Abstract 13913: Single Dose Safety, Pharmacokinetics, and Pharmacodynamics of a Potent PCSK9 Synthesis Inhibitor, AZD8233, in Subjects With Elevated Ldl Cholesterol

Background: AZD8233 is a chemically modified 16-mer antisense oligonucleotide linked to N-acetyl galactosamine (GalNAc) for efficient targeting of PCSK9 mRNA in hepatocytes to prevent the synthesis of PCSK9. We are reporting preliminary data from the first in human study. The aim with the study was to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single doses of AZD8233 in subjects with LDL-C ≥100 mg/dL. Methods: This was a randomized, single-blind, placebo-controlled; single ascending dose study (NCT03593785) of AZD8233 administered subcutaneously (SC) to 56 subjects enrolled in 7 cohorts (6 on active and 2 on placebo in each cohort). Doses studied ranged from 4 to 120 mg. Serial blood samples were collected to assess PK, PCSK9 and LDL-C profiles after administration of AZD8233. PK parameters were calculated using non-compartmental methods. Results: After SC administration, AZD8233 was generally well tolerated, no clinically relevant safety and tolerability findings were observed and no serious adverse events were reported. Peak plasma concentrations were achieved within 1 to 3 hours after dosing. After peaking, plasma concentrations declined biphasically with a terminal half-life of 2 to 3 weeks. A dose dependent decrease in plasma levels of PCSK9 and LDL-C was observed. The largest mean percent reductions from baseline were >90 % for PCSK9 and 70% for LDL-C. PCSK9 and LDL-C levels slowly returned to baseline or close to baseline levels over the 16 weeks post dose follow up period. Conclusions: The safety, PK and PD support further evaluation of AZD8233 in multiple ascending dose studies. The PD data indicate that a high level of PCSK9 and LDL-C reduction can be maintained over a dose interval of once monthly or less frequent at a dose below 100mg.