Abstract 15751: Pharmacodynamic Effect of ARO-ANG3, an Investigational RNA Interference Targeting Hepatic Angiopoietin-like Protein 3, in Patients With Hypercholesterolemia
Gerald F. Watts, Christian Schwabe, Russell Scott, Patrick Gladding, David Sullivan, John E. Baker, Peter Clifton, James Hamilton, Bruce D. Given, Javier San Martín, Stacey Melquist, Ting Chang, Natasa Rajicic, Ira J. Goldberg, Daniel Gaudet, Joshua W. Knowles, Robert A. Hegele, Christie M. Ballantyne
Abstract
Background: Angiopoietin-like protein 3 (ANGPTL3) regulates triglyceride (TG) and lipoprotein (LP) metabolism by inhibiting liver and endothelial LP lipases and reduces plasma LDL-C. In Phase 1 Study AROANG1001 (NCT03747224), single and multiple doses of RNA interference therapeutic ARO-ANG3 (100, 200, or 300 mg; n=36) in healthy volunteers substantially reduced ANGPTL3, LDL-C, and other LPs (AHA 2019) compared with placebo (n=16). Purpose: We report preliminary results following repeat doses (days 1 and 29) of ARO-ANG3 in patients with heterozygous familial hypercholesterolemia (FH) with elevated LDL-C despite statin therapy and average LDL-C of 130 mg/dL. An additional group (non-FH patients) had LDL-C > 70 mg/dL despite statin therapy. Methods: Seventeen FH patients received open-label, subcutaneous, ARO-ANG3 100 mg (n=6), 200 mg (n=6), or 300 mg (n=5). Nine non-FH, high risk patients with elevated LDL-C not at goal received either 200 mg ARO-ANG3 (n=6) or placebo (n=3) using a randomized double-blind design. Pharmacodynamic markers included serum ANGPTL3, LDL-C, TG, and others. Results: Results are reported as of 04 May 2020. In FH patients, ARO-ANG3 significantly reduced mean ANGPTL3 levels between 62-92% at week 16 in a dose-dependent manner (Table). LDL-C (23-37%) and TG (25-43%) were consistently reduced at all doses (Table). The mean percent reductions in non-FH patients for ANGPTL3 (85%), LDL-C (28%), and TG (29%) were comparable to those in FH patients, despite their initially lower LDL-C at baseline. As of 15 May 2020, there were no drug-related serious or severe adverse events (AEs) or discontinuations and most AEs were mild. The most common AEs reported in subjects receiving ARO-ANG3 were respiratory tract infection (30% of subjects) and injection site AEs (13% of subjects). Conclusions: In FH and non-FH patients, repeat doses of ARO-ANG3 significantly reduced ANGPTL3, LDL-C, and TG, with favorable safety.