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

• Nucresiran (Drug), also known as ALN-TTRSC04: Nucresiran 300 mg administered SC q6M
• Vutrisiran (Drug), also known as AMVUTTRA, ALN-TTRSC02: Vutrisiran 25 mg administered SC q3M

Primary outcomes

• 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 [Baseline and 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.

Secondary outcomes

• 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 [Baseline and 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.
• 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 [Baseline and 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.
• Change from Baseline in the mNIS+7 Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18 [Baseline and 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.
• Change from Baseline in Norfolk QoL-DN Total Score Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18 [Baseline and 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.
• Change from Baseline in mBMI Compared to the External Placebo Group from the APOLLO Study (NCT01960348) at Month 18 [Baseline and 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.
• 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 [Baseline and 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.
• 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 [Baseline and 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.
• 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]

Sex: All, ages: 18 Years to 85 Years

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

• Medical Director, Study director, Alnylam Pharmaceuticals

NIH grants: 2025