Describe the rationale and design of TRITON-PN, a phase 3, global, open-label, randomized study, evaluating the efficacy and safety of nucresiran in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).

ATTRv-PN is a progressive, fatal disease caused by misfolded transthyretin depositing as amyloid fibrils in nerves. RNA interference (RNAi) therapeutics like patisiran and vutrisiran, approved to treat ATTRv-PN, suppress hepatic transthyretin production (83% mean reduction at steady state for vutrisiran); however, therapies with greater, more consistent transthyretin reduction may improve outcomes. The pharmacodynamics of third-generation RNAi therapy nucresiran (ALN-TTRsc04) may offer this advantage.

TRITON-PN will enroll ~125 patients with ATTRv-PN. Key inclusion criteria include: age 18–85 years, ATTRv-PN diagnosis with documented pathogenic TTR variant, Neuropathy Impairment Score (NIS) 5–130, Polyneuropathy Disability Score (PND) ≤IIIb, and Karnofsky Performance Status ≥60%. Patients with New York Heart Association Class >II or prior TTR silencer use will be excluded. Patients will be randomized (4:1) to 300 mg subcutaneous nucresiran every 6 months or 25 mg subcutaneous vutrisiran every 3 months. The historical, external placebo group from the patisiran APOLLO study will serve as the control for the primary and secondary clinical endpoints. The primary endpoint is change from baseline in modified NIS+7 at Month 9. Secondary endpoints include change from baseline at Months 9 and 18 in Norfolk QoL-Diabetic Neuropathy Questionnaire and modified body mass index. Rasch-built Overall Disability Scale, 10-meter walk test, and modified NIS+7 will be assessed at Month 18. Serum TTR knockdown will be compared with in-study vutrisiran-treated patients.

The TRITON-PN study design and rationale will be presented.

TRITON-PN will assess the effects of nucresiran on disease-related measures in patients with ATTRv-PN. Nucresiran may provide greater clinical benefits and reduced treatment burden versus current RNAi therapeutics through deeper, more sustained transthyretin knockdown, lower interpatient variability, and less frequent dosing.