Background: Current LDLc lowering strategies, e.g., statins, ezetimibe, and PCSK9 inhibitors, offer variable efficacy (~30-60% reduction), limited durability (≤6 months), and varied tolerability. These agents are often used together to treat ASCVD, but such a multi-drug approach increases treatment burden, reduces adherence, and drives healthcare costs. Thus, there is a clear need for a single, durable therapeutic enabling safe, precise, and titratable control of LDLc reduction. While CRISPR-Cas9-based approaches like base editing are emerging for LDLc lowering, they carry risks of DNA damage and off-target toxicities. In contrast, CRISPR-based epigenetic editors silence gene expression without cutting or altering the genome, offering a safer alternative. Here, we present STX-1150, the first CRISPR-based epigenetic editor to achieve potent, titratable, and durable LDL-C lowering in non-human primates (NHPs) without genome modification. Methods: STX-1150 consists of an mRNA encoding an engineered CRISPR-CasX epigenetic repressor and a single PCSK9 -targeting gRNA encapsulated into lipid nanoparticles. In vitro and in vivo studies were performed to evaluate its efficacy, durability, and tolerability. Results: High-throughput in vitro screening identified a lead PCSK9 -targeting gRNA. In primary human hepatocytes, a STX-1150 prototype achieved >95% reduction in secreted PCSK9. In hPCSK9 transgenic mice, a single dose of the STX-1150 prototype decreased serum hPCSK9 by >95%, sustained for >310 days. In NHPs, a single IV infusion at the therapeutically relevant 0.75 mg/kg dose reduced LDLc by ≥50% for ≥1 year, with liver enzyme profiles comparable to controls. Notably, multi-dosing of STX-1150 at 0.75 mg/kg per dose in NHPs enabled titratable therapeutic effects, with a cumulative enhancement in LDLc reduction observed after each dose. Over 180 days, STX-1150 achieved sustained LDLc reductions of >40% to >60%, with similar liver enzyme profiles as the single dose study. Conclusions: STX-1150 is the first CRISPR epigenetic editor to demonstrate durable, titratable, and safe LDLc lowering in NHPs at therapeutic dosing <1mg/kg, without permanent genomic changes. By delivering potent and durable efficacy with multi-dosing flexibility, STX-1150 addresses key limitations of current lipid lowering therapies. This positions STX-1150 as a promising therapeutic option that could reduce treatment burden, improve adherence, and redefine the standard of care for LDLc lowering.