Abstract Body (Do not enter title and authors here): Introduction:
ATTR amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, commonly fatal disease. It has been shown that in ATTR-CM, worsening of NT-proBNP, 6MWT and hsTroponin-T are associated with an increased risk in mortality. Nexiguran ziclumeran (nex-z) is an investigational in vivo CRISPR-based, one-time therapy targeting the TTR gene to provide lifelong knockdown of serum TTR. This phase 1 clinical trial (NCT04601051) is the first and largest gene editing study in cardiovascular disease to date and is evaluating 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 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 levels) were assessed. Change-from-baseline to 12 months in biomarkers of disease progression (NT-proBNP, hsTroponin-T) and functional capacity (6MWT, NYHA class) were also evaluated.

Results:
Thirty-six patients (50% New York Heart Association [NYHA] class III; 31% variant ATTR-CM) were dosed with nex-z and completed at least 12 months of follow-up. Mean (95% confidence interval [CI]) percent change from baseline in serum TTR levels at day 28 and month 12 were -89% (-92 to -87) and -90% (-93 to -87), respectively. Geometric mean (95% CI) fold change from baseline to month 12 in NT-proBNP and hs-Troponin-T were 1.02 (0.88, 1.17) and 0.95 (0.89, 1.01), respectively. Median (IQR) change from baseline to month 12 in 6-Minute Walk Test distance was +5 meters (-33 to +49) and 92% of patients experienced an improvement or no change in NYHA class. Mild to moderate, transient infusion-related reactions were the most common treatment-related adverse event.

CONCLUSIONS:
A single dose of nex-z was well-tolerated and was associated with consistently deep, rapid, and durable reductions in serum TTR. Compared with the well-established natural history of the disease, this interim 12-month data update provides the first evidence that a CRISPR-based therapy can favorably impact functional capacity and clinical biomarkers known to be indicative of ATTR-CM disease progression.