A Phase 3, Open-Label, Multicenter, Extension Study of Acoramidis in Patients with Newly Diagnosed Variant Transthyretin Amyloid Cardiomyopathy (ACT-EARLY OLE)

The primary objective of this study is to evaluate the long-term safety and tolerability of acoramidis in participants with newly diagnosed transthyretin amyloid cardiomyopathy (ATTR-CM). This assessment is clinically relevant for understanding the extended safety profile of acoramidis in patients at an early stage of disease, which is essential for informing treatment decisions and long-term disease management strategies.

The secondary objectives include:

• To evaluate the effect of acoramidis on all-cause mortality (ACM) and cardiovascular mortality (CVM)

• To evaluate the effect of acoramidis on cardiovascular-related hospitalization (CVH)

• To evaluate the effect of acoramidis on heart failure (HF) events, where HF events are described as: outpatient HF event (O-HF), or urgent visit for HF (UV-HF), or hospitalization for HF (H-HF), or new onset of HF (NOHF)

• To evaluate the effect of acoramidis on symptomatic ATTR-CM

• To evaluate the effect of acoramidis on arrhythmic and cardiac conduction complications

• To evaluate the effect of acoramidis on musculoskeletal complications

• To evaluate the effect of acoramidis on objective imaging and biomarker measures of interest

This clinical trial enrolled a total of **155 participants** with newly diagnosed **transthyretin amyloidosis cardiomyopathy (ATTR-CM)**. The study population included both **male and female subjects** comprising **adults and elderly individuals**. Participants were selected based on their completion of the preceding AG10-501 study (ACT-EARLY study) within the past 60 calendar days, with a confirmed diagnosis of ATTR-CM according to the protocol definition. The trial included a **vulnerable population**. All participants were required to provide signed informed consent prior to study enrollment. Women of childbearing potential engaging in heterosexual intercourse were required to use highly effective contraception from Day 1 through 30 calendar days after the last dose of study drug. Male participants who had not undergone vasectomy and were sexually active with females of childbearing potential were required to use double-barrier contraception during the study and for 30 calendar days following the last dose, and to refrain from sperm donation during this period.

This is a Phase 3, open-label, multicenter extension study designed to evaluate the long-term safety and tolerability of acoramidis in participants with newly diagnosed variant transthyretin amyloidosis with cardiac involvement. The study investigates acoramidis hydrochloride administered as an oral tablet formulation. Participants must have completed the preceding AG10-501 study within the past 60 calendar days with a confirmed diagnosis of transthyretin amyloid cardiomyopathy. The maximum daily dose is 1424 mg, with a maximum total dose of 2598800 mg over a treatment period of up to 60 months. The estimated recruitment start date is November 2025, with an anticipated study completion date of April 2032.

The primary endpoint focuses on safety and tolerability assessment through evaluation of treatment-emergent adverse events and serious adverse events, adverse events leading to treatment discontinuation, abnormal physical examination findings of clinical relevance, abnormal vital signs of clinical relevance, abnormal electrocardiogram parameters of clinical relevance, and changes in clinical safety laboratory parameters of potential concern. Secondary endpoints include all-cause mortality and cardiovascular mortality, cardiovascular-related hospitalization, various heart failure events, development of symptomatic transthyretin amyloid cardiomyopathy, new arrhythmia and cardiac conduction complications, new diagnosis of or therapeutic surgery for conditions including carpal tunnel syndrome, brachial biceps tendon rupture or Achilles tendon rupture, lumbar spinal stenosis, hip and knee osteoarthritis, trigger finger, and rotator cuff osteoarthritis, as well as changes from baseline in echocardiographic and strain parameters that estimate myocardial structure and function, NT-proBNP, and high-sensitivity troponin I.

Participants enrolled in the study must be willing and able to provide signed informed consent prior to initiation of study procedures. Women of childbearing potential who engage in heterosexual intercourse must agree to use a highly effective method of contraception from Day 1 and continuing for 30 calendar days after the last dose of study drug. Male participants who have not had a vasectomy and are sexually active with a female of childbearing potential must agree to use a double-barrier method of birth control during the study and continue for 30 calendar days after the last dose of study drug. Males must also agree to refrain from sperm donation for a minimum of 30 calendar days following the last dose of the study drug.

The experimental medication utilized in this clinical trial is **Acoramidis (AG10)**, a chemical entity manufactured by EIDOS THERAPEUTICS, INC. The **active substance** is **acoramidis hydrochloride**, which is of chemical origin. The medicinal product is formulated as an **oral tablet** administered via the **oral route**. The maximum daily dose is **1424 mg**, with a maximum total dose of **2598800 mg** over the course of treatment. The maximum treatment period is **60 months**. The product is designated as the test medication in this **Phase 3**, **open-label**, **multicenter**, **extension study** evaluating long-term safety and tolerability in participants with newly diagnosed **variant transthyretin amyloid cardiomyopathy (ATTR-CM)**. This is not a **paediatric formulation** and is not classified as an **orphan drug** within the scope of this trial.

Efficacy will be assessed through multiple secondary endpoints in this extension study. **All-cause mortality** and **cardiovascular mortality** will be evaluated as key efficacy parameters. **Cardiovascular-related hospitalization** will be monitored throughout the study period. The occurrence of various **heart failure events** will be assessed, including outpatient heart failure, unscheduled visits for heart failure, and hospitalizations for heart failure, both individually and in combination. The development of **symptomatic ATTR-CM** as determined by the investigator will be recorded. New **arrhythmia** and **cardiac conduction complications** will be evaluated, including new onset of atrial fibrillation or atrial flutter, sustained ventricular tachycardia or sudden cardiac death, new onset atrioventricular block, and conduction disease requiring pacemaker implantation. The occurrence of new diagnoses or therapeutic surgeries for conditions including **carpal tunnel syndrome**, brachial biceps tendon rupture or Achilles tendon rupture, lumbar spinal stenosis, hip and knee osteoarthritis, trigger finger, and rotator cuff osteoarthritis will be monitored. Changes from baseline in **echocardiographic** and **strain parameters** that estimate myocardial structure and function will be measured. Changes from baseline in **NT-proBNP** and **hsTnI** biomarker levels will be assessed.