Abstract 4361462: RN0361, an siRNA Directed Against ApoC3 Demonstrates Potent and Durable Reduction of ApoC3 and Triglyceride Over 6 Months in the Clinic

Background: Apolipoprotein C3 (ApoC3) plays a significant role in regulating triglyceride levels and is becoming recognized as a contributor to cardiovascular disease (CVD) risk, particularly in patients with diabetes. Suppression of APOC3 with siRNA is recognized as an important therapeutic for the prevention of pancreatitis in patients with severe hypertriglyceridemia and potentially CVD in pts with atherogenic TG rich lipoproteins. Questions: RN0361 is a next generation siRNA designed to potently and durably reduce APOC3 levels. This First in Human study is designed to assess safety and the depth and duration of suppression of APOC3 and resultant downstream pathogenic factors (TG, VLDL-C and remnant cholesterol). Methods: A 6-month randomized placebo controlled Single Ascending Dose (SAD) study in otherwise healthy volunteers with a fasting TG level of >80 mg/dl with dosing from 10mg to 300 mg SC. Assessments of safety and tolerability were monitored by a Safety Review Committee (SRC), PK and PD (APOC3, TG, VLDL-C, ApoB) were also assessed. Results: The primary focus of the study was safety/tolerability. There were no SAEs. Most AEs were mild. The AEs reported as potentially related to study drug included mild to moderate self-limited Injection Site Reactions (ISRs) and self-limited transient ALT and AST elevations (typically seen with the GalNAc platform). Glycemia assessment included fasting plasma glucose and HbA1c, neither of which demonstrated a change from the placebo comparator arm. The PK profile was typical of the siRNA class, with a T max ranging from 4 to 9 hours and elimination half-life (T 1/2 ) of 3.11 to 12.5 hours. There was no measurable systemic exposure at 48 hours. The PD assessments focused on APOC3 knockdown and resultant lowering of TG, VLDL-C and Remnant cholesterol. Figure 1 demonstrates a dose responsive and durable (through D180) reduction in APOC3 (maximal suppression 93%), fasting TG. (max suppression 69%), VLDL-c and remnant cholesterol. Assessments of ApoB and LDL showed a trend to a decrease Conclusion: RN0361, a long acting and potent siRNA directed against ApoC3 was well tolerated with no dose limiting toxicities through the highest dose tested and demonstrated durable reduction of ApoC3, TG, VLDL-c and Remnant-c levels over at least 180 days. These data provide support for a best-in-class profile for RN0361 and support further development. A Ph2 trial in patients with significant hypertriglyceridemia is under way.