Abstract 17013: CTX320: An Investigational in vivo CRISPR-Based Therapy Efficiently and Durably Reduces Lipoprotein (a) Levels in Non-Human Primates After a Single Dose

Background: Genetic and epidemiological studies have identified elevated levels of lipoprotein (a) (Lp(a)) as a direct cause of atherosclerosis and related diseases. CTX320™ is an investigational in vivo CRISPR/Cas9 gene editing therapy designed to knock out the apolipoprotein (a) component of Lp(a) in the liver. CTX320 contains Cas9 mRNA and guide RNA (gRNA) formulated for efficient encapsulation into LNPs for in vivo administration . Here we assessed the efficacy, safety, and durability of CTX320 in primary human cells and non-human primates (NHPs). Methods: For in vitro studies, primary human hepatocytes were plated and dosed with CTX320 one day later. Cells were harvested after three days and analyzed via Sanger and next-generation sequencing. For NHP studies, cynomolgus monkeys were dosed with either vehicle control or CTX320 at doses ranging from 0.5 to 3 mg/kg. Baseline levels of plasma Lp(a) were established via ELISA prior to dosing and plasma Lp(a) levels were measured at multiple intervals after dosing until the end of each study. Results: In primary human hepatocytes, potent, dose-dependent editing of up to >80% was observed with CTX320. In NHPs, dose-dependent editing in the liver of ~10%, ~45%, and ~65% at the 0.5, 1.5, and 3 mg/kg doses, respectively, was observed after treatment with CTX320. Plasma Lp(a) levels were reduced by ~20%, ~80%, and ~90% from baseline in each of these respective groups. These reduced Lp(a) levels were attained by Day 15 and lasted for the duration of the study (Day 84). As is commonly observed with LNP delivery, transient elevation in liver enzymes was observed and resolved within 14 days without intervention. In a separate durability study in NHPs, a single infusion of CTX320 at 2 mg/kg led to significant and durable decreases in plasma Lp(a) levels. By Day 14, plasma Lp(a) levels had decreased by an average of 94% from baseline, which persisted through Day 224. The study is ongoing. Conclusion: CTX320 was well-tolerated in NHPs and resulted in high levels of editing in the liver that led to long-lasting reduction in plasma Lp(a). This data suggests CTX320 could be used to reduce plasma Lp(a) levels in humans.