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

Summary

In this phase 2, double-blind, placebo-controlled RCT, the oral PCSK9 inhibitor AZD0780 reduced LDL-C by 35–51% over 12 weeks on top of moderate-to-high-intensity statins (with/without ezetimibe), with dose-dependent efficacy and safety similar to placebo.

Key Findings

• Placebo-corrected LDL-C reduction at 12 weeks: −35.3%, −37.9%, −45.2%, and −50.7% for 1, 3, 10, and 30 mg doses.
• Efficacy was independent of baseline statin intensity and increased guideline goal attainment in a dose-proportional manner.
• Adverse event rates were comparable between AZD0780 (38.2%) and placebo (32.6%).

Clinical Implications

If outcome benefits are confirmed, an oral PCSK9 inhibitor could be integrated with statins/ezetimibe to achieve LDL-C goals in high-risk patients, potentially improving adherence and expanding use.

Limitations

• Surrogate endpoint (LDL-C) over 12 weeks; no cardiovascular outcomes assessed.
• Generalizability and long-term safety require further phase 3 trials.

Future Directions

Conduct phase 3 outcomes trials, evaluate long-term safety and adherence, compare head-to-head with injectable PCSK9 inhibitors, and assess cost-effectiveness.