Novel PCSK9 Inhibitor Achieves Significant Reduction in LDL Cholesterol Levels in Phase IIb Trial

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Data from the Phase IIb PURSUIT trial (NCT06173570) found that AZD0780, a novel proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor, produced a significant 50.7% decrease in low-density lipoprotein cholesterol (LDL-C) levels when added to standard-of-care statin therapy.^1,2 These findings, published by the Journal of the American College of Cardiology (JACC), offer hope to patients who were previously unable to achieve their goals in reducing their cholesterol levels on standard therapies, according to the study investigators.³

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

AZD0780, an oral, small molecule PCSK9 inhibitor, is currently being evaluated as a monotherapy or in fixed-dose combinations with other treatments. Previously released Phase I trial data show the therapy produced a statistically significant 51% decrease in LDL-C levels in addition to rosuvastatin treatment, translating to a total decrease of 80% from baseline in previously untreated patients with hypercholesterolaemia.³

“The development of a well-tolerated, daily pill that could reliably lower LDL-C to a patient’s target range would offer a substantial therapeutic advance,” the study authors wrote in JACC. “Because of the general consistency of LDL-C–lowering response with statins and PCSK9 inhibitors, prescribing these 2 classes of agents together when clinically indicated for LDL-C lowering of >50% could simplify the management of LDL-C and help patients quickly achieve their LDL-C goals with a high degree of predictability.”³

Trial Design

The randomized, double-blind, placebo-controlled, multicenter PURSUIT trial evaluated the efficacy and safety of AZD0780 in patients with hypercholesterolemia who were previously administered background therapy of moderate-to-high intensity statins. Eligibility criteria included a fasting LDL-C level of ≥70 mg/dL (1.8 mmol/L) and <190 mg/dL (4.9 mmol/L), with triglycerides <400 mg/dL on a stable dose of moderate- or high-intensity statins.

Investigators randomly assigned 428 patients in a 1:1:1:1:1 ratio to receive once daily oral AZD0780 at doses of 1 mg, 3 mg, 10 mg, or 30 mg, or matching placebo over 12 weeks, 426 patients starting treatment.

The trial’s primary efficacy endpoint was percentage change of LDL-C from baseline to week 12. Investigators also analyzed safety and tolerability, which included adverse events (AEs), vital signs, electrocardiograms, and laboratory assessments.

Compared with baseline, after 12 weeks, the placebo-corrected difference in least squares mean percent change of LDL-C with AZD0780 compared to placebo for the 1 mg dose was -35.3% (95% CI: -43.6% to -26.9%); for the 3 mg dose was -37.9% (95% CI: -46.3% to -29.5%); for the 10 mg dose was -45.2% (95% CI: -53.5% to -36.9%); and for the 30 mg dose was -50.7% (95% CI: -59.0% to -42.4%).

The results demonstrated that the effectiveness of AZD0780 was not affected by moderate or high baseline statin use. The proportion of high-risk patients who achieved the ACC/AHA guideline LDL-C goal increased in a dose-proportional manner. In terms of safety, AEs were reported by 38.2% of patients across the AZD0780 treatment cohorts compared to 32.6% in the placebo cohort.

“The majority of patients treated with AZD0780 reached their target LDL-C levels within 2 weeks, and 84.2% in the AZD0780 30 mg dose achieved their ACC/AHA consensus LDL-C goal at the 12-week primary endpoint assessment,” the study authors concluded. “Coformulation of a once-daily statin and a PCSK9 inhibitor could offer substantial benefits in terms of simplifying treatment regimens, enhancing patient adherence, reducing health care costs, and potentially improving CV outcomes through improved hypercholesterolemia treatment efficacy. The mechanism of action and pharmacokinetic characteristics of AZD0780 lend themselves well for a simplified treatment approach and use with other drugs.”³

References

1. AZD0780, a novel oral PCSK9 inhibitor, demonstrated significant LDL cholesterol (LDL-C) reduction in PURSUIT Phase IIb trial. News release. AstraZeneca. March 31, 2025. Accessed April 1, 2025. 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

2. A Study to Assess the Efficacy, Safety and Tolerability of Different Doses of AZD0780 in Patients With Dyslipidemia (PURSUIT). ClinicalTrials.gov. Updated October 8, 2024. Accessed April 1, 2025. https://clinicaltrials.gov/study/NCT06173570

3. Koren, M, Vega, R, Agrawal, N. et al. An Oral PCSK9 Inhibitor for Treatment of Hypercholesterolemia: The PURSUIT Randomized Trial. JACC. null2025, 0 (0). https://doi.org/10.1016/j.jacc.2025.03.499