AZD0780, Novel Oral PCSK9 Inhibitor, Demonstrates Major LDL Cholesterol Reductions

Results from the phase 2b PURSUIT (NCT6173570) clinical trial studying AZD0780 (AstraZeneca) have indicated a statistically significant low-density lipoprotein cholesterol (LDL-C) reduction when administered on top of standard-of-care statin therapy compared with placebo, according to a news release from AstraZeneca and a study published in JACC Journals.^1-3

High LDL-C levels can heighten the risk of adverse cardiovascular outcomes. | Image Credit: © Лозовая Людмила - stock.adobe.com

AZD0780, an investigational once-daily oral PCSK9 inhibitor for patients not currently reaching their LDL-C lowering goal despite standard lipid-lowering therapies, led to a 50.7% reduction in LDL-C (95% CI, -59.0% to -42.4%, P < .001) when taken at 30 mg daily in the PURSUIT trial. This efficacy data was observed regardless of whether participants received moderate- or high-intensity statin doses at baseline, making the positive effects of this treatment uniform across the target population.^1,2

“The PURSUIT phase 2b trial demonstrates the potential of AZD0780 to provide a much-needed once-daily oral treatment option to deliver greater LDL-C lowering on top of standard of care for millions of patients who remain at risk for serious cardiovascular events, including premature death,” Michael J. Koren, CEO and medical director of Jacksonville Center for Clinical Research and principal investigator in PURSUIT, said in the news release. “These results are particularly important because the majority of patients with atherosclerotic disease today do not reach their LDL-C goals, despite the availability of lipid-lowering therapies such as statins and injectable PCSK9 inhibitors.”¹

In another important outcome, treatment with AZD0780 30 mg resulted in 84% of trial participants (95% CI, 74.4%-90.7%) meeting their American Heart Association/American College of Cardiology guideline-recommended LDL-C target (less than 70 mg/dL), compared with 13% of enrollees (95% CI, 7.2%-22.3%) on background statin therapy alone, according to the investigators.^1,2

Patients receiving treatment with AZD0780 reported tolerating the treatment generally well. Furthermore, adverse events were found to be comparable between the total AZD0780 treatment groups (38.2%) and placebo (32.6%), while the frequency of discontinuations was also similar between groups, according to the investigators. With robust clinical trial results indicating efficacy and an encouraging safety profile, AZD0780 has the potential to revolutionize treatment of high LDL-C, which is a common type of dyslipidemia and key risk factor for atherosclerotic cardiovascular disease.¹

PCSK9 is a common target in LDL-C metabolism. Research has shown that signaling PCSK9 is effective in reducing plasma LDL-C levels, which in turn helps reduce the long-term risk of cardiovascular disease and major cardiovascular events. AZD0780, a small-molecule form of PCSK9 inhibitor, could become a new standard of care treatment if continued research is positive, and its status as a daily oral pill with no fasting restrictions could increase patient adherence and improve both short- and long-term outcomes.^1,2

“These new data reflect AZD0780’s ability to reduce LDL-C in patients who need more options to manage their cholesterol and related risks when standard-of-care therapy is not enough,” Sharon Barr, executive vice president of BioPharmaceuticals research and development at AstraZeneca, said in the news release. “AZD0780 has the potential to be a game changer that could offer LDL-C lowering with greater convenience for patients.”¹

REFERENCES

1. AstraZeneca. AZD0780, a novel oral PCSK9 inhibitor, demonstrated significant LDL cholesterol (LDL-C) reduction in PURSUIT phase IIb trial. News Release. Released March 31, 2025. Accessed April 8, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/AZD0780-a-novel-oral-PCSK9-inhibitor-demonstrated-significant-LDL-cholesterol-LDL-C-reduction-in-PURSUIT-Phase-IIb-trial.html#!

2. Koren MJ, Vega RB, Agrawal N, et al. An oral PCSK9 inhibitor for the treatment of hypercholesterolemia: The PURSUIT randomized trial. JACC Journals. 2025. doi:10.1016/j.jacc.2025.03.499

3. ClinicalTrials.gov. A Study to Assess the Efficacy, Safety and Tolerability of Different Doses of AZD0780 in Patients With Dyslipidemia (PURSUIT). National Library of Medicine. Last Updated October 8, 2024. Accessed April 8, 2025. https://clinicaltrials.gov/study/NCT06173570