Phase 3 Randomized Open-label Study on Efficacy and Safety of Vutrisiran vs. Patisiran in Hereditary Transthyretin Amyloidosis Patients

The primary objective of this study is to determine the **efficacy** of ALN-TTRSC02 in patients with **Hereditary Transthyretin Amyloidosis** (hATTR amyloidosis) by evaluating its effect on neurologic impairment. This is clinically relevant as neurologic impairment significantly impacts the quality of life and functional status of patients with hATTR amyloidosis, and effective management can lead to improved patient outcomes.

Secondary objectives include:

• To determine the efficacy of ALN-TTRSC02 on quality of life, gait speed, neurologic impairment, nutritional status, and disability.
• To demonstrate the non-inferiority of ALN-TTRSC02 compared to patisiran with respect to serum TTR levels.

The clinical trial involves a total of **91 participants** diagnosed with **Hereditary Transthyretin Amyloidosis** (hATTR amyloidosis). The study population includes both male and female subjects, aged between 18 and 85 years. Participants were selected based on specific criteria, including a documented TTR mutation and a Neuropathy Impairment Score ranging from 5 to 130. Additionally, individuals were required to have a Polyneuropathy Disability score of ≤3b and a Karnofsky Performance Status of ≥60%. The trial does not include a vulnerable population. Participants are expected to comply with study requirements and provide written informed consent. The study does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy and safety of **vutrisiran** in patients with **Hereditary Transthyretin Amyloidosis** (hATTR Amyloidosis). This is a Phase 3, global, randomized, open-label study. The trial aims to assess the impact of the investigational drug on neurologic impairment in affected individuals. The study will compare the effects of vutrisiran with those observed in a previous study involving **patisiran**. The trial is expected to last until May 2026, with recruitment having commenced in February 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented TTR mutation, and specific neuropathy and disability scores. Following successful screening, participants will be randomized to receive either the investigational drug or the comparator. The trial includes regular follow-up visits to monitor the participants' health and response to treatment, with assessments focusing on changes in neurologic impairment scores, quality of life, and other relevant health metrics. The end-of-study visit will conclude the trial for each participant, providing a final assessment of the treatment's efficacy and safety.

The expected duration of participant involvement is up to 78 weeks, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study protocols. The primary endpoint is the change from baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) compared to the placebo arm of the previous patisiran study. Secondary endpoints include changes in quality of life scores, walking test results, and serum TTR levels. The trial is not classified as low intervention, reflecting its comprehensive and rigorous design to ensure robust data collection and analysis.

The clinical trial involves the administration of **Amvuttra**, a 25 mg solution for injection in a pre-filled syringe. The active substance in Amvuttra is **vutrisiran**, classified as a nucleic acid-based RNA interference therapeutic. The pharmaceutical form is a solution for injection, and it is administered via infusion. The maximum daily dose is 25 mg, with a total maximum dose of 675 mg over a treatment period of up to 78 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to the experimental treatment, the study includes a comparator treatment with **Onpattro**, a 2 mg/mL concentrate for solution for infusion. The active substance in Onpattro is **patisiran**, also a nucleic acid-based RNA interference therapeutic. This solution for infusion is administered intravenously, with a maximum daily dose of 0.3 mg/kg and a total maximum dose of 7.2 mg/kg over a treatment period of up to 18 months. The administration of Onpattro is carefully monitored to ensure accurate dosing and participant compliance throughout the study.

The efficacy of ALN-TTRSC02 in patients with **hereditary transthyretin amyloidosis (hATTR amyloidosis)** will be assessed through a series of primary and secondary endpoints. The primary endpoint involves evaluating the change from baseline in the Modified Neurologic Impairment Score +7 (mNIS+7) of the ALN-TTRSC02 group compared to the placebo arm of the Phase 3 patisiran-LNP study (ALN-TTR02-004; APOLLO). Secondary endpoints include changes from baseline in several parameters of the ALN-TTRSC02 group compared to the placebo arm of the APOLLO study. These parameters are the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) total score, the Timed 10-meter walk test (10-MWT), mNIS+7, Modified body mass index (mBMI), and the Rasch-built Overall Disability Scale (R-ODS). Additionally, the percent reduction in serum transthyretin (TTR) levels in the ALN-TTRSC02 arm will be compared to the within-study patisiran arm.