Abstract 4135443: A Phase 1, Single Ascending Dose Study to Evaluate ALN-TTRsc04, a Next-Generation RNA Interference Therapeutic, in Healthy Participants for Potential Treatment of Transthyretin Amyloidosis

Introduction: Transthyretin amyloidosis (ATTR) is a progressive, debilitating, fatal disease caused by deposition of misfolded toxic transthyretin (TTR) amyloid fibrils in multiple organs and tissues. Major ATTR manifestations include polyneuropathy and cardiomyopathy. Ongoing amyloid deposition drives rapid progression of ATTR, leading to morbidity and mortality. ALN-TTRsc04 is an investigational small interfering RNA that targets hepatic TTR mRNA to reduce circulating TTR protein levels. Hypothesis: ALN-TTRsc04 rapidly knocks down serum TTR and is well tolerated. Aims: Describe safety, pharmacokinetics, and pharmacodynamics of single ascending ALN-TTRsc04 doses. Methods: This ongoing, Phase 1, randomized, double-blind, placebo-controlled study (NCT05661916) enrolled healthy adults (18–65 yrs; 18.0–30 kg/m 2 ) sequentially included in 6 cohorts receiving subcutaneous single ascending doses of ALN-TTRsc04 (5, 25, 100, 300, 600, or 900 mg) or placebo (randomized 3:1). Urine and plasma concentrations were measured on Days 1–2 and 1–4, respectively; change from baseline (BL) in serum TTR and AEs will be assessed over 12 months. Results: Overall, 36 and 12 adults (of similar age/sex distribution) were randomized to 1 of the 6 ALN-TTRsc04 groups or placebo, respectively. ALN-TTRsc04 plasma concentrations declined below lower limit of quantification within 24–48 hrs; mean (SD) plasma half-life ranged from 4.5 (1.5) hrs (300 mg dose) to 7.6 (3.2) hrs (100 mg dose). ALN-TTRsc04 was minimally excreted by renal route (<20%) after 24 hrs. Rapid and sustained knockdown in serum TTR occurred following all ALN-TTRsc04 doses ( Figure ). Mean (SD) serum TTR was 236.2 (47.4) µg/mL and 290.1 (73.3) µg/mL at BL and 22.2 (1.8) µg/mL and 289.0 (59.1) µg/mL at Day 15, for ALN-TTRsc04 300 mg and placebo, respectively. Mean percent knockdown at Day 15 was 90.3% vs 1.8%, respectively. Robust mean serum TTR knockdown of >90% from BL was seen with ALN-TTRsc04 doses ≥300 mg at Day 29 and sustained until Day 90 (or Day 180 with 300 mg dose, 92.6% reduction). Majority of AEs across doses were mild; none were considered related to treatment. No injection-site reactions or safety signals, including liver-related signals, were identified. Conclusion: A single ALN-TTRsc04 dose led to a rapid and sustained knockdown in serum TTR; a reduction >90% from BL was sustained until Day 180 with the 300 mg dose. All ALN-TTRsc04 doses have been well tolerated to date; data through 12 months will be assessed.