Abstract Body (Do not enter title and authors here): Introduction
Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, commonly fatal disease, with mortality rates that range from 6.3-25 deaths per 100 patient-years depending on stage of disease. Nexiguran ziclumeran (nex-z) is an investigational in vivo CRISPR-based, one-time therapy targeting the TTR gene to provide lifelong knock-down of serum TTR. This phase 1 clinical trial (NCT04601051) evaluated the safety of nex-z and its effects on TTR levels, functional capacity, and biomarkers of disease progression in patients with ATTR-CM.
Methods
Thirty-six patients with advanced ATTR-CM received a weight-based (0.7 or 1.0mg/kg) or a fixed dose (55mg) of nex-z as a one-time IV infusion. Safety and pharmacodynamics (serum TTR) were assessed. Change from baseline in biomarkers of disease progression (NT-proBNP, hsTnT) and functional capacity (6MWT, NYHA class) was also evaluated.
Results
Thirty-six patients with progressive disease (50% NYHA class III; 31% variant ATTR-CM) received a single dose of nex-z and were followed for a median (Q1, Q3) of 25 (23, 33) months. To date, 26 patients have completed 24 months of follow up. The mean (95% confidence interval [CI]) percent change from baseline in serum TTR levels at day 28 were -89% (-92%, -87%), which remained unchanged at month 24. Mean (95% CI) serum TTR levels at month 24 were 22.3 µg/mL (16.4, 28.3). Geometric mean (95% CI) fold change from baseline to month 24 in NT-proBNP and hs-TnT were 1.07 (0.84, 1.36) and 0.88 (0.81, 0.97), respectively. 6MWT remained stable and 82% of patients experienced an improvement or no change from baseline in NYHA class. No patients died within the first 16 months of the study; there were 3 patient deaths between months 17-26 corresponding to a mortality rate of 3.7 deaths per 100 patient-years. Treatment-related adverse events included transient infusion-related reactions (n=5) and aspartate aminotransferase increases (n=2). Comprehensive 24-month data across all endpoints for the full cohort of 36 treated patients will be presented.
Conclusions
A single dose of nex-z was well-tolerated and associated with consistently rapid, deep, and durable reductions in serum TTR. Compared with the natural history of the disease, these data suggest that a CRISPR-based therapy can favorably impact functional capacity, clinical biomarkers known to be indicative of ATTR-CM disease progression and potentially reduce adverse clinical outcomes.