Oral PCSK9 inhibitor shows promise in phase 1 trial

EAS 2024 – In a phase 1 study, the oral small molecule PCSK9 inhibitor AZD0780 lowered LDL-c in treatment-naïve participants with hypercholesterolemia when added on top of rosuvastatin.

This summary is based on the presentation of Rick Vega, PhD (Gaithersburg, MD, US) at the EAS Congress 2024 - AZD0780, the first oral small molecule PCSK9 inhibitor for the treatment of hypercholesterolemia: results from a randomized, single-blind, placebo-controlled phase 1 trial.

Introduction and methods

PCSK9 inhibitors, which effectively lower LDL-c levels, are currently only available as injectable medications. There is an unmet need for oral PCSK9 inhibitors. AZD0780 is a novel oral small molecule PCSK9 inhibitor that binds to the C-terminal domain of PCSK9, and does not disrupt the interaction between PCSK9 and the LDL receptor. The goal of this ongoing phase 1 study was to evaluate the effects of AZD0780 when administered as a monotherapy and on top of rosuvastatin in healthy treatment-naïve hypercholesterolemic participants.

This randomized, single-blind, placebo-controlled phase 1 trial enrolled healthy participants (18-50 years of age) with LDL-c ≥70 mg/dL and ≤190 mg/dL. In part A of the study, participants received AZD0780 as a single ascending dose of 30 mg (n=6), 60 mg (n=6), 120 mg (n=6) and 200 mg (n=5) dose or matching placebo (n=8) in the fasted state. In addition, 6 participants received AZD0780 120 mg in the fed state. In part B of the trial, participants were randomized to daily administration of AZD0780 30 mg (n=15), AZD0780 60 mg (n=15) or placebo (n=15) for 4 weeks. Moreover, in another cohort with 35 treatment-naïve participants with LDL-c >100 mg/dL to 190 mg/dL, participants received AZD0780 30 mg or placebo on top of rosuvastatin 20 mg for 4 weeks following a run-in period with rosuvastatin 20 mg for 3 weeks. The primary outcome was safety and tolerability. Secondary outcomes were pharmacokinetics and pharmacodynamic effects.

Main results

Safety

• AZD0780 was generally safe and well tolerated. There were no reports of serious adverse events, and most adverse events were mild to moderate in intensity.

Pharmacokinetics and pharmacodynamics

• In part A, there was a dose-dependent increase in AZD0780 in plasma after a single oral dose of AZD0780. The half-life of AZD0780 in plasma was approximately ~40 hours.
• There was minimal change in the concentration of AZD0780 in plasma when ADZ0780 was administrated in a fasted or fed state, indicating no restrictions in relation to food intake.

Efficacy

• In part B, the placebo-corrected change in LDL-c from baseline to 4 weeks was -30% (95%CI: -41 to -185) in the AZD0780 30 mg group and -38% (95%CI: -48 to -30) in the AZD0780 60 mg group. The change in LDL-c reached steady-state within 2 weeks.
• Comparable placebo-corrected changes were observed for ApoB and total cholesterol.
• Following the run-in period with rosuvastatin, treatment with AZD0780 30 mg for 4 weeks lowered LDL-c by 52% (95%CI: -52 to -48) in hypercholesteremic participants. The total reduction in LDL-c reduction was 78% from baseline with the combined rosuvastatin and AZD0780 treatment.
• There was a synergistic effect between AZD0780 and rosuvastatin.

Conclusion

In this placebo-controlled phase 1 trial, treatment with the oral PCSK9 inhibitor AZD0780 on top of rosuvastatin led to placebo-corrected change in LDL-c of 52% in treatment-naïve participants with hypercholesterolemia, leading to a total reduction of 78% from baseline with the combined rosuvastatin and AZD0780 treatment. AZD0780 was generally safe and well tolerated, and may be dosed without any restrictions in relation to food intake. “These results demonstrate that a fixed-dose combination of AZD0780 with a statin could be an attractive first-line treatment option to achieve guideline-recommended LDL-c levels in the majority of patients,” according to Rick Vega.

- Our reporting is based on the information provided at the EAS Congress 2024 -