Efficacy and Safety Evaluation of Eplontersen in Transthyretin-Mediated Amyloid Cardiomyopathy: A Phase 3 Double-Blind, Randomized, Placebo-Controlled Study

The primary objective of this study is to evaluate the effect of treatment with **ION-682884** compared to placebo at the end of the study on the composite endpoint of cardiovascular (CV) death and recurrent CV clinical events in patients with **Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)** receiving available standard of care (SoC). This is clinically relevant as it aims to determine the potential of ION-682884 to improve survival and reduce the incidence of recurrent cardiovascular events in this patient population, which could significantly impact patient management and outcomes.

Secondary objectives include:

• Evaluating the effect of treatment with ION-682884 compared to placebo at the 121 Week Study Visit on exercise tolerance and patient-reported outcomes in patients with ATTR-CM receiving available SoC.
• Assessing the effect of treatment with ION-682884 compared to placebo at the end of the study on CV clinical events, CV death, and all-cause death in patients with ATTR-CM receiving available SoC.

The clinical trial involves a total of **910 participants** diagnosed with **Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific inclusion criteria, such as a confirmed medical history of heart failure secondary to hereditary or wild-type ATTR-CM, and a requirement for stable medical treatment for heart failure prior to randomization. The trial population is characterized by a willingness to adhere to vitamin A supplementation and undergo genetic testing for transthyretin gene mutations if not previously conducted. Lifestyle considerations include the use of highly effective contraceptive methods for participants of child-bearing potential. The study also includes individuals with a New York Heart Association (NYHA) class I-III classification and a 6-minute walk test (6MWT) distance of at least 100 meters. The trial does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's effects across a diverse group of patients.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of ION-682884 in patients with **Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)**. The trial aims to assess the effect of treatment with ION-682884 compared to placebo on the composite endpoint of cardiovascular death and recurrent cardiovascular clinical events in patients receiving standard care. The study is expected to run from March 2020 to November 2025, with a total duration of approximately 5 years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as genetic testing for transthyretin mutations and confirmation of amyloid deposits. Following randomization, participants will receive either the investigational product, ION-682884, or a placebo via subcutaneous injection. The trial includes regular follow-up visits to monitor safety and efficacy, with assessments such as the 6-minute walk test (6MWT) and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores conducted at specified intervals. The primary endpoint will be evaluated at the end of the study using the Andersen-Gill method, focusing on cardiovascular events and mortality.

The expected length of participant involvement is up to 140 weeks, with conditions for early termination including significant adverse events or withdrawal of consent. Participants must adhere to protocol requirements, including the use of effective contraception and vitamin A supplementation. The study will conclude with an end-of-study visit to assess final outcomes and gather data for analysis. All deaths and cardiovascular events will be adjudicated by an independent committee to ensure accuracy and reliability of the results.

The clinical trial involves the administration of **ION 682884**, an experimental medication, which is a **solution for injection**. The active substance in ION 682884 is **eplontersen**, a nucleic acid-based antisense oligonucleotide. This medication is administered via **subcutaneous use**. The dosing regimen includes a maximum daily dose of 45 mg, with a total maximum dose of 1575 mg over a treatment period of 140 days. The medication is provided by Ionis Pharmaceuticals, Inc., and is designated as an orphan drug under the number ODD # EU/3/23/2828.

In addition to the experimental treatment, a **placebo** is used in this study. The placebo is a **sterile, preservative-free, parenteral solution** consisting of sodium chloride and riboflavin in water for injection. It is also administered subcutaneously in a volume of 0.8 ml. The placebo serves as a comparator to evaluate the efficacy and safety of ION 682884 in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).

The efficacy of the clinical trial will be assessed through a primary composite endpoint, which includes **cardiovascular (CV) death** and recurrent CV clinical events. These events encompass hospitalization for myocardial infarction, heart failure, arrhythmias, stroke/transient ischemic attack, and urgent heart failure visits requiring intravenous diuretics. All deaths and CV clinical events will be adjudicated by an independent Clinical Adjudication Committee (CAC) using the '2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials'. The Andersen-Gill method will be employed to compare the two study arms at the end of the study.

Secondary endpoints will include changes from baseline in the 6-minute walk test (6MWT) distance and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, assessed at Week 121. Additionally, comparisons of CV clinical events, CV death, and all-cause death between the study arms will be conducted at the study's conclusion. These assessments will provide a comprehensive evaluation of the treatment's efficacy in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) receiving standard care.