An Oral PCSK9 Inhibitor for Treatment of Hypercholesterolemia: The PURSUIT Randomized Trial

Most patients at high-risk for cardiovascular events do not achieve lipid goals advocated by American College of Cardiology/American Heart Association (ACC/AHA) guidelines despite the wide availability of lipid-lowering therapy. AZD0780 is a novel, oral, small molecule inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development as a once-daily treatment for hypercholesterolemia.

The phase 2 randomized, double-blind, placebo-controlled, multicenter PURSUIT trial evaluated the efficacy and safety of AZD0780 in patients with hypercholesterolemia already on background moderate-to-high-intensity statin treatment.

Eligible study patients had a fasting low-density lipoprotein cholesterol (LDL-C) level of ≥70 mg/dL (1.8 mmol/L) and <190 mg/dL (4.9 mmol/L), and triglycerides <400 mg/dL on stable dose of moderate- or high-intensity statins, as defined by ACC/AHA or local guidelines, with or without ezetimibe at baseline. The study randomized patients 1:1:1:1:1 to receive AZD0780 1, 3, 10, or 30 mg, or matching placebo, oral once daily, for 12 weeks. The primary efficacy endpoint was percent change of LDL-C from baseline to week 12. Safety and tolerability evaluations included the number of adverse events, vital signs, electrocardiograms, and laboratory assessments.

In total, the study randomized 428 patients, of whom 426 started treatment. Patients were 52.1% male, with an average age of 62.4 ± 7.6 years. At week 12, compared with baseline, the placebo-corrected difference in least squares mean percent change of LDL-C for AZD0780 1, 3, 10, and 30 mg vs placebo was -35.3% (95% CI: -43.6% to -26.9%), -37.9% (95% CI:-46.3% to -29.5%), -45.2% (95% CI: -53.5% to -36.9%), and -50.7% (95% CI: -59.0% to -42.4%), respectively. Baseline statin use, moderate vs high intensity, did not alter AZD0780 efficacy. The proportion of patients reaching the ACC/AHA guideline LDL-C goal for high-risk patients increased in a dose-proportional manner. Adverse events compared similarly between the total AZD0780 treatment group (38.2%) and placebo (32.6%).

AZD0780 demonstrated robust, dose-dependent reductions in LDL-C with a favorable safety and tolerability profile supporting further development of this once daily, oral treatment. (A Study to Assess the Efficacy, Safety and Tolerability of Different Doses of AZD0780 in Patients With Dyslipidemia [PURSUIT]; NCT06173570).