Open-Label Extension and Safety Evaluation of Acoramidis Hydrochloride in Symptomatic Transthyretin Amyloid Cardiomyopathy Post-Phase 3 ATTRibute-CM Completion

The primary objective of this study is to assess the **safety** and tolerability of acoramidis in participants with symptomatic **transthyretin amyloid cardiomyopathy** (ATTR-CM). This is clinically relevant as it aims to ensure that the therapeutic intervention does not pose undue risk to patients, thereby supporting its potential use in managing this condition.

Secondary objectives include evaluating the effect of acoramidis on:

• all-cause mortality and cardiovascular mortality,
• the 6-minute walk test,
• health-related quality of life as measured by the Kansas City Cardiomyopathy Questionnaire,
• the frequency of cardiovascular-related hospitalization.

The clinical trial involves a total of **236 participants** diagnosed with **Symptomatic Transthyretin Amyloid Cardiomyopathy (ATTR-CM)**. The study population includes both male and female subjects, with age categories ranging from middle-aged adults to older adults. Participants were selected based on their completion of 30 months of blinded study treatment in a previous study, indicating a specific health status and commitment to the trial process. The trial includes individuals who are part of a vulnerable population, highlighting the need for careful ethical considerations. Lifestyle factors such as diet and physical activity are not specified, but female participants of childbearing potential are required to adhere to strict contraceptive measures, indicating the importance of managing reproductive health during the trial. The selection criteria ensure that participants have the ability to understand and sign informed consent, emphasizing the importance of informed participation in clinical research.

The clinical trial is designed to evaluate the **safety** and tolerability of **acoramidis hydrochloride** in participants with symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM). This study is an open-label extension following the completion of the Phase 3 ATTRibute-CM Trial (AG10-301). The trial employs a non-randomized, open-label design, allowing all eligible participants to receive the investigational product, Acoramidis (AG10), in tablet form administered orally. The trial is expected to span from October 2021 to May 2028, with participant involvement lasting up to 60 months.

Participants eligible for inclusion must have completed 30 months of the blinded study treatment in the previous trial and must be able to provide informed consent. The study will consist of several key visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. Follow-up visits will be scheduled periodically to monitor safety parameters, including treatment-emergent serious adverse events (SAEs), adverse events (AEs), and any clinically relevant changes in physical examinations, vital signs, and laboratory parameters. The end-of-study visit will conclude the participant's involvement, assessing the overall safety and tolerability of the treatment.

Participants are expected to adhere to the study protocol, including the use of effective contraception for female participants of childbearing potential and male participants with partners of childbearing potential. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with study procedures, or withdrawal of consent. The primary endpoints focus on safety assessments, while secondary endpoints include all-cause mortality, cardiovascular mortality, changes in the 6-minute walk test distance, and transthyretin stabilization measures. The trial aims to provide comprehensive safety data to support the continued development of Acoramidis for the treatment of ATTR-CM.

The clinical trial involves the administration of **Acoramidis (AG10)**, an investigational medication developed by Eidos Therapeutics, Inc. The active substance in this medication is **acoramidis hydrochloride**, which is of chemical origin. The pharmaceutical form of Acoramidis is a tablet, designed for **oral use**. Participants in the trial will receive a maximum daily dose of 1424 mg, with the total dose not exceeding 2600224 mg over the course of the study. The maximum treatment period is set at 60 days. The medication is not formulated for pediatric use and is designated as an orphan drug, indicating its use in treating a rare condition.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the safety and tolerability of Acoramidis in participants with symptomatic **transthyretin amyloid cardiomyopathy** (ATTR-CM) who have completed the Phase 3 ATTRibute-CM Trial (AG10-301). Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

Efficacy in the clinical trial of Acoramidis (AG10) for participants with symptomatic **transthyretin amyloid cardiomyopathy** (ATTR-CM) will be assessed using several secondary endpoints. These include all-cause mortality and cardiovascular (CV) mortality, changes from baseline in the distance walked during the 6-minute walk test (6MWT), and changes from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS). Additionally, CV-related hospitalizations and changes from baseline in transthyretin (TTR) levels, which serve as an in vivo measure of TTR stabilization, will be evaluated. TTR stabilization will also be measured using established ex vivo assays, such as FPE and D39 Western blot, in the pharmacokinetic-pharmacodynamic (PK-PD) substudy.