45 Participants
TTR Genotype Status Mutant	6 Participants	5 Participants	3 Participants	14 Participants
TTR Genotype Status Other	0 Participants	0 Participants	0 Participants	0 Participants
TTR Genotype Status Wild Type	10 Participants	11 Participants	14 Participants	35 Participants
Weight	75.93 Kilograms STANDARD_DEVIATION 12.08	81.71 Kilograms STANDARD_DEVIATION 15.948	82.34 Kilograms STANDARD_DEVIATION 12.018	80.04 Kilograms STANDARD_DEVIATION 13.478

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 16	0 / 16	0 / 17
other Total, other adverse events	10 / 16	11 / 16	15 / 17
serious Total, serious adverse events	1 / 16	0 / 16	2 / 17