Daily oral PCSK9 inhibitor cut LDL cholesterol by 50% over 12 weeks
Key takeaways:
- A once-daily oral PCSK9 inhibitor reduced LDL in patients with hypercholesterolemia.
- Safety and tolerability profiles were favorable, according to investigators.
CHICAGO — In a phase 2b study, treatment with a once-daily oral PCSK9 inhibitor added to statin therapy resulted in a more than 50% reduction in LDL cholesterol at 12 weeks in patients with hypercholesterolemia.
Results of the phase 2b PURSUIT study, which evaluated AZD0780 (AstraZeneca), an oral small molecule PCSK9 inhibitor, were presented at the American College of Cardiology Scientific Session.
AZD0780 “works differently” than other PCSK9 inhibitors, Michael J. Koren, MD, FACC, CEO and medical director of the Jacksonville Center for Clinical Research, said during the presentation. AZD0780 prevents lysosomal trafficking and degradation of the LDL receptor can be taken without regard to food intake, according to Koren. Moreover, it could offer LDL lowering with greater convenience, as it’s an oral medication and the other PCSK9 inhibitors on the market are injectables, he said.
“The PURSUIT study results certainly support development of AZD0780 in larger studies with longer duration,” Koren said.
PURSUIT assessed efficacy and safety of four different doses of AZD0780, compared with placebo, in patients with hypercholesterolemia despite background statin therapy. The study, which was conducted at 55 sites in eight countries, enrolled adults (52% men; mean age, 62 years; 86% white) with a fasting LDL level of at least 70 mg/dL but less than 190 mg/dL, a triglyceride level below 400 mg/dL and stable use of moderate- to high-intensity statin therapy, with or without ezetimibe, before screening. Mean LDL level at baseline was 100.7 mg/dL and most patients (60%) were on a high-intensity statin.
Researchers randomly assigned 428 patients (two of whom did not start treatment) to once-daily placebo or AZD0780 1 mg, 3 mg, 10 mg or 30 mg for 12 weeks.
“AZD0780 demonstrated robust, dose-dependent, placebo-adjusted reductions in LDL cholesterol from baseline to week 12 by up to 50.7%,” Koren said during the presentation.
The placebo-corrected difference in percent change of LDL at 12 weeks was:
- –35.5% with AZD0780 1 mg;
- –37.9% with AZD0780 3 mg;
- –45.2% with AZD0780 10 mg; and
- –50.7% with AZD0780 30 mg.
AZD0780 had its peak effect at approximately 2 weeks and this effect was sustained over 12 weeks, Koren said.
The researchers also reported improvements in total cholesterol, non-HDL cholesterol and apolipoprotein B with AZD0780 at 12 weeks, according to Koren.
“Although the study did not formally hypothesis-test lipoprotein(a) reduction, we did find that the drug had the characteristics we would expect in a PCSK9 inhibitor,” Koren said. “Median Lp(a) was reduced by 19.5% at the 30 mg per day dose.”
A post hoc analysis looked at the percentage of patients who achieved the ACC/American Heart Association LDL goal of less than 70 mg/dL. With the 30 mg AZD0780 dose, 84.2% of patients achieved that target compared with 13% of patients assigned placebo.
Use of a moderate- or high-intensity statin did not appear to impact efficacy of AZD0780, according to the researchers.
Adverse events were similar between the placebo and AZD0780 treatment groups (32.6% vs. 38.2%, respectively). Serious adverse events occurred in 2.1% of patients assigned AZD0780, but none were considered to be related to the study medication, Koren said. No dose-limited side effects were observed over 12 weeks, Koren said.
The researchers noted several limitations of the PURSUIT study, including its short duration of study treatment.
“At this stage in development, it is premature to compare AZD0780 with other PCSK9 inhibitors either on the market or in development,” Koren said.
Looking ahead, “as a highly-effective and well-tolerated once-daily oral therapy, AZD0780 could become part of a simplified treatment strategy to help more patients quickly and reliably achieve ACC/AHA guideline LDL cholesterol recommendations. Future studies should address implementation science, including the immediate coadministration of a PCSK9 inhibitor with a statin for high-risk cardiovascular disease patients who require greater than 50% LDL cholesterol reduction,” Koren said.
AstraZeneca is investigating the potential of AZD0780 for use as monotherapy or in fixed-dose combination with other therapies, according to a company press release.
References:
- AZD0780, a novel oral PCSK9 inhibitor, demonstrated significant LDL cholesterol (LDL-C) reduction in PURSUIT phase IIb trial. https://www.astrazeneca.com/media-centre/press-releases/2025/azd0780-a-novel-oral-pcsk9-inhibitor-demonstrated-significant-ldl-cholesterol-ldl-c-reduction-in-pursuit-phase-iib-trial.html. Published March 31, 2025. Accessed April 4, 2025.
- Koren MJ, et al. J Am Coll Cardiol. 2025;doi:10.1016/j.jacc.2025.03.499.
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Koren MJ, et al. Featured clinical research V. Presented at: American College of Cardiology Scientific Session; March 29-31, 2025; Chicago (hybrid meeting).
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