PURSUIT Trial – Dose Dependent Reduction in LDL-C with AZD0780, Oral PCSK9 inhibitor

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By Inbar McCarthy on

Key Points

  • The majority of ASCVD patients fail to achieve guideline endorsed LDL targets 
  • The PURSUIT trial randomized 428 patients in a 1:1:1:1 ratio to receive oral AZD0780 1, 3, 10, or 30mg, or matching placebo for 12 weeks. 
  • 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. 

Despite the availability of several lipid-lowering therapies, only 1 in 3 patients with ASCVD achieve an LDL-C target of < 70 mg/dL after 2 years. Currently FDA-approved PCSK9 inhibitors reduce LDL-C by 50% or more but require subcutaneous injection which can be a barrier for some patients who prefer taking medications by oral administration. AZD0780, is an oral, small molecule, PCSK9 inhibitor which prevents lysosomal trafficking and LDL receptor degradation. 

The PURSUIT trial was a phase 2 randomized, multicenter, placebo controlled, dose-ranging phase II trial conducted in 55 international sites undertaken to assess the efficacy and safety of AZD0780 in patients with hypercholesteremia. The trial enrolled patients with an LDL-C ≥ 70 mg/dL and < 190 mg/dL and triglycerides < 400 mg/dL. Participants were required to be on a stable dose of moderate or high-intensity statin. The trial excluded individuals with an estimated glomerular filtration rate < 45 mL/min/1.73 m2, an acute ischemic cardiovascular event within 12 months of randomization, and poorly controlled type 2 diabetes mellitus with a hemoglobin A1c > 10%. 

In total, the study randomized 428 patients, of whom 426 started treatment. Patients were 52.1% male, with an average age of 62.4, and the mean LDL-C levels at baseline was 100.7. 

For the primary endpoint, AZD0780 significantly reduced LDL-C levels compared to placebo at 12 weeks in a dose-dependent manner. Placebo adjusted LDL-C reductions at 12-weeks were 35.3% for the AZD0780 1 mg group, 37.9% for the AZD0780 3 mg group, 45.2% for the AZD0780 10 mg group, and 50.7% for the AZD0780 30 mg group. In the highest dose group, AZD0780 30 mg, 84.2% achieved an LDL-C target of <70 mg/dL. Adverse events were similar between the entire AZD0780 treatment group (38.2%) as compared to placebo (32.6%).

In conclusion, AZD0780 demonstrated robust, dose-dependent, reductions in LDL-C of up to 50.7% from baseline to 12 weeks. The investigators commented that “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-C recommendations.”