TRITON-PN: A Study to Evaluate the Efficacy and Safety of Nucresiran in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (TRITON-PN)

TRITON-PN: A Phase 3, Global, Randomized, Open-Label Study to Evaluate the Efficacy and Safety of Nucresiran in Patients With Hereditary Transthyretin-Mediated Amyloidosis With Polyneuropathy (hATTR-PN)

The purpose of this study is to:

• Determine the efficacy of nucresiran in patients with hATTR-PN by evaluating the effect on neurologic impairment, quality of life, nutritional status, disability, and gait speed
• Demonstrate superiority of nucresiran compared to in-study vutrisiran with respect to serum transthyretin (TTR) levels

Study Overview

• Status: Recruiting
• Conditions: Hereditary Transthyretin-Mediated Amyloidosis With Polyneuropathy; hATTR-PN
• Intervention / Treatment: Drug: Nucresiran; Drug: Vutrisiran

• Study Type: Interventional
• Enrollment (Estimated): 125
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Clinical Trial Information Line; Phone Number: 1-877-ALNYLAM; Email: clinicaltrials@alnylam.com
• Study Contact Backup: Name: Clinical Trial Information Line; Phone Number: 1-877-256-9526; Email: clinicaltrials@alnylam.com

Study Locations

• Brazil
  • São Paulo, Brazil, 04038-002
    • Recruiting
    • Clinical Trial Site
• France
  • Le Kremlin-Bicêtre, France, 94270
    • Recruiting
    • Clinical Trial Site
• Italy
  • Florence, Italy, 50134
    • Recruiting
    • Clinical Trial Site
  • Milan, Italy, 20133
    • Recruiting
    • Clinical Trial Site
• Japan
  • Suita, Japan, 565-0871
    • Recruiting
    • Clinical Trial Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Recruiting
    • Clinical Trial Site
• Portugal
  • Porto, Portugal, 4099-001
    • Not yet recruiting
    • Clinical Trial Site
• South Korea
  • Seoul, South Korea, 06351
    • Recruiting
    • Clinical Trial Site
  • Seoul, South Korea, 05030
    • Recruiting
    • Clinical Trial Site
• Sweden
  • Stockholm, Sweden, 113 61
    • Recruiting
    • Clinical Trial Site
  • Umeå, Sweden, 907 37
    • Recruiting
    • Clinical Trial Site
• Taiwan
  • Taipei, Taiwan, 112
    • Not yet recruiting
    • Clinical Trial Site
  • Taoyuan City, Taiwan, 333
    • Recruiting
    • Clinical Trial Site
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Clinical Trial Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Recruiting
      • Clinical Trial Site
  • Texas
    • Dallas, Texas, United States, 75246
      • Recruiting
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Has documented diagnosis of hATTR-PN
• Has a diagnosis of hATTR amyloidosis with polyneuropathy with a documented TTR gene variant
• Has a neuropathy impairment score (NIS) of 5 to 130 (inclusive)
• Has a Karnofsky Performance Status (KPS) of ≥60%

Exclusion Criteria:

• 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
• 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 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5 upper limit of normal (ULN)
• Has total bilirubin >1.5 ULN
• Has estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73m^2
• Has other known causes of sensorimotor or autonomic neuropathy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nucresiran 300 mg; Patients will be administered nucresiran 300 mg subcutaneously (SC) once every 6 months (q6M) during the Treatment Period and Treatment Extension Period	Drug: Nucresiran; Nucresiran 300 mg administered SC q6M; Other Names: ALN-TTRSC04
Active Comparator: Vutrisiran 25 mg followed by Nucresiran 300 mg; Patients will be administered vutrisiran 25 mg SC every 3 months (q3M) during the Treatment Period followed by nucresiran 300 mg SC q6M during the Treatment Extension Period	Drug: Nucresiran; Nucresiran 300 mg administered SC q6M; Other Names: ALN-TTRSC04; Drug: Vutrisiran; Vutrisiran 25 mg administered SC q3M; Other Names: ALN-TTRSC02; AMVUTTRA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in the Modified Neuropathy Impairment Score +7 (mNIS+7) Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 9	The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness and deep tendon reflexes, electrophysiologic measurement of large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.	Baseline and Month 9

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline in Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QoL-DN) Total Score Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 9	The Norfolk QoL-DN is a standardized 35-item patient-rated questionnaire used to assess 5 domains: physical function, large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.	Baseline and Month 9
Percent Reduction in Serum TTR Levels in the Nucresiran Group Compared to the In-study Vutrisiran Group through Month 9		Up to Month 9
Change from Baseline in Modified Body Mass Index (mBMI) Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 9	The mBMI, which is a measure of nutritional status, is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome.	Baseline and Month 9
Change from Baseline in the mNIS+7 Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18	The mNIS+7 is a composite score that measures neurologic impairment which includes the following components: physical exam of lower limbs, upper limbs and cranial nerves to assess motor strength/weakness and deep tendon reflexes, electrophysiologic measurement of large nerve fiber function, sensory testing and postural blood pressure. The mNIS+7 is scored from 0 (no impairment) to 304 points (maximum impairment). A higher score indicates a worse outcome.	Baseline and Month 18
Change from Baseline in Norfolk QoL-DN Total Score Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18	The Norfolk QoL-DN is a standardized 35-item patient-rated questionnaire used to assess 5 domains: physical function, large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The minimum and maximum values are -4 and 136, respectively. A higher score indicates a worse outcome.	Baseline and Month 18
Change from Baseline in mBMI Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18	The mBMI, which is a measure of nutritional status, is calculated as the product of body mass index (BMI) (weight in kilograms divided by the square of height in meters) and serum albumin (g/L) to reflect fluid balance, such as fluid accumulation or dehydration. A negative change from baseline indicates a better outcome.	Baseline and Month 18
Change from Baseline in Rasch-built Overall Disability Scale (R-ODS) Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18	The R-ODS is a patient-reported measure of level of disability on a scale of 0-48, with 0 being the worst and 48 the best (no limitations); scores are based on activities of daily living and social participation. An increase in R-ODS from baseline suggests improvement in disability, and a decrease from baseline suggests worsening of disability.	Baseline and Month 18
Change from Baseline in Timed 10-meter Walk Test (10-MWT) Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18	The timed 10-MWT is a measure of ambulatory ability and measures the time (in seconds) that it takes a participant to walk 10 meters (gait speed). An increase in gait speed from baseline represents improvement, and a decrease from baseline represents worsening.	Baseline and Month 18
Percent Reduction in Serum TTR Levels in the Nucresiran Group Compared to the In-study Vutrisiran Group through Month 18		Up to Month 18
Percent Reduction in Serum TTR Levels in the Nucresiran Group Compared to the In-study Vutrisiran Group at Week 6		Week 6

Collaborators and Investigators

• Sponsor: Alnylam Pharmaceuticals
• Investigators: Study Director: Medical Director, Alnylam Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2025
• Primary Completion (Estimated): December 27, 2027
• Study Completion (Estimated): June 12, 2031

Study Registration Dates

• First Submitted: October 29, 2025
• First Submitted That Met QC Criteria: October 29, 2025
• First Posted (Actual): October 31, 2025

Study Record Updates

• Last Update Posted (Actual): May 14, 2026
• Last Update Submitted That Met QC Criteria: May 12, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: TTR; Amyloidosis; RNAi therapeutic; Polyneuropathy; Transthyretin
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Nutritional and Metabolic Diseases; Polyneuropathies; Amyloidosis
• Other Study ID Numbers: ALN-TTRSC04-004; 2025-522544-40-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Phase 2-4 trials:

Access to Anonymized individual participant data that support these results is made available 12 months after study completion and not less than 12 months after the product and indication have been approved in the US and/or the EU.

Access to data may be declined where there is likelihood a patient could be identified or other feasibility issue, where there is a potential conflict of interest, a planned business activities or an actual or potential competitive risk. Data will be provided contingent upon the approval of a research proposal and the execution of a data sharing agreement. Timeframes for data access may vary and can take up to 6 months or more.

Requests for access to data can be submitted via the website www.vivli.org. Questions can also be directed to datasharing@alnylam.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes