AstraZeneca’s AZD8233 Shows Positive Results for Hypercholesterolemia

AZD8233, an investigational antisense oligonucleotide (ASO), met the primary endpoint at 50 mg with 73% reduction in low-density lipoprotein cholesterol (LDL-C) levels from baseline in the ETESIAN phase 2b trial, AstraZeneca said in a statement.

The company presented the results from the ETESIAN phase 2b trial at the American College of Cardiology’s 71st Annual Scientific Session.

“We are pleased to announce that ETESIAN phase 2b for AZD8233 demonstrated a clear dose-response for both [proprotein convertase subtilisin/kexin type 9 (PCSK9)] and LDL-C levels,” Mene Pangalos, executive vice president of biopharmaceuticals research and development at AstraZeneca, said in a statement. “The results underscore AZD8233’s potential best-in-class efficacy profile and support its further development as a next-generation PCSK9 inhibitor that is easily self-administered monthly.”

The trial also met the secondary endpoints, including significantly reducing PCSK9 levels by 85%, with sustained reductions maintained over the dosing intervals, and through to week 14 at the 50-mg dosage.

The reduction of PCSK9 levels led to increases in low-density lipoprotein receptor levels, which results in lower LDL-C levels in the bloodstream, reducing the risk of developing coronary heart disease.

Additionally, AZD8233 was generally well-tolerated during the treatment duration.

“The positive results of the ETESIAN study, along with the clinical studies to date, reinforces our confidence that AZD8233 is a potential new treatment option that may be able to change the current standard of care for patients affected by hypercholesterolemia who have cardiovascular disease [CVD},” Brett Monia, CEO of Ionis Pharmaceuticals, said in the statement.

Ionis is collaborating with AstraZeneca on AZD8233.

Investigators evaluated 3 dose levels at 15, 50, and 90 mg, given monthly by subcutaneous injection over the 12-week dosing period.

The reduction from baseline to week 12 in LDL-C at the 15 and 90 mg dosage was 39% and 79%, respectively. Additionally, the reduction from baseline to week 12 in PCSK9 levels at the 15 and 90 mg dosage was 58% and -94%, respectively.

All active arms demonstrated reductions in LDL-C and PCSK9 levels at week 12 compared with the placebo. The trial was conducted in individuals with high-risk hypercholesterolemia on a high-dose statin.

Investigators found that more than half of individuals with CVD at high-risk of a major secondary event do not meet their LDL-C goals, despite taking a high-intensity statin. Additionally, elevated LDL-C is a key risk factor for CVD.

AZD8233 is a next-generation PCSK9 inhibitor with a unique mode of action and is the only PCSK9 ASO that acts upstream of PCSK9 inhibitors, targeting gene expression in the nucleus. It is designed to reduce blood cholesterol levels in individuals with hypercholesterolemia by targeting PCSK9, an important regulator of LDL-C.

The results from the SOLANO phase 2b trial assessing the efficacy, safety, and tolerability of AZD8233 in individuals with hypercholesterolemia is anticipated later in 2022.

Hypercholesterolemia, or elevated LDL-C levels in the blood, is an important risk factor of CVD.

Reference

AZD8233 reduced low-density lipoprotein cholesterol levels by 73% in patients with high-risk hypercholesterolemia in ETESIAN Phase IIb trial. AstraZeneca. News release. April 4, 2022. Accessed April 5, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/azd8233-reduced-low-density-lipoprotein-cholesterol-levels-73-patients-high-risk-hypercholesterolemia-etesian-phase-iib-trial.html