Novel PCSK9 inhibitor for high cholesterol passes phase II trial

A recent trial presented at ACC.25 has demonstrated the efficacy of AZD0780 in reducing low-density lipoprotein cholesterol (LDL-C) in patients with hypercholesterolemia, with a favourable safety and tolerability profile.

AZD0780 is an oral, small molecule inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) that is currently being developed as a once-daily treatment for hypercholesterolemia.

“The phase II PURSUIT study showed a favourable efficacy and safety profile of AZD0780, broadly comparable to other PCSK9 inhibitors, with the advantage of a once-daily oral therapy that can be coadministered with a statin,” said lead author Dr Michael J Koren, Jacksonville Center for Clinical Research, Flourish Research Group, Jacksonville, Florida, US.

Patients with hypercholesterolemia were included in this randomized, double-blind, placebo-controlled, multicentre trial. Eligible participants had a fasting LDL-C ≥70 mg/dL and <190 mg/dL and triglycerides <400 mg/dL treated with moderate- or high-intensity statins, with or without ezetimibe at baseline.

Koren and his team randomly allocated 428 patients to receive AZD0780 1, 3, 10, or 30 mg or matching placebo orally once daily for 12 weeks. They then estimated the percent change of LDL-C from baseline to week 12 and evaluated both the safety and tolerability through the following: number of adverse events, vital signs, electrocardiogram, and laboratory assessments.

Of the participants, 426 (mean age 62.4 years, 52.1 percent male) initiated treatment. Compared with baseline, the least squares mean percent change of LDL-C at week 12 was –35.3 percent (95 percent confidence interval [CI], –43.6 to –26.9) with AZD0780 1 mg, –37.9 percent (95 percent CI, –46.3 to –29.5) with 3 mg, –45.2 percent (95 percent CI, –53.5 to 36.9) with 10 mg, and –50.7 percent (95 percent CI, –59.0 to –42.4) with 30 mg. [J Am Coll Cardiol 2025;doi:10.1016/j.jacc.2025.03.499]

Safety profile

Baseline use of moderate- or high-intensity statin showed no influence on the efficacy of AZD0780. Notably, a dose-dependent increase was observed in the proportion of patients achieving the ACC/AHA guideline LDL-C goal for those at high risk.

In addition, the incidence of adverse events did not significantly differ between the total AZD0780 treatment groups and placebo (38.2 percent vs 32.6 percent).

“These results support further development of this novel, small molecule agent in larger studies with longer duration,” Koren said. “Future research using AZD0780 should address treatment simplification strategies to improve the current state of poor compliance with the ACC/AHA consensus guidelines for the treatment of hypercholesterolemia.”

Previous literature has shown the favourable safety profile of several PCSK9 inhibitors as a mechanistic class, with several studies reporting no specific adverse nonlipid effects of this treatment. [Cardiol J 2022;29:574-581; J Am Heart Assoc 2017;6:e006910]

In addition, multiple clinical trials and epidemiological studies have reported the safety of functioning circulating PCSK9, which appears to play no major role in human health. [Signal Transduct Target Ther 2024;9:13]

“The PURSUIT study did not identify any significant off-target effects of the small molecule AZD0780, and overall, patients tolerated the treatment well,” Koren said.