AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval.

Area of Science:

• Pharmacology and Toxicology
• Cardiovascular Safety
• Drug Development

Background:

• Hypercholesterolemia is a significant risk factor for cardiovascular disease.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are effective in lowering LDL cholesterol.
• AZD8233 is an antisense oligonucleotide targeting PCSK9 for hypercholesterolemia treatment.

Purpose of the Study:

• To evaluate the potential of AZD8233 to prolong the QT interval.
• To assess the cardiovascular safety of AZD8233 using a concentration-QT analysis.
• To determine if AZD8233 poses a risk for QT prolongation at therapeutic doses.

Main Methods:

• A concentration-QT analysis was conducted using data from a single ascending dose study.
• 73 healthy male subjects received subcutaneous doses of AZD8233 (4-120 mg).
• Time-matched ECGs and plasma concentrations were analyzed using a linear mixed-effects model.

Main Results:

• The placebo-corrected and baseline-adjusted QTcF interval (ΔΔQTcF) at a high clinical exposure scenario (1.39 μg/mL) was -2.2 ms (90% CI: -4.11, -0.28).
• The upper bound of the 90% confidence interval for ΔΔQTcF remained below the 10 ms regulatory threshold across all observed concentrations.
• No significant QTcF prolongation was observed even at 1.7-fold the expected Cmax.

Conclusions:

• AZD8233 does not induce QTcF prolongation at high clinical exposure levels.
• The cardiovascular safety profile of AZD8233 appears favorable concerning QT interval.
• These findings support the continued development of AZD8233 for hypercholesterolemia treatment.