This study aims to determine if AKCEA-TTR-L_Rx, an antisense oligonucleotide (ASO), is effective and safe as compared to historical placebo, for the treatment of hereditary transthyretin-mediated amyloid polyneuropathy (hATTR-PN).

hATTR-PN is a progressive and fatal axonal sensorimotor and autonomic neuropathy caused by misfolding/aggregation of transthyretin (TTR), a liver produced protein. Inotersen (Tegsedi™) is an ASO approved to treat hATTR-PN that acts by reducing TTR liver production. 

AKCEA-TTR-L_Rx is an ASO with the same sequence as inotersen conjugated to N-acetyl galactosamine (GalNAc) which targets the asialoglycoprotein receptors expressed abundantly on hepatocytes. In a phase 1 healthy volunteer study, AKCEA-TTR-L_Rx given at a 45 mg dose by subcutaneous injection (SC) every four weeks (Q4W) achieved approximately 90% serum TTR reduction compared to baseline. NEURO-TTRansform is a Phase 3 global, open-label study, with a historical control (placebo arm in NEURO-TTR) and an active reference arm (inotersen). Approximately 140 hATTR-PN patients will be randomized to receive either AKCEA-TTR-LR_x (n = 120; 45 mg SC Q4W) or inotersen (n = 20; 300 mg SC weekly). Key inclusion criteria include preserved ambulatory status (stage 1 or stage 2), confirmed TTR mutation, and Neuropathy Impairment Score (NIS) between 10 and 130. Key exclusion criteria include estimated glomerular filtration rate < 45 mL/min/1.73m², platelets ≤ 125 × 10⁹/L and urine protein/creatinine ratio ≥ 1000 mg/g. Co-primary efficacy endpoints at Week 66 (primary endpoint analysis) are change from baseline in: serum TTR concentration, modified NIS+7 and Norfolk Quality of Life-Diabetic Neuropathy. An interim analysis will be performed at Week 35.