TRITON-PN: A Phase 3 Study to Evaluate the Efficacy and Safety of Nucresiran in Patients with Hereditary Transthyretin Amyloidosis with Polyneuropathy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alnylam Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

27 Mar 2026 → ongoing

Decision date (initial)

2026-02-25

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alnylam Pharmaceuticals, Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacokinetic, Therapy, Pharmacodynamic

To determine the efficacy of nucresiran in patients with hATTR-PN by evaluating the effect on neurologic impairment

Secondary objectives 2

1. 1. To determine the efficacy of nucresiran on quality of life, neurologic impairment, nutritional status, disability, and gait speed
2. 2. To demonstrate superiority of nucresiran compared to in-study vutrisiran with respect to serum TTR levels

Conditions and MedDRA coding

Hereditary transthyretin-mediated amyloidosis with polyneuropathy

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

IPD plan description

Alnylam's policy restricts intended sharing of IPD to phase II to-IV clincial studies and after marketing authorization of the drug.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. 1. Male or female age 18 (or age of legal consent) to 85 years, inclusive, at the time of initial informed consent.
2. 2. Have a diagnosis of hATTR amyloidosis with polyneuropathy with a documented TTR gene variant
3. 3. Have a neuropathy impairment score (NIS) of 5 to 130 (inclusive; this criterion must be met at the Baseline Visit 2)
4. 4. Have a Polyneuropathy Disability (PND) score of ≤3b (this criterion must be met at the Baseline Visit 2)
5. 5. Have a Karnofsky Performance Status (KPS) of ≥60%Informed Consent
6. 6. Patient is able to understand and is willing and able to comply with the study requirements and to provide written informed consent.

Exclusion criteria 32

1. 1. 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
2. 7. 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)
3. 8. Has vitamin B12 levels below the lower limit of normal
4. 9. Has known human immunodeficiency virus infection; or evidence of acute or chronic hepatitis C virus or hepatitis B virus infection
5. 13. Anticipated to start an approved TTR stabilizing therapy (eg, tafamidis or acoramidis) within the first 18 months following randomization
6. 14. Received prior anti-TTR antibody treatment (ie, “TTR depleters”)
7. 15. 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
8. 16. 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
9. 17. Had acute coronary syndrome within the past 3 months
10. 18. Has uncontrolled clinically significant cardiac arrhythmia or unstable angina
11. 19. Has known type 1 diabetes
12. 10. Received prior or currently receiving TTR-lowering therapy
13. 20. Has had type 2 diabetes mellitus for ≥5 years
14. 21. Has untreated hypo- or hyperthyroidism
15. 22. Has had a major surgery within the past 3 months or has a major surgery planned during the study through Month 18
16. 23. Has an active infection requiring systemic antiviral, antiparasitic, or antimicrobial therapy that will not be completed prior to dosing (Day 1)
17. 24. Has other medical conditions or comorbidities which, in the opinion of the Investigator, could interfere with study compliance or data interpretation
18. 25. Has a history of multiple drug allergies or history of allergic reactions to any component of or excipient in the study drug
19. 26. Has a history of intolerance to SC injection(s)
20. 11. 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)
21. 12. Is currently taking diflunisal; if previously on this agent, must have completed a 3-day washout prior to dosing (Day 1)
22. 2. Has known other (non-hATTR) forms of amyloidosis or clinical evidence of leptomeningeal amyloidosis
23. 3. Has a New York Heart Association (NYHA) heart failure classification >2
24. 4. 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
25. 5. Platelet count <50,000/μL
26. 6. Absolute neutrophil count <1500 cells/mm³
27. 27. Has a life expectancy of <2 years based on Investigator's clinical judgement
28. 28. Is not willing to comply with the contraceptive requirements during the study period as described in Section 5.9.1
29. 29. Female patient who is pregnant or breastfeeding
30. 30. Unwilling or unable to limit alcohol consumption throughout the course of the study
31. 31. History of alcohol use disorder within the last 12 months before screening in the opinion of the Investigator
32. 32. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in the Modified Neuropathy Impairment Score +7 (mNIS+7) compared to the external placebo group from the APOLLO study at Month 9

Secondary endpoints 6

1. 1. 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 at Month 9
2. 2. Percent reduction in serum TTR levels in the nucresiran group compared to the in-study vutrisiran group through Month 9
3. 3. Change from baseline in modified body mass index (mBMI) compared to the external placebo group from the APOLLO study at Month 9
4. 4. Change from baseline in the following parameters compared to the external placebo group from the APOLLO study at Month 18: o mNIS+7; o Norfolk QoL-DN total score; o mBMI; o Rasch-built Overall Disability Scale R-ODS; o Timed 10-meter walk test (10-MWT)
5. 5. Percent reduction in serum TTR levels in the nucresiran group compared to the in-study vutrisiran group through Month 18
6. 6. Percent reduction in serum TTR levels in the nucresiran group compared to the in-study vutrisiran group at Week 6

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alnylam Pharmaceuticals Inc.

Sponsor organisation

Alnylam Pharmaceuticals Inc.

Address

300 3rd Street

City

Cambridge

Postcode

02142-1103

Country

United States

Scientific contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Alnylam Clinical Trial Information Line

Public contact point

Organisation

Alnylam Pharmaceuticals Inc.

Contact name

Alnylam Clinical Trial Information Line

Third parties 18

Locations

9 EU/EEA countries · 25 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 124 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications