An Open-Label Extension Study to Assess the Long-Term Safety of Eplontersen (ION-682884) in Patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)

The primary objective of this study is to evaluate the **safety** and tolerability of extended dosing with eplontersen in subjects with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM). This is clinically relevant as it aims to ensure that long-term administration of eplontersen does not result in adverse effects, thereby supporting its potential use as a therapeutic option for managing ATTR-CM.

Secondary objectives include evaluating parameters of efficacy following extended dosing with eplontersen in subjects with ATTR-CM within the overall population and within subgroups based on treatment allocation during the Index Study. This will help determine the effectiveness of eplontersen in different patient subsets, providing insights into its therapeutic benefits and guiding personalized treatment strategies.

The clinical trial involves a total of **915 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 their satisfactory completion of previous related studies or a confirmed diagnosis of ATTR-CM, as well as their willingness to adhere to vitamin A supplementation as per protocol. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. The study aims to evaluate the safety and tolerability of extended dosing with eplontersen in this specific patient group.

The clinical trial is designed to evaluate the long-term safety and tolerability of **eplontersen** in patients with **Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)**. This study is an open-label extension, allowing participants from previous studies to continue receiving the investigational product. The trial employs a non-randomized, open-label design, focusing on safety endpoints over an extended period. The estimated duration of the trial is approximately six years, concluding in August 2029.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on satisfactory completion of prior studies or a diagnosis of ATTR-CM. The inclusion criteria require participants to have completed the treatment period and end-of-treatment visit of the index study or to have a satisfactory participation record in a related study, as judged by the investigator and sponsor. Follow-up visits will be conducted periodically to monitor safety and efficacy, with assessments including laboratory tests, physical examinations, and electrocardiograms. The primary endpoints focus on changes in safety laboratory assessments and clinical tests, while secondary endpoints include changes in biomarkers and clinical outcomes.

The expected length of participant involvement is up to 36 months, with conditions for early termination including withdrawal of consent, adverse events, or protocol non-compliance. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to evaluate the long-term safety profile of eplontersen. Throughout the trial, participants will receive open-label treatment with eplontersen, and adherence to vitamin A supplementation will be monitored as per protocol requirements.

The clinical trial involves the administration of **Concavit Capsules**, which are soft capsules containing a combination of vitamins and nutrients. The active substances include **ergocalciferol BP**, **nicotinamide BP**, **riboflavin BP**, **all-rac-alpha-tocopheryl acetate BP**, **calcium pantothenate BP**, **thiamine nitrate BP**, **vitamin A BP**, **ascorbic acid BP**, and **pyridoxine hydrochloride BP**. These capsules are administered orally, with a maximum daily dose of 3000 IU and a total maximum dose of 3,285,000 IU over a treatment period of 36 months. The capsules are manufactured by Wallace Manufacturing Chemists Ltd and are not a pediatric formulation.

The experimental medication **ION 682884** is a **solution for injection** containing the active substance **eplontersen**, an antisense oligonucleotide. This medication is administered via subcutaneous injection. The maximum daily dose is 45 mg, with a total maximum dose of 1620 mg over a 36-month treatment period. The solution is provided by Ionis Pharmaceuticals, Inc. and is not formulated for pediatric use. The administration of ION 682884 is facilitated by the YpsoMate™ device, a single-use, disposable needle-based injection system designed to deliver a fixed dose from a prefilled 1 mL syringe into the subcutaneous tissue.

In addition to the solution for injection, **ION 682884** is also available as an **injection** form, containing the same active substance, **eplontersen**. This form is also administered subcutaneously, with the same dosing regimen as the solution for injection. The injection form is similarly provided by Ionis Pharmaceuticals, Inc. and is not intended for pediatric use. The administration of this form is also supported by the YpsoMate™ device, ensuring consistent and accurate delivery of the medication.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the prescribed regimen. The trial aims to evaluate the long-term safety and tolerability of eplontersen in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM).

The clinical trial aims to assess the efficacy of **Eplontersen** in patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM). Efficacy will be evaluated through a series of primary and secondary endpoints. Primary endpoints include the analysis of changes in safety laboratory assessments and clinical tests over time, such as platelet count, estimated glomerular filtration rate (eGFR), urine protein-to-creatinine ratio (UPCR), liver function tests (LFTs), thyroid panel tests, coagulation tests, and other clinical laboratory tests of interest. Additionally, physical examination findings and electrocardiogram (ECG) parameters will be monitored, along with the description of treatment-emergent adverse events (TEAEs) and anti-drug antibody (ADA) assessments.

Secondary endpoints focus on the analysis of changes in biomarkers and clinical and imaging tests over time. These include transthyretin (TTR) serum levels, the 6-minute walk test (6MWT), transthoracic echocardiogram (ECHO) parameters, and clinical outcome assessments. Patient-reported outcomes will be measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) questionnaire. Additional assessments include the SF-36, the 5-Level EQ-5D (EQ-5D-5L), and the Patient Global Impression of Severity (PGIS) and Change (PGIC). Biomarkers such as N-terminal prohormone of brain natriuretic peptide (NTproBNP), high sensitivity cardiac troponin T (hs-cTnT), creatine kinase-muscle/brain fraction (CK-MB), Galectin-3, and soluble suppression of tumorigenicity 2 (sST2) will also be evaluated. For subjects with hereditary ATTR-CM, additional assessments include the COMPASS-31, Polyneuropathy Disability (PND) Score, 10-meter walk test, and lower limb function test (LLF).