Abstract 12705: Identification and Characterization of Solbinsiran, a GalNAc Conjugated siRNA Targeting Angiopoietin-Like 3

Abstract

Introduction: While statins play an important role in reducing LDL-C levels and the risk of ASCVD events, residual risk from apolipoprotein B (apoB)-containing lipoprotein particles persists among patients with or at high risk of ASCVD. Hypothesis: Blocking ANGPTL3 activity or preventing its expression is a therapeutic approach to reduce apoB-containing lipoprotein particles. Solbinsiran (LY3561774), a novel Dicer-substrate small interfering RNA oligonucleotide, was designed to reduce the levels of ANGPTL3 protein expression. Methods: Nucleotide base sequences of a library of anti-ANGPTL3 siRNAs were selected using an in silico RNAi prediction algorithm on ANGPTL3 mRNA sequences conserved in humans and cynomolgus monkeys. Through a large-scale in vitro screen of the anti-ANGPTL3 library in human cells, the candidate solbinsiran sequence was identified as an efficacious siRNA. Solbinsiran in vivo efficacy was measured by RT-qPCR of liver from CD-1 female mice overexpressing human ANGPTL3 . The degree and durability of ANGPTL3 mRNA knockdown and circulating protein level reduction by solbinsiran was evaluated in cynomolgus monkeys administered single dose subcutaneous injections of either PBS or 3 mg/kg solbinsiran. Blood samples to measure ANGPTL3 protein were collected on Study Days -8, -5, and 0, and weekly after dosing until Day 113. Ultrasound-guided core needle liver biopsies were collected on Study Days 5, 28, 56, 84, and 113. Total RNA derived from the liver biopsy samples to measure ANGPTL3 mRNA was subjected to RT-qPCR analysis. Results: When given a single dose at 1 mg/kg subcutaneously, solbinsiran reduced human ANGPTL3 mRNA by 65% in hepatocytes as compared to vehicle-treated mice. A single dose of solbinsiran reduced liver ANGPTL3 mRNA expression by up to 72.9% (p<0.0001) and serum ANGPTL3 protein expression by 68.6% (p<0.001). Solbinsiran also displayed a long duration of activity, as indicated by a greater than 50% mRNA knockdown remaining 12 weeks after a single dose. Conclusions: These data supported the advancement of solbinsiran to Phase 1 clinical testing in participants with mixed dyslipidemia (ClinicalTrials.gov Identifier: NCT04644809).