An investigational drug, currently known as AZD0780, lowers low-density-lipoprotein cholesterol (LDL-C) to target levels in most patients whose cholesterol is still over target despite statin therapy, results from the phase 2b PURSUIT trial show.
AZD0780 inhibits PCSK9, a protein that regulates cholesterol metabolism. Inhibition of this protein has proven useful in lowering LDL-C. Current drugs in this class include two monoclonal antibodies, alirocumab and evolocumab, and a small interfering RNA, inclisiran. However, unlike current PCSK9 inhibitors, which must be injected, AZD0780 is an oral therapy.
“We’ve had PCSK9 inhibitors on the market in the United States for 10 years,” said investigator Michael Koren, MD, a cardiologist and CEO of the ENCORE Research Group in Jacksonville, Florida. However, “people are still not getting to goal,” he explained during his presentation of the results at the American College of Cardiology Scientific Session 2025 in Chicago, which were published simultaneously in the Journal of the American College of Cardiology.
Novel Mechanism
PCSK9 prevents LDL receptors from “recycling” to the surface of hepatocytes or liver cells where they remove LDL-C from circulation. PCSK9 inhibitors increase the density of the receptors on the hepatocytes, so they can lower LDL-C, Koren explained in an interview released on the journal website.
But this new drug takes a slightly different approach, he added.
Unlike other drugs in the class, AZD0780 does not interfere with binding between PCSK9 and the LDL receptor. Instead, it prevents lysosomal trafficking and degradation of the LDL receptor. This could make the drug more effective at freeing up LDL receptors to lower LDL.
The randomized, double-blind, placebo-controlled PURSUIT trial was conducted at 55 research sites in eight countries. The multicultural patient population consisted of 426 patients with LDL-C levels 70 mg/dL or higher despite taking statins, with or without ezetimibe. The trial was funded by AstraZeneca, the manufacturer of AZD0780.
Highest Dose Most Effective
The four daily doses tested — 1 mg, 3 mg, 10 mg, and 30 mg — showed a clear dose response, Koren reported, with the highest dose leading to the largest reduction in LDL-C. With 30 mg daily of AZD0780, the mean reduction from baseline was 46.6% over 12 weeks, whereas with placebo, levels increased slightly. The LDL-C goal of 70 mg/dL or less was reached by 84.2% of patients.
Rates of adverse events were low and similar to rates in patients taking the drug at other doses or taking placebo. Serious adverse events were experienced by just over 2% of patients taking the drug, but it was determined that these events were not related to the drug.
AZD0780 is a once-daily oral pill, whereas other drugs in this class must be injected. One of the benefits of the new drug is the simplicity of taking it, said Koren. And being able to give patients sample pills during the clinical encounter and a prescription that they can easily fill makes it easier for patients to achieve their targets.
Phase 2b trials typically involve smaller samples and shorter timelines than phase 3 trials and are designed to test efficacy and safety of various doses of a drug. A phase 3 trial could run for 1 or 2 years and determine whether the effectiveness and tolerability of the drug continue to be as good over a longer term.
“There’s a pretty good level of confidence that this drug will get into more extensive phase 3 testing,” said Koren.