Phase 3 Study to Evaluate the Efficacy and Safety of Nucresiran in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy
- Trial ID
- 2025-522544-40-00
- Protocol
- ALN-TTRSC04-004
- Sponsor
- Alnylam Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of nucresiran in patients diagnosed with hereditary transthyretin-mediated amyloidosis with polyneuropathy by assessing its effect on neurologic impairment. Secondary objectives include the evaluation of efficacy regarding quality of life, nutritional status, disability, and gait speed. Additionally, the study aims to demonstrate the superiority of nucresiran compared to vutrisiran in relation to serum transthyretin levels.
Participants
This clinical trial involves a total of 100 participants diagnosed with hereditary transthyretin-mediated amyloidosis with polyneuropathy. The study population consists of male and female patients aged between 18 and 85 years. Selection is based on a documented TTR gene variant and specific clinical assessments. Required characteristics include a neuropathy impairment score between 5 and 130 and a polyneuropathy disability score of 3 or less. Additionally, participants must maintain a Karnofsky Performance Status of at least 60%.
Plans and Procedures
This Phase 3, randomized, open-label study is designed to evaluate the efficacy and safety of nucresiran in patients diagnosed with hereditary transthyretin-mediated amyloidosis with polyneuropathy. The methodology involves comparing the effects of nucresiran to the comparator, vutrisiran. The primary objective is to determine the impact on neurologic impairment by measuring the change from baseline in the modified Neuropathy Impairment Score +7 at Month 9. Secondary endpoints include assessments of serum TTR levels, body mass index, and quality of life. The trial includes a screening process to confirm eligibility based on specific diagnostic and impairment criteria, followed by a baseline visit. Participants will undergo subsequent visits for monitoring through Month 18 to evaluate long-term outcomes such as the Timed 10-meter walk test and the Rasch-built Overall Disability Scale. The total duration of the study is estimated to conclude by September 2030.
Treatment
The experimental treatment consists of nucresiran, administered as ALN-TTRSC04. The pharmaceutical form is a solution for injection provided in a pre-filled syringe. The dosage is 1.67 mg per administration.
The comparator treatment is vutrisiran, marketed as Amvuttra. This medication is administered as a solution for injection in a pre-filled syringe at a dose of 0.28 mg via the subcutaneous route. This substance is classified as an orphan drug.
Efficacy
The efficacy of nucresiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy is evaluated through several parameters. The primary endpoint is the change from baseline in the Modified Neuropathy Impairment Score +7 (mNIS+7) at Month 9, compared to an external placebo group from the APOLLO study. Secondary endpoints include the following:
- Change from baseline in the Norfolk Quality of Life Diabetic Neuropathy (Norfolk QoL-DN) total score at Month 9.
- Percent reduction in serum TTR levels through Month 9 and Month 18, and at Week 6, compared to the vutrisiran group.
- Change from baseline in modified body mass index (mBMI) at Month 9.
- Change from baseline at Month 18 in mNIS+7, Norfolk QoL-DN total score, mBMI, Rasch-built Overall Disability Scale (R-ODS), and the Timed 10-meter walk test (10-MWT).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female age 18 (or age of legal consent) to 85 years, inclusive, at the time of initial informed consent.
- Have a diagnosis of hATTR amyloidosis with polyneuropathy with a documented TTR gene variant
- Have a neuropathy impairment score (NIS) of 5 to 130 (inclusive; this criterion must be met at the Baseline Visit 2)
- Have a Polyneuropathy Disability (PND) score of ≤3b (this criterion must be met at the Baseline Visit 2)
- Have a Karnofsky Performance Status (KPS) of ≥60%Informed Consent
- Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.
Exclusion Criteria
- All exclusion criteria can be found in the protocol (Section 4.2). 1. Has had a liver transplant or is likely, in the opinion of the Investigator, to undergo liver transplantation during the Treatment Period of the study
- Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m2 (calculation will be based on the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation; refer to Section 10.1)
- Has vitamin B12 levels below the lower limit of normal
- Has known human immunodeficiency virus infection; or evidence of acute or chronic hepatitis C virus or hepatitis B virus infection
- Anticipated to start an approved TTR stabilizing therapy (eg, tafamidis or acoramidis) within the first 18 months following randomization
- Received prior anti-TTR antibody treatment (ie, “TTR depleters”)
- Received an investigational agent within the last 30 days (or 5 half-lives of the investigational drug, whichever is longer), or are currently in follow-up of another clinical study. Any agent that has received health agency authorization (including for emergency use) by local or regional authorities is not considered investigational
- Has other known causes of sensorimotor or autonomic neuropathy (eg, autoimmune disease, monoclonal gammopathy) that the treating physician believes to be contributing to the neuropathy
- Had acute coronary syndrome within the past 3 months
- Has uncontrolled clinically significant cardiac arrhythmia or unstable angina
- Has known type 1 diabetes
- Received prior or currently receiving TTR-lowering therapy
- Has had type 2 diabetes mellitus for ≥5 years
- Has untreated hypo- or hyperthyroidism
- Has had a major surgery within the past 3 months or has a major surgery planned during the study through Month 18
- Has an active infection requiring systemic antiviral, antiparasitic, or antimicrobial therapy that will not be completed prior to dosing (Day 1)
- Has other medical conditions or comorbidities which, in the opinion of the Investigator, could interfere with study compliance or data interpretation
- Has a history of multiple drug allergies or history of allergic reactions to any component of or excipient in the study drug
- Has a history of intolerance to SC injection(s)
- Is currently taking tafamidis, acoramidis, doxycycline, or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 14-day washout prior to dosing (Day 1)
- Is currently taking diflunisal; if previously on this agent, must have completed a 3-day washout prior to dosing (Day 1)
- Has known other (non-hATTR) forms of amyloidosis or clinical evidence of leptomeningeal amyloidosis
- Has a New York Heart Association (NYHA) heart failure classification >2
- Has any of the following laboratory parameter assessments at screening: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 upper limit of normal (ULN) reference range b. Total bilirubin >1.5 ULN (>2 ULN in patients with Gilbert's Syndrome) c. International normalized ratio (INR) >2.0
- Platelet count <50,000/μL
- Absolute neutrophil count <1500 cells/mm³
- Has a life expectancy of <2 years based on Investigator's clinical judgement
- Is not willing to comply with the contraceptive requirements during the study period as described in Section 5.9.1
- Female patient who is pregnant or breastfeeding
- Unwilling or unable to limit alcohol consumption throughout the course of the study
- History of alcohol use disorder within the last 12 months before screening in the opinion of the Investigator
- History of illicit substance use within the past 5 years that in the opinion of the Investigator would interfere with compliance with study procedures or follow-up visits
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Cyprus | Recruiting | 31 Mar 2026 | 5 |
 France | Recruiting | 31 Mar 2026 | 9 |
 Germany | Recruiting | 31 Mar 2026 | 8 |
 Greece | Recruiting | 31 Mar 2026 | 5 |
 Ireland | Not Yet Recruiting | 31 Mar 2026 | 4 |
 Italy | Recruiting | 31 Mar 2026 | 25 |
 Portugal | Recruiting | 31 Mar 2026 | 8 |
 Spain | Recruiting | 31 Mar 2026 | 15 |
 Sweden | Recruiting | 31 Mar 2026 | 7 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Amvuttra 25 mg solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS | 0.28 | 18 | PRD9937020 |
ALN-TTRSC04 | Test | SOLUTION FOR INJECTION | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | 1.67 | 36 | PRD12488328 |