TRITON-CM: A Phase 3 Global, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Nucresiran in Patients with Transthyretin-Mediated Amyloidosis with Cardiomyopathy (ATTR amyloidosis with cardiomyopathy)

The primary objective is to evaluate the efficacy of nucresiran compared to placebo in reducing all-cause mortality and cardiovascular events in patients with transthyretin amyloidosis with cardiomyopathy. This endpoint is clinically relevant as it assesses the impact of nucresiran on major adverse outcomes in this progressive and life-threatening condition characterized by abnormal deposition of misfolded transthyretin protein in cardiac tissue.

The secondary objectives are to evaluate the efficacy of nucresiran compared to placebo on:

• Additional assessments of cardiovascular events and/or death
• Patient-reported health status and health-related quality of life

This clinical trial enrolled a total of **574 participants** diagnosed with **transthyretin amyloidosis with cardiomyopathy** (ATTR amyloidosis with cardiomyopathy), including both hereditary and wild-type variants. The study population comprised both **male and female subjects** aged **18 to 85 years**, with the minimum age adjusted to the age of legal consent according to local regulations where applicable. Participants were required to have a documented diagnosis of ATTR amyloidosis with cardiomyopathy and a medical history of **heart failure**, with at least one prior hospitalization for heart failure or clinical evidence of heart failure. All participants needed to demonstrate clinical stability, with no cardiovascular-related hospitalizations within six weeks prior to randomization. Screening **NT-proBNP** levels were required to fall between 300 ng/L and 8500 ng/L, or between 600 ng/L and 8500 ng/L for those with permanent or persistent **atrial fibrillation**. Participants could be receiving approved **TTR stabilizers** for ATTR amyloidosis and background therapy for heart failure, provided such treatments remained stable for at least 30 days prior to screening. The trial included a **vulnerable population**.

This is a phase 3 global, **randomized**, **double-blind**, **placebo-controlled** clinical trial designed to evaluate the efficacy and safety of **nucresiran** in patients with **transthyretin amyloidosis with cardiomyopathy** (ATTR amyloidosis with cardiomyopathy). The trial employs a rigorous methodology comparing nucresiran administered as a **solution for injection** against placebo to assess therapeutic outcomes in this patient population. The study is classified as a Category 2 trial and aims to enroll participants aged 18 to 85 years with documented diagnosis of ATTR amyloidosis with cardiomyopathy, which may be either hereditary (hATTR) or wild-type (wtATTR). The estimated recruitment start date is July 2025, with an anticipated study completion date in June 2032, reflecting a substantial trial duration necessary to capture long-term clinical outcomes.

The primary objective of this trial is to evaluate the efficacy of nucresiran compared to placebo in reducing all-cause mortality and **cardiovascular events**. The **primary endpoint** is defined as a composite outcome of all-cause mortality and recurrent cardiovascular events, including cardiovascular hospitalizations and urgent **heart failure** visits. Secondary endpoints include time to first cardiovascular event or all-cause mortality, all-cause mortality alone, recurrent cardiovascular events, and change from baseline in Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). These endpoints are designed to comprehensively assess both mortality benefit and quality of life improvements in this patient population.

Eligible participants must have a documented diagnosis of ATTR amyloidosis with cardiomyopathy and a medical history of heart failure with at least one prior hospitalization for heart failure or clinical evidence of heart failure. Participants must be clinically stable with no cardiovascular-related hospitalizations within 6 weeks prior to randomization. Screening **NT-proBNP** levels must be between 300 ng/L and 8500 ng/L, or between 600 ng/L and 8500 ng/L for patients with permanent or persistent **atrial fibrillation**. Patients may continue approved **TTR stabilizers** and background therapy for heart failure provided they have been stable for at least 30 days prior to screening. All participants must be able to understand and comply with study requirements and provide written informed consent.

The investigational medicinal product nucresiran (ALN-TTRSC04) is a nucleic acid-based therapy consisting of **siRNA** against **transthyretin mRNA**, covalently conjugated to trivalent N-acetylgalactosamine. The product is supplied as a solution for injection in pre-filled syringe. The maximum daily dose amount is 1.7 mg, with a maximum total dose amount of 4200 mg over a maximum treatment period of 84 months. The matching placebo will be administered to the control group following the same dosing schedule and administration procedures to maintain the double-blind nature of the trial.

Participant involvement in the study extends throughout the treatment period and follow-up phase, with the maximum treatment duration being 84 months. The study includes a screening visit to assess eligibility criteria, followed by randomization and regular follow-up visits to monitor efficacy and safety parameters. Study visits are designed to capture cardiovascular events, assess functional status, monitor biomarkers including NT-proBNP, and evaluate adverse events. The end-of-study visit will occur upon completion of the planned treatment and follow-up period or upon early termination. Conditions that may lead to early termination from the study include withdrawal of consent, development of exclusion criteria, unacceptable adverse events, investigator decision, loss to follow-up, or other administrative reasons. The trial design ensures systematic collection of data on mortality, cardiovascular events, and patient-reported outcomes throughout the study duration to comprehensively evaluate the therapeutic benefit of nucresiran in this patient population.

The experimental treatment in this clinical trial consists of **nucresiran** (also known as **ALN-TTRSC04**), a **nucleic acid-based** therapeutic agent. Nucresiran is a **small interfering RNA (siRNA)** directed against **transthyretin mRNA**, covalently conjugated to trivalent N-acetylgalactosamine. The investigational medicinal product is supplied as a **solution for injection** in a **pre-filled syringe**. The maximum daily dose is **1.7 mg**, with a maximum total dose of **4200 mg** administered over a maximum treatment period of **84 months**. The route of administration is **subcutaneous injection**. The product is manufactured by Alnylam Pharmaceuticals Inc.

The comparator treatment consists of a **placebo** for nucresiran. The placebo is administered to maintain the **double-blind** study design and allow for appropriate comparison of efficacy and safety outcomes between the active treatment and control groups. The placebo is matched to the experimental treatment to ensure blinding of study participants and investigators throughout the trial duration.

Efficacy will be assessed using a composite primary endpoint consisting of all-cause mortality and recurrent cardiovascular events, which include cardiovascular hospitalizations and urgent heart failure visits. Secondary endpoints will evaluate the time to first cardiovascular event (cardiovascular hospitalizations and urgent heart failure visits) or all-cause mortality, all-cause mortality as a standalone measure, recurrent cardiovascular events, and change from baseline in the Kansas City Cardiomyopathy Questionnaire Overall Summary score (KCCQ-OS). The trial will evaluate the efficacy of **nucresiran** compared to **placebo** on reducing all-cause mortality and cardiovascular events in patients with **transthyretin-mediated amyloidosis with cardiomyopathy**. Patients enrolled in the study must have screening NT-proBNP levels between 300 ng/L and 8500 ng/L, or between 600 ng/L and 8500 ng/L for those with permanent or persistent atrial fibrillation, which serves as a biomarker criterion for patient selection and may be relevant to efficacy assessment.