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.

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 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.

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 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
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 ALT or 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, 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.