Abstract 9747: Safety, Pharmacokinetics and Pharmacodynamics of Multiple Ascending Doses of AZD8233, Targeting PCSK9, in Patients with Dyslipidemia

Abstract

Introduction: Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces cardiovascular risk by lowering low-density lipoprotein-cholesterol (LDL-C) levels. AZD8233 is an antisense oligonucleotide in development for the treatment of dyslipidemia. In a single ascending dose study (NCT03593785), AZD8233 was well tolerated and effectively reduced PCSK9 and LDL-C levels in patients with elevated LDL-C. Here, we report results from a multiple ascending dose study of AZD8233. Methods: This was a phase 1, randomized, single-blind, placebo-controlled study (NCT04155645) in patients with dyslipidemia. Participants were receiving statins for ≥ 3 months, had an LDL-C in the range 70-190 mg/dL, and were 18-65 years old. Three cohorts of 11 participants received four subcutaneous injections over an 8-week period (days 1, 8, 29, and 57) of either AZD8233 (15 mg, 30 mg, or 90 mg; n = 8) or placebo (n = 3), and were followed up for 16 weeks post dose. The primary objective was to assess safety and tolerability; secondary objectives included assessment of pharmacokinetics and pharmacodynamics of AZD8233; circulating LDL-C was estimated using the Friedewald formula. Results: Overall, 34 patients were randomized and data are available from 33 patients; 15 were male, the mean age was 58 years, and baseline PCSK9 and LDL-C levels were comparable across treatment groups. Treatment with AZD8233 did not result in any clinically relevant safety or tolerability findings. Peak plasma concentrations of AZD8233 were reached within 0.5 to 5 hours post dosing, followed by a biphasic decline. A decrease from baseline in PCSK9 (69.7%, 79.9%, and 95.3%) and LDL-C levels (63.8%, 65.7%, and 83.3%) was observed at 12 weeks for the AZD8233 15 mg, 30 mg, and 90 mg groups, respectively vs placebo ( Figure ). Conclusions: Multiple doses of AZD8233 were generally safe, well tolerated, and reduced PCSK9 and LDL-C levels in a dose-dependent manner in statin-treated patients with dyslipidemia.