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A study to evaluate the safety and effectiveness of nucresiran and vutrisiran in patients with hereditary transthyretin amyloidosis with polyneuropathy

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This study focuses on a rare condition called Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy. In this disease, an abnormal protein builds up in the body, which can cause damage to the nerves, leading to issues with movement and sensation. The purpose of the study is to evaluate the effectiveness and safety of a new medication called nucresiran.

Participants in the study will receive either nucresiran or vutrisiran, which is a currently used treatment for this condition. These medications are administered as a subcutaneous injection, meaning the medicine is injected into the fatty tissue just under the skin. During the study, the effects of these drugs on nerve function and the levels of a protein called transthyretin in the blood will be observed over time.

The research process

The trial runs in 2 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    <b>study participation</b>

    Participation begins with the administration of either nucresiran or vutrisiran.

    nucresiran is provided as a 1.67 mg dose in a solution for injection.

    vutrisiran is provided as a 0.28 mg dose in a 25 mg solution for injection, which is administered via subcutaneous injection (an injection into the fatty tissue just under the skin).

  2. Step 2

    <b>monitoring period</b>

    During the first 6 weeks, changes in serum TTR levels (a protein measured in the blood) are monitored.

    At month 9, evaluations are conducted regarding neurologic impairment (nerve damage), quality of life, serum TTR levels, and body mass index (a measure of body fat based on height and weight).

    At month 18, further evaluations are performed on neurologic impairment, quality of life, body mass index, overall disability, and the 10-meter walk test (a test to measure walking speed).

Who can join the trial?

6 criteria

  • You must be a man or a woman between the ages of 18 and 85 at the time you agree to join the study.
  • You must have been diagnosed with hereditary transthyretin-mediated amyloidosis with polyneuropathy, which is a rare disease caused by a specific change or mutation in the TTR gene (a piece of DNA that provides instructions for making a protein).
  • You must have a neuropathy impairment score (NIS) between 5 and 130. This score is a measurement used to check how much damage has occurred to your nerves (the body's communication lines).
  • Your polyneuropathy disability (PND) score must be 3 or lower. This score measures how much the nerve damage affects your ability to perform daily activities.
  • You must have a Karnofsky Performance Status (KPS) score of 60% or higher. This is a scale used by doctors to measure your ability to carry out normal daily activities and your overall level of independence.
  • You must be able to understand the study requirements, be willing to follow them, and be able to provide written informed consent (a signed document stating you agree to participate).

Who cannot join the trial?

34 criteria

  • You have had a liver transplant (a surgery to replace a diseased liver with a healthy one) or the doctor believes you will need one during the study.
  • You have an uncontrolled cardiac arrhythmia (an irregular heartbeat) or unstable angina (chest pain that is unpredictable or worsening).
  • You have type 1 diabetes.
  • You have previously used or are currently using any TTR-lowering therapy (medicines designed to reduce a specific protein in the blood).
  • You have had type 2 diabetes mellitus for 5 years or longer.
  • You have hypothyroidism or hyperthyroidism (conditions where the thyroid gland is either underactive or overactive) that has not been treated.
  • You have had a major surgery in the last 3 months or have one planned during the first 18 months of the study.
  • You have an active infection that requires medicine like antivirals (for viruses), antiparasitics (for parasites), or antimicrobials (for bacteria) that will not be finished before the study starts.
  • You have other medical conditions that the doctor believes might make it difficult to follow the study rules or interfere with the results.
  • You have a history of multiple drug allergies or are allergic to any part of the study medicine.
  • You have a history of not being able to tolerate subcutaneous injections (shots given just under the skin).
  • Your estimated glomerular filtration rate (eGFR), which is a measure of how well your kidneys filter blood, is 30 mL/min/1.73m² or less.
  • You are currently taking tafamidis, acoramidis, doxycycline, or tauroursodeoxycholic acid, or you have taken them and have not waited at least 14 days since your last dose.
  • You are currently taking diflunisal, or you have taken it and have not waited at least 3 days since your last dose.
  • You have other forms of amyloidosis (a condition where abnormal proteins build up in organs) or evidence of it in the lining of the brain and spinal cord.
  • You have a heart failure classification higher than level 2, according to the New York Heart Association scale.
  • Your blood tests show ALT or AST (liver enzymes) that are more than 2.5 times the normal limit.
  • Your total bilirubin (a substance produced by the liver) is more than 1.5 times the normal limit, or more than 2 times the normal limit if you have Gilbert's Syndrome (a common, harmless liver condition).
  • Your INR (a measure of how long it takes your blood to clot) is higher than 2.0.
  • Your platelet count (cells that help blood clot) is less than 50,000 per microliter.
  • Your absolute neutrophil count (a type of white blood cell that fights infection) is less than 1,500 cells per cubic millimeter.
  • The doctor believes your life expectancy is less than 2 years.
  • You are unwilling to follow the contraceptive (birth control) requirements during the study.
  • You are a female who is pregnant or breastfeeding.
  • Your vitamin B12 levels are lower than the normal range.
  • You are unwilling or unable to limit your alcohol consumption during the study.
  • You have a history of alcohol use disorder within the last 12 months.
  • You have used illicit substances (illegal drugs) in the last 5 years in a way that might interfere with the study.
  • You have an infection of the human immunodeficiency virus (HIV), hepatitis C, or hepatitis B.
  • You plan to start a TTR stabilizing therapy (medicine that helps stabilize a specific protein) within the first 18 months of joining the study.
  • You have previously received anti-TTR antibody treatment (medicines used to reduce specific proteins).
  • You have taken an investigational agent (a drug being tested in a study) within the last 30 days or are currently part of another study.
  • You have other causes of sensorimotor or autonomic neuropathy (nerve damage that affects movement, feeling, or automatic body functions) that your doctor believes is contributing to your condition.
  • You have had acute coronary syndrome (a sudden reduction in blood flow to the heart) within the past 3 months.
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Investigated drugs

  • Nucresiran

    is an investigational medication being tested to see how well it works in reducing the symptoms of a condition called hereditary transthyretin-mediated amyloidosis with polyneuropathy. It is given as an injection under the skin.

  • Vutrisiran

    is a medication used as a comparison in this study to evaluate how effective the new treatment is. It is also administered as an injection under the skin.

What is already known about the treatment

  • Nucresiran

    This medication is administered as a solution via an injection under the skin and is currently being studied in clinical trials for its effectiveness. It is classified as a gene-silencing therapy used to treat a rare inherited condition that causes nerve damage by stopping the body from producing a specific harmful protein. By working at a molecular level to block the instructions used to create this protein, it helps prevent the buildup of toxic substances in the body.

  • Vutrisiran

    This is an approved medication provided as a solution for injection under the skin to treat a rare inherited disease that affects the nervous system. It belongs to a group of drugs that act as genetic regulators, working by interfering with the body's ability to manufacture a protein that causes nerve damage. By lowering the levels of this harmful protein, the medicine helps manage the progression of the disease in patients.

Investigated diseases

Hereditary transthyretin-mediated amyloidosis with polyneuropathy - This is a rare genetic condition caused by mutations in the TTR gene. These mutations lead to the production of abnormal proteins that misfold and form deposits in various tissues throughout the body. In this specific form, these protein deposits primarily affect the nerves. As the disease progresses, the accumulation of these deposits causes damage to the peripheral nervous system. This damage typically leads to increasing impairment in nerve function and physical movement.
Trial detailsLast updated 2 Oct 2026
Age18+ yearsPhasePhase IIITrial ID2025-522544-40-00Protocol codeALN-TTRSC04-004Estimated enrolment186 patientsSponsorAlnylam Pharmaceuticals Inc.

sourced from the EU Clinical Trials Register and site verification

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