Phase 3 Randomized Double-Blind Study of NTLA-2001 Efficacy and Safety in Transthyretin Amyloidosis with Cardiomyopathy Patients

The primary objective of this study is to evaluate the **efficacy** of NTLA-2001 in participants with Transthyretin Amyloidosis with Cardiomyopathy (ATTR-CM). This will be measured by assessing the composite risk of cardiovascular-related mortality and cardiovascular events compared to placebo. This objective is clinically relevant as it aims to determine the potential of NTLA-2001 to improve survival and reduce cardiovascular complications in patients with ATTR-CM, a condition characterized by the deposition of amyloid fibrils in the heart, leading to progressive heart failure.

Secondary objectives include:

• Evaluating the effect of NTLA-2001 on serum transthyretin (TTR) levels compared to placebo, which is important for understanding the biochemical impact of the treatment on the disease process.
• Assessing the impact of NTLA-2001 on participant-reported cardiomyopathy-related symptoms and quality of life compared to placebo, providing insights into the treatment's effect on patient well-being and daily functioning.

The clinical trial involves a total of **896 participants** diagnosed with **Transthyretin Amyloidosis with Cardiomyopathy**. The study population comprises both male and female subjects, aged between **18 to 90 years**. Participants were selected based on a documented diagnosis of ATTR amyloidosis with cardiomyopathy and a medical history of heart failure. The trial ensures that symptoms of heart failure are optimally managed and clinically stable within 28 days prior to the administration of the study intervention. Additionally, participants must have a screening NT-proBNP level, a blood marker of heart failure severity, greater than or equal to 1000 pg/mL, or greater than or equal to 2000 pg/mL if they have known atrial fibrillation. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and safety of NTLA-2001 in participants with **Transthyretin Amyloidosis with Cardiomyopathy**. The trial is set to commence recruitment on June 15, 2024, and is estimated to conclude by March 31, 2028. Participants will be involved in the study for a maximum treatment period of one month, with the primary endpoint being the composite outcome of cardiovascular mortality and cardiovascular events. Secondary endpoints include changes from baseline to month 18 in serum transthyretin levels and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score.

The study will include several visits, beginning with a screening visit to confirm eligibility based on criteria such as age, documented diagnosis of ATTR amyloidosis with cardiomyopathy, and a history of heart failure. Participants must have optimally managed heart failure symptoms and a screening NT-proBNP level above specified thresholds. Following the screening, participants will undergo randomization and receive either NTLA-2001 or a placebo. Subsequent follow-up visits will monitor the participants' health status, adherence to the study protocol, and any adverse events. The end-of-study visit will assess the final outcomes and collect data for analysis.

Participant involvement is expected to last for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events that compromise participant safety. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the integrity and scientific validity of the research findings.

The clinical trial involves the administration of **NTLA-2001**, a gene therapy product formulated as a dispersion for infusion. NTLA-2001 contains two RNA drug substances: **ziclumeran** and a single guide RNA targeting the human TTR gene. The product is administered via **intravenous infusion** with a maximum daily and total dose of 55 mg. The treatment period is limited to one day. NTLA-2001 is classified as an orphan drug and is specifically designed for the treatment of Transthyretin Amyloidosis with Cardiomyopathy (ATTR-CM).

**Dexamethasone** is provided in the form of 8 mg tablets, marketed as Dexamethason 8 mg GALEN® Tabletten. The route of administration is **oral**, with a maximum daily and total dose of 18 mg. The treatment period can extend up to two days. This medication is used as an auxiliary treatment in the trial.

**Cetirizine dihydrochloride** is available as 10 mg film-coated tablets, marketed under the name Cetirizin HEXAL bei Allergien 10 mg Filmtabletten. It is administered **orally** with a maximum daily and total dose of 10 mg, and the treatment period is one day. This medication serves as an auxiliary treatment in the study.

**Famotidine** is provided in the form of 20 mg film-coated tablets, marketed as Famotidin STADA® 20 mg Filmtabletten. The administration route is **oral**, with a maximum daily and total dose of 20 mg, and the treatment period is one day. Famotidine is used as an auxiliary treatment in the trial.

**Paracetamol** is available as 500 mg tablets, marketed as Paracetamol STADA® 500 mg Tabletten. It is administered **orally** with a maximum daily and total dose of 650 mg, and the treatment period is one day. This medication is used as an auxiliary treatment in the study.

**Electrolyte solutions** are administered via **intravenous use** with a maximum daily and total dose of 250 ml. The treatment period is one day. These solutions are used as a non-experimental treatment in the trial.

The efficacy of NTLA-2001 in the clinical trial will be assessed by evaluating the composite risk of cardiovascular (CV)-related mortality and CV events compared to placebo. This primary endpoint will provide a comprehensive measure of the treatment's impact on participants with **Transthyretin Amyloidosis with Cardiomyopathy (ATTR-CM)**. Secondary endpoints include the change from baseline to month 18 in serum transthyretin (TTR) levels and the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score. These secondary measures will offer additional insights into the treatment's effect on disease progression and patient-reported outcomes.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints, with the primary endpoint focusing on the occurrence of CV mortality and events throughout the study duration. The secondary endpoints will be measured at baseline and at month 18, allowing for a detailed assessment of changes over time. The use of validated scales and laboratory tests will ensure the reliability and accuracy of the data collected. The trial is designed to provide robust evidence on the efficacy of NTLA-2001 in managing ATTR-CM, with a planned completion date in March 2028.